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·Systemic
Lupus Erythematosus:
REVIEW OF THE LITERATURE AND
CLINICAL ANALYSIS OF 138 CASES
DY
NGCHEE HARVEY, JD)
LUREXCEE SIL'IMAX J11)
I'IILIT 1 TUM'113, 11
TOCKIRI) (OSLEY, MI)
ESYSSE HE SCHOENRI'II XII)
I'rom The Department of Jedicine of The Johny llopkins l'arrersity and Iloepital
SANS
TACHE
BILTIJIONE
THE WILLIAMS & WILKINS COMPINY
1955

·Copyright, 1955
TuF WILLIAMS & WIKI 15 Course
Made in Caled States of America
Reprinted from MFDLOVF, Vol 33, XO 4, December 1934

·SYSTEMIC LUPUS ERYTHEMATOSUS: REVIEW OF THIE LITERATURE AND CLINICAL ANALYSIS OF 133 C.ISES* A JICGEHCS HARITY, L411 REXCELSIUIJAX, PIILIP A. TUMULTY, CLOCKARD CONLLY AND EDITII II, SCHOLSRICHIT TABLE OF CONTENTS 293 203 295 205 -96 296 Ws 300 300 303 303 301 301 301 305 305 306 30G I Introduction II Histoneal Development III Pathology A Vascular lesions b Fibrinoid degeneration c Hematory lon bodies d Involvement of arious organ systems e Biopsy and dingnosis 1 Shin 2 Lymph nodes 3 Muscle IV Etiology and I'at bogenesis & Infection, including tuberculosis b Endocrinc factors Allergy or hypersensitivity d Relation to other "collagen" diseases V General Considerations # Classification b Incidence c Sex, race, age d Familial occurrence e Predisposing factors VI The Clinical Manifestations of Svetemic Lupus Erythematogts & General consideration, b Joint manifestations C Muco cutaneous manifestationa 1 The relationslup of discoid LC to SLL d Reda) manifeststone e Cardiovascular mifestations Pulmonary minifestations & Gastrointestinal manifestations h Liver, spleen and pancreus 1 Lymph nodes ) Nervous system manifestations k Retinal lesions VII Hematological Xanifestations a Red cells b White celle c Platelets d Coagulation defeets e bone marrow 307 308 308 303 312 312 316 320 324 326 331 339 313 315 3:17 319 351 353 353 359 360 360 368 • From the Department of Medicine of the Johns Hopkins University and II ospita! Clinical Fellow of the Amercan Cancer Society 291 ·292 A MGEHEE HARVEY ET AL. 369 VIII The LE Cell l'henomenon a Characteristirs of the cell b Factors responsible for formation coccurrence d Techniques of LI test e LE cells in other diseases IX, P.18my Protein Abnormalities a Albumin and globulin b Sedimentation rate c Other abnormalities X. Chronic Biologie False Positive Serologie Tests for Syphilis Incidence in SLL b The etiologic bachground of the chronic BFP phenomenon 1 Incidence and clinical diagnoses 2 Laboratory data 3 Relation to SLI XI The Clinical Course of SLL a General observations b Spontaneous remissions c The effect of pregnancy d The cause of death, XII The Treatment of SLE 1 Introduction b. Hormone therapy 1 Type of treatment 2 Discussion of general results 1 The initial response b The over all response 3 Effect on specific manifestations * Fever b Joint manifestations © Buco-cutaneous manifestations d Renal manifestations e Cardiac manifestations f Pulmonary manifestations K Gastrointestinal manifestations 11 Liver and spleen 1 Lymph nodes Retinal lesions k Hematological manifestations 1 Other protein abnormalities 4 Some generalizations concerning hormone therapy 5 Complications of hormone therapy C Other measures 1 Acetylsalicylic acid 2 Anti-malarials 3 Nitrogen mustards 4. Vitamin B12 5 Para-aminobenzoic acid XIII Prognosis 1 Introduction b Types of cages C Prog10919 from time of diagnosis XIV Summary 360 361 374 375 375 376 376 379 379 380) 380 352 382 383 381 381 381 355 396 387 358 388 389 391 392 392 391 398 398 398 400 103 104 105 405 406 407 407 407 402 110 115 115 416 416 117 417 418 HIS 121) 31 ·SISTEVIC LUPUS ERYTUCYTATOSUS 203 I. INTRODUCTION During the past few years there has been despread mterest in those di cac involving connective tissue lithough the etiology of systemic lupus erythematosus (SLE) is still unknown, knowledge of the creuse has advanced along several lines The discovery of the IE cell phenomenon has resulted in more accurate diagnosis and opportunity for broader clinical and experimental studies of this de case Important has been the allity to control many of the distressing clinical manifestations by the administration of adrenocorticotropir hormone (ACTII) anel sarjous adrenal steroids, asen though the basie evolution of the underlying process may not be altered In view of these recent des clopments, it seemed worthwhile to assemble the alatlable information about SLE and to review it in the light of our experience with this dicasc durmg the past eight year. The most important goal is discovery of its ctiology, Inut since thts information is lacking at present, a thorough review of the natual history of SLE may possibly stimulate nou avenues of approach to its study In 1917 the clinical course of Suri as observed in 32 patients at the Jobus Hopkins lopital was reviened (238) Su quently, an additional 106 patients proved to have this disease, have been obsercd It ts the purpose of the presenttation to analyze the clinical features as manifested in these 139 patients, and to rekew the pertinent material pres sously published concerning this discare In each of these 138 patients, the climcal diagnosis of SLE was established either hy autopsy examination, the finding of L E cells in the peripheral blood or through study of material obtained at operation Autopsy cxaminations were performed upon 32 patients Sex indmiduals underwent splenectomy lærause of thrombocytopenia and the characteristic changes of lupus were found in the removed organ LE cells were found in the peripheral blood of 79 patients, all of whom had a clinical course compatible with SLE In the remainder, the diagnosis was confirmed hy the finding of characteristic changes of biopsy of skin, muscle or lymph nodle Fifty-two of these patients were treated symptomatically, while the remainder received cortisone or ACTI Sixty-two of those receiving hormone therapy hase been followed for varying periods of time II. HISTORICAL DEVELOPEYT resics of the historical development of our knowledge of SLE scries to emphasize the remarkable variability in the clinical picture as evidenced by the number of years which pasued before the protean manifestations could be groupel together as parts of a systemic disease It also illustrates the difficulty of determining the full spectrum of a systemic disease whose course is characterized by exacerbations and remissions untii a specific diagnostic test becomes available First to attract attention were dermal lesions of lupus erythemato-115 de. scribed under the term "erythema centrifuge" by Biett in 1828 (24) Later Ielira gave a more detailed description and noted two types disc-lihe patches and detach-d or confluent lesions of smaller size (114) In 1831, Cazenave (40) introduced the term lupus erythematodes in order to distinguish this disease ·291 A, MCGEHEE HARVEY ET AL. from lupus vulgaris Kaposi designated the two forms described by Hebra as the discoid form and lupus erythematosus disseminatus. The first description of SLE was that by Kaposi in 1872 (135). He observed patients whose illness was characterized by fever, toxic manifestations, and cutaneous lesions resembling those of erysipelas to which he gave the name "erysipelas perstans facen” The significance of the systemic manifestations of this disease, and the relationship of the visceral lesions to those in the dermis were first emphasized by Osler (189) He not only described essentially all of the varied clinical manifestations known to occur, but also pointed out instances in which the disease ran its entire course to death without the development of cuttaneous manifestations The remarkable fact is that his description of the disease, as illustrated by the following quotation from one of his papers, has made without benefit of pathological studies "By exudative erythema is understood a disease of unknown etiology with polymorphic skin lesions, hyperemia, edema, and hemorrhage-arthritis occasionally, and a variable number of visceral manifestations of which the most important are gastrointestinal crises, endocarditis, pericarditis, acute nephritis and hemorrhage from mucosal surfaces. Recurrence is a special feature of this disease and attacks may come on month after month or even throughout a long period of years The attacks may not be characterized by skin manifestations The visceral symptoms may be present and to the outward view the patient may have no indications whatever of erythema exudatuvum" In 1904, Jadassohn (126) reviewed the disease and referred to the frequency of involvement of the joints, serous and mucous membranes and kidneys, and of constitutional manifestations such as fever, and prostration These important contributions of Sir William Osler and of Jadassohn were all but forgotten until the 1920's when interest in SLE was rekindled by a series of papers appearing during that period Goeckerman (80) presented a comprehensive clinical analysis of acute lupus erythematosus in 1923, and leucopenia and thrombocytopenia were added to the diagnostic criteria (136). The initial manifestations were recognized as following a definite pattern requiring differ entiation from other general disorders having dermal manifestations In 1924 Libman and Sacks (160) described four cases of non-bacterial endocarditis, two of which had cutaneous lesions of lupus erythematosus. The cardiac alterations were described in detail by Gross (92, 93) in a series of articles appearing between 1932 and 1910 One of the important landmarks was the publication in 1935 by Baehr, Klem. perer, and Schifrin (5) of a paper entitled "A Diffuse Disease of the Peripheral Circulation (Usually Associated with Lupus Erythematosus and Endocarditis)". In this paper the clinical and pathological findings in 23 cases were analyzed offering the most complete description of the clinical pieture up to that time These authors summarized the clinical course as characterized by irregular fever dannur ta romiseions of variable duration, involvement of synovial and their 23 patients were female Pathologically, I uw ·SISTEMIC LURUS ERYTHLVI ATOSUS 295 pericarditis, or both in 17 cases and verrucous endocarditis in 13 A number of different types of vascular lesions nere found on microscopic examination. These consisted of simple dilatation of capillary bels, endothelial proliferation in capillaries, arterioles, and venules, and degeneration or necrosis of vowel walls with adjacent thrombosis and hemorrhage peculiar hyaline thickening of the glomerular tufts was frequently seen and the c authors designated this change as the 'ware-loop" lesion Two years later, Denzer and Blumenthal (33) introduced the concept that SLE May a systemic disease not merely of blood vessels but of the derivatives of mesenchyme Later studies by Klemperer, Pollack, and Bacht (146) let them to the conclusion that the fundamental changes in SLE were manifested primarily in the collagenous tissues of the body, and that the widespread visceral lesions could be identified as local mantfestations of the basic connective tissue alteration In 1939, Reiſenstein and co-workers (210) presented an analysis of cases reported in the hiterature under a variety of titles, lut presenting what seemed to be a common symptom complex characterized by fever, polyarthritis, poly. serositis, endocarditis, erythematou cutaneous lesions, nephritis, anemia, and a remittent course. The title of this paper was, ".1 variable symptom complex of undetermined etiology with fatal termination including conditions described as the visceral erythema group (Oslor), disseminated lupus erythematosus, atypical verrucous endocarditis (Libman-Sarhs), fener of unknown origin, and diffuse peripheral vascular de casc (Christian)" Perhaps the most important advance in the dei clopment of our knowledge of this disease was the discovery of the L E cell (97) This is apparently a specihe feature of SLE which enables the diagnosis to be made with certainty in the majority of cases III TATIJOLOGY In the 50 years after 1872 shen Kaposi first described cases of SLE, the autopsy material presented in the literature provided no significant advances in our knowledge of the drcas, as the specific lesions were overlooked and death was usually attributed to intercurrent pneumonia or tuberculosis The report of labman and Sachs in 1924 was the best description of certan of the pathological changes in SLL Subscquently, Gross, Bachr, Klemperer, and Schifrin (5, 93, 144, 146), Jarcho (127), Gizler and Fox (78) and Denzer and Blumenthal (53), among others, made significant contributions , l'asctdar Lesions Bachr, Klemperer, and Schifrin (5) described vascular lesions throughout the finer ramifientiane of the guitamin on 1 varied fror lesions of sociated with thrombı obstrueting the lumen Also noted were degenerative and necrotizing lesions in the wall of such sesels associated at times with thrombosis and hemorrhage into adjacent tissues Most characteristic was the peculiar IL- ·296 A, MCGEHEE HARVEY ET AL hyalıne thickening of the capillary walls of the glomeruli which they designated as the "wire-loop" lesion Klemperer, Pollack, and Bachr (146) described the pathological changes in 35 cascs and pointed out that the alterations noted in the various organs must be regarded as manifestations of a single process involving the connective ti sues of the body The supporting tissue involved may be in the heart, the glomeruli, the skin, or in blood vessels which may in turn affect the function of any organ in the body The primary change was thought to occur in fibroblasts and in the ground substance These authors stressed the fact that a differential point between rheumatic fever and SLE is that in the latter disease, the alteration is predominantly a degeneration of fibroblasts whereas in the former, proliferation of fibroblasts resulting in Aschoff body formation is dominant. In distinguishing betwecn SLE and periarteritis nodosa, they stated that the changes in the connective tissue in the latter discnse are accompanied by a conspicuous inflammatory reaction in which participation of eosinophils is usually noteworthy. As a rule, in periarteritis, the vessels of larger caliber suffer the greater damage while amalt vessels and capıllaries may occasionally be affected. They point out that the converse is true in SLE (Fig. 1 A) 6. "Frbrinord Degeneration" Klemperer and his colleagues concluded that the morbid process in SLE revolved about a well-defined disturbance of collagen which may affect all organs and tissues of the body The essentially degenerative nature of this disturbance is expressed in its most striking form by the term "fibrinoid degeneration". They ('stated that this disease process represents a profound physico-chemical alteration of collagenous tissues \Vhile "fibrinoid degeneration" may be the most spectacular expression of this alteration in routine stains, the disturbance may also manfest itself in sclerosis of collagen which is particularly evident in the splenic lesions The alteration termed "fibrinoid degeneration", which has been applied to changes in collagenous tissue, is usually characterized by brilliant eosinophilic staining in the hematoxylın eosin preparations, metachromasia, positive silver staining, and positive staining for fibrin This leston remains a non-specific and little understood reaction which may be noted in a varicty of other conditions. In these the alteration is usually sharply localızed and Identified with obvious dirert tissue injury which may be caused by hacteria, toxins, vascular impairment, or a hypersensitiyity reaction c. llemotorylin Bodies In 1932 Gross (92) reported the presence of clumps and packets of hematowy linstaining bodies in the cardiac lesions of cases of Libman-Sachs disease Ile was of the opinion that these conglomerate masses were derived from nuclear material and that they were specific in nature (Fig. 1 B) Further description of these lesions nas made by Ginzler and Fox (78) in 1910. Since that time they have been noted in lesions of many organs in SLE including the heart, lymph nodes, kidney, lung, and spleen but always in tissue of mesenchymal origin. #

·297
SYSTEVIC LUTUS ERYTHEVATOSUS
FIG I A An acute necrotizing (psion in a veggel in the submucosa of the stomach in a
patient with SIC In contrast to the lesions of acute periarteritis nodosa, eosinophils are
rare in the cellular exudate about this vessel B Conglomerate muges of hematovylın
bodies in lymph node dint41ds

·298 AMCGEHCE HARVEY ET AL. Klemperer (143) found hematoxylın bodies in 41 of 45 cases of SLE studied histologically Microscopic analysis has shown that these bodlics arise from an alteration in the nuclei of cells which are exclusively of mesenchymal origin such as fibroblasts, histiocytes, endothelial cells, lymphocytes, and polymorphonuclear leucocytes They are reddish-purple in the hematoxylin-eosin preparations, and are free of any distinctue structure The single bodies described by Gueſt (91) are of cell size while the larger aggregates may be sci eral hundred microns in diameter, and may compose the largest part of a grossly visible structure such as a vegetation on a valic Studies have indicated that the phaga ocytized material of the LE «ell 18 histochemically similar to the small hematoxylın bodies described Since LE cells are rarely found in autopsy matcrial, although they may occur in a flud medium such as a pleural exudate or pericardial effusion, it is probable that phagocytosis of this material 14 uncommon m vivo Cytochemical studies of interest have been carried out on this material by Klemperer, Gueft, Lee, Leuchtenberger and Pollister (145). Spectrophotometrie absorption in the ultraviolet spectrum shows a strong band at 2537 Ångstrom units which is lost after treatment with trichloracetic acid. Digestion with riboscnuclease has no effect, while the Feuigen reaction for desoxyriboscnucleic acid is positive These observations provide evidence that the bodies are derived from nuclear chromatin, and that they contain desoxyriboscnucleic acid Pollister and Leuchtenberger (202) have postulated that the loss of affinity for methyl green together with the relatively strong Feuigen reaction indicates that the nucleic acid is in a depolymerized state. These bodies may be found in areas in which there are other changes in the extracellular portions of the connective tissue such as fibrinoid alteration of the collagen fibers, periarterial fibrosis in the spleen, and increase in metachromasia of the loose connective tissue ground substancc Berman and his associates (23) have ako noted the morphologic similarity between these hematoxylin bodies and the LE. cell inclusions, but they were unable to demonstrate depolymerization in methylgreen-pyronin preparations on bone marrow smears The observations of Koffer and Markert (148) are of interest in this regard They noted that ultraviolet radiations, x-ray, nitrogen mustard and peroxides in the presence of eosin produced depolymerization of de oxyribosenucleic acid in ritro While most authors have considered that hematoxylın bodies occur only in SLE, Worken and Pearson have described similar lesions associated with angiitis in the absence of the characteristic changes of lupus erythematosus (273). d Involvement of l'arrows Organ Systems In regard to the frequency with which changes are present at necropsy in the various organs, Klemperer (143) noted verrucous endocarditis in 55%, pericardial lesions in 70%, myocardial lesions in 35%, nire-loop change in the kidney in 60%, focal glomerular loop necrosis in 85% and "onion-skın" lesions in the spleen in 95% Jessar and his group (129) in 15 postmortem examinations recorded pericardial lesions in seven instances, myocardial lesions in cight, endocarditis in five, splenie lesions in eleven, and focal hepatic necros19 ·SYSTEMIC LUPUS ERITILLATOSUS 249 In fone In their series, relial abnormalities were accu in 13 0:2 es, ses en bring the wire-loop lesion and two renal infarets Generalized vasculitis Was & prom. ment feature in eight patients, pleuritis w 10, peritonitis in four. In one patrent lesions of both lupus erythematosus and dermatomyositis nere found at autoper These figures, which represent only the lcszons found after detit, are difficult to evaluate in view of the chronic and intermittent course of SLE. Yo detailed analysis will be presented of the pathological findings in our series of cases, but approptsate reference will be made to certain of the data in the sections to tollow It N noteworthy that the cutent of the murphological changes does not al- Ways parallel the keverity of the chirucal dipane at the time of death (43) As 19 ucli ilustrated in the following case summary, there may He A paucity of anatomical leons even though the disease runs a very fulsatnig course, Case 1 DI (2311X15) Thurs 26 ger old colored female housewife entered the hospita) July 2. 1353 con7.417.18 of a sore throat Two wechy before she noted diffnese in her fingers and its with progresion to the elbons and knees orcurring mostls in the morning There was no sueling, het or locas tenderness One week before, che developrd pleuritse p110 in her lrit chest For one week shchu a more tlırart She locine progressively more lethargic She had fever and ass gnen fenicillist aard eufouumides Lecarler thur febrile rection de not subside, she was brought to the hospital for studs On admission she had T 101°F, 120, R 2. HP 180/60 Thert ** a muculorapular eruption over the chechs, arme, back and thuglis luck hul in ersthematous appearance There was tenderness without swelling or local het in the muddle plangeal joints, wrists, ellytus, here and bures ruort shoned no hemorrhages or etudates Pharynx was a little hiperemite Sauell lymph norine apre felt at the angle of each , and in the right supra clavicular and left arillas regions There was tenderness over the thyrout which is not palpable The lungs ncre clear to percussion and auscultation. The heart was not enlarge and no murnutes Here nored The liver and spleen could not be felt The uterus aremod normal Rectal examination revealeil no abnormalities The neck was surple The crama) nerves are intact, and the deep tendon refieres were eque) and active During her two weeks in the hospit) her temperature varied between 101 and 105° There was a parallel increase in the pulse rate on the second hospital day some enlarge ment of the cervical lymph nodes was noted, but the evidence of pharyngitis wa4 subsidurig and the tenderness over the thyroid hat disappeared The folosing day she complained of olaritin Anthalt - 1 of 5,00 Routline gtains showed no bactena On July 7 a pericardia) friction rub was heard The fallen gooi nou el sounds and no dutention A lumbar puncture on the evening of July & revealed Carptly cloul fluid osth 350 bate cells per eum, all which ser polymorpbonuclear ·300 A MOGEHEE HARVEY ET AL. cells Routine cultures and those for tubercle bacıllı were sterile There was no lonering of the spinal fluid sugar On July 9 she became comatose with short gasping respirations There was periorbital edema and constant twitching of the left side of the face with occagonal twitching of the left leg Ptosts 128 noted of the left lid and the left arm fell limply when raised On that day funduscopic examination showed a soft exudate just beneath the right disc There wag cervical rigidity and definite enlargement of the cervical and axillary lymph andna allpeared in the left fundus The white count continued to rise, reaching 25,000, with no significant change in the differential On the day of death, the patient had a generalized convulsion The blood and spinal ffud STS were negative Serum globulin was 3 gmund the LC cell test wag negative The hematocrit was 29 X-ray of the chest showed a pleural reaction at the left base and what w39 interpreted to be underlying areas of atelectasis Later, a pleural effusion was noted, and the heart shadow was increased in SZC At autopsy no grogs lesions were noted other than the pleural effusion Microscopically, there was evidence of pleuritis and pericarditis and foci of necrosis were noted in Iymph nodes There was also found the type of pneumonitis seen in systemic lupus However, many sections were scarched before any classical lesions of SLI) were noted, and they were verı few in number Cytoid bodies were found in the nerve fitire layer of the retina. e Bropsy and Dragnosis Biopsy examination of skin, muscles, and lymph nodes has been widely used for the diagnosis of lupus erythematosus Although changes may be found whuch are compatible with the disease, particularly when considered along with the clinical picture, pathognomonic changes are unusual 1 Slin. In 1932 Goeckerman and Montgomery (81) evaluated the histological changes in the skin in 26 cases of discoid lupus and 18 cases of SLE. They noted, in comparison, similar changes in the discord and in the acute type but different in degrec The earliest alterations were described as the same in both instances with vasodilatation and ederna of the upper layer of the cutis They recommended that biopsies be made from a patch of more than two wecks duration as the carler lesions are similar to those produced by other cutaneous dtseases The acute changes were marked thinning with disappearance of the rete ridges, and intraepidermal or subepidermal vesicles No proliferative changes were noted in the walls of the blood vessels In the same year Vadden (164) also described the histopathological changes in the epidermis This was often thin, and edema of the papıllary bodies was so extreme that the epithelium sos torn away and bullae arose at the site of rupture Degenerative changes of the collagen and elastic fibers became marked carly, and there was homogenization of the connective tissue. Particularly prominent was dilatation of the blood vessels and lymph spaces in both superficial and deep cutis with mild periyascular collections of round cells and a few plasma cells Montgomery (175) noted that pathologically all transitions from localized (liscoid to vanous disseminate types may occur Dilatation of blood vessels and lymphaties was followed by extravasation of leucocy tes together with the de- ·SYSTEMIC LUPUS ERYTIILLATOSCS 302 velopment of relative and absolute hyperkeratosis, Leratotic plugging of hair follicles and sneat ducts, acanthosis of the prichle cell layer with adjacent regions of atrophy, lquefaction necrosis of the basal cell layer, a perivascular, chiefly lymphocytir, infiltration about the derma: appendages, and destruction of elastic tissue where the infiltration occurred in the acute type dilatation of the superficial capillaries and lymphatics and elema of the cutis with atrophy of the epidermis and {squcfaction accrosis of the basalcelayer became more promitent and the infiltration usually legs marked As the disease progressed atrophıc changes occurred in the sebaceous glands and hair follicles Liquefaction of the basal cell layer apparently results from elema of the lymph spaces and may be 20 marked as to result 18 subepithelial or intraepirkchal formation of bullae. One of the most exhaustive studies of the histopatiwlogy of the cutaneous lessons is that of McCreight and Montgomery (169) They made & histologic review of 110 specimens remos ed for bropy or on post mortem evammation, and noted the same histologie changes within the epidermis m chronic dracord sa in the systemir or disseminated types, although the degree of change was less pronounced in the dissemmated types They stated that it was apparent that to sungle pathological change would allow a definne diagnosis of pus erythema. 10924 Poseyer, a combat1on sncluding hyperkeratoys without parakeratosis, beratotic plugging of hair follicles, Isquefaction degeneration of the basal cell layer, edema of the cutis, dilatation of the superficial capslares, a cellular 19- filtrate composed primarily of lymphocytes and the absence of obhtcratne or proliferatne changes in the walls of the deeper blood vessels would certamly slegest the diagnosis (Fig 2) Fig 2 Biopey of skin from a patient with SLE Hyperkeratosir, vacualar degeneration of baasd epithehal cells, and iniammation, especially per vascular, we all typical of lupus erythematosus ·B Fia 3. 1.3 mph node biopsies from * patient with SIE . This section shou s an aren of fresht necrosis Tus lesion 19 nat specific for Irut very Rukkestive of acuta SL.L. 3 This peetinn is from & lymph nule biopay in the same patient taken one week afier Blarting treatment with ICTH. There is all area of recent healing necrosis with a border of foam cells.

·51 STEWIC LUTUS ERYTMIEVATOSUS 303 It was noted by Jessar and his co-a orkers (129) that in many instances the d.. agnor could not be made from skin biop y in patients who later developed classical mamfestations of the disease in sexteen patients in whom the diagnous was confirmed at autopsy, ning had had skin bropsies of which only three were positive Bandick and Ellis (34) sent a questionnaire to leading dermatological pathologiste u ho indicated that a positae diagnosis could be made 112 75 per cent of the cases with shin biopsy This may be true sf all other information is considered along with that outamed by histological examination of a cutaneous lesion % Lymph nodes then taken in conjunction with the clinical picture the changes noted in lymph nodes remored by lyopsy may be of help in diagnosis Ginzler and For reported a case in 1910 (78) showing extenssse changes in lymph nodes The earliest lesions consisted of foc of cellular necromosis with virtually no reactive inflammation These progressed to larger areas of necross with complete cell degeneration, disintegration, and pyknees in many of the arca", some cells underuent a pinkxsh-blue granular degeneration of the cytoplasız 12th pył nous apparently coalescing to form striking blm -violet staining masses resembling calcuum in hematoxy lin-atained material In retrospect, there were probably large aggregates of "lematovylın bodies" As the lesion progressed, foam cells appeared at the margins with subsequent searring at the junction of necrotic and vsable tissue Specific epitheiind cel format sons did not des clop and giant cells were not seen (Fig 3) Such lessons must be distinguished from those of "catseratsh" discase, acute tularcmic necros19, Bustoplasmonly and, perhaps, from those of unusual cases of glanders, lymphopathua senereum, tuberculosis, sarcosdosis, brucelloss, and Ilodgkin's disease in two cases in the present series the lymph noxle changes were diagnosed as Hodgkin's trase on one and reticulum cell sarcoma is the other Later derelopments made it clear that these patients had SLE 3 Jucle Madden (165) studied muscle top sperimens in 32 cases with dermatomyostis and tupus erythematosus 3 modulas my ost was seen in SIT of 21 specimene from patients uith lupus erythematolls The lesions were striking in only one who also had rheumatie (ner Their conclusion as that the muscle changes in dermatomy ostis and Fupus sere non-specific and similar changes occurred in theumatoid arthritis, rheumatic fever, scleroderna, thyrotoxxosis, atid & variety of other disorders Lonman (102) studied sprial sec. tions of muscles from 15 cases tuath lupus Slight to moderate degeneratxe changes were noted in 73%, while 37% of 30 control cases skzoned similar changes He also bored a ascular pattern on the venous side of the circulation composed of edema, cellular reaction and sclerosis These muscle and perineurovascular changes were identical with those seen in taxes of actre rheumatud arthritis The author concluded that the polymyositic and perineuntie nodules of lupus erythematosus are identical with those seen in theumatic arthritis and that both ere produced in this vascular pattern of reartion The inculence of focal degeneration of nerves was greater in the cases of lupus erythematosus than would be expected, but the significance of this was unknoks to the author Other observers hane noted an arteritis or phlebitis of the small vessels seen in muscles which ·304 A. ACGEHEE HARVEY ET AL. cannot be distinguished with certainty from that seen in periarterit19 nodosa and Theumatoid arthritis It has been our experience that biopsy examination is frequently of little help in establishing the diagnosis of lupus, no specific lesion being detected in patients who are later found to have the disease Thus, in our group of patiente, lymph node biopsy was nonspecific in 11 instances and positive in only two. Of 19 skin biopsies only 12 were positive, and only one muscle biopsy in 12 gave information of definitive value IV. ETIOLOGY AND PATHOGENESIS a Infections, including Tuberculosis Since the first description of SLE there has been much speculation about etiology. Most of the arguments, however, are based on no solid evidence. During the early years of this century, one group, mainly German, believed that the disease was associated with tuberculosis and this view dominated the literature until the detailed analysis of Keil (137) showed that it was lutenable Other observers thought the basis for the disease was a septicemia probably due to the staphylococcus Detailed bacteriological studies have given no support for this thesis. The disease is associated with a frequent incidence of complicating infectrons, particularly pneumonitis, and active tuberculosis may develop during the course of the illness In 1941, Kelvin (141) expressed the opinion that lupus 1125 due to an innate characteristic of the skin, probably congenital, which rendered it peculiarly susceptible to the action of tuberculotoxin. His conclusion was based on the result of tuberculin testing in a series of 148 cases of lupus and of 240 individuals with healthy shins or other dermatological conditions. Among recent articles relative to the possibility of infection as an etiological agent 15 that of Welsh (270) This author described the characteristics of streptococci 190lated from the nasopharynx, infected tonsils, apices of infected teeth, and blood of 16 patients with lupus erythematosus Similar, hut not identical, strep. tococci were isolated from patients with pemphigus, dermatitis herpetiformis, and erythema multiforme Mooiten and Clark (177) claimed to have isolated a virus from the blood of patients with SLE, but this work has not been confirmed by others b. Endocrinc Factors Certain evidence has suggested a possible endocrine factor in the pathogenesis of SLE Baehr, Klemperer, and Schifrin (5) noted the high incidence of SLE in females, and Rose and Pillsbury (221) cited the frequency with which the disease affects females within the active sexual phase of life The latter authors de scribed the effects of castration or natural menopause upon the course of SLE in six cases and emphasized the desirability of further investigation of gonadal function lioets (147) followed the 17-ketosteroid output in a patient with SLE and showed that during the chronic untreated phase she excreted amounts 29 large as followed the administration of ACTI at a later stage The author concluded that the ketosteroid excretion untreated rheumatic disease expresses the degree of automatic defense the body can develop at a giren stage ·SYSTEVIC LUPUS ERYTHEMATOSUS 305 c Allergy or Hypersenstlity Exidence has accumulated to indicate that certain types of angiitis are the result of anaphylactic hypersensitivity. However, in many cases of polyarteritis which spontaneously develop in the absence of any allergic reaction to a therapeutic agent, no specific antigen to which the patient 13 sensitive can be discovered the possibility of an allergır background as the cause of SLE is es en less clear That the disease may develop in its acute form following reaction to a foreign protein or to a drug does not constitute sound evidenre for an allergic etiology, Rich (213) believes that anaphylactic hypersensitivity probably plays an important role in polyarteritus nodosa, rheumatic fever, SLE, and rheumatoid arthritis Rırh and Gregory (217) found in rabbits subjected to protracted anaphylactic reactions of the serum sickness type lesions which were compatible with the sclerosis of the branches of the coronary arteries seen in theumatic fever and also in SLF They pointed out that there are a variety of reactions seen in the latter disease which are also characteristic of the serum sichness type of anaphylaxis, including fever, cutaneous eruptions, purpura, arthritis, necrotizing inflammatory arterial lesions, focal collagen degeneration, focal necrosis of lymph nodes and spicen, myocardit, valvulitis, sterile inflammation of serous membranes and sterile pneumonitis Fox (72) has reported a case of SLE developing after the administration of tetanus antitoxin Stokes, Beerman, and Ingraham (216) suggested that SLE is produced by an infectious-allergic mechanism leading to vascular allergic manifestations Teilum believed (230) that the hyperglobulinemia, periarterial fibrosis of the spleen, and "wire-loop" lesion of the glomerulus in SLE are all expressive of a w primary allergic "hyperglobulinosis" of the reticulo-endothelial sy stem He stated that the various phases of the tissue injury, such as "fibrinoid" degeneration with immigration of cells, granuloma formations, and fibrosis as well as primary necrosis can be followed most distinctly in the lungs where they represent a focal allergic pneumonia Some observers have suggested that the widespread use of chemotherapeutic agents may be correlated with the supposed inciease in the incidence of SLE, periarteritis nodosa, and other connective tissue diseases Gold (82) reported eight patients with acute or subacute SLE all of whom had lesions of the skin and photosensitivity In seven of the patients sulfonamide or penicillin therapy had preceded the onset, and in four there had been a sensitivity reaction to one of these drugs It seems likely, in our opinion, that these druys may act as a trigger mechanism for activation or intensification of the disease, and have no etiological relationship In a recent article Gold and Gowing (83) stated that an antigen-antibody reaction may be the basis of SLE while discoid lupus may represent a cutaneous reaction denoting hypersensitivity to an infective focus These two processes may occur independently or together d Relation to Other "Collagen" Diseases Banks (10) and others have grouped together a variety of disorders affecting connective tissue including rheumatic fever, rheumatoid arthritis, lupus erya ·306 A MCGEHEE HARVEY ET AL thematosus, periarteritis nodosa, dermatomyositis, and scleroderma Because of the occurrence of "fibrinoid" degeneration of collagen these observers assumed that the diseases may have a common etiological background. Baehr and Pollack (6) pointed out that connective tissue is the supporting and cementing framework of all organs and tissues and consists essentially of collagen laid down in fibrils and of a ground substance. They suggested that it has only three basic ways of reacting to injury: degeneration, fibrosis, and cellular reaction "Fibrinoid" degeneration may occur in any type of connective tissue injury, according to these authors, and is not specific for any one type They believed that "fibrinoid" degeneration of collagen is not a pathological process reliable as a common denominator for the classification of disease They stated that SLE and diffuse scleroderma have this morphological expression in common, but are so dissimilar clinically that they seem related neither to each other nor to rheumatic fever, rheumatoid arthritis, serum sickness, periarteritis nodosa, or thromboangntis obliterans in which similar collagen changes may occur. Ehrich (62) believed that in these vanous diseases there is production of an abnormal gamma globulin which circulates in the blood and produces injury to mesenchymal tissues When this is severe, there may be an increase in certain substances released from the damaged tissues and appearing in the blood such as mucopolysaccharides, non-specific hyaluronidase inhibitor, alpha globulins, and fibrinogen He proposed the term "dysgammaglobulinemia" to designate this group and also included primary amyloidosis and para-amyloidosis in this category Certainly it may be said that the etiology of SLE remains a mystery. A variety of stresses including infection, exposure to sunlight and to cold, various allergic reactions including those to therapeutic agents, trauma including minor surgery, and other situations are recognized as being possibly important trigger mechanisms or aggravating factors enhancing the activity of an underlying process V. GENERAL CONSIDERATIONS Classification Classification of reported cases of lupus erythematosus is difficult; because in many articles the clinical features are not stated clearly, and because no standard system of nomenclature has been followed The terms acute and disseminated, which now imply systemic involvement, have been applied in the past as descriptive terms to cutaneous lesions, there heing in many instances no evidence of systemic disease on the basis of the observations reported. Most attempts at classification have been based on the nature of the dermatological manifestations A frequently quoted classification is that of O'Leary (188) which divided cases into the following types 1. chronic discoid a localized b generalized with systemic symptoms usually mild to ahsent 2 subacute disseminate ·SISTEVIC LUPUS ERITHEXATOSUS 307 3 acute diyeminate Urbach and Thomas (260) have proposed a diffcrent scheme as follows. 1. chronic group a discord erythematodes b disseminated erythematodes 2 exacerbated group a discoid with acute or subacute exacerbation b disseminated with acute or subacute exacerbation 3 acute group a acute bubacute Many subtypes of the chronic discoid variety have been described, being named in accord with some prominent presenting feature such as lupus erythematous nodulars, verrucosis, etc Wilson and Jordan (271) investigated the mode of onset of the subacute and acute disseminated forms of LE with particular reference to the interrelationships of the various morphological cutaneous types to the underlying systemic disease process. They analyzed 265 cases of disseminated lupus erythematosus with associated cutaneous manifestations Among these were 96 subacute and 169 acute cases which fell into one of three groups In Group I, in general, the muco-cutaneous lesions were acute and often widely disseminated. The interval between the onset of the dermal lesions and the development of systemic manifestations was usually short In Group III the lesions were of the chronic inflammatory type, and associated with a longer interval between the occurrence of the cutaneous lesions and systemic involvement In Group II the lesions were of an intermediate type, occasionally showing atrophy, and as. sociated with an interval of intermediate duration between onset of the cutaneous lesions and systemie involvement. Attempts to classify the disease into acute and subacute categories other than with reference to the course of the skin lesions serves no useful purpose It is well-known that the course of the disease tends to vary from moment to moment as far as severity is concerned, and the "acuteness" of the illness merely denotes the severity of the constitutional manifestations present at any one period Arnold (3) and Haserick (103) advocated the term "systemic lupus erythematosus" in referring to the generalized form of the disease, and reserved the terms discord and disseminate to describe the skin lessons This seems the preferable use of terms at the present time The clinical picture presented by this disease, SLE, of which in our opinion the skin lesions whether chronic or acute are only a part of the same process, is so varied in its manifestations and course that no simple classification of clinical types is feasible b Incidence The exact incidence of SLE is obscured by the fact that many cases hare doubtless gone unrecognized It is not possible to determine whether the disease is now occurring more frequently, although a number of observers feel that it is ·308 ANICGENEE HARVEY ET AL. The development of the L E cell test has led to detection of many cases previously regarded as having other disorders. There is general agreement that SLE can no longer be regarded as an unusual disease entity. Dubois (36) reported that at the Los Angeles County General Hospital the disease was diagnosed in only 11 patients from 1918 through 1919 During the following two years, when an active search for nes cases was under way utilizing the L.E cell test, the diagnosis was made in 44 cases Houet er, these figures cannot be interpreted as indicating any change in the incidence of the disease. c. Ser, Race, and Age Of 23 cases reported by Baehr, Klemperer, and Schifrin (5), 22 were females. With the advent of the newer diagnostic tests, the discase has been recognized with somewhat greater frequency in males and numerous cases have now been reported in Negrocs Reported figures as to sev, race and age of onset are given in Table I Only recent articles are quoted because of the newer methods of diagnosis Among these it is seen that females predominated in all series The peak incidence was in the second, third and fourth decades, but the age at onset ranged from two to 67 years In general, the racial distribution was similar to that of the particular hospital population concerned Montgomery and McCreight (176) compared a large series of cases seen at the Mayo Clinic before 1938 with another observed since that year. They divided the cases into three categories: acute, subacute, and chronic. They noted an increase in the percentage of females in the latter series, but no significant change in the age at onset In Charl 1 is seen the age, sex, and race distribution in our own series of cases. d Familial Occurrence More than one member of a famıly may be affected with lupus erythematosus Legobbe (157) compiled a series of such reports by various authors describing the cutaneous lesions in more than one member of a family. Most were siblings In one family there were eight cases, and in another, four. There was no statement as to systemic manfestations The author reported three cases of lupus in the members of three families of common descent Jaworow sha (128) descried discord lupus erythematosus in three sisters Sequeira (231) presented cases of TABLE I Systemic lupus erythematosus, age of onsel, ser, and race incidence Authors Jessar (323 cases) Dubois (62 cases) Shear Profsky (33 cases) Present Series (138 cases) % Females 91 % White race 85 91 7S 81 17 27 yt Age onset Average Peak Range 84% (1040 yr) 5 5-60 yr 56% (over 30 3r) 50% (10-10 37) 3-563 5-135 2-67 yr ·SISTEMIC LUPUS ERYTHIES ATOSUS 309 DISSEMINATED LUPUS ERYTHEMATOSUS AGE ONSET, SEX ANO RACE INCIDENCE 10S CASES 30 20 WHITE PATIENTS 21 MALE 62 FEMALE COLORED PATIENTS MALE 19 FENALE NUNTER Or PATIENT $ 15 - 10 $ IN D DECADES CHART ) Age at onset and the sex jod race nedence so 105 cance of SL.L. two sisters with the disease Both children suffered from blueness of the ertremities during the winter months and one had albuminursa Shears and Prof. sky (231) noteu SLEi tuo meinbers of the same family, and Days and Cutndge (52) reported its accurrence in kentical twin sisters. e. Predisposing factors It hay long been observed that a number of factors have an apparent relatronship to the onset or eracerbation of the cutaneous or other manifestations of this dispase Among the most prominent of these which have been commented upon in recent reports are exponltre tu sunlight or ultraviolet rays, the presence of focal infection or reaction to foreign protets inclutmg tubercutoprotein, reactron to a varicty of Therapeutic agents melding guld, sudfouamides and pencillin, aud finally emotional trauma Foral infections, for example, were noted in pasentially half of the parents olieers ed by Shearn and Profsky (234) Jessar and his CD-jvorhers (129) found no relationshup of the disease to upper respiratory infections but not that snel tivity to sunlight was a precipitating factor in 172 of their lases. In many reports there was a frequent story of the use of sulfonamides or other antibiotiry lyut no clear evidence of a temporal relationship to onset Gold (82) presented a study of eight patients tith acute or subacute disseminated lupus, ait of whom had lesions of the skin and sertiity tu sunlight In vever, sulfonamide or penicillin Therapy had preceded the onset, and in four there as a history of a sensitivity reaction to one of these drugs Many observers have felt that any allergic type of reaca tion was purely coineidental or, perhaps, responuble for a flare-up of the disease after its onset Another view was that allergic reactions are an intric manifestation of the disease process This is a difficult point to decide since only recently has it been possible to reach a reasonable conclusion as to the initial manifesta. tions of thrs disease, and to determine the time of its onset with accuracy. Slocumh (238) has stated that patients with rheumatoid arthritis who hasc ·310 A, MCGEIIEE HARVEY ET AL developed chronic hypercortisonism may exhibit during hormone withdrawal a panmesenchymal and panangutic reaction If the reaction is sei ere there may be fever, pericarditis, pleurisy, signs of pulmonary consolidation, renal involvement and hypoalbuminemia In 15 patients the L.E. cell test was positive and in four there was a false positive serologic test for syphilis Smice it is not uncommon for exacerbation of SLE to occur during withdrawal of cortisone administration, st scems most reasonable to assume that these patients had this disease which had previously been manifested by arthritis alone Prolonged administration of hydrazinophthalazine in the treatment of hy. pertension has been followed in some patients hy a syndrome which resembles SLE (60, 182) Manifestations included fever, arthritis, polyserositis, and pneu. monitis In several instances the L E cell test gave positive results. The signifi cance of these observations remains to be clarified, but as will be discussed later hypertension is uncommon in patients with SLE In a recent article, Perry and Schroeder (196) noted this complication in 81 per cent of 211 patients who had received treatment for tno to 22 months, the total amount of the ollending agent ranging from 23 to 350 grams The fully developed picture resembled SLE, according to the authors, but in only one case were L E cells found. Most of the patients in our own series had excellent general health prior to the onset of SLE Several of them, however, had a history of antecedent chronic or recurrent upper respiratory infections, including sinusitis and tonsillitis, but this group is too small to have significance. The incidence of various clinical manfestations of allergy was carefully sought in our patients While a wide variety of allergic phenomena frequently occurred after the disease had made its appearance clinically, they were not common prior to that time (Table II) It was as if the development of SLE gave rise to a state of altered reactivity which was then associated with the frequent occurrence of allergic phenomena Repeated acute exacerbations of SLE followed drug reactions which seemed to serve as trigger mechanisms for a series of events which sometimes terminated in the patient's death In certain cases it appeared that a particular drug or other allergic reaction initiated the disease process, but usually close analysis of the history revealed the prior existence of symptoms. From the therapeutic standpoint, patients with lupus should be given drugs or other agents likely to induce an allergic reaction with even more caution than in individuals without this discase The following case summary illustrates these difficulties This patient had a long illness and was told repeatedly that she had an "allergy" In retrospect it is probable that she had chronic SLE with remissions and relapsea Case 2 MC ($611028), a 42 year old white school teacher, entered in May, 1953 complaining of generalized edema of 10 months' duration At age 13 she developed parotid swelling ac- --.rar st u with periorbital edema and conjunctival injection At age st one nisu ulila- ·SYSTEMIC LUPUS ERYTHEMATOSUS 311 TABLC II Illergic manifestations in systemic lupus erythematosus (Present Serieg-105 Cases) Before Diagnosis After Dungaosas 11 2 Xone Xone None 1 None 2 Urticaria - usually attributed to food sy fever Contact dermatitis Drug reaction ACTII Penicillin Sulfonamides Streptomycin Chloramphenicol Gold Quinine PABA Tureomycin Otherg Yone None 2 4 6 5 3 2 + 1 Yone Jone No data 1 2 8 . Frequently resulted in severe exacerbation of the lupus erythematosus persisting long after cessation of drug administration in three instanrcs patient sensitive to tuo or more drugs with arthralgia thaught due to fish One year later she was told she had virus pneumonia on four occasions during a four month period She was critically all with fever, malaine, myalg..., arthralgia, underwent several thoracerteses, and had pericarditis At age 38 she had parotid swelling associated with local inflammation and pus n as evacuated into the buccal cavity She developed facial edema folloring the administration of sulfonamide from this period on her strength progressively declined She had several episodes of "flu" each year characterized by fever, malauge, my algia, and arthralgia One year before admission she noted onget of dependent edema associated with swelling of her face She noted blueness and numbness of her fingers on exposure to minimal cold six months later she had swelling about the eyes associated with a scaly, erythematous eruption [dema progressed and alopecia developed On admision, the temperature was 101°F (R), pulse 90, respirations 34, blood pressure 115/65 She appeared chronically ill and had anagarca The shin as dry, scaly, and thickened In the periorbital areas there was edema and the skin was ery thematous and scaly, The finger tape rere atrophic The mucous membranes were pale Cytoid bodies were noted in the fund. There were palpable cervical and exillary lymph nodes Medium rlles were beard at both lung biases A soft systolic murmur was noted to the left of the sternum The hver was palpated two finger-breadths belox the costal margin There was ascites There as slight swelling of the fingers, but others 190 no objective evidence of arthritis although she complained of paing over many joints There was no afemia The white cel) count wag 8,000 with a normal differential Serum albumin has 19 gm .globulin 3 gmn X-ray of the chest revealed a pleural reaction on the right with some fluid Tests for LE cells were positive on several occasions Electrocardiogram shonerlarnus tachycardis, lon amplitude of the QRS and T waves Thema ---- 14.-L. lowered to 100 mg a day and her weight as 114 lb ·312 A MICGEHEE HARVEY ET AL VI, TJIE CLINIC IL MANIFESTATIONS OF SYSTEVIC LUPUS ERYTHEMATOSUS a General Considerations The picture of the disease at onset may assume a wide variety of patterns A single organ system may be involved such as the skin, joints or kidneys, or several systems may be implicated The skin and joints are most frequently affected singly, but any of the organ systems may be, suggesting that the patient has a loralized disorder rather than a generalized process The following is a list of diagnoses made by various physicians who saw our patients during the early stages: 1 Rheumatic fever 13 Epilepsy 2 Rheumatoid arthritis 14. Acute psychosis 3. Other disorders involving the 15 Drug reaction skın 16 Septicemia 4 Latent syphilis 17 Dermatomyositis 5 Idiopathic thrombocytopenia 18 Lymphoma 6 Anemia due to other causes 19. Scleroderma 7 Leucopenia due to other causes 20 Tuberculosis 8 Pleurisy due to other causes 21. Trichinosis 9 Virus pneumonia 22 Brucellosis 10 Raynaud's disease 23 Bacterial endocarditis 11 Fever of unknown origin 24, Functional illness 12 Acute nephritis The initial manifestations may be so vague that it is difficult to be certain when the disease has actually begun The patient may state, for example, that she "has always been sensitive to the sun" or has had recurrent mild aching in joints since childhood Often the patient does not appreciate the connection hetween the present illness and some isolated incident in the past, such as pleurisy or a skı eruption, and fails to report it The observer may be uncertain whether a particular past incident such as an episode of pneumonia or an outbreak of hives was due to SLE Table III is a summary of the initial manifestations of 105 of the patients in our series As pointed out by Ross and Wells (223) the more important manifestations of the systemic disease were adequately described in the older literature, but many of these early reports are capable of interpretation only in the light of recent know ledge Many cases, until the advent of the newer diagnostic tests, were unrecognized or were diagnosed according to the major presenting difficulty such as rheumatoid arthritis In many with dermatologic manifestations, little attention was paid to such systemic symptoms as fever, malaise, weakness, fatigue, loss of weight, and arthralgia Edema is a frequent finding and may be focal or diffuse. Skin lesions may appear early or late or not at all during the entire course of the illness There is no classic pattern of the disease, although a large percentage of the patients have joint or cutaneous manifestations, as well as constitutional difficulties with fever, fairly early in the couree of the illness.

·SYSTEMIC LURUS ERYTHEMATOSUN 315 TABLE IV-Continued Vuruber of Patients Harvev et al (195) Dubois (62) Jessar et Shearn & al (+1) Pirofsky (34) 1-total 36 10 21 18 $50 127 11 11 8 5 10 6 Le . pain 37 22 35 > 15 57 70 62 65 39 23 16 11 urinary 1-total (Some abnormality such as alfrumnuria, abnormal sediment) al (mild) (moderate-Reverc) (uremia) Venorrhagia Central nervous system 1's choses Convulsions Ilemiplegia 1ological false positive STS Positive akin biopsy Positive lymph node biopsy Poestive muscle biopsy Leucopenia (1 count below 4,500) Anemia (helow 11 gin) Thrombocitopeni 3 LE cell test (% positive, no performed) 23 31 15 13 17 2 15 11 (of 19) 1 (of 13) 1 (of 12) 9 7 2 28 19 33 52 (23) 70 95 78 26 82 (96) 69 78 10 69 (60) 74 97 31 i 94 (31) * There were not proven by the treponema immobilization test They indicate positive tests of the routine type which were of low titre in the absence of definite history of or lesions pathognomonic of syphilis observer must search the background for past illnesses which might be related A present occurrence may gain meaning from what has happened in the past The discase may appear with a confusing array of manifestations resulting from multisystem involvement in which it is difficult to detect any obvious continuity Joint, and with somen hat tesser frequency, muco-cutaneous manifestations are commonly present in episodic fashion and are helpful in pointing towards the correct diagnosis The follow ing case history with a number of isolated episodes involving various organ systems, and the final diagnosis of SLE made only after many years, illustrates some of the features discussed above Cases L W.(240196), s 19 year old colored female, was admutted for the fourteenth time on ctober 3, 1953 Except for mild hypertension and light albumDUTI3 with pregnancies she ·314 A, MICGEHEE HARVEY ET AL TABLE IV Percentage incidence of certain manifestations of systemic lupus erythematosus Number of Patients Harvey et al (105) Dubmis (62) Jessar et Shearn 4 al (44) Pirofsky (54) 71 86 82 97 100 95 100 68 91 52 43 40 16 58 85 39 11 12 9 14 7 3 10 15 11 18 26 16 6 77 N 27 90 31 85 12 42 37 co General Weight loss Fever Skin All types Butterfly Photosensitivity Pigmentation Purpuric Mucosal Hives Alopecia Raynaud's Joints Arthritis and arthralgia "Typical rheumatoid" with deformity Lymph nodes General enlargement Localized enlargement Splenomegaly Hepatomegaly Jaundice Eye grounds-total Cytoid bodies Hemorrhages Exudates Lunge Pleurisy with effusion Pneumonid, lupus bacterjal Cardiac Total incidence Enlarged heart Cardiac failure Systolic murmur Libman-Sachs lesions 27 20 34 21 15 32 3 30 24 10 5 8 31 11 32 41 44 12 ng 20 56 16 60 55 50 24 39 20 23 70 34 24 71 42 52 15 8 44 12 of 38 autopsied) 45 16 (of 38 autopsted) 14 5 23 Pericarditis Myocarditis (incl gallop rhythm) 18 21 18 18 32 Hypertension Conduction defects ·SYSTEVIC LUPUS ERYTHEVATOSUS 3177 Dubois (56) noted that arthritis was the most common presenting feature in his 61 cases, being the initial manifestation in 31 per cent The picture was usually typical of early rheumatoid involvement and in most acute cases there was arthralgia of the prorimal interphalangeal joints as well as of the elbows, knees, and ankles In his cases fusiform swelling of the proximal interphalangeal Joints was common in the exacerbations of the disease, and a persistent deformity was described in 30 per cent He observed, as have other, that patients may complam of arthralgia, with or without joint swelling, for many years prior to any other evidence of systemic involvement. Lowman (162) examined the synovial tissues pathologically in five patients with SLE coming to autopsy and noted that the vascular changes were identical with the pattern of reaction secn elsen here The stroma showed cdema initially and subsequently fibroblastic response with ultimate fibrosis The synovial lining cells only occasionally showed hyperplastic changes He stated that the vascular reaction was similar to that secn in active rheumatoid arthritis In a patient who had had classical rheumatoid arthritis for many years, recently autopsied in the Johns Hopkins Hospital (autopsy * 21097), the typical histological changes of that disease were described including massive rheumatic nodules showing collagen degeneration Also seen were typical lesions of lupus erythematosus in the spleen and heart Bennett and Dallenbach (20) studied at autopsy the synovial membranes from two untrcated cases The synovial tissucs revealed remarkable deposits of fibrın upon and within the intima Other morphologic evidences of inflammation were almost absent "Fibrinoid" change in synovial and sub-synovial connective tissue was also observed in scattered areas These two patients died after illnesses of 29 and 10 months and had res ealed similar alterations clinically with persistent arthritis After this long period of arthritis there were no adhesions across the joint clefts and pannus had not developed at the perichondral margins of the cartilage surfaces The cellular components of the inflammatory erudate were minimal, and the changes were thought to be unlike those of rheumatoid arthritis In a group of 105 of our patients, there were only ten ho did not have joint involvement While arthritis may occur at any period during the course of SLE, it was frequently one of the earliest manifestations, and in 63 per cent joint involvement occurred during the initial episode of illness Arthritis was often the sole early manifestation, leading to the misconception that the patient had some other type of joint disease such as rheumatoid arthritis In nther instances, the initial episode of arthralgia or arthritis was associated with additional evidences of discase, such as eruption, fever, or pleuritis In patients presenting with arthritis, a long period sometimes elapsed before other typical manifestations of SLE appeared as is illustrated by the following case Case 4 KL (* 461514), a 36 year old white male, * 23 admitted for the first time on January 6, 1950 Twenty years before admission he developed migratory polyarthritis which spon. taneously subsided For the subsequent 12 years he was sell, at which time a small erythematous patch appeared on his nose When treated with 1odine and ultra violet light a ·310 A. MCGEHEE HARVEY ET AL had been well until 1936 when she had an acute pleuntisand developed pols arthralgrattrib. uted to an infected tooth The arthralgia persisted intermittently, but she was relatively well until 1916 when she developed fever, nausea, vomiting and blooily diarrhea A diagnosis of bacillary dysentery was made but not proved, and she recovered over a period of three weeks. In 1919 she complained of exertional dyspnea and because of a mitral systolic murmur and arthralga, a diagnosis of rheumatic heart disease was made At the same time she ideveloped a cutaneous eruption involving the face and upper trunk whicb was called "scabies" In June, 1953 she was admitted complaining of abdominal cramps, rectal bleeding and loss of 65 lb in weight over the preceding five years The blood pressure 160/100, the hematocrit 21, bloor STS doubtful and serum globulin concentration 5 gm per cent Albuminuria is noted and after hemorrhoidectomy she became oliguric for a brief period. On October 1, 1953 she entered the Gynecological service complaining of crampy pain in the leſt lower quadrant and bouts of hematuria For four months she had felt weak, had mild sweats", od "shaking" pains in the chest ller hematocrat was 17, and the NPN 71. The urinary sediment was loaded with white cells and erythrorytes Urine culture showed Colu aerogenes L E cells were found in the peripheral blood There as also evidence of myocardial involvement with heart failure It acems clear that this patient had had SLC for at least 17 years with episodes in which there was involvement of the pleura, joints, heart, skin, intestinal tract, and finally the Lidnes with renal insufficiency Complicating the last episode was a urinary tract infection After treatment of the infection she was placed on cortisone and has been asymptomatic for several months Joint Manifestations Kapo (135) observed the occurrence of arthralgia in SLE and noted that joint complaints may precede the fulmmating phase of the illness Joint manife - tations including arthralgia and arthritis appear in the majority of cases. Reifenstein and his co-workers (210) reviewed 18 cases and noted articular manifestations in all Migratory arthritis was noted in 23 of 30 cases described by Coburn and Moore (43), while Baehr and ro-authors (5) observed joint involiement in 17 of 23 cames Slocumb (237) described ten patients in whom the joints were acutely painful and swollen with local redness and heat Six of the patients had acute and subacute attacks of swelling, pain and redness of the joints with residual joint swelling, stiffness and pain between attacks One developed a chronic, progressive, deforming arthritis Much more commonly seen, in our experience, than these striking objectie changes is the complaint of arthralgia with mild, soft tissue swelling without redness or much local tenderness. Friedman, Suartz, Trubek and Steinbrocker (74) stated that the articular manifestations may be classified into three major groups: first, myalgias and arthralgias, second, acute or subacute migratory polyarthritis; and third, chronic progressive polyarthritis with deformity They noted that the cases are often misdiagnosed as fibrositis, rheumatic fever, or rheumatoid arthritis. Shearn and Pirofsky (231) stated that the migratory polyarthritis seen in this disease may be similar to that of rheumatic fever, and that more than half of their patients had varying degrees of hest, swelling and local redness. Roxs and ITells (223) found the joint changes indistinguishable from those of theumstoid arthritis in nine of their 34 cases They stated that advanced destruction of the articular cartilages as scen in rheumatoid arthritis was not frequently demonstrated ·SYSTEVIC LITIS ERITIEU TOSU'S 319 migratory in character, though localization in a few joints, particularly the hands, wrists, and hnecy, also was common. In slightly less than one-half of the patients, the arthritis was characterized by local signs of inflammation, such as redness, suelling, and heat. In the remainder such signs ucre absent, there being only arthralgia Characterastically, there was a disproportion between the seter. ity of the discomfort and the objective evidences of arthritis Sheletal deformities were frequently associated with chronic arthntic inyoliement. In 28 of 95 patients with arthritis it was deserihed as typical of rheumatoid arthritis (Fig 4). In some patients contractures, muscle atrophy, and joint deformity (Fig. 5) were marked, nt times being completely drabling In contrast were individuale who had severe pains for many years without developing disability or deformity. The pain varied greatly in mtensity, at times being mild and fleeting, at other times excruciatingly severe so that the patient could not be touched without crying out Tenderness in the muscles and the periarticular tissues frequently accompanied the arthritis commonly there was an element of both myoytis and arthritis At times there was a marhe degree of muscle involvement, manifested by soreness and tenderness of the muscles and less frcquently by pi ere muscle atrophy This was most prominent about the shoulder girdle and the upper extremities In two instances the muscles were so extensively in olved that the diagnosis of dermatomyositis was suspected until post-mortem examination in one instance and the discovery of L E cells in the other The pronounced degrec of wasting of the shoulder girdle muscles gave rise to the possibility of some type of primary myopathy in a few instances Spontaneous acmission of the joint involvement was common, the arthritis F10 # This patient had bad SLI, for eleven months Note the symmetrical enlargement of the middle phalangeal joints and the atrophy of the intrinsic hand muscles ·318 A. ACGENEE HARVEY ET AL, florid erythematous eruption appeared on the butterfly area of the face, soon spreading to involve the forearms and shoulders At the same time there was marked myalgia. The eruption persisted, but he sag otherwise nell until three years prior to adnussion when he had a febrile illness associated with polyarthritis, diagnosed as influenza He was admitted in January, 1950, because of another recurrence of fever and arthritis, at which time LD cells were found in the peripheral blood and skin biopsy showed changes compatible with lupus erythematosus During the clinical course of SLE, attacks of joint pains recur episodically, the periods of active joint involvement lasting from a few days to months or even years Several of our patients complained of peculiar fleeting pain in ono joint, lasting but a few hours and then disappearing only to reappear in another joint Joint involvement was usually prominent during any period of exacerbation. Stross of various sorts seemed to precipitate this occurrence; for example, heavy exertion, operative procedures, drug reactions, intercurrent infections (commonly of the upper respiratory tract) as illustrated in the following cases: Case 5 AG (* 195127), a 37-year old sbite female, was admitted July 29, 1951 When 8 years sulfonamide for a suspected urinary tract infection following which she developed an scule illness with severe polyarthritis, spiking fever, chills, malaise, weight loss, and weakness On admission her joints showed changes which were described as being typical of rheumatoid arthritis LE cells were found in the peripheral blood Case 6 1.1.--- JA 105 Tn 1915 she from this until the time of admission In 1920 she had chonoretipit Ihree weeks before ad mungon after unusually strenuous exertion, she developed redness and swelling in her hands, wrists, elbows, ,hamatic rore ood ved an Six sonka nrin to her second admission she was again given couldpress nt he Any joint in the body may be involved by the arthritic process of SLE Vost commonly implicated in our cases were the hands, wrists, elbows, shoulders, knees, and ankles In several instances the temporomandibular joints and the spine and hips were involved Severe involvement of the spine and pelvic joiots at times suggested Marie-Strumpell arthntis The joint pains were most often ·SYSTEMIC LUTUS ERYTHEV 4105US 321 case. He noted that the disease may run its entire course without cutancous lesions Jessar and his co-workers (129) noted a shin eruption in 81 percent of 323 patients. The lesions were pruritic i 16 per cent, and a typical butterfly distribution was noted in 43 per cent, in half of whom it was a preterminal manifes. tation The shin insoli cment varied from mild erythema to vesicular and bullous lesions with at times erosion, crusting and scar formation Dubois (56) recorded absence of ski lesionis in 16 per cent of his series of 64 cases In the remainder, the dermal manifestations were pleomorphic in character karying from macules to bullous lesions Ile recognized that int olvement in the butterfly area may be transient with a mild erythema lasting for a few days or it may be chrome extending over a period of years Accompanying it may be edema of the skin and periorbital tissues resembling angioneurotic edema Scala ing may occur and even in the disseminated lesions of SLE, atrophy may take place. With healing, pigmentation may remam and at times leucoderma de clops in areas previously the site of cutaneous activity Lesions on the extremities are not uncommon and consist of small erythematous macular areas or erythematous papules scattered over the arms and legs which may ulcerate and heal by scarring On the hands there may be areas of erythematous mottling which blanch on pressure although the lesions may become fired and at times undergo necrosis This author stated that the most characteristic lesions other than the discoid Baehr, Klemperer, and Schifrin (5). They stated that at the onset or later in the course of the disease vascular lesions become visible on the shin as erythematous macules or patches which tend to become confluent The erythrma may involve the butterfly region and also be present on other areas of thc face and nech, particularly those exposed to the sun They also noted the characteristic erythematous changes located on the ends of the fingers, about the nailbeds, on the thenar and hypothenar eminences, and on the terminal portions of the toes and the ball of the foot, Arcas subject to friction or mechanical trauma developed erythematous changes and purpuric or petechis! arcas were often seen within the erythematous patches They noted the pigmentary changes and also the development of shallow ulcers on the mucous membranes surrounded by an erythematous or hemorrhagic areola When viewed under the capillary microscope the involved skin about the nailbed contained many more patent and dilated capillaries than normal which were visible through a hazy film due to the exudation of serum into the subcutaneous tissues This exudation may be sufficient to elevate the corium and result in the formation of small blebs Kell (139, 140) has written extensively on the morphologie variants in the skin in SLE, their relation to other diseases, particularly upon their differentiation from the lesions of dermatomyositis Wilson and Jordan (271) stated that in the great majority of cases atrophy does not develop in the acute lesions of disseminated lupus, but that this is not universally true. They reported that, in addition to the pseudo-atrophy due to ·320 A. MCGEHEE HARVEY ET AL FIG 5 X-ray of the hand in a patient with SLE who had chronic arthritis The osteo porotic changes and the alterations in the carpal areas including nerroning of the joint spaces were interpreted as similar to thoge seen in rheumatoid arthritis subsiding for varying periods of time, not anfrequently for many years, as already indicated and as illustrated by the following case Case 7 HT (#415738) was a 34 year old white female, whose allness began 16 years before amission in June, 1952 with onset of migratory polyarthritis with redness, swelling, and heat which was present intermittently for ten years but left no residual changes in the joints After freedom from pain for six years the loner spine hecame involved in the "arthritic" process Though she lost 20 15 in weight, she was not aware of fever For an indefinite period, she had had a recurrent erythematous eruption over the butterfy area and the chest as well as episodes of angioneurotic edema Light years before adm19310n she was found to have a positive STS although there was no history of syphilis Vevertheless, she was given antisyphilitic treatment, folloning whuch her joint symptome became worse In Jube, 1952 she was admitted to the surgical service because of pain in the lumbo-sacral spine thought due to a ruptured intervertebral dish L E cells were found in the peripheral blood She was given a course of cortisone with the thought that the pain in the spine might be a manifestation of SLI but there was no response She was operated upon and a ruptured disk was found c. Juco-cutancous ſanifestations Osler emphasized the polymorphic nature of the skin lesions, and pointed out that dermal involvement is merely the external manifestation of a syatemic dis ·S} STEMIC LUPES ERITHEVLATOSUS 323 Fra 6 The typical "butterfly" eruption in this patient with SLL had been present for one year posure to the sun Reaction to various drugs was also frequently followed by a "lighting-up" of the muco-cutaneous lesions. Raynaud's phenomenon was present in ten patients in each instance it preceded the development of other manifestations of SLE by many years, and was always associated with arthritis Ten patients had tender subcutaneous nodules which appeared on the extremi. ties near large joints, and in two instances they were felt behind the ears and over the occiput The appearance of these nodules was always associated with an acute exacerbation of arthritis Purpuric lesions were not uncommon and in 16 instances were associated with thrombocytopenia In 15 patients the cutaneous alterations were accompanied by mucosal lesions These wcre almost always within the oral cauty and occurred during an acute episode of the disease, though not necessarily a severe one At times they were erythematous or petechial patches, and at other times herpetic type ulcers developed These were painful, became secondarily infected, and were a source of distress In 31 patients the cutaneous manifestations of SLE preceded all others, at times by an interval of many years In one instance, for example, there was dermal involvement alone for 14 years Case 8 A A (#588185) WAS A 4-year old white female admitted October, 1951 Sixteen years before admission an erythematous eruption had appeared on her back after exposure to tho ·322 AJICGEHEE HARVEY ET AL thinning of the epidermis and stretching due to underlying edema, chronic discoid lesions with true atrophy were observed to develop on sites of previously acute lesions in five cases Montgomery (175) pointed out that the cutaneous lesions of lupus erythematosna may simulato clinically tho enlar... 11.1 are sarcoidosis, psoriasis, pityriasis rubra pilaris, scleroderma, acrocyanosis, dermatomyositis and erythema multiforme Montgomery noted also that the incidence of epitheliomatous change in the chronic lesions of lupus erythematosus is less frequent than in lupus vulgaris, and believed that chronic lupus must not be regarded as a precancerous condition. Epitheliomas have developed usually as a sequel to radiation therapy, and are most often of the squamous cell type. Subcutaneous nodules were described by Hebra and Kaposi Ross and Wells (223) encountered subcutaneous nodules in two of their 31 patients, and Bennett, Zeller, and Bauer (21) have found such nodules on histologic examination to be indistinguishable from those encountered in cumatic fever or rheumatoid arthritis, Lewis (158) has noted that the lesions of lupus erythematosus affect precisely those areas of the skin supplied by "atonic" veseels. These he designated as nesu sels failing to respond in the normal manner to the intracutaneous injection of epinephrine and posterior pituitary substance. The flush area of the face, the anterior triangle of the neck, the palms and soles, the dorsa of the hands, the ears, and to a lesser extent the buttock are supplied by vessels of this category. All but 16 of 105 of the patients in our series had some type of cutaneous manifestation during their illness The most frequently involved areas were the face, the neck, the V-area of the chest, the upper extremities, fingers and lower extremities The trunk and thighs were less frequently implicated. The most commonly observed alterations were erythematous, scaling, pruritic lesions which sometimes occurred in patches, at other times coalesced to invoke a wide area There was often marked vascularization of the lesions with the development of small telangiectases This was most frequently observed on the face and about the fingers. On other occasions the involved skin had an erythematous blush, often with a violaceous hue This tras particularly common on the malar emninences, presenting the classical "butterfly." appearance (Fig. 6). of importance to point out is the frequency with which these patients had transient urticaria and edema of the angioneurotic type. Such lesions are frequently not recognized to be manifestations of SLE In 13 patients alteration in pigmentation was marked, patches of increased pigmentation contrasting with areas of vitiligo In four there was such pronounced alteration of pigmentation and such striking thickening of the skin and subcutaneous tissues, particularly about the hands and other joints, that it stas impossible to exclude scleroderma on clinical grounds alone. In four the cutaneous lesions trere associated with varying degrees of alopecia Twelve patients stated that their cutaneous manifestations were definitely made 11 orse by er.

·SISTEMIC LUPUS ERITHEY ATOSUS 323 picture, the discoid form may undergo an acute exacerbation with dissemination of lesions and constitutional symptoms, cxamination of skin biop y material reveals changes transitional to those encountered in the fixed variety (as in the report by Goeckerman and Montgomery), the exeiting causes of the acute phase are manfold including sunlight, ultraviolet light, roentgen rays, exposure to cold, and drug reactions Although these drugs have been used in the treatment of other cutaneous diseases, in none had the clinical course been complicated by a series of phenomena identical with or strictly comparable with those of acute lupus It appeared, therefore, to Keil that the symptom compler typical of acute lupus may appear in the course of the discoid form under the influence of these agents In the cases reported by Dubois (50) two began as the chronic discord form One was a male who had had discoid lesions for 18 years at which time dissemination occurred with the finding of L E. cells The evidence is impressive that chronic discoid lupus may suddenly pass into a stage of acute systemic involvement This course of events took place in thrce patients in our group, as exemplified by the following casc Case 9 SG (X570399) was a 41 ycar old colored Scmale admitted in April 3, 1951 For Bix years she had been treated in the Dermatology Clinic because of chronic discord lupus involving her forehead and scalp with subsequent loss of hair In all other respects her health had been excellent Six weeks before admission she developed a sore throat followed shortly by fever, acute polyarthritis, pain in the left chest, anorexia, and weight loss She continued to run Sever, the temperature varying between 100-102°F and rising to 101-105°F shortly before adm1841on On examination at the time of entry she was acutely ill, complaining of severe pains in her joints She was much underweight There was marked alopecia Dr Lloyd Ketron described typical lesions of discord lupus on her face There was moderate gen. cralized lymph node enlargement Cytoid boulies were seen in both fund. The beart and lungs were normal While the patient complained bitterly of painful joints, there were no objective changes There was albuminuria, hyperglohulinemia, moderate anemia und slight leucopenia Repeated tests were negntre for L cells However, a lymph node biopsy showed changes compatible with SLI After ACTH administration licr temperature roturned to normal and the joint pains vanished She gained weight and felt much improved The skin Icsions healed slowly It was frequently observed in our own scries that the mucocutaneous altcrations first made their appearance or became exaggerated following the administration of certain drugs, particularly heavy metals, the sulfonamides, penicillin, and jodine This same deleterious effect was noted after exposure to the sun, the use of ultraviolet light or the administration of vaccines The stress of an operation or an infection might be followed by the development of an eruption or the spread and exaggeration of one already present The cutaneous alterations in this disease may be very bizarre as shown by the following case (are 10 CG (4553529) 43 a 41 year old white male admitted in October, 1950 with a 10 year history of migratory polyarthritis and five years of generalized swelling, redness and scaling ·324 A. MCGEJEE HARVEY ET AL. sun A scar later "red spots" were observed on her right cheek She has told that she had lupus erythematosus, and was treated with gold with clearing of the lessons Nine years later the erythematous eruption reappeared on her cheek after expnsure to the sun Once again she was treated intermittently with golil Balts and the rash appeared recurrently for a period of three years In April, 1951 she was treated with ascorbic acid at which time the eruption became more sidespread Two years prior to admission and 14 years after the ins. tial eruption, she had suddenly developed fever and pain in her shoulders and wrists which became red, hot, enollen and extremely painful LE cells were found in the peripheral blood In forty patients the cutaneous lesions did not develop for varying periods after other manifestations had made their appearance. Thus, in 14 instances five years or longer elapsed between the onset of SLE and cutaneous changes, and in six instances the lapse of time was more than ten years In a smaller number the cutaneous alterations occurred simultaneously with other manifestations, in particular, fever and joint pains. 1 The relationship of discord LE to SLE. Opinion has varied as to the relationship of discord lupus to SLE. Belote (19) expressed the belief that the chronic discoid and the acute disseminated forms represent variations of the same disease In contrast is the statement by Baehr (4a) that "in spite of its name this disease (discoid lupus) bears no relation whatsocver to systemic lupus". In the series of 96 patients reported by Wilson and Jordan (271) it was observed that patients with chronic discoid lupus might develop acute or subacute lupus erythematosus disseminatus at any time, particularly incident to exposure to the sun, other types of ultraviolet radiation, X-ray therapy, chronic infection or treatment with gold in their patients chronic skin lesions preceded subacute disseminated lupus in 26 per cent and acute lupus erythematosus in 20 per cent. Shcarn and Pirofsky (234) observed that six patients exhibited facial eruption diagnosed as chronic discord lupus prior to the development of SLE For periods as long as 25 years thesc lesions remained localized and the patients had no systemic complaints. In the series of Montgomery and McCreight (176) 22 per cent of the patients with acute and subacute systemic lupus had discoid lesions of the skin as an early manfestation Montgomery (175) made the statement that in a third of 30 cases of acute disseminate lupus erythematosus, the disease started as the chronic localized discoid type and that pathologically all transitions from localızed discoid to various disseminate types of lupus erythematosus may occur Of interest also is the statement by Rein and Kostant (211) that a high percentage of biologic false positive Wassermann reactions occurred in patients with chronic localized discord lupus suggesting that it represented a systemic disturbance even when the physical changes were localized to limited areas of the skin. Keil (139) stated that there 13 a tendency among internists to regard the acute variety of lupus erythematosus as an independent entity based on two grounds: (1) the frequent absence of atrophy in the cutaneous lesions, and (2) the severity of the clinical symptoms with a poor prognosis in the acute phase. lle thought that they probably represent variants of the same disorder, and presented four principal reasons for linking them: there are gradual and progressive transitions between acute lupus and the ordinary chronic discoid variety in the morphologic ·SYSTEVIC LURUS ERYTHEY 4 TONUS 327 Irc 7 Glomerulus showing the "wire-loop lesion" Specific vascular lesions may be difficult to find even in patients who have classical fulminating SLE at the time of death Stickney and Keith (241) studıcd 15 cases of SLE in which renal lesions were present in four the dışcase terminated m uremia with a blood urca of more than 60 mg in these patients as in five others there was albuminuria, microscopic hematuria, and cylindruna All of the cases studied by these authors showed good renal function until the final stages of the disease The most definite lesion was a proliferation of the endothelial cells of the glomerular capıllaries Hyalınc thickening of capillary walls and an irregularity and thickening of the basement membrane were also observed in one case there were pathologic changes characteristic of glomerulonephrtis and in one, evidence of subacute or early chronic glomerulonephritis In both instances the evidence of renal damage was known to have anteclated the onset of the cutaneous lesions Their conclusion was that a common distinct renal lesion does not exist and that clinically the duration of renal abnormalities is much longer than the pathologic changes found would indicate Iloncier, their conclusion is hardly tenable in view of the wide experience indicating the relaticly Hugh specificity of the well-developed "wire-loop" glomerular capillary changes A study was made by Krupp (150) of the urinary sediment in what he terms "visceral angiitis", mcluding cases of periarteritis dolosa and lupus erythematobus Of 21 cass the urinary sediment was normal in three, and in four others of the type that may occur in association with any febrile aliness In 14 there was a severe renal lesion and an unusual type of sediment was encountered Ile compared these observations with the findings in glomerulonephritis and stated that ·320 A. MCGEHEE HARVEY ET AL. of his hands Je stated that transiently during this period hug hands #ould suell and be. come deeply reddened for two to three days, following which the skin would become very scaly While the swelling was confined to his hands, the redness extended up the lorearma These peculiar episodes occuried about once a week and were brought on by using the hands in rainy weather" The year before admission his face also became red, swollen, and scaly, particularly after exposure to the sun Subcutaneous noduleg were noted about the affected joints On admission his hands were so swollen that they looked like loving gloves, and were a brilliant watermelon color This unusual degree of swelling would come and go within a period of a few hours There were hard, non-tender sulcutaneous swellings about the large joints These were evanescent Biopsy of the skin showed changes considered to be typical of lupus erythematosus and L E cells were demonstrated A few weeks prior to death in August, 1952 he was given a new preparation of ACTII, following which his temperature rowe, and he became testless and disoriented It was thought that he was having an exacerbation of this illness He soon became gravely ill with high fever disorientation and signs of meningcal irritation 1 Cryptococcus was cultured from the spinal fluid At post-mortem examination, in addition to typical changes of SLE in the spleen, hidneys and the mitral valve, torulosis of the brain and meningen was found d Renal Manifestations The occurrence of chronic nephritis in this disease as well recognized by Osler. In 1935, Baehr, Klemperer and Schifrin (5) described conspicuous alterations in the glomerular capillaries The kidneys are usually larger than normal with smooth surfaces sometimes dotted with petechial hemorrhages The most frequent microscopic alteration is an endothelial proliferation in the glomerular capillaries which may be mild or severe, leading to occlusion of the vessel and, if extensive enough, to the development of renal insufficiency. Another lesion of fairly common occurrence is focal necrosis of the capillary tufts, frequently associated with hyalıne thrombi. These lesions have been interpreted as an exaggerated or extreme form of the so-called "wre loop" Jesion. Allen (2) refers to it as a verrucal capillaritis after the fashion of verrucal endocarditis. The alteration thought to be pathognomonic is the so-called "wire loop" lesion (Fig. 7) which is present in about 60 per cent the opsied cases It consists of an irregularly thickened basement membrane nhich stains intensely with eosin It may involve only a single capillary loop or there may be a number of such lesions The extent of the lesions varics greatly, and whether or not renni insufficiency develops probably depends on the number of glomeruli involved. Baggenstoss (7) pointed out that the various tubular lesions are not prominent until glomerular changes are advanced when one may observe hydropic vacuolization, fatty change, and hyaline droplet formation in the proximal convoluted tubules Tubular atrophy may be prominent and focal interstitial collections of lymphocytes and plasma cells are scen In a few of our autopsied cases, the typical lesions of a subacute or chronic diffuse glomerular nephritis have been present with no "spre loop" alterations, and no histological changes of lupus in other organs. In at least one instance the histological picture was that described as intercapillary glomerulonephritis. The absence of the specific lesions of SIE in the kidney or other organs at the time of death does not preclude the diagnosis of SLE as implied by Parelhoff (192).

·SYSTEVIC LUPUS ERITIIEVATOSUS 320 at post-mortem examination. One patient followed for many months, during which time repeated urine examinations klere normal, u asfound to have numerous histological lesions of SLE in the kidneys The lack of conststent correlation between the chimcal and post-mortem findings may explain why patients who are followed for periods, during which they appear to have normal renal function, occasionally rather dramatically develop signs of severe renal damage Thirtyfour of the 38 autopsied patients showed some degree of an oliement of the kidneys by SLE The following case report portrays the clinical course of a patient who had severe renal disease. Case 11 AI E (+485050) was a 20-year old white female admitted in July, 1950 In 1915 she had an episode of "virus pneumonia", following which she never fully regained her strength In the fall of 1916 she had swelling of the left inter finger and several months later developed migratory pain in the elbows, knees and toes with mild swelling In 1947 she was found to have a positive blood STS although there was no familial history of syphulitic infection, the patient denied nny scrual contacts, and had had no physical evidence of syphilis She was treated with basmuth and mapharsen intermittently without reversal of her STS Sbe was then well until the spring of 1919 when she developed stiffness of the neck, pain in the right foat, anorexia, and loss of 10 lb in weight She sas admitted in September, 1919, at which time she had slight generalized lymph node enlargement, tenderness in her peripheral joints, the fingers showing fusiform swelling, and a positive STS The urine examination disclosed specific gravity 1 020,2+ albumin, 5 to 10 WBC, loaded with RBC, no casts (menstruating) The hematocrt was 33 and the white cells 6,000 Total serum protein ung 63. albumin 33, and globulin 30 gm % It way thought that she had rheumatoid arthritis By November the joint paids had hecome more severe and she was more anemue She had generalized lymph node enlargement, and her hands were cold and blush She was given a transfusion, and started on gold ther. any ller urine contained albumin, a len RBC and WBC and a moderate number of casts The treponemal immobilization test was negative, and it *as concluded that she had a biologically false positive STS She developed progressive signs of renal Insufficiency with azotemia An acneiform eruption appeared on her face and smull white ulcers were noted on the gum margins Vascularization was observed about the nail bases In December, 1919, when she was readmitted for ACTI therapy she sns acutely all, the temperature ranging between 1024 and 101° The hematocrit u 33%, sedimentation rate, 38 mm/hr l'rinalysts revealed +++ albuminuria, 10-20 red cells and 1-5 granular casts per hpf PX 15 56 mg%, scrum globulin, 33 gm % Two days after starting on 140 units of ACTII intramuscularly temperature had fallen to nithin normal limits and she had lesa joint pun She developed a severe beadache and the blood pressure rose from 135/75 to 170/100 mm JIG Although the dose nas immediately reduced to 40 units daily, by pertension persisted, she becane generally edematous, developed beart failure and the ACTHI was discontinued at the end of the third seek In spite of a slight reduction in the urinari abnormalities the Increased from 56 to 93 mg during treatment (but fell to 58 mg % one month later) and the PSC'escretion, 66% in 2 hours one month before trestment, was 7% to weeks after treatment The hematocrit feli progressively durtog treatment to 20% Symptoms of active lupus sere suppressed during ACTII and for four months thereafter except for a rebound of fever and arthritis for two weeks immediately following treatment She was readmitted in July, 1950 because of recurrence of anorexia, fever and joint pain of one month's duration The pressure was 140-180/100-110 mm IIg Albuminuria and formrd elenients in the urine were niore plentiful NPV Has 120 mg%, PSP excretion, negligible The beart was grratly enlarged and there was a pericardial friction rub For the ·328 A DICGEHEE HARVEY ET AL. the presence in one sample of urine of elements characteristic of all three stages of glomerulonephritis had never been observed in their laboratory. In contrast the urine in the 14 cases of "visceral angutis" presented in the same specimen red cells, red cell casts, oval fat bodies, fatty and wary easts and frequently broad casts in addition to abnormal quantities of protein. He felt that such an unusual urinary sediment is a diagnostic aid These findings were further documented in a subsequent report (171). It was stated that the picture seemed to be characteristic during the acute phase of lupus and to disappear with remission Numerous other reports referring to renal lesions in this disease have appeared Brenner, Lefi, and Hochstein (31) described a case of lupus erythematosus without skin lesions in which the clinical picture was that of the nephrotic syndrome with hypertension and with renal insufficiency. Griffith and Vural (91) described the urinary findings in 17 cases and attempted to correlate the abnormalities mth pathological data There was no consistent correlation noted between the clinical and pathological findings Hypertension was infrequent during the early phases in their cases and when present was associated with advanced renal abnormallties Dubois (56) stated that the nephropathy when present is usually of the nephrotic type with the initial appearance of albuminuria accompanied at times by minimal abnormalities in the sediment. Later, there may be a mild increase in blood pressure with the appearance of edema The non-protein nitrogen and cholesterol in the serum may be elevated. In one of his cases renal manifestations predominated at the onset of the clinical disease There was evidence of renal disease in 69 of a group of 105 of our patients In 41 instances the involvement was mild, slight albuminuria and/or hematuria being present, without significant reduction of renal function. In 24 cases renal disease was considered to be moderate to severe in extent, and 12 patients died in uremia Four patients experienced the acute onset of generalized edema, albuminuria, hematuria, and elevation of blood pressure in the period prior to admission, suge gesting an episode of acute nephritis At the time of admission to this hospital, one of these had an entirely normal urine, a PSP excretion of 65 per cent and RARH with albumin and red blood cells in the urine There was no evidence of renal disease in 36 patients Two of these came to autopsy and were found to have normal kidneys However, it would be wrong to assume that all 36 had no renal involvement due to SLE or to other causes One of the striking features of this study was the inability to correlate the degree of renal involvement disclosed clinically and the extent of renal damage found at post-mortem examination Frequently it was noted that patients with little clinical evidence of renal disease had involvement of the kidneys at autopsy. There were instances in which minor changes in the urine and normal renal function tests were associated with extensive structural alterations in the kidney's ·SYSTEMIC LUPUS ERYTHIEMATOSUS 331 which could clearly be attributed to SLE, and it 11.33 thought that the changes resulted from the hemolytic anemja and transfusion reactions Case 13 K B. (* 156326) was a 59-3 ear old white female admitted in January, 1919 licr illness began 10 Alaseb, 1947, with "Au" followed by polyarthritis, weakness, and continued fever She subsequently develnped subcutaneous podules, generalized lymph node enlargement, chronic pneumonitis and pericardial effusion ffer urine contained a trace to 1+ albumin The sediment va*ciesr The PSP excretion wag 50 per cent in two hours While on trcatment #ath ACTII, the NPN rose from 25 to 45 mg % The blood prescure varied between 150/90 and 150/100 mm /11g Shortly before death in January, 1950 she developed episodes of bloody diarrhea alternating with periods of constipation llor abdomen became greatly distendeu and she appeared to have a paralytic leus L-ray showed greatly distended loops of small intestine She also had numerous convulsive seizures At post mortem eramination there were scattered "were loop" lesions of lupus in the kidneys, and a marbed arteriosclerotic nephritis The catire intestinal tract was edematous Many of the gmall vessrls showed an arteritis, the mucos) was infiltrated with plasm cells, and there were greas of ulceration There was periarten) fitsrosis in the spicca Case 14 JO (260256) *24 a 52 year old a bite female, admitted in January, 1913, with a history of arthritu and typical butterfly eruption for 18 months She had a bilateral pleural effusion The white cell count was 3,000 Shortly before death, four months later, she developed generalized convulsions and became aphasic She also had an episode of gross henia turist and the NPX rose to 58 mg % These manifestations were thought to be associated with SLI, At autopsy lesions of SLL were found in several organs but the real manfestations were the result of kidney abscesses duc to E coli, and a severe ulcerating cystitis She was also found to have a large meningiorns, but no Vascular lesions of SLE were discovered in the kidacy s or brain e Cardiorascular Janifestations Although Osler mentioned the occurrence of endocarditis and pericarditis, attention was first fox'used on the heart with the description in 1924 by Libman and Sacks (160) of a syndrome based on four cases which bore resemblances to sheumatic fever and subacute bacterial endor arditis. The term which they applied to these cardiac changes was “atypical serrurous endocarditis" In 1931 Baehr () reported 17 cases of non-rheuniatie serrucous endocarditis in which there were striking vascular changes m the kidneys and in other orgins Ten of these patients had the butterfly lesions of lupus erythematostus In 1932 Gross (92) described the valvular, endocardial, and myocardial lesions in 11 cases of verrucous endocarditis, seven of which had the dermal lesions of SLE The same author (93) in 1940 analyzed the heart lesions found in the cases of SLE reported hy Bachr, Klemperer, and Schín Microscopic changes rerc invariably noted In 17 of 23 cases macroscopic vegetations were described on the valve, the valve pochet, and the mural endocardium Aschoff berlies itere absent, As were the valvular endocardial recuplications and palr-ade formations peculiar to rheumatic fever There was a marked tendency to salvular necrous There were frequent vascular lesions in the pericardium and myocardrum of a type rarely observed in rheumatic fever Vascular lesions were not confinet to the heart, but were found in other organs particularly the vessels of the kidney ·330 A, MICGEILE HARVEY ET AL. first time she complained of severe difficulty in enallowing and x-ray showed changes thought to be compatible with seleroderma of the eosphagus Because of high fever and Ratata • • • • ces • ATT examination revealed the kidneys to have extensive alterations due to lupus There were patches of organized pneumonia There was pericardial thickening and focal myocardial scarring Her esophageal ulcers were secondary to arteriolar lesions proluced by lupus Of the 38 patients who came to autopsy, SLE alone was responsible for varying degrees of renal damage in 26. In the remainder, the principal lesions were considered to be due to infection, lower nephron nephrosis or arteriosclerosis, the changes of SLE either being minor or absent It has been said that patients with SLE seldom develop an appreciable degree of hypertension during the course of the illness, Eleven of the 31 cases reported by Shearn and Pirofsky (234) had elevation of systemic blood pressure In fire It was in association with severe renal involvement, in one related to toxemia of pregnancy, and in another developed during cortisone therapy but persisted after its discontinuation In our own series, 15 patients had blood pressures greater than 140/90. Eight of these had hypertension associated with azotemia, and in several of this group the hypertension did not appear until the onset of nitrogen retention In four of these 15 patients there was evidence of a severe degree of arteriosclerosis in addition to the SLE One was recovering from a recent episode of an acute glomerulonephritis following a streptococcal infection, and another developed hypertension while on cortisone. A final patient had mild hypertension in association with uncomplicated SLE Therefore, in this group, with but one exception, significant elevation of the blood pressure occurred only when renal involvement was so extensive that nitrogen retention had occurred, or when other factors, such as arteriosclerotic degeneration or infection, were associated with lupus Fucother patients who had varying degrees of renal lupus at post-mortem examination and who died in uremia had no elevation of blood pressure In only one patient given cortisone were the renal lesions which have been produced in animals by this hormone observed (216) These changes were minimal Several patients who were given ACTII and/or cortisone for protracted periods of time shoned no signifcant evidence of renal involvement at postmortem examination While renal injury is common during the course of SLE, it is a serious error to assume that SLE is the cause of all manifestations of renal disease which occur. It must be emphasized that other causes, particularly infection, play a significant role in damaging the kidneys either alone or in association with the underlying disease The following brief case reports illustrate this point: Case 12 1916 had albumin, 1. ---.-la- ·SYSTEBIIC LUPUS ERYTIIEVATOSUS 333 B Fio 9 Valvular and myocardial lesions in a patient who died with SLE A There are fibrinous vegetations attached at the angle of union of the mitral valve with the myo cardium This is a typical location for these lessons in SLC in contrast to rheumatic fever B Swollen collagen fibers with small round cell exudate are present in the myocardium Such lessons lack the large mononuclear cells of typical Aschoff bodies On the other hand, Rich (214) believed that the focal myocardial interstitial collagen degenerations may be only quantitatively different in SLE and rheumatic feser lle showed the morphological identity of many of these myocardial collagen degenerations in SLE and rheumatic fever as well as in cases of periar. teritis nodosa, and anaphylactic hypersensitivity both in man and in animals In the autopsies in our series it has been noted that the valvular endocarditis is ant to be on the under surface of the mitral valse, often at the base, in contrast to the usual location of the vegetations in rheumatic fever on the outer surface of the valve There may be striking clinical findings referable to the cardiovascular system at various stages in the disease Systolic murmurs are not uncommonly found as noted by Shearn and Pirofsky (231) but when the patient has fever and anemia their significance is difficult to evaluate. Four of their patients also had a diastolic apical murmur In two of these, endocarditis of the mitral valve was found at post-mortem examination In another with a presystolic rumble small vegetations were present on the auricular surface of the mitral valve near the frec margin and the chordae tendinae cre thickened In 14 of their patients symptoms and ·332 A MCGEHEC HARVEY ET AL. Baggenstoss (7) described the frequent occurrence of diffuse or focal fibrinous pericarditis If healing had occurred the pericardial sac was obliterated by fibrous adhesions The exudate contained polymorphonuclear cells, and organization by fibroblasts appeared early He stated that the only distinctive lesion was the socalled "hbrinoid degeneration of the interstitial ground substance and collagen fibers". The ground substance became deeply eosinophilic, and there was irregular thickening of the collagen fibers which were highly refractile and intensely eosinophilic (Fig 8). Typical verrucous endocarditis was noted in 40 per cent of the cases studıcd by this author. Such lesions appeared as dry, granular vegetations up to 3 to 4 mm in size which were single or conglomerate. On microscopic examination there was an intense valvulitis characterized by fibrinoid degenera. tion of collagen which protruded on the surface becoming visible as a vegetation, There was an accompanying necrosis of tissue and an exudative reaction which was usually more severe than one observes in rheumatic valvulitis (Fig 9A) These changes led to the development of granular basophilic masses consisting of nuclear debris along with basophilic fragments of cytoplasm, the so-called "hemotoxylın body". In the myocardium similar lesions characterized by fibrinord degeneration of interstitial collagen fibers associated with an exudative reaction were described (Fig. 9B). These lesions were thought to be different from those in rheumatic fever where proliferative phenomena are predominant. junio FIG & This illustration shows a focal area of collagen snelling and degeneration in the epicardium of a patient sho died with SLC ·SYSTEMIC LUPUS ERYTHEYLATOSCS 337 А B FIG 11 Teleoroentgenogram of the chest in a patient who died and was found to have extensive myocardit is due to SL A Several months before the development of cardiac manifestations B After admission to the hospital fiecause of cardiac insufficiency times they were scattered and focal The intimal lining of the small coronary vessels was sometimes involved with occlusion and resultant anemic necrosis These vascular lesions were entirely sumilar to those seen as a consequenre of rheumatic fever At other times the heart muscle fibers were atrophic or replaced by patches of connective tissue or infiltrated with cells less than half of the patients with lupus myocarditis had manifestations of cardiac insufficiency In the remainder, cardiac function was not overtly affected by the myocarditis In this group of patients, there were no who were not considered to have disease of the myocardium on clinical grounds and sho were given ACTH without restriction of salt in one instance, and when renal function was depressed in the other Both patients rapidly des cloped heart failure and at post-mortem examination extensive lupus myocarditis sas discovered Thus, an individual may have a significant amount of myocardial disease with little or no clinical evidence of its presence it is, therefore, important to avoid stress on the cardiovascular system during the active phase of this drease Following an acute episode of lupus, a period of time should be afforded for myocardial healing to occur The analogy to the clinical course of rheumatic lever is apparent The clinical course in two patients thought to have myocarditis and SLE 13 described in the following case reports Case 19 This 31-year old colored female (I V $614097) entered complaining of dy apnea Inlay, 1952 she developed a sore throat followed in three weeks by migratory polyarthritis in June, 1952 polyarthritis reappeared with fever and one month later substernal pain and pon in the left lower chest which was at first pleuritic in type The symptoms gradually subaded In August, 1932 an L E cell test was positive She had no fever, but there was ·336 A. MCGEHEE ITARVEY ET AL. In two instances, at post-mortem examination, an unsuspected purulent pericarditis was found which contributed to the death of the patient. The following case report presents the findings in one of these patients: Case 16 IC (A-47972) as a 13-year old Xegro female admitted in March, 1913 She had had SLE for three years Terminally, she developed high fever, and there were signs of a large effusion in the pericardium, and also in the pleural spaces These were considered to be due to SLE At autopes, however, in addition to lupus it was found that she had had a staphylococcal septicemia with multiple abscesses in the heart muscle and a purulent pericarditis In one-third of the patients in our series who came to autopsy, the verrucous bacteral vegetations described by Libman and Sacks were found. They were present predominantly on the mitral valve but the other valves were occasionally implicated The presence of the endocarditis usually had no effect on the heart or circulation Generally, the only manifestation was a soft apical systolic murmur. A similar type of murmur was frequently heard in patients who came to postmortem examination and had no valvular abnormality In two patients, signs of mitral stenosis were noted during life although at autopsy the only abnormality of the mitral valve was Libman-Sack's endocarditis. Case 17 A V (#445357) was a 40-year old white male nbo died in January, 1919, seven years after the apparent onset of SLE On the initial examination the first mitral Bound was de. scribed as loud and snapping A systolic and a crescendo pre systolic murmur were noted at the mitral area X ray of the beart shoved prominence of the pulmonary conus and EKG revealed right avis deviation It was considered that he might have both rheumatic heart disease and SLP, but at post-mortem examination only the lesions of Libman-Sacks were Been on the mitral valve In two cases there was a superimposed infection, in one instance on the tricus. pid and in the other on the aortic valve: Case 18 heard It was thought that he had acute bacterial endocarditis superimposesupull du UVA valve wbich had been implicated by the lupus process Ile was successfully treated with massive dosages of aureomycin and penicillin Since that episode he has had persistent mild congestive heart failure of the autopsied patients, 55 per cent had some form of myocardial involvement and in 80 per cent of these the myocardial changes were considered to be due entirely to SLE (Fig 11). In three instances, myocardial damage was thought to be the result of coronary arteriosclerosis and hypertension; and in a single incidence, myocardial failure was the result of multiple abscesses in the myocardium secondary to staphylococcal sepsis At times the alterations produced m the myocardium by the lupus process were very extensive, at other ·SYSTEVIC LUPUS ERYTHEN 4 TOSUS 339 Taylor (205) the persistent pulmonary consolidation was the most prominent part of the patient's illness, being noted for a period of over eight months Foldes (71) described a chronic interstitial pneumonitis which leads to atclectasis and may cause respiratory failure Baggenstoss (7) noted this type of picumonitis, and in addition observed a peculiar basophilic mucinous edema of the al eolar walls and the peribronchial and periyascular tissues in association with an interstitial pneumonitis and alveolar hemorrhages He stated that these lesions are distinct from the ordinary pyogenic bronchial pneumonia, with or without organization, which so frequently complicates the terminal stages of SLE In this "atelectasızıng" pneumonitis the alveolar walls and persbronchial and pensascular connective tissues are apparently the primary sites of an inflammatory process obliterating the alveolar spaces Even with the recent expansion in our knowledge of this disease picture the frequency with which pulmonary manifestations occur bas not been generally noted Dubois (56) refers to the presence of pleurisy and pleural effusion in 55 per cent of his series but makes no mention of intrinsic pulmonary in olvement Israel (124) stated that pulmonary in olvement is common but that specific lesions such as disseminated perivascular changes, chronic interstitial pneumonia and massive pleural effusion are relatirely infrequent He recognized the frequency with which bacterial pneumonia complicates the disease Since pulmonary manifestations occasionally dominate the clinical picture he advised search for L E cells in patients with recurrent pneumonia, and infiltrations or pleuristes of unknown cause These various types of intrinsic pulmonary involvement were observed in 46 of 105 patients in our own study Twenty patients had pulmonary changes considered to be produced by SLE, $had pulmonary tuberculosis, five lobar preumonia, two lung abscesses, nine lobular pneumonia, two aspiration pneumoms and one repeated hemoptyses ✓ Seven of the twenty patients suspected of having "lupus pneumonitis" came to autopsy and were found to have characteristic findings These consisted of byalme membranes in the alveoli, focal necrosts of alveolar walls with capillary thrombi, areas of organizing interstitia) pneumonja and hemorrhage, and metaplasia of the bronchiolar epithelium These are changes thich are similar to those seen in rheumatic pneumonitis, periartentis nodosa, "anaphylactic" pneumonitis due to sulfonamide allergy as well as in scrum sickness (213) The nature of these pathologic alterations is such as to produce foral atelectasis and, if extensie, there may be interference with the transport of oxygen across the alveolar mentbrane, resulting in cyanosis and dyspnea (Fig 12) The clinical manifestations in these patrents with proven "lupus pneumonitis" Here vaned In beteral instances as ilustrated by the follow mg ** cases reports the lungs were extensa cly avoli ed and respiratory manifestations became predominant as the liness advanced Case 21 RS (561950), a 61 year old white male, **s admitted in January, 1931 complaining of fatigue lor est to eight monthg Generalizeu soreness of his muscles and joints associated with anorexis, nausea, and pergiptent diarrhea, hegan five months prior to admiggion Ile ·338 A. BICGEHEE HARVEY ET AL. ---- 1 - :: four weeks She then noted dyspnea but digitalization and salt restriction resulted in no improvement fier dyspnea was progressive and she developed orthopnea and edema of the ankles The blood pressure was 95/70, and numerous rales were heard at both lung bases The left border of cardiac dullness was in the anterior axıllary line The sounds were of poor quality, and a gallop rhythm was heard Electrocardiogram revealed inverted T waves compatible with the diagnosis of myocarditis Treatment was instituted with cortisone Fler pressure remained low, and the gallop rhythm persisted for a few days but then rapidly improved Case 20 This 31-year old colored female (E M *639062) was admitted in Vlay, 1953 complaining of polyarthritis In 1940 she was told that she had "bad blood" but her spinal Auid was normal During 1951 she developed recurrent stiffness and pain in the hands In January, 1953 a diagnosis of rheumatoid artbritis was made and she was placed on cortisone She became dyspneic and in February developed chills, fever, and malarse One month before admission she was digitalized Physical examination on admission showed temperature 101 8° F , pulse 121, respirations 36, blood pressure 100/60 The precordium was active with visible pulsations at the aper and base The heart was enlarged, the rate was rapid and there was gallop rhythm There was hepatomegaly The L E cell test nas positive Biopsy of s lymph node showed massive caseous necrosis with calcification probably due to tuberculosis X-ray of the chest showed enlargement of the left cardiac border with prominence of the hilar vessels There were many well localized calcified densities throughout the upper chest and in the axillac as well as in the neck, thought to be calcified lymph nodes Llectrocardiogram revealed abnormally low Twaves and night avis deviation Vital capacity was reduced as was the maximum breathing capacity She was thought to have disseminated tuberculosis, possibly precipitated by the previous cortisone therapy, and antibiotic treatment and nydrazıd There was remarkable improvement with defervescence Her heart becane smaller in size and the gallop rhythm disappeared She developed bradycardia The cor. trsone dosage was lowered to 150 mg, then to 100 mg She was discharged much improved after hve weeks The T waves in all three leads returned to a normal appearance, and there was a change from right axis to slight left axis deviation Abnormalities in conduction were present in six patients. In tuo there was auricular fibrillation; in three, first degree heart block, and in one, a right bundle branch block The latter, however, was considered to be congenital and not due to lupus ſ Pulmonary Janifestatrons It 19 well recognized that pleural insolvement is one of the hallmarks of SLE, but less generally appreciated that intrinsic pulmonary inyols ement is frequently present The clinical signs are usually those of a chronic pulmonary consolidation which must be differentiated from complicating pulmonary infections or lung ini olvement due to other causes Osler recognized that pulmonary lesions may occur. Later, Tremaine (255) reported a case with long-etanding consolidation of the lung thought now to be due to lupus. In the case reported by Rahor and ·SYSTEMIC LUTUS ERITIEMATOSUS 341 gressed and she died Autopsy revealed typical changes of lupus scattered diffusely through. out both lungs There was also a muld interstitial myocarditis These two patients illustrate some of the clinical features of extensive involvement of the lungs by SLE. Respiratory symptoms were prominent throughout their course, which was marked by the development of progressive tachypnea, dyspnea, and cyanosis, unrelieved by the administration of ovygen. The physical alterations were never very pronounced, scattered fine or course råles being the only evidence of pulmonary involvement X-rays showed only non-specific fibrotic changes. It is of interest that while ACTII had a beneficial effect in reducing the fever and the joint and skin manifestations of lupus, the pulmonary alterations were little affected. The clinical course of these patients was suggestive of that noted in patients with "peculiar pneumonia" described by Tumulty, Berthrong, and Harvey (237) although the morphological changes were at least quantitatively different In contrast to these patients are too in whom autopsy disclosed spotty lupus involvement of the lungs which was unsuspected during life Physical examination of the lungs failed to show significant changes in one instance, the v-ray also was reported as clear but in the other, extensile "non-tuberculous' infiltration was described The physical evidences of upus pneumona" may be minimal and extensive involvement remains undetected unless serial x-rays are taken. A chronic pneumonitis was not uncommon in our experience as illustrated by patrents who had persistent signs of pulmonary involvement for fully six months In addition to this group in whom pulmonary lesions were demonstrated histologically, 13 patients were considered on clinical grounds to have this specific type of pulmonary involvement Five are of particular interest because the pulmonary changes were evident for many months The cough was usually hacking and dry but was occasionally productive There were only scattered fine and coarse riles heard Outspoken signs such as dullness and change in the character of the breath sounds were unusual The observed physical and roentgenographic changes were usually located in the basılar portions of the lung fields In reviewing the clinical course of these patients, we are impressed by the frequency with which elevation and hxation of one or both diaphragms were observed, with areas of plate-lube atelectasis above (F18 13) In such areas one may hear showers of course and sticky ráles Since these patients are still alive, at 18 impossible to be certain that these pulmonary changes were due to lupus, but the inability to isolate any pathogenic organism from the sputum or blood, and repeated failure to alter the changes through the administration of one or several antibiotics, makes lupus the likely cause These episodes of "lupus pneumonitis may occur at the beginning of the discase, or anytime thereafter They not infrequently recur In addition to the group of patients who were believed to have had a chronic "lupus pneumonttis", eight patients had an acute episode of pneumongtis The clinical characteristics of these acute episodes 1ere the same as in the chronic form described above ·340 A. NOGEHEE HARVEY ET AL. Fra 12 Roentgenogram of the chest an a patient who died with SLE and was found to have extensive "lupus pneumonitis". During life there a ere manifestations of severe pulmo. nary insufficiency became extremely weak and feverish Shortly before admission he developed a non-productive cough A mass was found in the right kidney At operation thus proved to be a benign cyst Post-operatively his condition grew worse Ile developed persistent tachycardia and acceleration of the respiratory rate, despite the usc of oxygen A pleural fraction rub Was heard over the right anterior chest The temperature varied between 101° and 103'. The LE cell test was positive On the thirteenth post-operative day, ACTII was started in a dosage of 50 mg intravenously daily The temperature became normal, and the pulec and respiratory rate decreased When, however, the ACTH dosage was reduced, the fever returned and the respiratory distress became more marked Administration of penicillin and streptomycin failed to alter the course Tachypnea and tachycardis became excessive, and he died with severe pulmonary insufficiency At post-mortem examination there were exten. sive changes of lupus throughout both lung fields, with hyalınc membranes lınıng the al. veols, areas of organized pneumonia and hemorrhage, and metaplasia of the bronchial epithelium Case 22 ES (#537561) 208 8 62 year old shite female who in 1939 had an illness characterized by fever and arthralgia following which malaise persisted In December, 1919 she developed polyarthritis which became progressively worse She was found to have fever, anemis, leucopenia and bematuna In February, 1950 she developed an erythematous eruption or the butterfly area On admission in May, 1930 she as critically it with dy apnea, cyanoxis, and tachycardia With ACTH administration ber temperature fell to normal, the joint manifestations subsided, and the erythema faded However, she continued to have tachy. cardia, dyspnea, and cyanosis, and there were persistent signs of pneumonitis in both lower Jung fields X-ray shoned diffuse infiltration at both baseg Her respiratrry dentrega pro ·SYSTEVIC LUPUS ERITREJLATOSUS 311 gressed and she died Autopsy revealed typical changes of lupus scattered diffusely through out both lungs There was also a mild interstitial nyocarditis These two patients illustrate some of the clinical features of extensive involvement of the lungs by SLE Respiratory symptoms were prominent throughout their course, which was marked by the development of progressive tachypnea, dyspnea, and cyanosis, unrelieved by the administration of orygen. The physical alterations were never cry pronounced, scattered fine or course râles being the only evidence of pulmonary involvement X-rays showed only non-specific fibrotic changes. It is of interest that while ACTH had a beneficial effect in reducing the fever and the joint and abun manifestations of lupus, the pulmonary alterations wcre httle affected. The clinical course of these patients was suggestive of that noted in patients with "peculiar pneumonia" descnbed by Tumulty, Berthrong, and Harvey (257) although the morphological changes were at least quantitatively different In contrast to these patients are two in u hom autopsy disclosed spotty lupus involvement of the lungs which was unsuspected during life Physical examination of the lungs failed to show significant changes in one instance, the x-ray also was reported as clear but in the other, extensive "non-tuberculous" infiltration Mas desenbed. The physical evidences of "lupus pneumonia" may be minimal and extensive involvement remains undetected unless serial x-rays are taken. A Chronic pneumonitis was not uncommon in our experience as illustrated by patients who had persistent signs of pulmonary involvement for fully six months In addition to this group in whom pulmonary lesions were demonstrated histologically, 13 patients were considered on clinical grounds to have thus specific type of pulmonary involvement Five are of particular interest because the pulmonary changes were evident for many months The cough was usually haching and dry but was occasionally productive There were only scattered fine and coarse råleg heard. Outspoken signs such as dullness and change in the character of the breath sounds were unusual The observed physical and roentgenographic changes were usually located in the basılar portions of the lung felds. In reviewing the clinical course of these patients, we are impressed by the frequency with which elevation and fixation of one or both diaphragms were observed, with areas of plate-lhe atelectasis above (Fig 13). In such arcas one may hear showers of course and sticky ráles Since these patients are still alre, it 18 impossible to be certain that these pulmonary changes were due to lupus, but the inability to isolate any pathogenic organism from the sputum or blood, and repeated failure to alter the changes through the administration of one or several antibioties, makes lupus the likely cause These episodes of “lupus pneumonitis" may occur at the beginning of the disease, or anytime thereafter They not infrequently recur form described above ·312 AMCGEIIEE HARVEY ET AL. А B FIG 13 Roentgenogram of the chest in a patient with SLE ho had clinical evidence of moderately severe pulmonary involvement Yote the elevation of the diaphragm and the plate-like areas of atelectasis A Antero-posterior view in full inspiration B. Lateral view Three patients gave a history of "virus pneumonia” which preceded by a number of weeks or even longer other manfestations of SLE These episodes were characterized by a protracted course, dearth of physical signs, failure to respond to antibiotics and a continuation of fever and malaise until the development of other abnormalities made the diagnosis clear. It is important to note that bacterial infections of the lungs were common during the course of SLE and may be confused with true "lupus pneumonitis". Thus, in this group of 46 patients, six had pulmonary tuberculosis, one with an associated tuberculous empyema, five had pneumococcal lobar pneumonia, nine had lobular pneumonia due to a variety of organisms, two succumbed from aspiration pneumonia and two had a lung abscess. It is often difficult to determine on chnical grounds alone whether one is dealing with pneumonitis due to lupus or to some bacterial infection The error may be made of assuming that a particular pulmonary manifestation is due to lupus when a bacterial agent is responsible The therapeutic implications of such an error are obvious, as is illustrated by the following cases: Case 23 LD (*532508) was a 19 year old Yegro female admitted in March, 1950 A month before she developed "black spots" on her face followed by the insidious onset of malazbe, poly. arthralgia, anorexia, pain in the chest, and cough fler tongue and face became swollen On admission her temperature was 101° and there was extensive angioneurotic edema LE cells were found in the peripheral blood, and she was started op cort1907 with improvement and had a generalized convulsion She as readmitted in July and given penicillin 819 ·S} STEMIC LUPUS EILYTHENLATOSI'S 313 cortisone with some improvement One week before the final admission in September, 1950 pain began in the right chest and her cough became severe She became oliguric and the XPX rose progressively Cortisone was given but halted when convulsive seizures returned Basılar rales were heard and x-rays showed an infiltrative process at the right base She was considered to have "lupus poeumonia" There was no responsr to therapy with penicillin At postmortem examination there was a large abaceas cavity in the posterior segment of the right loner lole communicating with the bronchus, surrounded by a large area of consolidation Pseudomonas kas cultured from the heart blood and the lung abscess it was clear that the patient had had a scpticemia with focal areas of necrosis scattered in the spleen, brain, kidneys, and liver It was thought that the lung alscogs might have been the result of an acute attentis due to lupus, with gecondary infection, although she may have aspirated foreign material during a convulsion In addition there mere periarterial fibrosis in the spleen, "ware Inop" lesions in the kidneys and abacterial vegetattons on the mitral valve Case 24 P X (569753), & 41 year old white female, for eight years bad transient episodes of arthralgia, for two years 4 recurrent facial eruption, and for 814 months typical butterfly rash On admision in April, 1951 she was in uremia Shortly after entry she had a shaking chill, signs of pneumonitis developed at the left base, and there was elevation of the temperature She was treated with penicillin with subsidence of symptoms and signs, but shortly after the penicillin was discontinued she again had a chill, signs of pneumonitis and pneumococei were found in the blood Oace more she responded to penicillin but only temporarily She gres rapidly worse and thirty five days before death she 99 begun on 25 mg of corti tone daily which was gradually increaged to 100 mg At postmortem examination a totally unsuspected miliary tuberculosis the found, as well as lesions typical of SLE Involvement of the pleura is common during the course of SLE Sixty patients in our series had one episode of pleurisy and fourteen had repeated attachs The pleurisy was usually dry but at times was associated with a small to moderate effusion The effusion was never massive unless there was some complicating infection such as tuberculosis The episodes of pleurisy occurred at various periods during the illness, at times being one of the earliest manifestations Pneumonitis was almost always associated with pleural involvement in addition to typical pleursy, a number of patients complained of vague aching pains in the chest, although no objective signs were present Episodes of pleural pain at times persisted for several wechs and were very distressing g Gastrointestinal Janifestations In Osler's cases gastrointestinal manifestations were prominent Certain authors have suggested that his were not cases of SLE because later reports had not confirmed the frequent occurrence of gastrointestinal symptoms in this disease However, with increasing experience it has become clear that the gastrointestinal tract is frequently the sic of typical vascular lesions with associated clinical symptoms in various reports the manifestations noted have included anorexia, nausea, vomiting, diarrhea and abdominal pain severe enough to simulate an acute surgical condition of the abdomen Dysphaga has also been reported (0) Various authors have attributed the abdominal pains to peritoneal Kerosit or involvement of the retroperitoneal connective tissues Referstein and his associate (210) found esidence of peritonitis in 72 per cent of their ·34 A, MCGEHEE HARVEY ET AL. autopsied series with perihepatitis and enlargement of the liver in one-third. Pancreatitis was also noted. Dubois (56) stated that gastrointestinal symptoms were prominent in 40 per cent of his cases In one instance the initial symptoms were referable to this system and gastrointestinal difficulties represented the chief complaint in almost 10 per cent. The abnormalities were due to vascular involvement in the bowel wall with infarction or hemorrhage. Most of the patients had abdominal pain which was constant or cramping, associated with vomiting and with diffuse abdominal tenderness Occasionally, diarrhea, sometimes bloody, was noted. In our cases manifestations indicating involvement of the gastrointestinal tract were not uncommon Seven patients had anatomical lesions of the esophagus. Three complained of epigastric burning and at postmortem examination an extensive diphtheritic esophagitis was found in all Four had ulceration of the esophagus in association with collagen degeneration and arteritis of the characteristic type seen in lupus. The findings in one of these patients are of particular interest: (Case 11) (Fig. 14A) Seven patients complained of abdominal cramps associated in four with hemorrhage from the bowel in three an acute arteritis with thrombosis of small vessels had resulted in ulceration of the small intestine In one the bleeding was in association with obstructive jaundice and in another with hemorrhage secondary to thrombocytopenia. Two of these patients deserve special mention. (Case 13) (Fig 14B). A B narom after harum swallow in a patient with SLE who complained greatly distended loops of small intestine At autopsy Duy Vu testine showed an arteritis and there were areas of ulceration ·SYSTEVIC LUPUS ERYTIET ATOSTS 315 Case 25 SR (*561970) nas a 61 year old white male who was admitted in January, 1951 Eight months prior to admission he began to have malaise and musculoskeletal aching Shortly thereafter he developed anorexia with nausea and persistent diarrhea A leu fecha pror to death in March, 1951 he begin to have frequent bloody stools and required repeated transfusions lle also had severe epigastric distress At post mortem examination there was extensive artentis with thrombosis of the vessels of the small intestine resulting in multiple ulcerations There was also a diphtheritic csophagitis, and extensive lupus pneumonitis The large bowel was involved in five cases and abdominal pain and diarrhea sere prominent clinical manifestations In four of these there was arteritis with ulceration of the mucosa Ileocecal tuberculosis accounted for the symptoms in one Another patient had persistent diarrhea and bloody stools, but no postmortem examination was perfomed h The Lurer, Spleen, and Pancreas lepatomegaly occurs in patients with SLE, but it is not an outstanding feature and jaundice is unusual Griffith and Vural (91) noted hepatomegaly in ex of 18 cases Pathological findings in the liver of these 18 patients were slight to moderate with fatty degeneration in six, some necrosis of liver cells in one, and in the remainder no significant alterations Dubois (56) shoned an illustration of an arteritic lesion in the liver in a nine year old girl with classical SLE Hepatomegaly was found in 31 per cent of his cases This author noted that seasels in the pancreas may be involved and he cited one patient who developed epigastric pain radiating to the back, associated with vomiting, and a scrum amylase level was 2100 units In addition to lesions characteristic of SLE autopsy revealed acute pancreatitis secondary to disease of smali arterioles The earliest reference to periarterial fibrosis in the spleen is that of Libman and Sacks (160) Shaumann and Introzzi (233) in 1931 described this change in three cases Klemperer, Pollack and Baehr (146) in their report of 19 cares of SLE first called attention to the frequency with which thus lesion is noted Karser (131) studied 18 cases, and in most the splcen was definitely, but not markedly, enlarged Periarterial fibrosis was found in 15. It was noted as present "when the periarterial collagen of the penicilliary or follicular arteries, which normally is closely packed and without evdence of hyalinization, was found to be present in at least three layers, around at least half the circumference of the vessels, producing the appearance of concentric rings" (Fig 15) In a control study, including 070 consecutive autopsies, some degree of periarterial fibrosis was found in 22 cases, an incidence of 2 3 per cent In no instance, boneler, was it as extensive either in size or in distnbution as in SLE The reported incidence of splenomegaly in SLE has aried considerably coburn and Noore (43) noted it in seven of 30 cases Jessar and his co-workers (120) reported enlargement of the spleen in 17 per cent of 168 patients Dubois (56) stated that the frequency of splenomegaly has been over-emphasized, having been noted in only 8 1 per cent of his cases lle stated that it is usually present in association with hepatomegaly when there is an hemolytic anemia ·318 A MCGEHEE ILIRYCY ET AL In one other instance, in which there was striking lymphadenopathy, a diag. nosis of reticulum cell sarcoma was made on the basis of a biopsy. The lymph nodes and the spleen decreased in size after administration of nitrogen mustard This patient was later proven at autopsy to have SLE. , Nerrous System Janifestations Only recently has the frequency of nervous system involvement been recognized Daly (48) noted the common occurrence of a "toric delirium" manifested by confusion, disorientation, restlessness and irritability. In the terminal stages, coma frequently supervened. A psychotic picture with delusions and hallucinations sometimes developed, He also observed convulsions in a number of patients who were not azotemic He stated that in the experience of others, neurologic examination may be entirely normal or disclose scattered findings indicating involvement of the motor system, such as cflexia, clonus, and a positive toc sign Examination of the spinal fluid showed some increase in protein content in 10 to 15 per cent of the reported cascs. Further evidence of the frequency of nervous system abnormalities was presented in the analysis of the first 32 cases of the present series (258). In the previous year Sedgwick and Von Hagen (230) had described cases of SLE and periarteritis nodosa wath neurological manfestations In Jessar's series (129) convulsions were present in 9 per cent, toxic psychosis in 5 per cent, and hemiplegia in 2 per cent Neuronitis, focal central nervous system lesions, cerebral hemorrhage and chorca were scen in isolated instances Dubois (56) noted that multiple central nervous system manifestations may occur due to cerebral angutis He presented illustrations demonstrating vascular changes in a spinal cord arteriole and periphlebitis in the floor of the third ventricle of a patient who had convulsions and mental deterioration during the course of SLE Thirty-five per cent of his cases had scizures of which 30 per cent were attributed to the disease and 5 per cent to treatment. IIc stated that seizures are most common in the terminal phase of the illness. In his experience another common terminal event, as was previously pointed out by Tumulty and Harvey, was the occurrence of hemiplegia due to lupus vasculitis This author has also seen one case of severe polyneuritis, apparently due to nutrient artery involvement, similar to that described by Heptinstall and Sowry (118) Dubois noted signs of meningismus with a pleocytosis of scveral hundred leucocytes, cither lymphocytes or polymorphonuclear leucocytes, along with increased protein in four cascs In his series organic psychoses of various types occurred in 29 per cent. Piper (198) reported one case in which yascular involvement of the spinal cord produced an infarct with resultant paralysis of the lower extremities Russell, Hascrick and Zucker (224) analyzed a series of 114 patients with SLE, 15 per cent of whom were reported to have had convulsions. Fifteen had scizures only during the terminal phase. Four had isolated grand mal seizures during the active prcterminal phase They report on 28 patients with positii c L. E. cell tests, sei en of n hom had convulsions In two instances the diagnosis ·SYSTEMSC LUPUS ERYTHEMATOSES 319 of diopathic epilepsy had been made years prerious to the onset of recognized SLE Orher neurological manifestations such as manc behus sor, mental confu-1011, neurogenic bladder dysfunction, amaurosis and paraplegia wcre noted terminally in the three patients Two types of electroencephalographic alterations were described. 1) records characterized by moderately high voltage activity at a rate of 3 to 7 cycles per second wath delta hares which frequently exhibited disparity between the two sides, and, 2) abnormal records of medium voltage activity having a rate of 6 to 8 cycles per second and show ing a diffuse pattern often interspersed with long or short runs of normal alpha activity Glaser (79) recently reviewed the central nervous system manifestations in SLE. The vascular lesions had a predilection for the gray matter of the cerebral corte, particularly the presulcal areas, which may explain the frequent occurrence of convulsive serzures The parenchymatous changes, consisting of focal or disseminated encephalorealacia often with hemorrhage or cyst formation, here secondary to the involved vascular supply More than one-third (37 per cent) of the cases in our series developed some abuormality of the nervous system Eighteen had convulsne seizures in three instances these were associated *ith hemiplegia and mone with motor aphasia Four Sıvıduals had a tosie psychosis in addition to convulsions Two of the patients with convulsions had repeated sttacks over a penod of several years. Twenty had one or more acute psychotic episodes In four these were associated with convulsie seizures and in two with a transient bilateral ptosis Other instances of abnormal nervous function included two patients with hemiplegia, one with potasuum intoxication during uremia due to SLE, and another with mani. festations simulating myasthenia gravis One patient died of a complicating Torula meningitis Neurological dysfunction almost invariably developed during a very actre phase of the disease Only two of the 10 patients had nervous system lesions during a chronic or subacute phase, both had repeated epileptic seizures Since these nervous system alterations were so commonly associated wath an exacerbation of the disease, thes are ominous signs To 12 of the 18 individuals who had convulsive seizures during the couree of their illness, SLE alone we considered responsible In to instances there was hypertension and azotemia and at postmortem caammation, there tras invalıc ment of the kidneys by SLE In case 14, already described, there was a dural mchangiomi in the left panetal area In another patient the seizures occurred during the terminal phase of lupus, complicated by streptococcal septicemia and uremss In another, in addition to 8 mild elevation of the non-protein nitrogen, the illness was complicated by an hemorrhagic tendency in 14 of the patients who had psychotic episcxles, SLE was the only demonstrable canse In three instances the psychosis appeared when the patient had an intercurrent infection, and in two others the course has complicated by hypertension and azotem:3 In another hepatic disease may have played a part Of the 40 patients manifesting disordered brain function, 31 either were never KIVEN ACTH or cortisone or had their persous system manifestations prior to ·350 A. GEHIE HARVEY ET AL. receiving them In three instances in which nervous system abnormalities occurred while ACTH or cortisone was being given, the reaction developed when the dose had been reduced with a subsequent exacerbation of the lupus process Convulsions and a psychotic reaction occurred in five cases following an allergic reaction to ACTHI, and in each instance were associated with other indication, of an exacerbation of the SLE. As mentioned above, three patients had transient bilateral ptosis during their illness The course of one is of unusual interest: Case 27 RS. (#160926), a 17 year old white female, was admitted in September, 1952 with the story that 18 years previously she began to feel exhausted She lost her appetite, frequently felt nauseated and had recurrent headaches She developed a low-grade fever The following year she noted diplopia and ptosis of the left lid A diagnosis of myasthenia gravis was made The spleen was palpable, and she had 5 per cent eosinophils She was given Leostigmine with equivocal improvement She returned in a few months stating that her symptoms had vanished, and sbe no longer needed neostigmine In 1936 she developed a typical eruption of lupus erythematosus on her face and ears In 1910 she developed polyarthralgia which lasted for many years Early in 1952 she had an exacerbation of the migratory polyarthritis and a low grade fever on the day of admission she developed a pleuritic pain in the left chest. A doubtful STS was recorded There was no history of syphilis and the treponemal immobilization test was negative The L E cell test was positive In reviewing the course of this patient's illness, it seems reasonable to conclude that the neurological manifestations which she had fully 17 years prior to admission were due to SLE and not to myasthenia gravis. The two other patients who developed neurological changes during a chrome state of SLE should be briefly mentioned In one of these also, the initial cpisode in the illness was neurological in nature: Case 28 eramisation except questionable ptosis of the left lid It was thought that she lugnt sur had a mild cerebral vascular accident, but it seemed most likely that this was an hysterical 171.mitment with she had a 1 biological al blood It , and that SLT was responsible Care 29 ON ($606719), a 24 year old white female, was admitted in May, 1952 because of convulsive setzures hich she had had since childhood When she was eight ycars of age she was struck on the head with a golf club Shortly thereafter she began to have "peculiar absencesbich were interpreted as petit mal attacks At 16 years she had her first grand mal attack and these occurred at irregular intervals thereafter then she was 19 years of age her knees became swollen, bot and tender and after that time she had almost constant migratory joint pains Four years prior to admission, she developed an eruption on her ·SYSTŁVISC LURUS ERYTHEMATOSI'S Best god buttocks 1s 3913 the blood STS * 35 posutne, although there *18 ro turstorr to Auggest a philig On admission she had an erythematous eruption on ber legs and buttorke Iler fingers showed the (vxform changes seen in thermalos arthritis Tur blond STS 189 Degative The spinal Huid ng normal EEG showed a fucus with high pessy the night temporal regran L1 «eils here found It is possible that this patient's epileptic seizures may have been due to cerebral damage caused by SLE Blthough other causes cannot be excluded While abnormalities of the brain frequently occur during the course of SLE, nervous system involvement may kare some other basis as illustrated by Cases 10 and 14 Lumbar punctures ucre performed m 30 of our patients in eight without spcciho nervous system abnormaltres ($1x sere acutely th with high fever), the sjyna) Hund findings were normal un all but one shu had an intel prestire of 200 mm CST, 18 mononuclear cells per mm And A protein concentration of 01 mg. In the 22 with signs of ners Jus system dysfunction at the time of pune ture (14 hai convulsions), the results were abnormal in len The protein concentration was elevated (above 50 mg per cent) in seven of thene ten case during serzures or coma (one case) Three of the seven and one other had abnormal colloidal mastic curves in one patient who had had com vulsions the protein was 930 mg per cent, and the mastie cure 1245535432 la another case, the proteus concentration was 128 me per cent after a series of Bmzures, and 25 mg per cent aftes tch days Four months later, folloring a second seres of convulsions the protein was 70 mg per cent in another case the protein was 03 mg per cent when no neurological manifestations were present, and on another occasion 86 mg per ecat following several convulste episodes pleocytosis, predominantly polymorphonuclear, was demonstrated in the spmal Nurd of cach of three cases (250, 330 and 550 VBC por mm *) One was case 10 th ryptokorcal meningitis The other two had a concomitant leuconytom13 at the peripheral blood, but an infectious agent was not uncovered in eather case h Retinal Lessons In 1933 Pallat (197) desenbed the funduscopic changes in 48 cases of chronic lupus, 11 16 of hach he found solated changes resembling healed tuberculous chorouts de parly as 1029 Bergmester (22) had reported lesions sinch he thought sore metastatic tubercles in the retina in a patient with SLE in nom necropuy disclosed disseminated tulxrculosis The eyes were not examined histologically, but from the description st seems likely that there were cotton-11001 exudatex at rytod bodies In the cases reported by Baelr, Klemperer, and Schulru (3). 12 of 23 had fully rrudates in the fund with perivascular hemor. rhagey ax kell as circumpapyflary edema i to cases kurz (154) in 1938 193 probably the first to consider that there white patches tonsist of gangisaform elegeneration of rehbers (50-rallcit cytold holes) lle thought that the louons were similar to the Roth pots ken in patients with barterul rndocarditis, and that they were torx and not emtole m nga Jaumener (168) described them ·352 A BICGEHEE HARVEY ET AL FIG 16 Typical cytoid bodies in the reting of a patient with SLE The nature of the lesions was confirmed by histological examination ophthalmological and histological findings in the fundi of five cases and noted five types of lesions. 1) small, fluffy, yellowish-white to white spots located in the superficial layers of the retina, never larger than the size of the disc, usually in the posterior part of the fundus, similar in appearance to the cotton-sool exudates seen in hypertensive retinitis, Histologically, these lesions were demonstrated to be typical cytoid bodies in the nerve fiber layer of the retina (Fig 16) 2) Small superficial retinal hemorrhages related neither to the larger retinal Vessels nor to the shite spots Histologically, these were found in the nerve fiber layer of the retina 3) Shght papilledema, never of sufficient degree to allow actual Ineasurement of an elevation of the disc. 4) A slight generalized blurring of the choroidal reflex believed to represent sub-retinal edema 5) Septic chordites which could not be detected ophthalmoscopically but was noted on histological study as a slight round cell infiltration of the choroid in every case. Jessar and his group (129) noted retinal lesions in 20 per cent of their senes, ·SYSTEMIC LUPUS ERYTHEJLATOSUS 353 TABLE V Ocular manifestations seen in 105 cases of systemc lupus erythematosus Lexion Number of Paucots C; toid bodies Conjunctivitis Exudates Occlusion central retipal rein Small hemorrhages Capillary aneurysms Epiclentus Papilleder 28 5 (2 of these bad repeated episodes of folcular conjunctivitis) 6 2 (1 with bypertensive cardiovascular disease) 11 (2 had uremia, ) severe abemus) 1 (during intensive ACTH treatment) 2 2 (both with convulsions-1 bad azotemis and bypertensive cardiovascular disease) Retraal hemorrhagea with bliad- Деня six patients having cotton-wool exudates, five flame-shaped bemorrhages, one retual ederns, one vasculitis with irregular beading, and one punctate corneal erosion. Hollenhorst and Henderson (120) have recently reviewed the ocular manifestations in SLE, and the alterations found included superficial retinal exudates, hemorrhage, papillederna, embolic petechiae, per vasculitis, and arterial ocelusion. It is our impression that when included with other suggestive clinical manifestations which may not be diagnostic, the finding of retinal cytoid bodies in the absence of hypertension or diabetes is a helpful point in the differential diagnosis of SLE. These lesions may be transient and repeated funduscopic examinations should be carried out during the course of the illness Table V Lists the ocular lesions found in our cases This does not give a true picture of the incidence of cytoid bodies as many of the patients seen early in the series had only a single eye examination VII, NEILATOLOGICAL MANIFESTATIONS Hematological abuormalities occur in virtually all cases of SLE at some time during the course of the disease The appearance of the L.E. ceil is the only specific change, but other alterations in the formed elements of the blood constıtute a fairly characteristic pattern. In occasional cases, these aberrations are the outstanding and at times the presenting manufestations. In such instances the Dature of the underlying disorder way be overlooked, and the patient thought to have a primary blood dyscrasia. a Red Cells The high incidence of aneria in SLE has been frequently emphasized (5,170). In a detailed report of blood changes in 111 cases Michael, Vural, Bassen and Schaefer (172) noted that only 25 patients had hemoglobin values of 12 grams per 100 ml. or bigher at the time of the first examination In 32 cases the ralue ·354 A ALCGEHEE HARVEY ET AL was between 10 and 11.9 grams, in 37 cases between 8.0 and 9 9 grams and in five cases below G grans Of 16 patients who had initially normal hemoglobin values 15 subsequently developed anemia. The degree of the anemia seemed to be related to the duration and severity of ilness. It was usually normocytic and normochrome. A similar anenia was present in 33 of the 31 cases reported by Shearn and Pirofsky (234), and in 11 of these the hemoglobin concentration was less than 9 grams per 100 mi. In a group of 323 cases Jessar, Lamont-Havers and Ragan (129) found anemia (below 12 grams) to be present at some time during the disease in 80 per cent. Forty-eight of Dubois' (56) 62 patients had bemoglobin values below 11 grams. The anemia in most cases appears to be the result of retarded erythropoiesis. The decreased production of red cells is not associated with morphologic evidence of erythroid hypoplasia of the bone marrow (vide infra). The absence of jaundice, reticulocytosis and erythroid hyperplasia of the marrow in the majority provides evidence that the anemia is not primarily hemolytic in character. Hemorrhage, renal insufficiency and the presence of superimposed infection may contnbute to the severity in some cases. Moderate normocytic, normochromic anemia was commonly encountered in our cases. Seventy per cent rere anemic then first examined, and 78 per cent are known to have had anemia at some time during the course of the disease. Analysis of 120 cases revealed that 3G had initial hematocrit values of 36 per cent or greater (hemoglobin 12 grams per 100 ml or more), 64 had values between 30 and 35 per cent, 17 betsreen 24 and 29, and only three under 24 per cent. Of the group who initially had no appreciable anemia (hematocrit 36 per cent or over), ten subsequently became anemic. In a few, however, the disease han its course and terminated fatally without the development of subnormal hemoglobin values. Profound anemia occurred in some in association with hemorrhage, renal insufficiency or a hemolytic process Thirty-five per cent of the patients were transfused on one or more occasions Once agemis became established, there 729, in general, little tendency for it to progress, and most patients had only moderate lowering of hemoglobin even in the terminal stage of the disease. A few showed striking spontaneous improvement in hemoglobin concentration, the blood values sometimes returning to normal. an ghnwari minnt merrell abnormaliells, in a dot elevated except in association with bemolytic anemia, after netvori ugu, viduring hormone therapy. In rare instances a fey nucleated red cells were seen C. minnatianto ponie value SLE cytes urried H , out.

·STSTEMIC LUPUS ERYTHEMATOSUS 355 Allbough anemis usually appeared ta result from retarded erythropoiesis, only one patient had a true hypoplastic anemia. This patient (Case 6), who had had a polyarthritis, developed purpura essch ciated with anemia, neutropenia, thrombocytopenia, and hypoplastic marrot. These manifestations appeared after a second course of chloramphenicol. L.E. cells were repeatedly demonstrated. Although some granulocytes have appeared, she continues to bare anemsa, leucopenis and thrombocytopenia three years later In occasional cases a hemolytic process may occur as an important manifestation of SLE (23, 44, 55, 83, 151, 172, 177, 199, 231). This type of Anema is uucomnaon, occurring in less than 5 per cent of reported cases Heraolytic anemis, when it occurs, may be the initial mamfestation or may sppear later. In those instances in which it preceded other evidences of SLE, e diagnosis of " diopathic** acquued hemolytic ademia was made. Of interest in this regard is a case reported by Lee, Michael and Vural (156) who considered the finding of L. E. cells in a patient with acquired hemolytic anemia a "false positive" result because other manestations of SLE were not present. In all of the reported cases of hemolytic ademia, hemoglobin values below 6 grams were recorded, and onset of the process has been acute Data of well documented reported cases and three of our own are included in Table VI Reticulocytosis of marked degree and normoblastic hyperplasia of the bone toartow have been uniforzaly observed The spleen has been palpable in most instances and enlarged in every case in which the weight was reported However, characteristic anatomical lesions of SLE were not always present Red cell auto-agglutining or a positive Coornbe test have been demonstrated in most cases Hemoglobinemis and hemoglobinuria have been described in a few instances. Spherocytosis of the med cells has been reported only once. In the few cases in whicb splenectomy was performaed, no appreciable effect on the hemolytic process was observed, but Adisunistration of ACTH or cortisone has been effective in inducing remission in several patients The Coombs' test may remain positive even thougb complete bematological remission occurs during cortisone administration (199). Prsciotta and his associates (109) demonstrated that the LE, factor in serum can be separated from the substance which is absorbed on the red cells and wbich gives nee to the positive Coombs' test In occasional cases, including one of our own, severe hemolytic anemua furst appeared following the administration of blood transfusions (125, 151). Hemolytic anemua was present in three of our cases (Table VI). Ia one, a fulmaunating hemolytic process with bemoglobinuria arst appeared long after the Onset of other manifestations of SLE This patient is of interest because splenectomy was performed two years before the onset of anemia: Case 30 IC (4-7972), s 13 year old colated girl, had a positive aerologe test for ayphilis (STS) In the absence of syphilic manifestations at 30 seven Both parenta bad postare STS At *ge 11 she developed avere thrombocytopenc purpura She had had intermittent psia 17 the elbow sad kaees for seven months There was considerable loss of blood from Dose ·356 TABLE VI Hemolytic anemia in SLE Source Patient Palpable Spleen Osmotic Fragility Auto- 1gglutinns Coombs' Test He mogio bi- Duria Response to Splenectomy Response to ACTH or Cortisont Splenic Lesion 15 WT Yet Cold Aggl. 1 82 Dureat poe, in- No direct per Completo hoinatologic remission on oortuote 43 WF Yes Normal None Neg Yes - 1. Paciotta, Galiberti, Groonwalt and Engatrom (198) 2 Michael, Vural, Buben Bad Schacer (172) 3 Michael, Vural, BAND und Schworer (172) Michael, Vural, Banen and Bclinefer (172) 6 Dubou (86) 10 WF Yes Cold agel present No Transient favor ablo response No lupus leRONA 34 WF Yes Pos NO BWF Yes Normal - Pos direct No Nono 0 Dubor (58) 17 WF No Weight 387 Gm. Periarte. rial fibrosia Normal 7 Duboio (66) 13 WF Pos direct and No indirect Por direct No A. MCGEHEE HARVEY ET AL. Corapleto remiasion on ACTII Complete remsalon on ACTIT No response to ACTF, 30 mg daily Neg cold KERI Cold Agel ро 1 2000 Yea Normal to slightly increased None Weight 610 Gm Typical lupun lemon 28 WF Yes Pos No & Shearn and Pirofoky (234) 8. Kubo and Baverlen (151) 10 Dubois (66) 18 WF No response ? Inado quate trial Present Yes 16 WF NO Present Neg direct and Indirect No NO TOAPODAS Wought (autopoy) 850 Gm Periarterial fibrosis Weight (autopay) 130 Gr Typical lupus lemono Porarterial fibrosis 17 NH A-47972 (Cus 30% 15 CF Present 12. JHIHI - 473012 Case 123 cm Previously removed No Yes Spleen pres sously Temoved Nobe YO 18 22:31 S05022 (Caes 31) 34 WF Yea Normal Prevent Pou direct No None Completa remission on ACTH Prompt ro- Ispue when trottnent ducontinued Weight (rutopay) 200 Gm Ilordosiderosia Weight 185 Gm No lupus legione ·TIEMATOSUS 5T8YESUC LUPES ERYTTIEMATOSUS w Yv and gumns The hematocht was 2 per cent, hite cells 6300 and platelets 12,000. Spletne As performed, the spleea weightag 14gra and showing the typical penarte 2 SLE There was e prompt rise in the platelet count to normal values and throm any other Devet recurred She developed a tranneat pericardial et asion postoperativels. Se after splenectomy the hematocrit 99 40 per cent, white cout 6000 and the 28,000 Six months later, she developed joist mapiteatations typaca) o hoe arddritus at this time beraatocrit was 112, white count 5100 and platelet ce The polyarthritis subsided and she was well for the zext yeat, wbes obe read- 1ecial eruption typical of BLE, polyarthnt, generalized lymphadenopathy . The hematocrit was 41, but usder observation the patient developed be with a rapid fall 1 hemoglobia conceatsation The red tells showed aglutination but Donath-Landsteuer und Ham tests were negative EOE and hemoglobinurie pergated until death Autopsy showed widerprender and there was to accessory splenic trakve found The mechanism of the bemolytic anemia in SLE bas not been there are ones Dubois (55) suggested that it might be hypersplenic in orig. Som reports that splenectoray has little or no effect on the rate of tot grote together with our observation that the hemolysis in one patient splenectomy lease little to support this hypothesis. A more better that the process is the result of an abnormal proteis which maye and lead to their destruction. Whether this abnormal praten om antibody is not known. It k&s bsea repeatedly demonstratech, was serum of some patients with SLE may cause agglutination of women kell as the red cells of the patient That the abnormal protect fellis undicated by the positive durect Coombs' test not intresserade these patients, and the positive indirect Cootabs' teta tamned Striking kutoagglutination of the red cells, and a year may occur in SLE in the absence of detectable evidencia destruction. Severe autoagglutination was cated in some by Aegerter and Long (1). Evans and co-workere (67fonder test in each of four patients with SLE, although note de comentar: creased blood destruction, whule the test was preitise amined by Zoutendyk and Gear (270, 280). The Coreano approximately 25 per cent of the cases (sumber of the words Rosenfield and Vogel (222). Three of four patients at the formed had a positive result in the study of Sheam :: Y three were suspected of having a hemolytic anemia The Coombs' test was performed on 34 of our paz hemolytic anemi. The test gave positive results is árindirect test was also positive. Agglutisation de albumin kes dexaonstrated u two cases with an others, but did not occur in the fout addstrona jest ming with positive Coorbs' tests Extraordinary autoagglutination of red ****ystave cases and was particularly pronounced in f, kdebar Imeiedustely after blood was drawn, chi* patreat, examined with the sist lamp 89 rater ·358 A. BOGEHEE HARVEY ET AL seen to flow through the conjunctival vessels in aggregates. This patient had a peculiar mottling of the skin thought to result from the intravascular clumping of red cells, but there was no evidence of increased blood destruction. Cold agglutinins were present in significant titer in three cases, including one with hemolytic anemia, but one patient with pronounced manifestations of Raynaud's syndrome had no demonstrable cold agglutinins or cryoglobulins. Some patients with SLE seem to have a remarkable ability to develop antibodies against red cell antigens Callender, Race and Paykoc (36, 37) reported a case in which multiple transfusions were followed by the demonstration of five separate antibodies including three which were previously undescribed. Five atypical antibodies were found in the serum of another patient with probable SLE (265). Anti-Kell antibody has been demonstrated in a patient with the disease after transfusions (225). A patient with SLE who developed hemolytic anemia following multiple transfusions was reported by Kuhns and Bauerlein (151) to have three atypical hemagglutining. In other instances hemoglobinuric transfusion reactions have been attributed to Rh isosenitization (8). Several authors have commented on the frequency of transfusion reactions in patients with SLE. In three of the nine cases reported by Aegerter and Long (1) transfusions were followed by reactions not attributable to ABO or Rh incompatibility. In the patients studied by Michael, Vural, Bassen and Schaefer (172) transfusion reactions seemed to be more common than in the general hospital population. In some instances these were ascribable to the development of atypical isoagglutinins (201). More than 200 transfusions have been given to 39 patients in our series. The frequency of untoward reactions has been low, Occasionally there has been a brief febrile response or urticaria, but patients displaying these manifestations have subsequently been transfused without repetition of the reaction. One patient had a hemolytic episode with hemoglobinuria following a transfusion of apparently compatible blood. However, he received blood on numerous occasions before and after this episode without reaction. Atypical hemagglutinins were demonstrable in the serum of several patients, who did not have transfusion reactions. The serum of one patient contained a peculiar hemagglutinin which did not correspond to any of the recognized red cell antigene. In a few instances multiple isosensitization Fas demonstrated. b. White Cells In the cases reported by Goeckerman in 1923 (80) leucopenia was frequently present and at times severe. Since then numerous observers have reported abnormalities in the white cell count with leucopenia (white count below 6000) being observed in from 25 to 85 per cent of the cases Extreme leucopenia (below 2000) has been unusual. Deviation of the white count from the normal range has mint amenta un to 30,000 vation of when the initial phase is severe (5, 6, 56, 129, 160, 172, 221, 234).

·SYSTEMIC LUPUS ERYTHESLATOSUS 361 depression of the platelet count bas been of only moderate degree In some cases, however, thrombocytopenia increased with the severity of the disease In one series of 83 cases (172) 31 had platelet counts below 150,000 when first examined and 13 were known to have had thrombocytopenia at some time Horever, severe bleeding occurred in only one case. Marked thrombocytopenia was present in six of 62 cases in another series (56). Information concerning the platelets 18 available in 86 of our cases In 23 of these platelet counts at times were definitely abnormal Twelve patients had Vsevere thrombocytopenia, with counts of less than 50,000 per cu mm This group includes those cases in which thrombocytopenic purpura was the outstanding manifestation of SLE. Seven other patients had platelets between 50,000 and 100,000 per cu. mm but abnormal bleeding was not impressive. In four cases counts ranged between 100,000 and 150,000 The remaining 63 showed no evidence of platelet deficiency A few patients developed thrombocytopenie as the disease progressed toward the terminal stage, but in niany, platelets remained abundant until death In occasional cases of SLE thrombocytopenic purpura is the outstanding feature of the disease The hemorrhagic disorder may occur when other manifestations are trivial, or may actually antedate them by months or years. These patients have been thought to have idiopathic" thrombocytopenic purpura, and the platelets may return to normal either spontaneously or as a result of splenectomy Data from 13 cases of this type collected from the literature and nine cases from our own series are presented in Table VIII It will be noted that in many cases no symptoms preceded the occurrence of thrombocytopenia. Other matufestations of SLE first appeared as long as seven years after the onset of purpura. In slx cases typical discoid lupus had been present before the onset of thrombocytopenic purpura, but in some of these the appearance of other mamfestations of SLE was long delayed It is noteworthy that the thrombocytopenic purpura occurring in this disease may be clinically indistinguishable from "diopathic thrombocytopenic purpura There may be no anemia other than that accounted for by hemorrhage, the white cell count may be normal, the spleen may not be palpable, and the bone marrow pattern is typical of “idiopathic" purpura. Furthermore, splenectomy has been regularly followed by elevation of the platelet count, often to normal levels. In most patients subjected to this procedure, there has been po recurrence of thrombocytopenia even though death from SLE ultimately occurred in most recorded instances the weight of the spleen was increased. Periarterial fibrosis in the spleen tas not uniformly demonstrable, even though searched for carefully. In 1949 Rich (215) reviewed cases at the Johns Hopkins Hospital in which a clinical diagnosis of "diopathic" thrombocytopenic purpura had been made, and in which the spleen was available for microscopic examination. In sıx periarterial fibrosis was noted. Two of the six patients developed clinical evidences of SLE and died more than two years after salanantamur had hapa ntamed ·360 A. BICGEHEE HARVEY ET AL. morphonuclear cells was often associated with a moderate shift to the left. Tbirty per cent of our patients had more than 5 per cent juvenile neutrophils, and & few had as many as 20 per cent. It was not unusual to find an occasional myelocyte in the blood; in four cases the number ranged between three and eight per cent Data pertaining to eosinophils were tabulated for 106 cases prior to therapy. In 46 of these, differential cell counts had been performed, but dưect eosinophil counts had not been made. No eosinophils were seen in the blood smears in 17 cases. In 13 others as many as two per cent were counted at times. Seven patients had as many as three to four per cent eosinophils and six had five to eight per cent. Only two patients had higher proportions: one with 17 and one with 24 per cent. Pronounced eosinophilia was associated with extensive skin lesions, and was not attributable in these cases to detectable causes other than SLE. Direct eosinophil counts were available in 60 cases. The number was less than 50 per cu. mm. in 31 cases; between 50 and 100 in 11, and between 100 and 200 in ten. Six patients had between 200 and 400 eosinophils per cu. mm., and only two had counts in excess of 400. Atypical lymphocytes were often present in small numbers, usually comprising not more than one per cent of the white cells. However, two patients had eight and nine per cent atypical lymphocytes. Two of our patients transiently had severe granulocytopenia In one the neutropenia was associated with a hypoplastic anemia which was thought due to chloramphenicol. In this case the total white count was 1600 with 91 per cent lymphocytes and only five per cent granulocytes. One other patient with SLE was thought to have acute agranulocytosis at the time of admission. She had a white cell count of 2600 with 78 per cent lymphocytes, six per cent juvenile neutrophils and six per cent polymorphonuclear cells. There was a history of recent ingestion of several headache remedies. Granulocytes appeared in normal proportion within a few days at a time when the SLE was rapidly progressing c. Platelets Purpura has often been encountered in SLE and was described by Kaposi (135), Osler (189) and numerous other authors. Each of the four patients of Libman and Sacks (160) had prorninent petechial and other hemorrhagic mantfestations, and one is known to have bad thrombocytopenia. Keil (138) in 1937 reviewed the earler literature on the bemorrhagic tendency in this disease and pointed out that several mechanisms are involved including vascular factors, azotemia and thrombocytopenia. Purpunc spots, petechiae, hero orrhagie vencles and bullae, bleeding into the mucous membranes, from the nose, gums and from the gastrointestinal tract were described. Platelet counts were not recorded in many case studies, but more recent evidence indicates that the purpuric bleeding in nationta with SLE Nevertheless, thrombocytopenia has been observeu i wlany women 56, 61, 75, 78, 133, 134, 160, 163, 172, 221, 234, 251, 258, 272). In most instances ·SYSTEMIC LUPUS ERYTHEMATOSUS 361 depression of the platelet count has been of only moderate degree in some cases, however, thrombocytopenia increased with the seventy of the disease. In one senes of 83 cases (172) 31 had platelet counts below 150,000 when first examinet and 43 were knoten1 to have had thrombocytogeous at some time. Ilorever, severe bleeding occurred in only one case. Marked thrombocytopenia 129 present in six of 62 cases in another series (56) Information concerning the platelets is available in 88 of our cases In 23 of these platelet counts at times were definitely abnormal. Twelve patients bad Vsevere thrombocytopenia, mtb counts of less than 50,003 per cu, mm This group includes those cases in skich thrombocytopenic purpura yas the outstand. ing manifestation of SLE. Seven other patients had platelets between 50,000 and 100,000 per cu mm, but abnormal bleeding was not impressive. In four cases counts ranged betiscen 100,000 and 150,000 The remaining 63 showed no evidence of platelet deficiency A few patients developed thropsbocytopenia as the disease progressed toward the terminal stage, but in many, platelets remained abundant ustel death. In occasional cases of SLE thrombocytopenie purpura is the outstanding feature of the discase The hemorrhagic disorder way occur when other mandestetions are trivial, or may actually antedate them by months or years These patients have been thought to have diopathic thrombocytopenic purpura, kad the platelets may return to normal other spontaneously or AS & result of splenectomy. Data from 13 cases of this type collected from the literature and mine cases from our own series are presented 133 Table VBI It will be noted that in many rases no symptornis proceded the occurrence of thrombocytopenie. Other man Testations of SLE Girst appeared as long as seven years after the onset of purpura In eix cascs typical discoid lupus had been present before the onset of thrombon cytopedic purpura, but in some of these tho appearance of other m.223festations of SLE was long dclayed It is notoworthy that the thrombocytopenic purpura oceurnag in this disease may be cinically indistingishable from "rdiopathie" thrombocytopenic purpura Thero may be no anemia other than that accounted for by hemorrhage, the write cell count may be bormal, the spleep may not be palpable, and be bone marrow pattern is lypical of "d:opathic" purpura Furthermore, splenectomy has been regularly (olloned by elevation of the platelet count, often to normal levels In most patients subjected to this procedure, there has been no recurrence of thrombocytopenia Even though death from SLE ultimately occurred. In most recorded instances the esght of the spleen was increased. Pemarterial fibrosis in the spleen *s not uniformly demonstrable, even though searched for carefully In 1949 Rich (215) reviewed cases at the Johns Hopkins Hospital sa bich a clinical diagnosis of "Idiopathic" thrombocytopenic purpura had been made, and o which the spleen was available for microscopic examination lo six periarterial fibrosis was noted Two of the six patients dercloped clinical evidences of SLE and died more than two years after splenectomy had been performed. Autopsy in one care shored visceral and cutaneous lesions of SLE One other patient, tot suspected clinically of having SLE had seceral lesions of this disease at autopsy ·TABLE VIII Thrombocytopenic purpura in SLE 362 Source Patient Aatecedeot Manifestations Palpable 1 Plate lets Hgb HBC LE Cells Efect of Splenectomy Edect of ACTH or Cortisode Splenic Leston Ultimate Outcome 1 Wise (272) 7 7 Immediata eSAtiot of purpura 2. Lyon (103) 18 WF Node Thrombo. ? cytopenio pur pur for four Yeart 12 MT Intermittent thigh yeal 22,000 80% Dain, fever and erythroatous rush for two montha I None Teoorded 20,000! 3600 6 months after splenectomy developed cutatodua lupuo, fever, nephints and diod Plateleto remained normal Weight 323 Gm No Platelets returned to normal Proiona described spontaneously efter one month but Jatieds died of SLE 8 Jonce and TOODED (138) 7 5000 1 7 Plateleta returned to normalia 3 montbs Developed cutaneous lupus 6 months after splenectomy 4 Mulbradt (173) 13 WF Cutaneow lupus ho 10,000 38% 5000 3 Kel (138) 18 WF Nose Thrombocytopenio purpura for four MORTE ? 1,000 to 80 69,000 18,800 - Purpura subeaded promptly A. MCGEHEE HARVEY ET AL. & Edelman (01) 7600 - 4 WM Duod fupus or 10 30,000 37% tsoo for two years - BO 7100 68% 3200 7. Brady and Nea 30 F Butterly rash, (30) Replintu, fever for B modtlus Dred of intracranial hemor- Thago TW106 normal in Developed outa neova lupua 3 years after aplenectomy. Died of SLE 7 years poatop Platelets prior to death 200,000 sughtfy enlarged. (Died of hemorrhage Autopky Hyalnization of showed lupus leatona in kidarterioles ney Slightly enlarged. No recurrent of thrombo. No lesions cytopenis in one year. Other manifestations of SLE per. einted Periarterial fibre Dispod lupus it ago 13, Tocurrent at 18 with fever, petechiae, hechaturis, 0733. death. Megakaryooytes in creased in DITOW -firmediate cerer tlon of bleeding Platelets rose to 7200 I 1 Ottavianlund 16 HF Acute thrombon 320,900 85% L'estona (100) cytopedio pur pura atapewtb pereistest bruin in hendeney thereafter Michael Vunl 31 WF NODE Buca and Behaneler (172) 7 ? Poe Cortion of bleed int Well for 7 year after opleDAG tomy, then developed SLE and died Plateleta prior to deach 245,000 ·2800|40% IG Mobel, Fural 1 WF FACW eruption for ? 10,000 ? ? -Cessation of blood- Doreloped mustatation of Bened and tbroo year ing Platelets re- BLE ? year after splenec- Schaefer (177) Surnad to no tomy and died 11 Fredmab. 14 CM Cutaneout lupus, yes 6300 Poo Platelet returned 2 Died altor several moka, pro- Kleschmoldt fove for four to normal during sumably of SLE and Schwerti weeks therapy with 69) ACTII and cortione, but subre quent relapse failed to respond 12 Johnson (730) 37 WY Ducond lopua lor 7 3000 S 4 Gro 3903 Rase of platelet Weight 140 Gas Blont torial 7 yeats alter 17 year, malaue count in 48 houra. splenectomy Arthralgaand artbelgia eventually to facial erythema panelated 393 000 1 Jobben (130) 11 WF 2 7 I 000 $ i Gru Platelet ronto Plateleta road to 543,000 Died 150,000 la 24 boure following Malva keror ringe from Bplanio pediclo 10 weoko post-op 16 JITI 5 00186 49 WF Non Purpurs for Do 10,000 7 Gro 3656 renartorial fibrosia Died of hemorrlingo one year 15 JUIL 5505027 34 WT (Urticaru for many yeu 33,000 11 Go to Por Platelsta promptly No ran in platelet Weight 183 Gr No No recurrence of thrombo. (Cao) yenne Arthralgia 7000 returned to nor couot during periarterial fibro-1 cytopenia Platolet ovat for 8 years ma! ACTH, 100 mg 813 two years after splenectomy Thrombocyto daily for 4 wech, 135,000 Mild heralytic pati purpura BAMA perzutad for 20 months 18 JTII A 13 CF (Arthralgia for 1 DO 11.000 B Gm 4300 Platelete prozoptly JWeight 148 Gm No recurrence of thron.bo. (C-30) month returned to tin Penarterul bro cytopenia Pationt died of nal lupus 2 years aftor splenec tomy, and terminally had 17 JIH $714622 betuolytis ageman 19 WM Butterfly tosh on DO 18,000 8 7 6 5900 to fro, trosted with Weight 420 Gm Died 22 months after anset, 27.000 rold, followed by (autopay) Pers of combined effects of us arterial fibrocus temnio lupus and bomor. Appearance of inga. Bone marrow at purport, IT months before Autopay hyperplaatio with many toegakaryocytes douleioa SYSTEVIC LUPUS ERYTHESLATOSUS a10 363 ·364 TABLE VIII-Continued Source Patient Antecedent Manifestatos Palpable Spleen Platelets Hgb WBC LE Cells Efect of Splenectomy Effect of ACTH or Cortisont Splenic Lesion Ultimate Outcome 18 JHIT #207012 6200 Neg Plateleta returned to normal within 4 days 3 timea Dora 120 Remained well with normal T'eriartenal fibro platelet count for 14 years, then had fulminating roour. rence of purpurs and died of intracranial homorrhago 19 JUIII #274052 36 WF Mild urticaria forno <60,000 11 I GO years l'orpura for 6 weeks Acute arthritis of knee followed oneet of purpura. 39 WT Recurrent trah of no 30,000 10 Gm lupus on face for 8 years without other danifestatrons T'urpurs for 1 year, 37 WF Urticarial reaction you 32,000 15 Gm to pencilbn 7 4300 to 5500 Prounptreosa platelet count within 24 hours Weight 134 GO Periarterial fibro- POR No recurrence of purpure, Developed fulminating souto lupus 3 years after Aplenectoiny. Dled of pneumococcal septicemia 20 J1111 *081252 5900 Neg Prompt oceation of bleeding Plateleta 87 000 on Bth day year before A. MCGEHEE HARVEY ET AL. 21, JITH 0274370 Three tradient episodes of pleu rony Purpura for 5 weeks 61 WF Pain in kneen And yes 12,000 Gm ellow 9 years before. Severe purpura for 3 months arthral- Yea 50,000 567 gie, Enger, elbowo, kneed of 11 Year Purpurs 4 Weeks, 6 months pregtaat. 4400 Neg Prompt ringan platelets within 24 hours to 340,000 by oth day. Weight 145 Gm. No recurrence of purpura, Periarterial fibro Developed transient pleu. nitio pain, trapeient painful awellang of fingers within year after splodectomy Platelet count 274,000, 18 months after splenectomy Weigbt 300 m No recurrence of purpura, Periarterial fibro-1 IIad pericarditis and fever en postoperatively. Appeared well 3 years after aplencotomy. Weight 170 Gm Died in 3 woola of intracranial Periarterial fibro bemorrhage Kidney desdon 818 of lupus and many megs karocyter la MRITOW At sutopay 22 IIII #23565 22 WF Transien 8900 1 ·SYSTEMIC LUPUS ERYTHEACATOSOS 365 Rich believes that pronounced periarterial fibrosis of the spleen rarely, of ever, occurs in conditions other than SLE. the occurrence of thrombocytopenic purpura as an early manifestation of the disease is not rare. In the discussion which followed the report by Montgomery and McCreight (176), three cases were mentioned ia which thrombocytopenic purpura treated by splenectomy had preceded other manifestations of SLE, In two of the cases of Gold and Gowing (83) thrombocytopenic purpura antedated other evidences of SLE by several yeats. A patient desenbed by Damesbek and Rheigold (50) as kaving "diopathic" thrombocytopenic purpura was noted to have had a painful polyartantis associated with a "butterfly" rash of lupus erythematosus five years before the Obset of abnormal bleeding. It is clear that a previous history of joint pau, pleansy, skip eruption or other manifestation may have great significance in & patient with thrombocytopenic purputs. This is effustrated by one of our own cases: Case 51 MR. (*505002), a 34 year old white bousepesse, has been coder observation 8120e early 2950 She has bad episodes of urticara bloce early adolescence At the age of 24 sbe developed mild aching and stages of fagers and knees with occasional swelling of the protimoal interpbalangeal jasats At that time abe was given liver injections for "anema2" At she Lad toxemia of pregnancy with hypertension, whicd subarded after delivery of a stailborn child Ia the following year she felt nervous and & FIXED a Dver injection followios wluch she developed severe urtscarss Two years later, because of inabukty to become pregnant, she received 102ections of bormones During this therapy che developed nedoschegampel persisted Thereafter, als bad prolase epistares dad cutaneous ecchymoses Examination revealed so splenomegaly, but there was thrombocytopenia and the sternal martow 28 auld to be compatible with 'ydsopstbus" thrombocytopenic purpura One year later there were numerous petechise and ecebymoses The tip of the spleen was palpable. but there &3 no evidence of joint disease The platelet count taxged between 32,000 and 68,000 per eu mm She also had a soild hexzolytic enerous hasociated with a vositive Coaraba' test and auto-antibody in the seri2 The hematocrt **34 per cent And hemoglobin 119 grame, the verum bsrudin 3 5 mg per 100 ml , fecel excretion of urobilinoged increased, and reticulocyte counte sa bigh as geven per cent Numerous L. E cells were detiopstrated Alecrow meant contbibed many megakaryocytes with no evidence of platelet formation The white cell count sanged between 5000 and 7000 She was treated intensively with ACTII The demolytic anemia subesded, the bemataent valge reaching 41 per cent, the white count rose to 17,000, but there was no rige so the platelet count and hesnorrbage lesione continued to appear After therapy was discontinued there was recurrence of artbralga and the bertatocrit and white counc fell to pretreatment values The purpura permuated and five Boatba later ebe returned for splenectomy The spleen weighed 155 gtut , sed ehowed no periartenal fibrosis. The platelet count rose withio a few bours to 214,000 There bas been so recurrebre of purpura or of thrombocytopeng iyo years te fplenectomy She has undergone a nortaal pregnancy, cunog wbiçb ber joint modifestations subsided The cord blood as well as blood drawn from the newborn fernale child did not form .. E cells, and the infant's platelet count at bestà *s$ 275,000 Two weeks after delivery, the patient had 4 trangcat episode of 17tik and recurrence of her joDt Symptoms Nevertheless, she has temaped temarkably well and at present u again prenset The mechanism by which thrombocytopenis is produced in SLE u unknown. Although splenectomy is usually followed by a sustained rise of the platelet count, there is attle to suggest that the platelet deficiency is secondary to disease ·361 TABLE VIII-Continued Source Tatlet Angredent Aianifestators Flatelets ligb WBC LE. Cells is Edect of Splenectomy Lfect of ACTII or Cortisgae Splenic Lesion Ultimata Outcome 8200 Nes Tlatelets returned to Dorial with I days 3timet normalelse Remained well with normal Terlatterlibro platelet count for 16 year pio they had fulmulasting roour renosol purpura apd died of latracranial bemory bongo 4300 to 6500 - Prompt rain places fot count withia 21 hours Weight 151 m. Periarterial fibro sia No recurrence of purpura Developed fmidating acuta lupus 3 years after splenectoiny, Diod of prou. moooceal coptímoulin 10 JHIT #207012 30 WT Mdd urticarla for no <60,000 11 8 Gra tan lurpurs ford wech Acutel arthrill of Inne followed onset of purpura 27 353 274052 30 W 7 )Recurrent rabolno 30,000 10 Cm lupuu on face for yeart without other manifcala tlova. Purpurs for 1 year. 20, J1 &&&{242 37 ** Vrticari partios y 12,000) 16 Gm to picillin 7 ytan before Thrretratatont parxien ol plou Tiny Purpun for 6 teko 11 JANT 174370 BWF Pain la koer Aad 3 12,000 m elbona na before fevere Purpun fur 3 thonths 22 JIII 323545 23 WF Transient arthrul se 50,000 $ a, frgera, ntlow, tree of ther Purpura was, months Tregneat. 8000 Nrg Trompleraration of bleeding, Plateleta 87 000 OD 8 dry A, MCGEHEE HARVEY ET AL. 1100 Nrg Prompt rims is platelma within 24 hours to 316,000 by oth day Weight 145 Gm No Tourrence of purpura. I'criarterinibro Developed trenaleat place pia rtla pia, transient inful Swelling of fingers within yBar After splopectomy. Matelet count 274,000, 16 Inonths after aplenectomy Wescht 300 Gm NO recurrence of purpur Per arterial fibro 11ad parienditle and fover poetoperatively. Appeared Mall 7 grass allar plenor tory. Weight 170 CID Died looks of intrach! Perlaterial fibro- hemorrhat Kidney leelons of lapun and many tekno karocyte la Autopay. 8870 ·SYSTEMIC LUPUS ERYTHEYATOSOS 365 Rich believes that pronounced periarterial fibrosis of the spleen rarely, if ever, occurs in conditions other than SLE. the occurrence of thrombocytopenic purpura as an early manifestation of the disease is not rare In the discussion which followed the report by Montgomery and McCreight (176), three cases were mentioned in wuuch thrombocytopeasc purpura treated by splenectomy had preceded other manifestations of SLE. In two of the cases of Gold and Gowing (83) thrombocytopenic purpura antedated other evidences of SLE by several years. A patient described by Damesbek and Rheingold (50) as having "idiopathic" thrombocytopenic purpura was noted to have had a painful polyarthritis associated with a "butterfly" rash of lupus erythernatogus five years before the onset of abnormal bleeding. It is clear that a previous history of joint pain, pleursy, skin eruption or other manifestations may have great significance in a patient with thrombocytopenic purpura. This is ilustrated by one of our own cases: Casa 31 M.R (505022), a 34 year old white bousewife, bas been under observation since early 1950 She has had episodes of articaria since early sdolescence At the age of 21 sbe de. veloped mild aching and stiffness of finger and knees with occasional swelling of the proví. pregnant, ebe received injections of bormones During thus therapy she developed menor- Thagia which persisted Tbereafter, she had profuse epistaxes and cutaneous ecchymoses Examination revealed no splenomegaly, but there was thrombocytopenia and the sternal marrow WAS said to be compatible with "ndiopathic" thrombocytopenic purpura One year later there were numerous petecbide add ecchymoses The tip of the eplera was palpable, but there was no evidence of joint disease the platelet count ranged between 32,000 and 63,000 per cu min Sbe also had a mild bemolytic anemia Associated with a positive Coombs" test and auto-antibody in the serum The hematocht was 34 per cent and hemoglobio 119 penL-LT t... Aca Ah AR Tode to 17,000, but there was no 1188 11 tbe platelet count and hemorrbage lesions continued to appear After therapy #38 discontinued there was recurrence of arthralgia and the hematocrt and white count fell to pretreatment values The purpura persisted and five months later sbe returned for splenectomy The epleen weighed 185 gm, and showed no pertarterial bbrosis The platelet count rose within a few hours to 214,000 There has been no recurrence of purpura or of thrombocytopenis two years after splenectomy She has undergone a Dorial preguancy, dunng which ber joint manifestations subsided The cord blood as well as blood drawn from the newborn female child did not form L E cells, and the infant's platelet count at birth was 275,000 Two weeks after delivery, the patient had straosiest episode of intis and recurrence of ber joint symptoms Nevertheless, she has remained remarkably well and at present 19 agaib pregnant The mechanism by which thrombocytopenia ss produced in SLE unknown. Although splenectomy is usually followed by a sustained rise of the platelet count, there is little to suggest that the platelet deficieney is secondary to disease ·368 A. MCGEHEE HARVEY ET AL. coagulation defect was not discovered. In two cases prolongation of the clotting time was associated with severe thrombocytopenic purpura. In one of these patients studied in detail the prothrornbin concentration was normal, an assay for anticoagulant was negative, and no defect other than thrombocytopenia was discovered. One patient without hemorrhagic manifestations was found to have a persistently prolonged clotting time, at times considerably in excess of one hour, with adequate platelets and normal prothrombin, An anticoagulant assay in this case was negative, and the cause of the coagulation defect was not detected. The prothrombin time was determined in 38 of our cases. In 25 it was normal. In seven there was moderate prolongation, indicating that prothrombin was reduced to about 50 per cent of normal. Sıx patients had marked prolongation of the prothrombin time, with estimated prothrombin concentrations of less than 30 per cent of normal. The most profound hypoprothrombinemia was encountered in the boy, previously mentioned, who had a hemorrhagic disorder associated with a long clotting time. Marked prolongation of the prothrombin time in one case was associated with cirrhosis of the liver and in another with hepatitis In the cases in which a circulating anticoagulant was demonstrated, prolongation of the prothrombin time was shown to be caused by the anticoagulant rather than by prothrombin deficiency. Administration of vanous Vitamin K preparations was without significant effect in these patients. No hemostatic defects were demonstrated in many of the patients who had purpura and epistaxis. Even the capillary fragility test was usually negative, unless the platelets were severely reduced. Ve. Bone Marrow The bone marrow has been examined in a large number of cases of SLE since the discovery of the L.E. cell phenomenon. In most reports the description is limited to observations on the occurrence of L.E. cells in incubated preparations. Michael, Vural, Bassen and Schaefer (172) examined the marrow in 32 cases In only one was it hypocellular. An increase in the proportion of plasma cells was often present and in one case reached 18 per cent. Marked erythroid hyperplasia was noted in association with hemolytic anemia. In general, however, the marrow pattern was normal. Smears of aspirated marrow were examined in 36 of our cases. L.E. cells were often seen when incubation in vitro preceded preparation of the smears, but were naror annountered in direct smears. The marrow in most instances appeared to - fuam patient had developed a hypoplastic anemia fotowwy lui www. chloramphenicol, Megakarocytes were markedly reduced, the proportion of myeloid cells was low, and there was an increase in lymphocytes. In other cases thaich there was pronounced when the it and were 11 1 ·SYSTEMIC LCPUS ERYTHEMATOSUS 369 usually present in pormal proportion when anemia was profound. There was a definite tendency torrards an increase in the dumber of plasma cells in the marrow. The plasmacytosis was of only slight degree in most instances, and in 17 of the 36 cases ranged between one and five per cent. In two cases a marked increase in the proportion of plasma celle was notod, values of 11 and af 17 per cent being obtained. The abnormally high proportion of plasma cells, together with the tendency for the red cells to be agglutinated on the smears, at times presented & pattern which was rather suggestive of myeloma. In those patients with throrabocytopenic purpura, megakaryocytes were abundant, at times appeared inmature, and showed no evidence of platelet formation. In the presence of bcmolytic anemia, the proportion of nucleated red cells in the marrow as high, In several cases surgical biopsy of tbe marrow was performed. In addition, sections were examined in all of the autopsied cases. The marrow was normally cellular or hyperplastic and megakaryocytes were present, even in those patients dying from thrombocytopenic bemorrhage. Avm. TRE L.E. CELL PRENOSIENON a Characteristics of the Cell A typical L.E. cell consists of a mature polymorphanuclear neutrophil containing within its cell membrane a mass of homogeneous material which stains redpurple with Vnght's stain. This masa 13 round or oval and I usually several times as farge se a normal red blood cell Because of this inclusion, the LE. cell 13 characteristically larger than a normal neutrophil, the segments of the nucleus are displaced to the periphery, and only a thin crescent of cytoplasia can be seen about the edge of the mass (Hg. 17). "Rosettes" are frequently found in association with L.E cells. These are aggregates of polymorpbonuclear peutrophuls surrounding Wasses of homogeneous material. Also noted are extracellular globules of the same homogeneous matemal. These free globules and the material at the centers of the "rosettes' possess the same staining characteristics as the material within the LE. cells. The L.E cell was first described in 1918 by Hargraves and his associates (97), who identified these structures in concentrated bone marrow preparations 10 more than twenty-five cases of SLE. It soon became apparent (95) that the cell is not found in direct smears of marrow but is formed inntro following aspiration. Ilaserick and Sundberg (111) corroborated these findings. Factors Responsible for Formation Hargraves (05) and Ilasenck and Bortz (105) reported that LE, cells could be produced by mixing plasmas of a patient sth SLE sod normal bone marrow elements. The first report of L.E. cells in bully cost preparations of peripheral blood was made by Sundberg and Lick (249). Moffatt, Barnes, and Weiss (174) reported that the cells could be produced in mxtures of the plasma of patients »ith SLE and either normal peripheral blood or concentrated normal white celis There 19 Nov general agreement (17) that at least three factors are necessary ·370 A. MGEKEE HARVEY ET AL. for the formation of these cells: (1) & substance present in the plasma of many patients with SLE; (2) nuclear material derived from leucocytes and altered through the influence of the plasma factor; and (3) active phagocytic cells which engulf the altered masses of nuclear material. The plasma factor has been demonstrated to be associated with the gamma globulin fraction (23, 109, 152, 156). It is an immunologically distinct component of the gamma globulin, for antibodies against it can be produced in rabbits (108). It is readily destroyed by bacterial action, but when kept under sterile conditions will retain its potency for several months (95, 101, 156). Activity persists after heating plasma to 59°C., and is destroyed by heating to 65°C. (95, 101). The plasma factor is not inhibited in vitro by the addition of testosterone, estradiol, progesterone, or cortisone (87, 101). Para-aminobenzoic acid inhibits L.E. cell formation, but the mechanism is unknown (101). The repeated use of active plasma seems to potentiate its effect upon normal marrow cells, and it has been suggested that the accumulation of proteolytic enzymes resulting from the breakdown of cells serves to accelerate the process of nucleolysis (23). The L E. factor may at times be demonstrated in body fluids other than plasma. Watson, O'Leary, and Hargraves (267) found neutrophils with inclusion bodies which resembled L.E. cells in the fluid of blisters made by the application of cantharides cerate to the skin of patients with SLE. Other observers have demonstrated them in pleural fluid, pericardial fud, cerebro-spinal Auid, and urine (112, 149, 229, 261). Bridge and Foley (32) showed that the L.E. factor may cross the placenta. The mode of action of the plasma L.E. substance is unknown. Interest has centered about its possible relationship to desoxyribosenuclease (DNase). Kurpick and his associates (152) estimated the activity of this enzyme in the serum of twenty-three patients with SLE and compared these values with the results of L.E. cell tests. In some instances the L.E. cell factor was demonstrable in serum devoid of DNase activity. Furthermore, destruction of the DNase activity by heat did not eradicate the L.E. factor. Henstell and Freedman (117) reported the finding of a substance in normal human polymorphonuclear cells and lymphocytes which inhibits DNase. Kurnick and his colleagues (153) also demonstrated this factor and in addition, found, in human leucocytes, an inhibitor of the L.E. cell phenomenon These two factors were similar in that both were destroyed by proteolytic enzymes, but not by nucleolytic enzymes, neither permeated a cellophane membrane, and both had the same stability under temperature variation. These observers suggested that the depolymerization of desoxyribose-nucleic acid, which presumably occurs in the formation of L.E. cells, is due to a derangement of the intracellular DNase-DNase inhibitor system. It was postulated that the plasma L.E. factor may act to release intracellular DNase from inhibition. The inclusion bodies of the L.E. cells, the central masses of the rosettes, and the free extracellular globules are believed to originate from the nuclei of leuco-

·FIS IT Smears of the hull cost of fiepaninized blood (1) anu nyron i showing ID:
colle Wnght's stain X10M
371

·372 A MCGEHEE BIARVEY ET AL. cytes, although platelet or megakaryocytic sources have been suggested (109). It is now widely accepted that these structures arc composed primarily of nuclear materials which have undergone a distinct type of lysis under the influence of the plasma L E. factor. In his orginal report, Hargraves (97) suggested the nuclear origin of the inclusion bodies because of the manner in which they reacted to the Feulgen reagent. Lee, Michael and Vural (156) found that the inclusion bodics stained positively with both Feulgen reagent and methyl green, suggesting the presence of des. oxyribose-nucleic acid They also obtained the Feulgen-methyl green ratios of these bodies, and the results indicated that much of the DXA was probably in the depolymerized form. These observations suggested that the inclusions might bear some relationship to the hematoxylın-staining bodies scen in tissue sections (78, 92, 143) Berman and his associates (23) agreed with Klemperer that the hematoxylın-staining bodies and the L E cell inclusions are identical by virtue of their morphology and tinctorial properties, but in their own studies of L E. coll preparations did not find conclusixe evidence for the presence of large amounts of depolymerized DXA Dameshek and Bloom (49) found that the L E. cell inclusion may contain riboscnucleoprotein of cytoplasmic origin, and did not find glycogen, lipids, acid or alkaline phosphatases. llargraves (97) obscrved neutrophils engulfing nuclear matenal in supravital preparations but did not provide details about the source of the nuclear masses. Moyer and Fisher (183) saw neutrophils engulfing lymphocyte nuclei. Rohn and Bond (218) described initial degeneration of nucles of polymorphonuclear neutro phils to amorphous masses, following which intact granulocytes engulfed the globules They did not obscrve autolysis of lymphocytes in their preparations Stich, Feldman and Morrison (245) also concluded that the L. E inclusion body originates from nuclei of polymorphonuclear neutrophils They noted that the lobes of these cells became rounded and pyknotic, and the interlobar filaments disappeared. This produced a structure which they termed the pre-L E cell". The rounded, homogeneous, deeply stained nuclei were then thought to be extruded from these degenerating neutrophils to be engulfed by other intact granulocytes The formation of L.E. cells has been studied by a number of other investigators (212) Rebuck and Berman (209) obseried their evolution by applying serum from a patient with SLE to the abraded skin of normal subjects By examination of cover slips remoi ed at appropriate time intervals from the abraded area, they noted that the nuclei of polymorphonuclear neutrophils first underwent degeneration, then appeared as frce masses, which ucre engulfed by other neutrophils They thought that occasionally degeneration and swelling of a single lobe of a neutrophil might occur, thus producing an L E. cell without the step of phagocytosis. As noted by Hargraves (97) the phagocytic cell is almost always a mature polymorphonuclear neutrophil. However, mctamyelocytes, band forms of neutrophils, mature eosinophilic and basophilie polymorphonuclear cells, and monocytes hate bech noted to participate in this phenomenon (150, 183, 218) Even ·SYSTEMIC LOTUS ERYTHESLATOSUS 373 lymphocytes are said to be active by Berman and his associates (23), but this report has not been confirmed. LE. cells are formed equally well in preparations containing heparin, oxalato or citrate (95), and can also be demonstrated in clotted or defibrinated blood or marrow (11, 13, 66, 87, 155). Suksts and Conley (248) and Eppes god Ludovic (66) used blood handled in silicone-treated equipment and found that L.E. cells were produced in the absence of both anticoagulants and blood cosgulation, L E. cell formaation is considered to be an in urtro rather than an in viro event, since these cells are not ordinanly seen in direct smears of blood or marrow. How. ever, they occasionally have been found in post-mortem preparations (94, 185). Klemperer (141) found in post-mortem scctions of the pleura a structure identical in appearance with the L.E. cell. Eppes and Ludove (66) segrched many direct spears of finger tip blood containing LE, factor and found only one neutrophilic leucocyte which appeared to be engulfing amorphous, pink-stained material, but the resemblance to an L.E cell was not complete. Chomet and his associates (42) found LE cells in direct smears from a patient with fulminating SLE. LE cells are formed very rapidly in vitro, but a definite interval of time is required for their appearance. Ilaserick (101) made smears of an incubating specímen every 60 seconds and found leucocyte clumping first appearing at 5-6 minutes and L.E. cells at 12-13 minutes. Lee, Michael, and Vural (156) in similar studies found the cells after two minutes' incubation, but stated that the maxi. Of the three factors necessary for the formation of L.E celis only the plasma substance need be obtained from a patient with SLE. The nuclear material and phagocytes can be derived from normal blond or bone marrow (95, 105, 106, 174). blood of patients with a variety of diseases including chronic leukemia (183), stored blood (69, 183), and blood or marrow of numerous mammals (23, 103) Ross and Wells (223) were unsuccessful in attempts to use pigeon marrow. Several efforts have been made to produce L.E cells experimentally. Castillo and his associates (41) injected guinea pigs intraperitoneally with the blood of patients with SLE and reported that female animals lost freight and developed ſever and leucopenia. Preparations of defibrinated blood of these animals contained structures which were thought to resemble L E. cells, and examinations of the tissues histologically showed abnormal alterations about blood vessels. These experiments were repcated in our laboratory by Schoenrich (228). Nine Freekly injections of plasts from a patient with SLE did not cause weight loss, fever or leucopenia. Examination of preparations of the blood of the animals before and after the injections showed structures which superficially resembled L.E. cells, but typical cells were not scen, No lesions suggestive of SLE were sen in the tissues at autopsy, but the kidneys of one animal showed focal regal lesions resembling the hypersensitivity nephritis produced by injection of horse serum in rabbits.

·374 A, MCGEHEE HARVEY ET AL. Inderbitzin (122) described the production in normal blood of structures resembling L.E. cells by the use of anticoagulants of high molecular weight. The sodium salt of polyvinyl alcohol-polysulfonic acid ester (PVAS-Roche) and several related compounds, after incubation with normal gamma globulin, were said to induce the formation of these cells. Haserick (102) added certain fungi to dog bone marrow and noted the appearance of structures resembling L.E. cells. Kurnick and his associates (152) were unable to produce the cells by incubating normal leucocytes with bovine desoxyribosenucleic acid. Finch, Ross and Ebaugh (68) produced antiserum agamst leucocytes. On addition of the antiserum to leucocyte preparations, they observed clumping of the white cells, phagocytosis of intact or degenerate cells by other leucocytes, and the formation of structures "indistinguishable from Hargrave's LE. cel!". On examination of their photographs and preparations, we are unable to find structures which we would identify as L.E cells. Although nucleophagocytosis is apparent, the engulfed nuclei have not undergone the peculiar hyalinization which is characteristic of an L.E cell. Zimmerman, Walsh and Heller (278) reported experiments similar to those of Finch and his associates. Nucleophagocytosis was prominent in their preparations Some cells showed homogeneous inclusions and were said to resemble L.E. cells. c. Occurrence The L.E cell test has been reported to be positive in a large proportion of cases of SLE. Some authors (103, 245) have obtained positive tests in 100 per cent, but most have encountered patients in whom the cells could not be demonstrated (155, 176, 234, 248). Dubois (57) found the test positive in only 48 of his 70 cases L.E. cell tests were performed in 96 of our cases and were positive in 79, an incidence of 82 per cent. It is impossible to determine the true frequency of positive tests in SLE because there is no method by which the diagnosis can regularly be established with accuracy. In the absence of a positive test, the diagnosis often is not made. More than 50 patients examined at the Johns Hopkins Hospital were suspected of having SLE but were not included in the present series because proof of the diagnosis was lacking In all of these cases, L.E. cell tests were negative, often on repeated study. Nevertheless, many had typical clinical manifestations of SLE, and one patient who subsequently died was proved to have this disease at autopsy. L.E. cells could not be demonstrated in 17 of our patients with unequivocal SLE. The disease was active in all and some were critically ill Histologic proof of the diagnosis was available in nine. Three patients had only a single test, but in the others as many as 12 examinations had been performed using heparinized blood, bone marrow, and in some clotted blood and guinea pig blood, all with negative results. In our experience the activity of the disease is not well correlated with the number of L.E cells. Some of our patients have had remissions lasting several years during which the cells were repeatedly demonstrable in considerable numbers ·SYSTESTIC LIPDS ERITBELLATOSUS 375 d. Techniques of L E. Test A sumber of methods have been recommended for clinical use in the detection ofLE. cells. Examibation of the buffy coat of heparinized bone marrow has been largely supplanted by use of peripheral blood Bully coat smears prepared from bepannized blood after incubation in viro have been very satisfactory. Several investigators have preferred to examwe bully coat tmears frow defibrinated (66, 106) or clotted blood (83, 155, 277) It has been claimed by some (87, 155, 166, 277) and denied by others (57) that techniques employing clotted blood are more Kerstrve than those in whick 42 anticoagulant is used. Hargraves (96) beleved that platelets or their degradation products might augment L E. coli formation. However, two of our patients with severe thrombocytopenia were repeatedly found to have LE cells so bully coat preparations Splenectomy in one case as followed by a tremendous rise en platelet count but was without effect on the number of L E. cells Even the proponents of the clotted blood technique admit that the preparations tend to be hypocellular, that there is much cellular distortion and that nucleophagocyto99 is increased As a result these preparations aro more difficult to interpret than are those of hepanzuzed buffy coat We have never been able to demonstrate L E ceils by use of the clotted blood technique when they were not detected using heparirsized blood. The addition of the patient's plasme or serum to cells obtained from normal blood or marrow 29 a more cumbersome technique which is of particular value sphen the patient bas pronounced granulocytoperia Animal blood or marrow has been preferred by somo investigators (103) Hegardless of the technique used in the preparatson of the smears, great care 18 required as thejs examination LE srlls may be overloobed unless a diligent search is pursued Phagocytosis of erythrocytes, of intact white cells, or of cell aucler is often encountered in buffy coat preparations, and the resulting structuses may resemble LE cells Therefore, rigid cntena should be used for their identification. Special attentson should be oven to the intracellular inclusion body, which 18 structureless, hyaline and homogeneous in appearance Repeated examinations may be necessary in order to obtat a positive test. In one of our cases, 18 studies were performed during two year fenod but only two were positive another patient had 32 negative tests during a prolonged period of active discase before L E cells vere finally demonstrated In this casos, extracellular masses of hyaline thatenal had repeatedly been noted ¢ LE Cells in Other Diseases Isolated cases have been encountered in which LE cells were said to have been found in the absence of other evidences of SLE. Fale positive tests have been reported in one case each of perpicious agerais (23), dermatitis berpeti. formis (23), leukemia (69), miliary tuberculosis (156), candida albicans infection (76), “myeloma (3); acquired hemolytic anemia (156) and glomerulonephritis (192) In the case of acquired hemolytic anemia, it seems not unklely that the heradłytic process was a manifestation of SLE, and the patient with glomerulo- ·374 A. MCGEHEE HARVEY ET AL, Inderbitzin (122) described the production in normal blood of structures resembling L.E. cells by the use of anticoagulants of high molecular weight. The sodium salt of polyvinyl alcohol-polysulfonic acid ester (PVAS-Roche) and several related compounds, after incubation with normal gamma globulin, were said to induce the formation of these cells. Haserick (102) added certain fungi to dog bone marrow and noted the appearance of structures resembling L E cells. Kurnick and his associates (152) were unable to produce the cells by incubating normal leucocytes with bovine desoxyribosenucleic acid. Finch, Ross and Ebaugh (68) produced antiserum against leucocytes On addition of the antiserum to leucocyte preparations, they observed clumping of the white cells, phagocytosis of intact or degenerate cells by other leucocytes, and the formation of structures "indistinguishable from Hargrave's L.E. cell". On examination of their photographs and preparations, we are unable to find structures which we would identify as L.E. cells. Although nucleophagocytosis is apparent, the engulfed nuclei have not undergone the peculiar hyalinization which is characteristic of an L.E. cell. Zimmerman, Walsh and Heller (278) reported experiments similar to those of Finch and his associates. Nucleophagocytosis was prominent in their preparations. Some cells showed homogeneous inclusions and were said to resemble L.E. cells. c. Occurrence The L E. cell test has been reported to be positive in a large proportion of cases . Ant... 1m nar nont LE cell tests were performed in 96 of our cases and were positive in 79, an incidence of 82 per cent. It is impossible to determine the true frequency of positive tests in SLE because there is no method by which the diagnosis can regularly be established with accuracy. In the absence of a positive test, the diagnosis often is not made. More than 50 patients examined at the Johns Hopkins Hospital were suspected of having SLE but were not included in the present series because proof of the diagnosis was lacking In all of these cases, L.E. cell tests were negative, often on repeated study. Nevertheless, many had typical clinical manifestations of SLE, and one patient who subsequently died was proved to have this disease at autopsy. LE cells could not be deraonstrated in 17 of our patients with unequivocal SLE The disease was active in all and some were critically ill. Histologic proof of the diagnosis was available in nine. Three patients had only & single test, but in the others as many as 12 examinations had been performed using heparinized 11.-2nd guinea pig blood, all with the disease is not well correpatients have had remissions lasting several years during which the cells were repeatedly demonstrable in considerable numbers.

·SYSTEMIC LUPUS ERYTHEMATOSUS 375 d Techniques of L E. Test A number of methods have been recommended for clinical use in the detection of L E. cells Examination of the buffy coat of heparinized bone marrow has been largely supplanted by use of peripheral blood Buffy coat smears prepared from heparinized blood after incubation in vitro have been very satisfactory. Several investigators have preferred to examine buffy coat smears from defibrinated (66, 166) or clotted blood (85, 155, 277). It has been claimed by some (87, 155, 166, 277) and denied by others (57) that techniques employing clotted blood are more sensitive than those in wbich an anticoagulant is used Hargraves (96) believed that platelets or their degradation products might augment LE cell formation. However, two of our patients with severe thrombocytopenis were repeatedly found to have L.E cells in buffy coat preparations. Splenectomy in one case was followed by a tremendous rise in platelet count but was without effect on the number of L.E cells. Even the proponents of the clotted blood technique admit that the preparations tend to be hypocellular, that there is much cellular distortion and that nucleophagocytosis is increased. As a result these preparations are more difficult to interpret than are those of heparinized buffy coat We have never been able to demonstrate L E cells by use of the clotted blood technique when they were not detected using heparnized blood The addition of the patient's plasma or serum to cells obtained from normal blood or marrow is a more cumbersome technique which is of particular value when the patient has pronounced granulocytopenia Animal blood or marrow has been preferred by some investigators (103). Regardless of the technique used in the preparation of the smears, great care is required in their examination Le cells may be overlooked unless a diligent search 18 pursued. Phugocytosis of erythrocytes, of intact white cells, or of cell nuclei 19 often encountered in buffy coat preparations, and the resulting structures may resemble L E cells Therefore, rigid cnteria should be used for their identification. Special attention should be given to the intracellular inclusion body, which 19 structureless, hyaline and homogeneous in appearance Repeated examinations may be necessary in order to obtain a positive test. In one of our cases, 18 studies were performed during a two year period but only two were positive Another patient had 12 negative tests during a prolonged period of active discase before L.E cells were finally demonstrated. In this case, extracellular masses of hyaline material had repeatedly been noted e. L E.Cells in Other Diseases Isolated cases have been encountered in which L.E. cells were said to have been found in the absence of other evidences of SLE False positive tests have An (192). In the case of acquired hemolytic anemia, it seems not unlikely that the hemolytic process was a manifestation of SLE, and the patient with glomerulo- ·376 A. BICGEHEE HARVEY ET AL nephritis had other manifestations suggestive of this disease. Amyloid in the bone marrow may give rise to structures similar to L E. cells (256), and may have been responsible for the apparent false positive test in the case of myelona. Phagocytosed nuclei may resemble these cells and probably account for some false positive results. Walsh and Zimmerman (266) demonstrated L.E. cells in three patients with severe reactions to penicillin At least one of these had had previous manifestations suggestive of SLE, and reactions to drugs are known to be common in this disease. Slocumb (238) reported that L E cells had been found following withdrawal of cortisone in 15 patients thought to have theumatoid arthritis and to whom sufficient hormone had been given to produce "hypercortisonism". There is no mention in this report of the results of L E. tests prior to therapy. In view of the great frequency with which polyarthritis is the presenting manifestation of SLE, the possibility must be considered that these patients had SLE prior to the administration of cortisone. Recently a syndrome resembling SLE, occasionally associated with positive L.E. cell tests, has been described in patients with hypertension after prolonged treatment with hydrazino-phthalazine (60, 182, 196). The nature of this syndrome and its relation to SLE remain to be clarified. In several large surveys, no false positive tests were found among hundreds of patients with diseases other than SLE (57, 103, 156, 165, 167, 223, 245, 248). Uniformly negative results were obtained in periarteritis nodosa, scleroderma, rheumatic fever, various hypersensitivity reactions and many other disorders unrelated to SLE. LE. cell tests have been performed in our laboratory on many hundreds of patients. In every instance in which the cells were found, the patient had a clinical disorder which was compatible with the diagnosis of SLE. The clinical records of more than 700 patients with negative tests were reviewed, and the final diagnoses are shown in Table IX. IX. PLASMA PROTEIN ABNORMALITIES ormalities of the plasma proteins occur with great frequency in SLE. In some cases, protein disturbances have been detected years before clinical evidences of the disease appeared. The mechanism by which these changes are produced and their relationship to pathogenesis remain obscure. However, certain of the clinical manifestations of SLE are attributable specifically to plastna protein alterations. a. Albumin and Globulin Coburn and Moore (43), using the Howe technique, found the albumin fraction low and the globulin high in each of 17 patients. Abnormalities of the albumin-globulin ratio have been encountered frequently by other investigators and were noted in 69 per cent of the cases of Shearn and Pirofsky (234). Twentyeight per cent of Dubois' patients (56) had serum globulin concentrations in excess of 3 8 gm. per 100 ml. Hyperglobulinemia (over 30 gm. per 100 ml.) was present in 42 per cent of 167 cases collected by Jessar and his associates (129).

·TABLE IX Karullo of LE cell tests performed in the hematology laborolonies of the Johns Hopkins Hospital Parrot Nur ber of Cases Exed Norbes Positive 0 4 0 Systequc lupus erythematosus 06 75 Vadiagnosed dieser with cloical sad laboratory Sadings coulpatible with SLE, perisctentis or other cobbective tissue disease Colaneoua lupus erythematosus without systemic manifesta. toar 0 Scleroderma 7 D Naynaud's syndrome 5 0 Periarteritis nodoss and temporal ostentis 9 0 Dermatomyonte 3 Rheumatoid arthritia 136 0 Felty's syndrome 3 Retter'a ayndrome 1 Paliodrome arthritis Gonorrhea: arthritis 3 Gout 2 Osteoartbrits arthritis, type and catae vakrown Nbeurtstic fever 38 Glomerulonephritis 20 Acuta pleuritis and pericarditis 15 Diseaser of the eye secluding useits, episcleritis, retinitis, chororditus 21 Hypersensitive reactions to actibiotice including penicillin, horse serum, gold, blood tranouposa 21 Allerge raatia, asthma, urticarta 11 llenoch-Schönless purpura Dresser of the skya including Acho rosacea, seborrbere derra. titia, erythema multiforme, erythema aodosum, eczemstoid and stopic dermatitia, exfoliative dermatitis, pempbagus. paonans 0 Castrointestinal disorders Lacluding ulcerative colitis, regional catentis, cholecy at1118 10 0 Infections of many types Tacluding tuberculosis, teprosy, ab Acesses, miscellaneous bacterial and viral dwesses 45 Neoplans, malignant and besign 0 Ademana (aplastic, iron debciency, Dergicious, myelapht:1910, hemolytic) 18 Acqusred hemolytic anemia, "dropatbre" 4 Leucopenia, cause unknown & Itemophilus and pseudobemophilia 3 D "Idiopathic" thrombocytopeme purpura 0 Thrombotic thrombocytopenic purpura 0 Leukemia, lymphoma, myeloma, myeloid metaplasia 17 l'enpheral vascular disease 8 0 Endocrise disorders includjog diabetes, byperthyrordum 12 Currbour of the liver 10 Sarcoid 4 0 Amyloidosis Neuromuscular diseases including epilepsy, pentpheral neustio. dexterali distano of usele 13 Psychiatre disorders 26 Feter ol yadetermined args 32 * All of these tests are performed by skilled research technicians who had do kaowledge topcerning the paljent or the chimica) dagooris Negative results were obtaired la kuadrets of other coures of miscellaneous dues > 1 Go ·378 ... MEGEMEE HARVET ET AL. Serum protein fractionations were performed in 105 of our cases and 58 per cent had globulin concentrations over 30 gm. per 100 ml, Values in excess of 4 gm. were not unusual, and in rare instances were 29 high as 8 gm. The concer. tration of albumin in the serum was less than 3.5 gmo. per 100 ml, in approxrmately half of our cases, and in several instances was lower than 20 gra. Pronounced elevation of the plasma fibrinogen concentration was noted in the few cases in which this determination ssas made. Coburn and Moore (43) performed electrophoretic analyses of the serum of two patients and found that the gamma globulin was elevated but alpha and beta fractions frere normal. Electrophoretic studies were also done by Keiner (212) and by Walker and Benditt (261), who found an increase in the alpha-2 globulin fraction in addition to reduced albumin and increased gamma globulin Bille (25) observed that in clinically mild cases the albumin tended to be normal. Electrophoretic analysis of plasma by the Tiselíus technique in several of our cuses showed high gaminas globulin and fibrinogea concentrations. Smith (239), using a filter paper method, studied the serum protein patterns of 15 consecutive cases from our group, Increase of gamma globulin was present in all, and the albumin was moderately reduced in ten. In six patients with httle or no evidence of renal disease the alp 2-2 globulin was elevated, but this fraction was reduced in four patients with nephritis and azotemia. In no case was the beta globulin reduced. The pattern in five cases showed a melding of the gamma and beta spots, simulating the pattern often seen in Laennec's cirrhosis. Qualitative abnormalities of the seruna proteins in SLE are demonstrable by a variety of tests. There 19 no regular association between the L E. factor and any of the other POSITIVE LE CELLS GLOBULIN OVER 3 GRAMS PER (OJ ML POSITIVE CEPHALIN FLOCCULATION tive CHART I Relationship between hyperg! cephalin-cholesterol flocculation in 76 cases tive results ssd would, therefore, be represi itive L E. cell te o cases all three isang outade all ·SYSTEBIIC LUPUS ERYTHEMATOSUS 379 protein abnormalities The relationship between this factor, the total serum globulin and the cephabn flocculation test in 75 of our cases is shown in Chart 2. b. Sedimentation Rate Elevation of the erythrocyte sedimentation rate has occurred with great frequency in all of the series of cases in which the results of this test were recorded. Jessar and his associates (129) found an increase in 89 per cent of 245 cases The rapid sedimentation is undoubtedly attrbutable to the tendency of the red cells to clump, a phenomenon believed to depend on abnormalities of serum globulin together with an increase in fibrinogen The sedimentation rate was determined by the method of Wintrobe in all of our cases, in most on repeated occasions. Very rapid sedimentation was the rule. The value at one hour was often limited by the packang of the red cells and was, thus, largely a function of the hematocrit value Increase in sedimentation was usually observed even though the disease was clinically quiescent However, in eight cases normal rates were observed during periods of active disease. In five of these eight cases the serum globulin was below 30 gm. per 100 ml Most of the patients who had normal rates had positive L E cell and cephalin focculation tests c. Other Abnormalities The serum of patients with SLE often gives positive cephalin flocculation and thymol turbidity tests, presumably another evidence of serum protein abnormality. Three-quarters of the patients examined by Jessar (129) had positive cephalın flocculation tests These tests were performed on at least one occasion in 82 of our cases Cephalın flocculation was present in 67 cases There was, in general, good correlation between the results of the two tests Positive tests were often obtained during asymptomatic intervals Red cell auto-agglutination and the positive Coombs' test sometimes encountered in SLE are attributed to an abnormal serum protein which has the properties of an auto-antibody The circulating anticoagulant demonstrable in the plasma in rare cases of this disease is also thought to be an abnormal protein Cryoglobulina were demonstrated in the plasma of three of six patients with SLE studied by Barr and his associates (15) The significance of these coldprecipitable proteins is unknown In several of our cases in which hypersensitivity to cold was manifested by Raynaud's phenomenon, cryoglobulins were not detectable The complement activity of serum is often reduced in SLE Vaughan, Bayles and Favour (262) observed that the degree of depression was roughly correlated with activity of the disease They believed that an apparently reciprocal relationship of complement activity to gamma globulin levels may reflect immune phenomena of importance, and point out that depression of complement activity occurs at the height of antigen-antibody reactions. Elliott and Mathieson (61) macasured coroplement activity in 27 cases of SLE and attempted to correlate the level with other serum protein changes Decreased activity of complement was found in the majority and 1789 associated with albuminuna, decreased serum ·378 MCGEREE HARVEY ET AL Serum protein fractionations were performed in 105 of our cases and 58 per cent had globulin concentrations over 3.0 gm. per 100 ml. Values in excess of 4 gtu. were not unusual, and in care instances were as high as 8 gm. The concentration of albumin in the serum was less than 3.5 gm. per 100 ml. in approtmately half of our cases, and in several instances was lower than 20 gr. Pronounced elevatioa of the plaszna fibrinogen concentration was noted in the few cases in which this determination was made. Coburn and Moore (43) performed electrophoretic analyses of the serum of two patients and found that the gatama globulin was elevated but alpha and beta fractions were normal. Electrophoretic studies were also done by Neiner (212) and by Walker and Benditt (261), who found an increase in the alpha-2 globulin fraction in addition to reduced albumin and increased gamma globulin. Bile (25) observed that in clinically mild cases the albumin tended to be norsual Electrophoretic analysis of plasma by the Tiselius technique in several of our cases showed high gamina globulin and fibrinogen concentrations. Smith (239), using a filter paper method, studied the serum protein patterns of 15 consecutive cases from our group. Increase of gamma globulin was prescat in all, and the albumin was moderately reduced in ten. In six patients with little or no evidence of renal disease the alpha-2 globulin was elevated, but this fraction was reduced in four patients with nephritis and azotemia. In no case was the beta globulin reduced. The pattera in five cases showed & melding of the gamma and beta spots, simulating the pattern often seen in Laennec's cirrhosis. Qualitative aboormalities of the seruna proteins in SLE are demonstrable by & variety of tests There is no regular association between the L.E. factor and any of the other POSITIVE LE CELLS GLOBULIN OVER 3 GAAMS PER JOOML POSITIVE CEPHALIN FLOCCULATION CRART 2 Relationship betfreea hyperglobulinemis, positive L E cell tests, and positive cephalid-cbolesterol focculation in 76 cases of SLE. In tro Caleg a1) ibree tests gavo nega. tive reeults tod would, therefore, be represented by dota lyng outside all of the circles ·SYSTEMIC LUPOS EAYTHESISTOSOS 379 protein abnorzaghties. The relationship between this factor, the total serum globulin and the cepšalia fiocculation test in 75 of our casts is shown in Chart ? b. Sedimentation Rate Elevation of the erythrocyte sedimentation rate has occurred with great {requency in all of the senes of cases in which the results of this test were recorded Jessar and bis associates (129) found an iscrease in 89 per cent of 245 cases. The rapid sedimentation is undoubtedly attabutable to the tendency of the red cells to clump, a phenomenon believed to depend on abnormalities of serum globulin together wih an increase in "Sibrinogen. The sedimentation rate was determined by the method of Wiatrobe in all of our case, in most ou tepeated occasions Very rapid sedimentation was the rule. The value at one hour was often limited by the packag of the red cells and was, thus, fargely a function of the keraatocnt value. Increase in sedimentation was usually observed even though the disease was clinically quiescent However, in eight cases normal rates were observed during periods of active disease. In five of these cight cases the serum globulin as below 30 g per 100 ml Most of the patients who had normal rates had positive LE cell and cephala flocculation tests c Other Abnormalitres The serum of patients with SLE often gives positive cephalin flocculation and thymol turbality tests, presumably another evidence of serum protein abnormality Three-quarters of the patients examined by Jossar (129) had positive cephalın flocculation tests These tests perc performed on at least one Occasion in 82 of our cases Cephalı focculation was present in 67 cases There was, in general, good correlation between the results of the tra tests Pasitire tests were often obtained durog asyraptomatie intervals. Red cell auto-agglutinatoa and the possive Coombs' test sometimes encomtered u SLE are attributed to an abnortaal berura protein which has the properties of an autoantibody The circulating anticoagulant demonstrable in the plasma u rare cases of this disease is also thought to be an abnormal protein Cryoglobulins were demonstrated in the plasma of three of six patients with SLE studied by Barr and his associates (15) Thc signuficance of these cold. precipitable proteins is unknown In several of our cases it mbich hypersensitivity to cold was manifested by Raynaud's phenomenon, cryoglobulins were not detectable The complement activity of serum is often reduced in SLE Vaughan, Bayles and Favour (262) observed that the degree of depression was roughly correlated with activity of the disease They belesed that an apparently reciprocal relationship of complement activity to gamina globulin level may reflect itamune phenomena of importance, and point out that depression of complement Activity occurs at the height of antigen-antibody reactions. Elliott and dfathieson (68) mesured complement activity in 27 cases of SLE and attempted to correlate the level with other serum protein changes. Decreased activity of complement was found in the majority and war associated with albuminuria, decreund serum ·378 A, MCGEHEE HARVEY ET AL. Serum protein fractionations were performed in 105 of our cases and 58 per cent had globulin concentrations over 30 gm per 100 ml. Values in excess of 4 gm. were not unusual, and in rare instances were as high as 8 gm. The concentration of albumin in the serum was less than 35 gm. per 100 ml. in approximately half of our cases, and in several instances was lower than 20 gm. Pronounced elevation of the plasma fibrinogen concentration was noted in the few cases in which this determination was made Coburn and Moore (43) performed electrophoretic analyses of the serum of two patients and found that the gamma globulin was elevated but alpha and beta fractions were normal Electrophoretic studies were also done by Reiner (212) and by Walker and Benditt (264), who found an increase in the alpha-2 globulin fraction in addition to reduced albumin and increased gamma globulin. Bille (25) observed that in clinically mild cases the albumin tended to be normal. Electrophoretic analysis of plasma by the Tiselius technique in several of our cases showed high gamma globulin and fibrinogen concentrations Smith (239), using a filter paper method, studied the serum protein patterns of 15 consecutive cases from our group. Increase of gamma globulin was present in all, and the albumin was moderately reduced in ten. In six patients with little or no evidence of renal disease the alpha-2 globulin was elevated, but this fraction was reduced in four patients with nephritis and azotemia. In no case was the beta globulin reduced The pattern in five cases showed a melding of the gamma and beta spots, simulating the pattern often seen in Laennec's cirrhosis. Qualitative abnormalities of the serum proteins in SLE are demonstrable by a variety of tests. There is no regular association between the L E factor and any of the other POSITIVE LE CELLS GLOBULIN OVER 3 GRAMS PER 100 ML. POSITIVE CEPHALIN FLOCCULATION att cell trets, and positive sts gape aega. the circles ·SYSTESSIC LYFUS EITTRESLATOSUS 379 protein abnormalities. The relationship between thus factor, the total serum globulin and the cephalin flocculation test in 75 of our cases is shown in Chart 2. b. Sedimentation Rate Elevation of the erythroeyte sedimentation rate has occurred with great Frequency in all of the series of cases in which the results of this test were recorded. Jessar and his associates (129) found an increase in 89 per cent of 245 cases The rapid sedimentation is undoubtedly attributable to the tendency of the red cells to clump, a phenomenon believed to depend on abnormalities of scrum globulin together with an increase in fibrinogen The sodimentation rate was determused by the method of Wiatrobe in all of our cases, in most on repeated oxcasione. Very rapid sedimentation was the rule. The value at one hour was often limited by the packing of the red cells and was, thus, krgely a function of the bematocrit value Increase in sedusentation was usually obserred even though the disease was clinically quiescent Horever, in eight casos normal rates were observed during periods of active disease la five of these eight cases the serum globulia was below 30 gra per 100 ml Most of the patients who had normal rates had positive L E. cell and cephalin flocculation tests ¢ Other Abnormalities The serum of patients with SLE often gives positive cephalın flocculation and thymol turbidity tests, presumably another evidence of serum protein abnormalty. Three-quarters of the patients examined by Jessar (129) had positive cephalia Rocculation tests These tests were performed og at least one Occasion in 82 of our cases Cephalk flocculation was present in 67 cases There was, in general, good correlation between the results of the two tests Positive tests were often obtained during asymptomatic intervals Red cell auto-agglutination and the positive Coombs' test sometimes encountered 2 SLE are attributed to an abnormal serum proten shich has the properties of an auto-antibody The circulating anticoagulant demonstrable in the plasma in rare cases of this disease is also thought to be an abnormal protein Cryoglobulins were deraonstrated in the plasma of three of sus patients with SLE studied by Barr and bus associates (15) The aigzuficance of these coldprecipitsble prolours is unknown It several of our cases ia shuch dyperscasitivity to cold was memuested by Ragnsud's phenomenon, cryoglobulins were not detectable The complement activity of serum is often reduced in SLE Vaughan, Bayias and Favour (202) observed that the degree of depresion tras roughly correlated with activity of the disease They believed that an apparently reciprocal relationship of complement activity to samma globulin levels may reflect immune phenomena of importance, and point out that depression of complement activity occurs at the height of antigen-antibody reactions Elliott and Mathiesoo (61) mesured coroplement activity in 27 cases of SLE and attempted to correlate the level with other scrum protein changes Lecreased activity of complement was found in the majority and w&S Associated mth albuminuns, decreaand serum ·380 A. MICGEHEE HARVEY ET AL albumin, increased sedimentation rate, positive or anticomplementary results of complement fixation tests for syphilis, leucopenia and positive L.E. cell tests. Normal values for serum complement were noted in patients with SLE without these associated manifestations. The serum complement activity was pot correlated with the concentration of total globulin in serum or with the results ta......: ceut me result was positive and doubtful in another 11 per cent. In their opinion, this test has no prognostic significance. Ross and Wells (223) found positive agglutinations in four of seven patients with SLE, but the titers were usually lower than in patients with rheumatoid arthritis. Schleicher (227) has reported a test for "erythrocyte aggregation factor" in the serum of patients with this disease, but others (70) have not found it to be specific or of diagnostic value. SLE is characterizard ha otrilpine hon--:- 1 constitutes about 40 per cent of each of these mucopolysaccharides and buman serum contains definite amounts of bound hexosamine as glucose and galactosamine. Boas and Soffer (27) studied the serum levels of hexosamine in 19 patients with SLE and found that it was increased above the normal range of 85 to 138 mg.% in 17. In 11 patients the levels fell during treatment with ACTH or cortisone, but as the dosage was reduced rose again. The initial fall appeared in from three to seven days. Elevation of hexosamine levels may also be found in other disorders such as leukemia, carcinomatosis, rheumatic fever, periarteritis nodosa, and various chronic infections (28). It may also rise in certain acute illnesses such as pneumonia, myocardial infarction and after trauma. These authors state that at present they cannot interpret their results as relatively little is known of the source, metabolism, and fate of hexosamines or mucoproteins. They are probably related to the depots of mucopolysaccharides throughout the body such as in cartilage, ground substance, blood vessels, and skin. X, CHRONIC BIOLOGIC FALSE POSITIVE SEROLOGIC TESTS FOR SYPHILIS a. Incidence in SLE The occurrence of positive serologic tests for syphilis (STS) in SLE is as observation which led early workers to relate the two diseases etiologically (259). It was soon recognized that these were for the most part biologic false positive (BFP) reactions (77). Coburn and Moore (43) found positive or anticomplementary Wassermann tests in 11 of 30 cases. They stressed the presence of elevated gamma globulin and showed by electrophoretic separations that the substance responsible for positive serologic tests was chiefly in this protein fraction. Many other authors have reported on the incidence of false positive reactions (56, 129, 140, 176, 234). Rein and Kostant (211) examined serum ·SYSTEMIC LUPUS ERITIEBLATOSTS 391 from 178 patients with various types of lupus erythematosus, subjecting each specimen to a battery of six serologic tests Syphilis had been ruled out 29 (ar es possible by history and physical examination. A tugh percentage of positive results was obtained even in patients mth localized discoid lupus. Zellman (270) studied the incidence of seropositivity in SLE and reviewed some of the pertinent Literature. Of 83 cases from the Johns Hopkins Hospital reported by him, 18 per cent were seropositive with standard serologic tests with lipid antigens Of these, one patient was considered to have syphilis, the remaining 14 being possible BFP reactors. The incidence of seropositivity reported by ather workers in SLE range from 0 to 44 per cent As Zellman properly emphasized, however, beither his orn cases nor any series recorded in the literature could be regarded as accurately representing the incidence of the BFP phenomenon in SLE, ence the frequency of occurrence of syphilis in these cases was not determined with certainty Tho Treponemal Immobilization (TPI) Test, devised by Nelson and Mayer (186), is based on the discovery that in syphílıtıc afection two distinct antihodies appear in the scrum: ()) reagin, which reacts with lipid antigens, and (2) an antibody which wmobilazes and kills living T pallidum The TPI Test 29 highly specific for syphilis (snd other treponematoses), and the immobrlızıng antibody doce not occur in the serum in the absence of treponemal infection. In untreated ayphilla tho TPI Test is approximately 100 per cent positive by the time of and at any time after the secondary outbreak. In trcated early syphilis the TPI antibody may permanently disappear, though at a slower rate and in fewer cases than does reagin. In treated late syphults, on the cantrary, the TPI antibody persists indefinitely and probably for life in at least 07 per cent of cases. These facto make the TPI Test of the utmost importance in the recognition of the BFP phenomenon, Moore and Alohr (179) point out that BFP cactors are divisible isto to groups, which they have designated as acute and chronic. The acute reactions characteristically occur during or immediately following a heterogeneous group af bacterial, viral, plasmodral, or nickettsial mfections, and reagin or a reagun- Uke substance spontancouzly disappears from the scrum mthin a period usually not erceeding six months. In the chrone BFP reactors, on the contrary, there 19 20 ideathable precedent scute infection; 22d reagin persists indefinitely, probably for a life time. The BFP reaction in SLE 2s of the chronic varety. In SLE, a positive STS may represent either the chronic BFF phenomenon or concomitant syphilitic infection The incidence of the BFP phenomenon, in series of patients with SLE scrologically examined eimultancourly with standard and Trt tests, may be étpected to vary with three factors: the sensitivity and multiplicity ("battery testing of the standard krologic techniques employed, the population group, racial and socioeconomic, from which the patients are drown; and, perhaps, the stairs of SLE at which the serologic tests are made. Standard serologic tests for syphilig were performed in all of our 138 cc ·382 A. AGEUEE HARVEY ET AL and positive results were obtained on at least one occasion in 38. TPI Tests were carried out in 20 of these 38 cases. The test was not utilized in any STS Degative patient; and STS negatire-TPI positive concomitant syphilitic infec. tions may, therefore, have been missed. The TPI Test was positive in seven patients, who thus had both SLE and syphilis. All seven of these patients were Negroes, Negative results were obtained in 13, who were, therefore, chronic BFP reactors. Thus, in the verified SLE patients of our scries the incidence of the BFP phenomenou tras about 20 per cent. It has been pointed out (110) that the discovery of the chronic BFP phenomenon may precede any clinical manifestation of SLE by a number of years. This was observed in several of our cases. d. The Etrologic Background of the Chronic BFP Phenomenon Pertinent to these observations and proceeding in parallel with this analysis of the clinical features of SLE, is & study of the etiologic background of the chronic BFP phenomenon by Moore and his associates. The discussion which follows is based on a brief preliminary report (180) and on unpublished information (178). The sole criterion of admission of a patient to this study is his identification as a chronic BFP reactor by means of the TPI Test. About 160 such patients have been so identified, 110 of whom have been carefully studied with long term clinical observations and frequently repeated laboratory tests. 1. Incidence and clinical diagnoses. As to the incidence of the chronic BFP phenomenon these workers have shown that about 40 per cent of white persons of the upper socioeconomic and educational level who are routinely discovered to have a positive STS, in the absence of any history or physical evidence of syphilis and of reasonable opportunity for infection, do not have syphilis and are BFP reactors In the 110 patients so far analyzed, all are white, 70 per cent females; and the majority in the age group 15 to 35 years. The circumstances that led to discovery of the original positive STS was routine testing of healthy individuals in 62 per cent Esghty-seves of the identified chronic BFP reactors in this series have been observed for 3 to 20 years. Of these, the present clinical diagnoses are (a) Six patients have SLE, all verified by the demonstration of L.E. cells Only one of these was clinically recognizable at the time of first discovery of the chronic BFP phenomenon. The remaining five have developed clinical evidences of SLE while under study because of the BFP reaction. (b) Sux patients have rheumatoid arthritis. In two of these (one an 8 year old girl with Still's disease) the arthritis was present at the time of first discovery of the BFP reaction; in the remaining four, arthritis has developed dunog Bubscquent observation. (c) Fifteen bad multiple episodes of illness which conform to the clinical pattern of relatively mild and chronic SLE, but in rhom the diagnosis has not been verified by tbe finding of L.E cells. Each of these patients has had at ·SYSTESSJC LUPUS ESYTUEMATOSUS 353 5 cases least two and usually several of the 17 manifestations to be listed below; and the 15 patienta bave bad a total of 58 of these symptoms and/or signs: 8 cases Fever, unexplained, usually prolonged and low grade Artbntis and/or significant arthralgia, usually of the hands 8 cases cod fingers 5 cases Splenomegaly 5 cases Serositas (pleuntus or pericarditis) 5 cases Cutaneous lesions (usually discoid LE) Ocular lesions (usually chorioretinal) 3 cases Raynaud's phenomenon 3 cases Malaise (noteworthy and prolonged) 3 cases Phlebothrombosis of major vessels, without obvious cause 3 cases Psychoses 2 cases Photosensitivity 2 cases Vucosal lesions 2 cuses Chores 1 08.50 Thrombocytopenic purpura 1 case Hematuris 1 CBSC Convulsans } casc Nephritis (this patient died) (d) Twenty-two patients have had 55 episodes of illness in kich the same group of symptoms and/or ngns as those listed above, plus one or two additional ones which may occur in SLE This diagnosis is less convincingly sug. gested than in the preceding group, primarily because toultiple episodes were less frequent; sad ma nono of the 22 kave L.E cells been found as yet The manifestations are, in order of frequency 16 cases Arthritis and/or arthralgia 30 cases Fever, unexplained 10 cases Malaise, agruficant & cases Mucocutaneous lesions, bizarse Purpura (not thrombocytopenie) Convulsions 3 cases Psychoses 2 TASC$ Ocular lesions 1 case Nodules I case Paroxysmal auricular tachycardia Hepatomegaly (e) One patient has Gaucher's disease, with a later superimposed autoimamune hemolytic anemia thought possibly to be due to SLE (not verified). (1) Fre patients have bizarre undiagnosed serious illn cases. (g) Thirty-two patients are so far clinically normal 2. Laboratory data Frota the laboratory point of view, these chronic BFT Fractors frequently sbor hematologic changes and diarders of gamma globulin which are fremse commonly present in SLE. 3 cases 3 cases I CASC ·386 A MCGEHEE HARVEY ET AL. any of the others Anorexia, weight loss, malaise, and fever were commonly present. While fever was usual, several patients with active lupus were afebrile for many weeks. The development of an infection seemed to serve in several instances as the trigger for enhancement of activity and more rapid progress of SLE. Some patients with latent or chronic SLE were observed to enter a critical phase of activity soon after the acquisition of an infection. c. The Effect of Pregnancy In the instances which have been reported pregnancy has had a variable influence on the course of SLE ELis and Bereston (65) gathered information from their dermatological colleagues concerning the effect of pregnancy on the disease and of the disease on pregnancy. In a number of instances activity of the SLE increased or the mother died, but in many others no change occurred. Spontaneous abortion occasionally resulted. When chronic discoid lesions were the only manifestations there was seldom any change during pregnancy. In our series pregnancy occurred once in six and twice in five other patients In several instances there was no definite effect of the pregnancy on the course of the disease. In four cases, the initial manifestations developed during the gestation period. Two patients had phlebitis accompanied by fever and malaise soon after delivery, and subsequently developed typical manifestations of SLE. Another, while six months pregnant, had an episode of migratory polyarthritis for the first time. Improvement followed delivery. Two years later she again became pregnant and the joint pains recurred. Once again there was improvement following delivery, but shortly thereafter other manifestations of SLE ---years developed zancy, she began ing delivery she became free of symptoms, and was well for a period of 16 years. Three weeks prior to admission she became acutely ill with a chill, fever, myositis, polyarthritis, pneumonitis and a cutaneous eruption. L E. cells were found in the peripheral bloo Excessive post-partum bleeding led to investigations which established the diagnosis of SLE in one patient. She was a 27-year old Negro female who bled excessively following a tonsillectomy in 1946 In 1919 and again in 1950 there was post-partum hemorrhage requiring transfusions Following the second occurrence, it was discovered that she had a prolonged clotting time, hyperglobulinemia, moderate thrombocytopenia and a positive L.E. cell test. One patient has been observed during two pregnancies and in both experienced a complete remission, with disappearance of L E. cells from the blood Within four weeks after delivery, there was recurrence of symptoms. Two patients had a therapeutic abortion performed during the course of active SLE. In one instance this procedure tras followed by an acute exacerbation of the underlying disease. In the other the course of the illness was not affected. Spontaneous abortion occurred only once ·SYSTEIO LUPTS ENITHEY ATOSUS 387 d. The Cause of Denik Although it is difficult + *A8 made to det patents 10 whom an autopsy wulsy true in an illness such. As SLE in which one - vlgan systems may be involved, and in which the extent of the pathological alterations is hard to evaluate quantitatively These 38 patients could be divided into two groups: those in whom death appeared attnbutable to progression of the basic disease and those in whom factors other than SLE appeared to be the cause Twenty-ttro patients were placed in the first group and 16 in the second. Group I. All of these patients died during an Acute exacerbation of SLE, and during their course showed progressive involvement of one or more organ systems. In five the episode which led to death ras precipitated by a drug reaction, in two due to para-aminobenzosc acid and one each to eulfonamide, gold, and streptocoecal vaccine In another five it scemed clear that death was attnbutable to fulminating SLE; but surprisingly httle structural change was found at autopsy, and it was imposible to ascribe death to dysfunction of any particular organ It was, in the words of the pathologist, “as if they had died & "chemical deatli", leaving bebind no structural clues as to its nature" Three patients died with pulmonary insufficiency, due to typical "lupis pseumonitis" In onc of these profusc diarrhea and hemorrhage, resulting from arteritis of the intestinal wall with secondary ulceracion, was e contributing factor One patient died with & massive cerebral hemoorthage when a small eneurysm Associated with lupus ertentis ruptured A second became comatose following repeated convulsive seizures and died She also developed multiplo intestual ulcerations with bloody diarrhea Nine paticnta died with severe impairment of renal function, but is several there were contnbutiog factor In addition to extensive kidney damage, one patient also had alterations of SLE in the brain and lungs Another had obstructive jaundice, generalized blecdmg and a terminal E cola bacteremis. The third developed subacute bacteral endocarditis on e vele sbowing the changes described by Libman and Sachs A fourth espirated a large amount of romutus during a convulsive sciture and went into prolound shock with the subsequent development of acute renal tubular necrosis A fifth nes unexpectedly found to have miliary tuberculosie 19 addition to profound kidney disease caused by SLE A sixth of interest because a sesere renal infection res co-existent with cttonsive alterations in the kidneys due to SLE The final one tad a severe hemolytic anemus complicated by acute renal tubular necrosis In two patients a severe hemorrhagic tendency, in one syth thrombocyto penis, was considered an important factor in causng death The final case in this group has found to have artenoselerotic heart disease and died with a pulmonary embolus In addition to the other complicalug features already outlined, five patients had a terminal bacterial lobular pneumonia ·388 A MCGEHEE HARVEY ET AL. Group II. The cause of death in the second group was in every instance but one considered to be an infection. This exception was an individual who died in uremia, due to renal arterio- and arteriolosclerosis, the evidence of involvement of the kidneys by SLE being negligible The frequent occurrence of severe, oftentimes fatal, infection in patients with SLE should be emphasized. Five members of this group had extensive tu. berculosis, in two instances with miliary spread, and in two complicated by the development of pneumococcal lobar pneumonia and purulent pericarditis Only one of these five received treatment with ACTH. Two patients had pulmonary abscesses, in one instance due to a pneumococcus, and in the other due to Pseudomonas aeruginosa. The latter was accompanied by a fulminant septicemia with focal areas of necrosis scattered throughout the body. A third patient bad a huge tubo-ovarian abscess with peritonitis and a beta hemolytic streptococcal bacteremia An acute exacerbation of SLE, terminated by the development of type IV pneumococcal pneumonia with an overwhelming bacteremia, was the cause of death in one. Two patients had widespread urinary tract infection with multople renal abscesses and E. coli bacteremia Another developed a Salmonella bacteremia originating from aspiration pneumonia One succumbed to a beta hemolytic streptococcal bacteremia following an acute pharyngitis One patient with extensive renal lesions due to SLE, died of a staphylococcal bacteremia with multiple abscesses in the heart muscle, purulent pericarditis, and abscesses in the brain and kidneys. The final patient in this group died of Torula meningitis XII. THE TREATMENT OF SLE a Introduction Although this discussion will be primarily concerned with more specific forms of treatment, it is important to emphasize that many general measures are in the mounamamont of patients with SLE. The control of pain algesics, the treatment of complicating the use of local applications to reduce the discomfort from cutaneous lesions, transfusions for the correction of anemia, and digitalis and salt restriction in the event of heart failure are examples of numerous therapeutic procedures which should be utilized when indicated. It is our impression that limitation of activity during the active phase of this disease is desirable Undue exposure to the sun is to be avoided, and drugs should not be administered unless definitely needed, in view of the tendency for individuals with SLE to develop allergic reactions. In view of the protean nature of the clinical manifestations of SLE and the tendency to spontaneous remission, it is difficult to evaluate the effect of treatment A wide variety of therapeutic agents have been tried. These include salicylates (254), tuberculin (38), gold (16, 195), bismuth (191, 232), arsenic (84), heliotherapy (9, 113), sulfonamides (201, 268), penicillin (181, 247), streptomycin (88, 207), aureomycin (29), chloramphenicol (132), para-aminobenzoic acid (274, 275), nitrogen mustard (58, 200, 219), anti-malarials (47, 86, 142, 191, 226, 213, 269) and vitamin B12 (85) With the possible exception of ·SYSTEMIC LOPUS ERYTUSULATOSTS 399 the satscylates and certain anti-malarial compounds none of these has been demonstrated to have an important beneficial effect. 0. Hormone Therapy Shortly after Reach and his associates (116) described the effect of cortisone in rheumatoid arthritis, ACTII and cortisone were administered to patients with SLE. Strikiog clinical improvement was described (63, 89, 100, 252). In most of these early reports treatment is given for brief periods of time, and dosage schedules varied greatly is most instances relapse occurred on dis continuation of therapy, but in some patients the disease remained quiescent for many months Later, results in larger groups were reported Seven patients, treated by Brunstiag and co-workers (33), were given 200 to 300 mg of cortisone for a few days and then 100 mg daily. The agas of acute disease were promptly relieved, but relapge occurred when the dose was reduced Soffer, Levitt and Baehr (212) reported on 14 critically ill patients, suren mitsally 150 to 200 mg. of cortisone or 100 to 150 units of ACTH daily Subsidence of fever, “oucity" and joint pain occurred more rapidly with ACTII (12 to 18 hours) than with cortisone (two to sourdays). Relapse, which pecurred in all, appesred soaker upon cessation of ACTI administration (within 24 hours) than after cortisone (five to six days). Leucopena, thrombocytopenis, abnormal urinary findings and LE. celle perusted during treatment, suggesting to the authors that the primary ducasc process was unaltered They stated that the prompt relapses indicated the necessity for prolonged treatment Suilar findings were reported by Irons and his collcagucs (123). Hascrick, Corcoran and Dustan (107) concluded that is desperately all patients, designated as in "acute lupus crisis", massive doses of cortisons were indicated The treatment consisted of 50 to 100 mg at one to txo-lourly intervals satii a response was obtamed One patient recessed 2300 mg. over a 24-hour pero The most comprehensive reports are those of Dubois (59), Soffer and Bader (210), and most recently, Soffer, Exster and lammerman (241) Certain of their results will be considered subsequently. Shcar and Purafsky (231) reported beneficial effects a 14 of 20 patients treated sith these hormone, Four died during therapy and two others with severe renal impairincnt succumbed shortly after treatment was d19continued. Our preliminary results with corticotropin and cortisone over a 12-month period beginning June, 1049 have been descnbel (39). Some patients after single Courses of treatment of 14 to 59 days duration entered periods of reason Lasting several months Duning the past three years a mider experence has been Kined. Sitty-two of our patients have received ACTII or cortisone In most instance the usuardiate responso luss berti sisfactory when adequatc doses nere adinastered However, cascs dufficult to control symptomatically even with intensive treatment have ben encountered, and a number of patients hare required conunustion of tralment over long xriddle of the 62 patients trate 18 hane dio ·390 & VEGEKEE HARVET ET AL. Among the 62 treated patients in our series, the youngest was 13 years; the oldest, 71. Sıx were adolescents (13 to 19 years) and six were 60 or more years old. The average age among the males (43 years) was slightly higher than that among the feraales (38 years). These patients had had the disease for Periods rangiog from one month to 26 years. Forty-sit had been ill for at least one year and 26 for at least four, The clinical diagnosis of SLE was reinforced in 53 of the 62 patients by the demonstration of L.E. cells and in some instances by biopsy, This analysis covers the penod from June 9, 1949, when the first patient was treated, to August 1, 1953. More patients were started on treatment during the first two years of the study (38 patients) than during the last two years (24 patients). The average period of observation in all patients, both living and dead, Was 20 months; in the 49 who have survived, 25 months. The patients with fever were carefully screened for the presence of an infection before treatment was begun. Since the correct diagnosis had not been made, the majority of patients had previously received a wide variety of therapeutic TABLE XI Clinical and laboratory manifestations of systemisc lupus erythematosu* ex 69 pahends of the #tart of ACTU of cortisone therapy Mapsfeststian Patients 50 6 34 32 Fever Maleise Arthritis Muco-cutaneous Lymph gland enlargement Pericarditis and/or myocarditis Pleuritis and/or pseumonitis Hepatomegaly Gastro-intestinal Retina) cytard bodies Bplenomegaly Ademus (less than 40% bemutoent) Leucopenía (less than 5000 per mom') Eosinopenis (less than 100 per tam Elevated Bedrmentation rate (15 mm per kr or bigher) LE cells Regal &boarmalities Protetoria Hematuria Cylindruria Azotemia (NPN greater than 39 tag %) Hypoalbuminemis (less than 30 mm) Hyperglobulssemus (30 m or hugber) Positive cepbala-cholesterol docculation Thymol turbidity (grester than 35 units) Brotaullslein retention (greater than 10 mg % in 30 min) Brological frise poustive STS 28 23 18 8 19 34 38 (of 60) 57 46 (or 53) 28 25 17 13 > {of 58) 39 (of 68) 42 fot 52) 30 (of 51) 8 (o? 18) 8 ·SYSTEMIC LUPUS ERYTHEMATOSUS 391 measures Thirty had been given penicillin; 26, one or more of the sulfonamides; 18, one or more courses of gold; and an equal number, sslicylates. Smaller numbers had received bismuth, mapharsen, streptomycin, aureomycin, chloro mycetin, terramycin or hydroxy-phenyl-cinchoninic acid. With the exception of the salicylates, these agents were of no benefit, The clinical and laboratory findings in our patients at the time treatment was begun are presented in Table XI 1. Type of treatment. For a number of reasons there has been considerable variation in the treatment schedules of ACTH or cortisone administered. With reference to ACTH, the response to a given dose was not uniform, and the amount that could be safely administered was at times limited by such complications as renal or cardiac disease Early in the study, the dosage schedules were often limited by the available supply. There were frequent changes in the preparations available, purity of compounds, and preferred routes of administration We were seeking the optimal treatment program, and schedules were frequently changed by impressions gained from accumulated experience. The type of hormone, dosage, route of administration, and duration of treatment were determined for each individual by the severity of illness, the physiological functions disturbed, and the patient's response to treatment. Certain general rules have been applied The patients were in most instances started on dosage levels as follows: 80 to 120 units of lyophylized ACTH intramuscularly daily in four divided doses, 20 to 40 units of the sime material intravenously in 5 per cent glucose solution by slow drip over a trrelve hour period daily; or 40 to 60 units of highly purified ACTII in gelatin intramuscularly daily in two equal doscs. The initial darly dose of cortisone was in most patients 200 to 300 mg, either intramuscularly (once daily or every 12 hours) or orally in four or six divided doses (Table XII). Each patient was continued on the initial regimen for several days. If there was no beneficial response, the dose was raised in a stepwise manner until a favorable effect was obtained or indications of overdosage appeared. The amount on which clear-cut evidence of improvement appeared was continued until the major signs and symptoms were suppressed to the maximum degree The dose was then reduced in a stepwise manner; that is, by 10 to 20 units ACTII daily TABLE XII Initial datly dosc, duralton of treatment and total dose of ACTII and corleone administered to 69 polsents with SLE Ialtia! Daily Dose Duntos (day) Tout Dove Scoalest Largest Shortat Longer! Splast Largest 140 32 units 20 6 8 313 units 300 3.490 1000 49 ACTI-intramuscular ACTI-intravenous Ilchly-punked ACTI-intra muscular Cortisont-intramuscular Cortisone-on 23 25 g 100 100 400 744 2 3 39 300 DE 4115 ·390 A. MCGEHEE HARVEY ET AL Among the 62 treated patients in our series, the youngest was 13 years, the oldest, 71. Sıx were adolescents (13 to 19 years) and six were 60 or more years old. The average age among the males (43 years) was slightly higher than that among the females (38 years). These patients had had the disease for periods ranging from one month to 26 years Forty-six had been ill for at least one year and 26 for at least four. The clinical diagnosis of SLE was reinforced in 53 of the 62 patients by the demonstration of L.E cells and in some instances by biopsy. This analysis covers the period from June 9, 1919, when the first patient was treated, to August 1, 1953. More patients were started on treatment during the first two years of the study (38 patients) than during the last two years (24 patients). The average period of observation in all patients, both living and dead, was 20 months; in the 49 who have survived, 25 months. The patients with fever were carefully screened for the presence of an infection before treatment was begun Since the correct diagnosis had not been made, the majority of patients had previously received a wide variety of therapeutic TABLE XI Clinical and laboratory manifestations of systemic lupus erythematosus in 68 patients at the start of ACTH or cortisone therapy Banifestation Patients Fever Malaise Arthritis Muco-cutaneous Lymph gland enlargement Pericarditis and/or myocarditis Pleuritis and/or pneumonitis Hepatomegaly Gastro-intestinal Retinal cytoid bodies Splenomegaly Anemia (less than 40% hematocrit) Leucopenia (less than 5000 per mm') Eosinopenia (less than 100 per mim') Elevated sedimentation rate (15 mm per br. or higher). LE cells Renal abnormalities Proteinuria Hematuria Cylindruna . - nov 50 54 47 43 34 32 28 26 23 18 8 49 34 38 (of 60) 57 46 (of S3) 28 25 17 13 19 (of 58) 39 (of 58) 42 (of 52) 30 (of 51) 8 (of 18) 8 Bromsulfalein retention (greater than 10 mg % in 30 min) Biological false positive STS ·81STEMIC LUTUS ERYTHEVATOSUS 393 252, 253). Of our 62 patients, 39 hed an excellent immediate response to the first course of treatment. In six, however, there was no improvement in the function of one of several vital organ systems. For example, nephritis in two patients remained unchanged although fever and joint pains disappeared, while in another cardiac enlargement and murmurs persisted. The response in five patients was satisfactory, but proceeded at a slower pace. In eight patients higher daily doses, than those necessary in the majority of our patients (100 units ACTH intramuscularly, 40 units ACTH intravenously or 300 mg. cortisone orally) were required. In six, as the dose was progressively raised improvement occurred rapidly, as though a critical threshold level had been reached Su patients had little or no response. Four of these after a transient defervescence remained very ill in spite of daily doses of 120 to 140 units lyophylized ACTII, 40 to 60 units of highly-punfied ACTH or 300 to 400 mg of cortisone Two died during treatment. In one patient, the chief deficit, thrombocytopenia, was unaffected by 100 to 120 units of ACTII daily for 29 days The sixth received only 1100 mg of cortisone over an eleven-day period In three patients with renal involvement, treatment was stopped because of hypertenson; and in a fourth, who had cerebral manifestations, because of hypertension and drowsiness The doce was reduced too rapidly in five patients and severe relapses ensued. In 42 of the 62 patients the course of events after the first period of treatment, during which the patient had improved, was observed. Of the other 20 patients, four died during treatment, four were unaffected by treatment, and ten were continued on treatment at home After a single course of treatment the disease in 15 of these 42 remained quescent over perods ranging from one to 42 months. The average remission was 12 months, but this is misleading because only five of the 15 patients had remissions of one year or longer, the median duration being six months Nincteen other patients exhibited the "rebound" phenomenon, described above. The remissions following the rebound lasted from one to 47 months, nine months on the average. This value is also misleading for only four of the 19 had remissions of one year or longer, the median being five months. The rebound began during the period of dose reduction in seven and continued for seven to 17 days In eight patients it began after treatment, as early as one day and as late as ten days; lasting between tbrce and 21 days. In the four others bref relapses occurred during both the dose reduction and immediate post-treatment periods. In eight patients the relapses following treatment did not subside and the patients continued ill Thus, remissions occurred in 34 of the 42 patients in Table XIII are presented the remissions of one year or longer which have occurred in ninc patients following the initial circumscribed course of ACTII or cortisonc. A remission denotes cather the absence of clinical signs and symptoms or only mild activity. The occurrence of a lasting remission did not seem de pendent on the seventy of this illness at the time of treatment ·392 A MCGEHEE HARVEY ET AL. intramuscularly or 25 to 50 mg, cortisone every two to four days If there was a recrudescence, the dose was again raised. If, on the other hand, there was no recrudescence or the manifestations were of a minor nature, reduction of the amount of steroid proceeded and treatment was discontinued. The decision to begin lowering the amount of hormone was based more on clinical manifestations than on the results of laboratory tests. Intensive treatment was not continued because of the persistence of such abnormalities as elevation of the sedimentation rate or serum globulin concentration. As a result of this method of approach, the total dosage utilized in any single course of treatment varied greatly as did the duration of hormone administration (Table XII) The tabulated values include those for patients who died --.--.-nd on "maintenance" 1.11 iring the immediate post-treatment period. In those who demonstrated return of activity of the disease treatment was not reinstituted for at least one week unless the patient became very ill. It was observed in several instances that relapse during this first week after therapy was temporary, and a period of essentially complete remission of several months duration ensued. This temporary relapse has been designated as the "rebound phenomenon" (39). When relapse followed a long remission another course of treatment, usually similar to the first, was given If no lasting remission followed a single course of hormone administration the patient was placed on continuous maintenance therapy. In general, the decision to re-institute treatment has been based on the severity of the recurring features of the disease, the importance of the organ system involved, and the patient's previous response to treatment. Forty patients were given circumscribed courses of treatment alone without maintenance therapy. Twenty-one bad one or more courses of ACTH, and nine patients one or more courses of cortisone. Separate courses of ACTH and cortisone, as many as four, were administered to eight. Of 23 patients placed on maintenance treatment, twelve had previously received circumscribed courses of ACTH or cortisone, whereas in the other eleven maintenance therapy represented extension of the first course of hormone. In all, ACTH was given to 47 patients and cortisone to 38. The total number of courses was 112, of which 25 constituted maintenance treatment. In all patients, with the exception of a few in whom metabolic studies were being carried out, the intake of sodium chloride was limited to 4 gm. daily or less. In patients with cardiac or renal disease more stringent salt restriction was instituted. Supplementary potassium chloride, 3 to 6 gm. daily, was given to all patients except those with renal disease. Alkalinizing compounds were given between meals. The patients were seighed and the blood pressure recorded daily. 2. Discussion of general results a. THE INITIAL RESPONSE. The rapid and striking improvement in patients mth acute SLE given ACTH or cortisone has been repeatedly documented (33, 39, 59, 63, 89, 100, 107, 123, 234, 240, 242, ·SISTEMIC LCPCS ENITHEVATOSUS 393 252, 253), Ol our 62 patients, 39 had an excellent immediate response to tbe first course of treatment. In sit, however, there was no improvement in the function of one of several vital organ fystems. For example, nephritis in two patients remained unchanged although fever and joint pains disappeared, while in another cardiac enlargement and murmurs persisted. The response in five patients was satisfactory, but prorerded at a slower pace. Ia eight patients higher daily doscs, than those necessary in the majority of our patients (100 units ACTR intramuscularly, 40 units ACTII intravenously or 300 mg cortisone orally) were required. In eix, as the dose was progresively raised improvement occurred rapidly, as though a cntical threshold level had been reached Ses patients had little or no response Four of these siter & transient defervescence remained very ill in spite of daily doses of 120 to 140 units lyophylized ACTII, 40 to 60 units of highly-purified ACTII or 300 to 400 mg of cortisone. Two died during treatment in one patient, the chief deficit, thrombocytopenía, Tras unaffected by 100 to 120 units of ACTH daily for 29 days The sixth received only 1100 mg of cortisone over an cleven-day penod In three paticnts with real involvement, treatment was stopped because of hypertension; and in a fourth, who bad cerebral manifestations, because of hypertension and drowsiness The dose was reduced too rapidly in five patients and severe relapses ensued In 42 of the G2 patients the course of cvents after the first period of treatment, during which the patient had improved, was observed of the other 20 patients, four died during treatment, four were unaflected by treatment, and ten were continued on trcatment at home After a single course of treatment the disease in 15 of these 42 remained quinscent over periods ranging from one to 42 months The average remission was 12 months, but this 39 misleading because only five of the 15 patients had remissions of one year or longer, the median duration being six months Ninctecn other patients exhibited the "rebound" phenomenon, descnbed above. The remissions following the rebound lasted from one to 47 months, nine raonths on the average Thus value is also misleading for only four of the 10 had remissions of one year or longer, the median being five months. The rebound begen during the period of dose reduction in scren and continued for seven to 17 days. In eight patients it began after treatment, as carly as one day and as late as ten days; lasting betteen three and 21 days In the four others brick relapses occurred dunng both tho doe redurtion and immediate post-treatment periods In eight patients the relapse following tratenent did not subside and the pscicnts continued 111. Thus, remissions occurred in 31 of the 42 patients. In Tablo XIII are presented the remissions of one year or longer which have Accurred in pine patients following the initial cucumented course of ACTII or cortisone. A remission denotes either the absence of clinical signs and symptoms or only mild activity. The occurrence of a lasting remission did not trem detundent on tho x erity of this illness at the time of treatment.

·392 A. MCGEHEE HARVEY ET AL. intramuscularly or 25 to 50 mg. cortisone every two to four days. If there was a recrudescence, the dose was again raised. If, on the other hand, there was no recrudescence or the manifestations were of a minor nature, reduction of the amount of steroid proceeded and treatment was discontinued. The decision to begin lowering the amount of hormone was based more on clinical manifestations than on the results of laboratory tests. Intensive treatment was not continued because of the persistence of such abnormalities as elevation of the sedimentation rate or serum globulin concentration. As a result of this method of approach, the total dosage utilized in any single course of treatment varied greatly as did the duration of hormone administration (Table XII). The tabulated values include those for patients who died during treatment but do not include those for patients placed on "maintenance" therapy, defined as treatment for longer than three months. Whenever possible the patients remained in hospital during the immediate post-treatment period. In those who demonstrated return of activity of the disease treatment was not reinstituted for at least one week unless the patient became very ill. It was observed in several instances that relapse during this first week after therapy was temporary, and a period of essentially complete remission of several months duration ensued. This temporary relapse has been designated as the "rebound phenomenon" (39). When relapse followed a long remission another course of treatment, usually similar to the first, was given. If no lasting remission followed a single course of hormone administration the patient was placed on continuous maintenance therapy. In general, the decision to re-institute treatment has been based on the severity of the recurring features of the disease, the importance of the organ system involved, and the patient's previous response to treatment. Forty patients were given circumscribed courses of treatment alone without maintenance therapy. Twenty-one had one or more courses of ACTH, and nine patients one or more courses of cortisone. Separate courses of ACTH and cortisone, as many as four, were administered to eight. Of 23 patients placed on maintenance treatment, twelve had previously received circumscribed courses of ACTH or cortisone, whereas in the other eleven maintenance therapy represented extension of the first course of hormone. In all, ACTH was given to 47 patients and cortisone to 38 The total number of courses was 112, of which 25 constituted maintenance treatment In all patients, with the exception of a fer in whom metabolic studies were being carried out, the intake of sodium chloride was limited to 4 gmn. daily or less In patients with cardiac or renal disease more stringent salt restriction was instituted Supplementary potassium chloride, 3 to 6 gm. daily, was given to all patients except those with renal disease Alkalınizing compounds were given between meals The patients were weighed and the blood pressure recorded daily. OnDONE The rapid ·SYSTEMIC LUPUS ERYTREXATOSUS 393 252, 253). Of our 62 patients, 39 had an excellent immediate response to the first course of treatment, In six, however, there was no improvement in the function of one of several vital organ systems. For example, nephritis in two patients remained unchanged although fever and joint pains disappeared, while in another cardiac enlargement and murmurs persisted. The response in live patients was satisfactory, but proceeded at a glower pace. In eight patients higher daily doses, than those necessary in the majority of our paticats (100 units ACTI intramuscularly, 40 units ACTH intravenously or 300 mg, cortisone orally) were required. In sír, as the dose was progressively raised improvement occurred rapidly, as thougb s critical threshold level had been reached. Ste patients had little or no response. Four of these after 4 transient defer. vescenco remained very ill in spite of daily doses of 120 to 140 units lyophylized ACTII, 40 to 60 units of highly-purified ACTIT or 300 to 400 mg of cortisone Two died during treatment. In one patient, the chief deficit, thrombocytopenia, Was unaffected by 100 to 120 units ACTI daily for 20 days. The exth received only 1300 mg, of cortisone over an cleven-day perod. In tåree patients with renal involvement, treatment was stopped because of hypertension; and in a fourth, who had cerebral manifestations, because of hypertension and drowsiness The dose a reduced too rapidly in five patients and severe relapses ensued. In 42 of the 62 patients the course of events after the first period of treata ment, during which the patient had improved, was observed. Of the other 20 patients, four died during treatment, four were unaliccted by treatment, and ten were continued on treatment at home After & single course of treatment the discase in 15 of theso 42 remainel quiescent Ol er periods ranging from one to 42 months. The average remission was 12 months, but this is misleading because only five of the 16 patients had remissions of one year or longer, the median duration being six months Vineteen other patients exlubited the "rebound" phenomenon, described above. The remissions following the rebound lasted from one to 47 months, nine maanths on the average This value is also misleading for only four of the 19 had remissions of one year or longer, the median being five months, Tho rebound Legan during the period of dose reduction in seven and continued for seven to 17 days in eight patients it began after treatment, as early as one day and As late as ten days; lasting bets.cen three and 21 days. In the four others briet rolanges occurred during both the dose reduction and immediate post-treatment periods, In eight patients the relansrs following treatment did not subside and the patients continued ull Thus, remissions occurred in 31 of the 42 patients. In Table Wit are presented the temissions of one year or longer which have Occurred in ninc patients following the iniusi circumscribed course of ACTII or cortisone A remission denotes cither the absence of clinical 616s and symptoms or only mild actinty, The occurrence of a lasting remercion did not seem defindent on the eventy of the linees at the time of treatment.

·391 A. ACGEHEE HARVEY ET AL. TABLE XIII Clinical remissions longer than one year following initial circumscribed course of ACTII OF cortisone Treatment Rebound Case Hutory No. Age, Set, Lolor Date begun (units or mys Total dose (unata or mgi ) Duration (dayu) Duration of Remission fronto im. HR, 508063 BS, 510202 HI. N , 526500 OG, 532488 GP, 501114 SG, 570399 RT, 577426 HT, 416738 TM, 579323 בת 1 33 MW 43 FW 30 FW 37 FW 47 MW 44 FC 39 FW 40 FT 50 FW July, 1949 Aug, 1919 Jan , 1950 Mar, 1950 June, 1949 May, 1951 Aug, 1951 June, 1952 July, 1951 A A с с A А A с A 33333333 subsequent Therapy 76 45 1132) Yes 7 48 No 100 39 1780Yes 3 47 No 200 17 2050) No 42 | No 400 14 2425 No No 100 59 1113 No 34 Yes 2024 385 Yes 329 No 50 27 838 No 24 No 300 20 3050) No NO 40 29 570 Yes 10 14 No im, 1 V IV. po From our experience there appear to be no significant differences between ACTH and cortisone in regard to remission pattern or the development of the rebound phenomenon, Of 42 patients receiving a course of ACTH initially, 26 had remissions, the median duration being five months, and 16 of the 26 exhibited the rebound phenomenon. Of 15 patients receiving cortisone during the first course, eight had remissions, the median duration being six months, and three of eight exhibited the rebound b THE OVERALL RESPONSE. On August 1, 1953, 18 of our patients were dead, 42 were alive, and the status of the other two was not known Of the 42 living patients 25 were not on treatment. Nineteen of these were asymptomatic or exhibited mild activity after one or more courses of ACTH or cortisone. Sıx were seriously ill Seventeen of the 42 living patients were on hormone treatment Upon reviewing the overall course of events in these 62 patients, several patterns of response emerged (Table XIV). In nine patients the disease had remained quiescent or mildly active for various periods of time after & single course of treatment. Ttro of these have had no further treatment during the past four years and two have not been treated for 344 years Two of these patients were critically ill with evidence of widespread disease at the time treatment was begun. One of these has been at work constantly over these four years been relatively asyrnptomatic. The case history of the other is summ! critically fever, O G. ($532488), a 37 year old white í cutaneous lesione 8, myositis, and p 1950 On exam high fever (1 y ·819TENC LUPUS ERYTHEXATOSUS 393 TABLE XIV Palleries of response to ACTX and corlusone treatmeni 11 82 polenlo with tystemic lupus erythemaforut Pattern of RADE 36 0 3 11 a 10 Quicecent or mildly actuyo after stopping treatment (A) alter one ciscutented course (b) after multiple TONICS (c) after prolonged course Quiescent or mildly active but on maintenance treatment (a) after long remission following first conree (b) alter abort remission (6) (c) after failure to obtais & remission Progtestve active disease la) in spite of one or more courses (1) No further treatment because of previous complications (b) in spite of maintenance treatment from the start Dred (R) after remissions of several duration (0) n few months after treatment had been stopped because of complication (c) abortly after treatment (a) during treatment Recent cares satisfactory responan Current status not known 2 IR 3 Total . fesiona, polyarthritsa, subcutanenue nodules, and Buzcla pala and leadernens, The berzato. crit 26 20% and increased to 31% alter 1500 ml of whole blood The corrected and menta- Lion Tale ww23-30 min Ahr, and L. E cells were fotend - trenn 400 mg intramuscularly the Erst day, 300 og eccond day In matuction to 100 mg over the next three days with an increase to 200 mg Agata became Juction over the best week At the end or fotat or chest paio, od the subcutaneous ito weeks of treatment the dematocrte roke Ka reticulocytosis of 30% at the end of elevied until one week after thenpy when 1 2 fully active without tytoploss of 114 of and salles so the morsiog or after Inactivity • Ort WLS OS cach occasion 39% ithe dite cell imita L E cells were aot one, two and . in a satisfactory state of remission after is shown signs of tively. The first 2ong other manifestations. The nephntis has remained inacli\0', .. utaneous nodules of these bad had acule Lp have round ·100 4. NICGEHEE IARYCY ET AL. TABLC Ny-Continued Author's Series Manifestations Soffer and Bader's Series ratlets Effects of therapy Patients Effects of therapy Leucopenia 31 12 Clevated sedimen tation rate 57 Inesease in WBC 10 great Tajority, usually within 2 cehs Reduced to normal in 29 in 2-3 weeks, improved in 9, persisted in 19 Disappeared in only 5 with few cells before therapy 16 Increase in WBC in 9, no change in 5, reduce tion in 4 Increased in 6, decreased in 5, change in 7 Persisted no L L cells 46 (of 53) 18 Renal abnormal. stjes Proteinunn 28 llematuria 25 18 Persisted Cylindruna Azotemit 17 13 14 10 Persisted in 14, cleared in Halong with defervescence Persisteil in 11; reduced in 5, cleared in 9 l'ersisted on 9, cleared in 8 Increased in 7, no change in 4 and returned to normal in 2 l'ersisted in 17, improved in 9 Reduced in most in 2-3 wcehs Cleared in 12, decreased in 5 Persisted Persisted in 5, returner to normal in 5 26 (of 5S) 39 (of 58) Hypoalbuminemia Hyperglobulinemia l'ositive cephalın. cholesterol focculation Clevated thy mol turbidity Excessive bromsulfalein retention False-positive STS 21 Returned to normal in 6, decreasel en Reduced in all 8 8 Sero-reversal in only 1 out further treatment One patient devcloped arthralgia for the first time at the end of her first course of ACTH. Of 11 patients with joint difficulties who were continued on maintenance doses of cortisone, the arthritis has been controlled by doses ranging from 33 to 200 mg daily. C MUCO-CUTANEOUS MANIFESTATIONS. Forty-three patients had some form of skin involvement at the start of treatment The site and form of the lesions varied grcatly as shown in Table XVI During treatment the cutaneous lesions cleared completely in 31 patients and incompletely in mine. In tho cases there was complete cleanng during the first course of treatment, but less improvement with subsequent courses in one case there was no improvement, There was great variation in the rapidity of response; complete elearing of ·53 STEVIC Ltri's FRITIIEUATOS 101 TUE 1 Elled af 1T'HI and corkannt therapy on las10vs much-culourous monifestations of systemic lupus erythematusies Vanifestation Patients Efects of Thetar "Butterfts" erytem 25 16 Butler!ı"ersthenia galing and stries Perrungual erythema Seattered erythem tous mcules (le red Hithin 2 weeks, Junog 11 urek in most It became te afiry 1-4 arcks, Juring Prat are in most Crated within 3 werda ('leared att un 2 arche lurrug Ond neck in ?אחת tenaire erythrmand etling $ Ilayaknientation Foal leuroderma Focal subscutaneous swelling Sultaneous acules Raynaud's pivenomenor Wapera Mucosal lenjena, lucent 5 3 5 2 5 16 ? cleared after wech proses prom pletels alter ? weeks Persisted in all To change in 2 portal repron nt crunn (toned wittun 1-4 weth Desapare in Safter ! Cleared munt 3 he Hrgrouth of his 10 11. f after therapy Cleared within 2 archi 7 manual improvement orcurred As early as three days or as luto us four sechs after start of treatment Generally, more rapat and more compleer kelmg centraal in patients with lesions of recent onset aux there with any thema with mut ralem or scarring In li patients there was at the end of treatment a muri917 of the type of than um olvement proverit pres rourly in mnt meanffs 11 w ten spiere in Hegre and in nine the shin clears in a few days without further theraps The cutaneous manifestations usually portrm when the diapazon keame ** stemully active once again Then *$r exirrelation between the length of the cirtaneu remision and any particular type of lejon Int me intere there as a long cutaneou remix2011. Case BS 151022) h 51214 an epsxde ni fexrt Anil pleutin) in Ortoter 1745 Three months www.fore mutason ta tugust 1919 rte desetape mteulopapular Insons 1st the hands hech foramil (the arms and later piirnevel 4 suprares oser le lacr and neck Teshin femins on alınarak #e7e 11 per) of hapus aithi nahrnia anu maling and the altegtim-18 *** confirmed l tuagens Inder KTK treatment 17%) uzata intramusculuh ner Is da») healm *menuptate fier sapping irralment there * us a muld reals we heted audreuil Ajantanmus } verpt for an «*cna) mild setuhome ir kinantots normal #er the ett fuur vents Iming the patterite procesing more than on MXN ofriment, there was 119 Telery for greater edimination of the runproux lp1004 łyring successive Mp4 In alt me pret en un molement, neste pris 10aly prment, mit after the dirt on offraiment (ne patient after treatment of localiza! "elime***e!" she rinitate desplosiła ritenute peralızeleninen ·-102 A HCGLUEE HARITY ET AL, Case 58 J I (* 186666), a 38-year old colored nomin, was admitted in December, 1931 with fever, fatigability, dermatitis, arthralgia, lepatomegaly, anemia, leucopenia and hyper globulinemia The cutaneous lesions were restricted to the head, the Lridge of the nose and the ears with pruritie, atrophic, and exudative arc.s During.ICTII,350 units intravenously over 18 days, the cutaneous lesions became inactive Six months later the discoid” lesions Decame active once again and in addition she developed an intensely pruritic, erythematous maculo.papular cruption over the entire body She was again given ACTII intravenously. 555 units over 25 d1s During the hrst ten days, both forms of dermatitis became inactie, but the involved areas developed a pitch-black discoloration (Fig 18) This hyperpigmenta tion faded appreciably over the next three months. Sıx other patients developed prominent brown pigmentation of healing areas during treatment In patients with long-standing skin involvement it persisted to some degree after treatment In patients with skin disease of recent onset it disappeared In five patients focal subcutaneous swellings, resembling angioneurotic edema, disappeared during treatment. In one case (Case 10), however, the dose FIG 18 Case 38 This patient developed intensive pigmentation of the involved arr14 of the skin during treatment with ACTII ·SYSTEMIC LUPUS ERITTEXLATOSUS 403 of ACTII had to be raised to high levels (180 units intramuscularly daily and C0 units intravenously). Nine patients had subcutaneous nodules, usually near diatased jaints These became solter, then smaller, and in five patients disappeared about to meeks after the beginning of therapy. Raynaud's phenomenon disappeared after one to three weeks of hormono administration in five patients exhibiting it. Ten of the 16 patients with alopecia had a regrowth of bair, but in four this 17:29 not apparent until after therapy. Among the six shost slopecia persisted, treatment way of short duration, interrupted or in low dorage Seven patients had mucosal lesions all of which disappeared during the first two weeks of treatment. d. RENAL MANIFESTATIONS. From the early expeneacce of several investigators (33, 39, 63, 115, 240, 242, 253), it appeared that the renal lessons of SLE were seldom benefited by ACTH or cortisone In patients with renal insuficiency, their administration was often followed by an in wesght, edema, elevation of blood pressure, mitrogen retention, and sometimes pulmonary doma. Additional experience served to modify this opinion In Dubois' perics (59) senal abnormalities, including proteinuria, formed elements ra the unne, and mitrogen relention cleared completely in fise patieads given intensive hormone therapy. In all five, evidence of neplıropatky was of recent onset In two others, manifestations indicating renal ia volvement appeared dumng cortisone treatment and disappeared after the doso ras raised. Flaserick (107) noted decrease in proteinuria and hematuria in several patients given large doecs of cortisone Botter and Dader (240) reported that herstuns and cylindruria persisted in spite of vigorous treatment, but in five of ten patients with azotomia the blood urea nitrogen returned to normal levels coincident with defervescence and rehydration. Thirty-six of our 62 paticats exhibited one or more renal aboormalities before treatment. Twenty-eight had proteinuria In 14 of these no dramatic change securred during therapy In the other 14 the proteinuria cleared completels, but in most instance it was probably associated with the fehnle state and not due to involvement of the kidacys by SLE. Twenty-five patients had hemsturia which pas mucroscopic in all but three No chango occurred in 11 patients, in five there was an appreciablo reduction; und in nine, the hematuris cleared dunog treatment. Howerer, 10 even of these rung the breaturis yan minumal in degree Custs atio doled in the unde of 17 patients before treatment. In er, these persisted during treatment; in three, they disappeared during some courses, persisted in others; and in eight patients they cleard coropletely. In 13 patients the non-protein-nitrogen (XPS) concentration in the blood before tratment was clovated (greater than 33 mg per 100 ml.). During treatzent the XIX fell to within normal limits ia to, acreed lighuy in four; and increased apprecisbly (het ecn 2 and 143 mg per 100 ml.) in reven. in 12 patients with renal insufficiency there was no improvement in kidney ·404 A, MICGEREE HARVET ET AL. fuuction in five; in sıx, treatment was stopped or the dose rapidly reduced because of sudden elevations of blood pressure, body weight or non-proteinnitrogen concentration. The most favorable response is described in the following report: Case 99 II D ($575863), a 50-year old wbite male foremad, had been well until January, 1950 when he developed generalized muscle pains and polyarthntis In November, 1950 en 18-day course of cortisone resulted 10 to provement, but immediately after withdrawalthe arthr:129 returned He was then placed on maintenance costisose, 100 mg. daly being required for relief Four months later he suddenly kad severe weakness and headache thought due to "cortisone reaction" Cortisone was discontinued and gold started in March, 2951. After a few injections he developed blurred vision, pessorbital edema and severe weakness Cold therapy was stopped and after BAL administration vision returned. Soos thereafter be developed hyperteosioa, anemia, leucopedie, proteinuria, hematuria and cylindruna. On Admission in June, 1951 he appeared chronically i!l with musce atrophy and weakness, Arthritis, subcutaneous nodules, retinal eytod bodies, cardiomegaly and blood pressures of 160-175/K-110 mm IIg Unnalysis revealed proteinuria (++++); 10-15 red cells, 5-10 wbite cells, 2-B hyaline and granular casts per bigh-power feld. Maximal specific gravity of the urine was 1017 Phenoleullonphthalein excretion was 5% in two hours. NPN was 48 mg; eerum albumin 18 gm % Muscle biopsy revealed pervascular inflammation and atropby Le cells were found On July 3, 1951, a 28-day course of intravenous ACTI WA begun Muscle weaknega, arthralgia, subcutaneous nodules, and cytoid bodies disappeared The blood pressure felt slowly to 140/90 rom ead heart size returned to normal Protesouris P88 reduced to one plus and there were fewer formed elements in the urinary sediment PSP excretion increased to 66% in two hours. NPN rose rapidly to 60 mg % during the firat week then fell to 36 mg % during the third week The serum albumin increased to 25gm Jaring treatment and to 4 2 om seven weeks later Ankle ederna disappeared during treatment, and there wae loss of Aux pounds to weight Eleven weeks after discharge he was readnitted with myositis, artritis, subcutaneous Dadules and lymphadenopathy. The blood pressure was 105/70 mm 11g. Unnalysis showed only a trace of albumin, and there was concentration to 1 027. NPN was 36 mg % and the gerus albussia, 34 gtu % PSP etcretioa, hanerer, vas 40% in two hours During a 16-day cauree of ACTH tbere was agala striking improvement The PSP excretion rose to 82% on the oth treatmeat day and the serum albumin to 4 6 gm % Over the next 21 months the patient was virtually asymptomatic and at work, the urinalysis, NPN sed serum albumin remained normal, but the PSP excretion fell gradually to 56% 19 two hours e. CARDIAC MANIFESTATIONS. Exghteen of our patients showed evidence of pencardial disease at the start of therapy. Only one had & massive effusion and this was unaltered Five of 18 with pericarditis also had renal involvement with azotemia. In three of these there was no change during treatment in either renal or pericardial disease. In one receiving a maximum of 100 mg. cortisone daily, there was further cardiac enlargement and a pericardial rub appeared. In one patient all evidence of pericarditis (substernal aching, friction rub, cardiac enlargement and peripheral edema) cleared within the first week. Of the 13 patients with pericardial but no renal disease, there was no change 10 six, further cardiac enlargement in one, and improvement in six after one to two weeks of therapy Peripheral edema, present in three, disappeared by the end of the second week. A patient with normal cardiac findings before treat- ·SYSTEMIC LUPUS ERYTIEBUSTOSUS ment developed a pericardial effusion siter two years on maintensore cortisone treatment, 50 mg. dauy. Seventeen had evidence of myocardial involvement at the beginning of treatment In the eight patients who also had renal discase, the results of therapy #cre variable: no change in five, a gallop shythm developed in one and in two the heart site became normal after three weeks coincident with improvement in renal function, On the other hand, eight of the nine patients sith myocarditis but good renai function improved during trcatment in three desperately ill patients in severe corduar failure, the response was dramatic. Cyanosis, substernal pain, orthopnes, gallop rhythm, palpitations and penipheral deins cleared by the end of the Bccord week; cardiac enlargement decreased; and the patients were up and about the yard by the end of the third week of therapy. ?wo have been continued on cortisono and the improvement maintained Treatment was abruptly stopped in the third after reactivation of a duodenal ulcer Continuation of digitalis and butun restriction is not been entirely satisfactory and the heart bas become larger and orthopaca has reappeared. Two patients not considered to have myocardial discs.se on clinical grounds developed heart failure khila rreiving ACTH and at autopsy extensive "lupus Dyocarditis" was found There wg no significant effect of treatment on cardiac murmurs in any case. { PULMONARY MANIFESTATIONS Pleuritic pain, present in 15 pa. tients, disappcared as early as the third day of treatment, usually mthin the first week, but in two instances not for three neeks Light of the 16 had pleural changes on x-ray, in four, there is a definite cffusion These changes cleared after one to three weeks of therapy in seven Of nine other patients with both pleural changes and focal ateloctauc naeumonitis at one or both lung bases, iso Rhoned completo cleaning during treatmeat; four, almost compicte clearsag, and three, clearing during some courses and na change during others Maximum improvement trually did not occur until the third seek. The following caso illustrates healing of pulmonary manifestations during treatment followed by a long remaregion Cart 0 GP (501114), 47-year old white burdeiginAD, had had constant fever and sharia for 11 month and prorreurTe djapnes for bree montka before ACTJI therapy was martelon June 9, 1919 Ai tha time, Atclectatic tales posre heard al both lung Broch and chest x-rar rerealed disc-like ar438 of atclesians at both bases (Fig 13) Within 24 hours afteraturting treatment ferer and arthne diappeared, and the sedimentation to *w normal on the fourth day Dyepnea Kas releveul and sales ha vananed by the mou at the second werk. The chest x-ray, Cadca at the end of his 59 day court of ACTII, rereafed consente aprost. ment le remained symptom try and at fork over the port J months after which hormone therapy *** trgumes Irrsure of the appxearance of microscople betaluns 8. GASTROIXTISTIYAL YAXIFESTATIONS Sytoploms referable ta the alimentary tract were present to patients at the start of hormone therapy. Some complained of the difficulty is allowing A sore, salien md tongur *** ·406 3. MCGEHEE BARVEY ET AL the cause in one and abated under cortisone. Three patients had prompt regurgitation of food after eating but in only one did x-ray studies reveal esophag. eal disease (Fig 14 A) During a brief course of ACTH given to this last patient there was no improvement. In the other three patients regurgitation of food ceased promptly after the start of treatment. Seven patients complained of crampy abdominal pain which was generalized in one instance and epigastric in six. In four no basis other than SLE was found. During treatment the pain slowiy subsided and was gone at the end of two weeks in three The pain continued in the fourth, but she received only 100 mg. of cortisone daily. One patient had less epigastric distress during treatment, but it persisted She was jaundiced, and this was uninfluenced by treatment. Two patients had epigastric distress suggestive of peptic ulceration. One had had a slight deformity of the duodenal bulb roentgenologically. The pain subeded during the first week but at the end of treatment the developed fever, acute generalized abdominal pain, tenderness and distention. It was suspected that an ulcer bad perforated, but the pain spontaneously disappeared within 24 hours, although the fever continued for two weeks In the other patient the pain subsided during the first week of therapy but recurred. She developed hematemesis and at necropsy an acute gastric ulcer was found. Nausea and vomiting were prominent manifestations on admission in 13 patients. In all instances these cleared during treatment. One patient developed melena during treatment and at autopsy there were many ileal ulcers. It is possible that impaired fibroblastic activity secondary to ACTH administration may have impeded healing of the ulcerationg. h. LIVER AND SPLEEN. In the 15 patients with hepatomegaly in whom liver size was closely observed during treatment this organ became progressively smaller in all but one. In 12 the liver edge was not palpable after one to four weeks. Evidence of hepatic dysfunction as reflected by excessive brozpsulfalein retention before treatment was present in five of 16 patients. In two, there was less retention during treatment, from 3.0 to 1.1 and 1.9 to 0.7 mg per 100 ml, respectively in the other three, only slight reductions occurred. One patient had a serum bilirubin of 3.5 mg.% and alkaline phosphatase activity of 82 Bodansky units. During treatment, which dever exceeded 100 mg cortisone daily, the hyperbilirubinemia disappeared and the alkaline phosphatase sctivity gradually fell to 20.9 units, only to rise to 58 0 units shortly before death. The liver was Dot palpable and the cephalin flocculation and thymol turbidity tests fere normal. At post-mortem examination the liver was studded with miliary tubercles. Cardiac abnormalities were soted io nine of the 12 patients in whom kepatomegaly disappeared during treatment. In five the heart was eignificantly enlarged by x-ray and in three patients in whom it true measured the venous pressure was elevated. During treatment, beart size returned to normal in tro of the five and venous pressure to within normal límits in all three patients The spleen was readily felt in only eight patients before treatment The ·BYSTEIIC LUPUS ERYTHICSLATOSUS 407 splenomegaly subsided within the first week in seven and after three weeks of therapy in the other who had the greatest enlargement noted. 1. LYMPIT NODES In all but three of 34 patents sith lymphadenopathy the nodes could no longer be felt aſter three days to three wecks of hormone ad. ministration In more than one-half of the patients they were not palpable by the end of the first week of treatment These changes were particularly impresstve in the following patient: Case 11 II. F (* 527492), • 10-year old wale wataan, had fuad attacks of urticaris and angio neurotic edemn for many years Two months before treaiment sise developed fever and generalized lymph pode edistgement OA admission in February, 1350 the codes, partieu. larly in tbe neck, were so large and tender that the taitial diagnosed conndered sacluded Itodeksa's disease, colecttous monobucleosts and tuberculous adenitis Lymph node biopsy (Fig 3) showed local areas of necros), and LE cells were found in the peripheral blood She was given ACTSI, 100 usata daily intramuscularly on the third day ole was alebnile and only one wall supraelavicular lymph node could be felt she received a total of 815 unita of ACTII over 15 days A second lymph node biopsy obtained on the seventh trestment ds> revealed changes which were similar to, but much less prominent than those seed to thim stipecisoen. She was well for five months at wbich time cervical adenopathy reappeared OD ACTil sbo Bgain improved rapidly and had a remission of lour months duration Sub requently, she was given cortisote intermittently When laat examined in February, 1953 he was taking 80 mk of cortisone daily and there was no lympb pode enisrgement Two of thc three patients whose lymph nodes remained large bsd a satisfactory response to treatment in other respects In the third the nodes were calcified, probably due to tuberculosis At the end of treatment lymphadenopathy reappeared transienlly 2 soven paticats. RETINAL LESIONS No consistent effect on the cytod bodies was oucrved during ACTII or cortisone therapy in 18 patients K. HIEMATOLOGICAL MANIFESTATIONS Redaclls At the time of treatment, 19 of our 62 patients had some degree of anemia (hematocnt less than 40%) wuch ras in most tastance9 nombochromic and nominocytic of the 34 patients with moderato or severe anemia, se hematocrit values below 35%, 17 improved during treatment with hematocrit elevations averaging eight units. Morcorer, nine of the 37 patients gained even to 16 pounds in weight during this period, Tho hematocnt rie usually began at the end of the Erst week, but in 15 did not reach is muimum for three sechs or more. Or 12 improved paticnts followed, five had further increascs during the post-traiment period, avo maintained improvement and in tro the hematocnt returned to pretreatment levels mithun to werks In eix patients with progressive stoirmua tho anemia get worse. In the other 11 ancasic patients no rise in hematocrit followed hormone therapy. Seven, horrever, were followed for no longer than two weeks. Thule cello In 31 of our treate punts the white cell count tres delar 3000 per tand,', in 23 16 as normal, and in five aboyr 30,000 Of the 34 with lcucopcara belorr therapy tho had a further reduction in the ·108 A. MCGEHEE HARVEY ET AL. count, 1500 to 1800 per mm.", respectively. In the other 32, increases of 200 to 12,000 per mm.' took place; the average being 4,800. This occurred between three days and five weeks after beginning treatment, the average being two weeks. The following case illustrates the effect of treatment in a patient with severe leucopenia: Case 42 J.F. (#636867), an 18-year old white girl, had had an extensive facial raah for one month and fever, anorexia, malaise and muscle aching for two weeks. On admission she was anemic and the white count was 500–1200 per mmShe received a 29-day course of H P. Acthar-gel MAAIL IC treatment, the white cell count was 6,100. In the patients with a normal white count before therapy, increases occurred with the same frequency and were of the same magnitude. Of the five patients with leucocytosis before treatment, two bad tuberculosis There was no apparent infection in the other three. During treatment the white count decreased in two and increased appreciably in the other three. The largest cellular increments occurred precipitously in a patient who developed a staphylococcal septicemia during ACTH treatment; a patient with widespread tuberculosis, and another who developed a Cryptococcal meningitis. These examples serve to emphasize that when a sudden leucocytosis occurs the physician should suspect a complicating infection. Eosinophils. The eosinophil count in patients with SLE tends to be low During treatment the count fell to zero in 34 of 61 patients. No change occurred in five whose initial counts were low and in three patients the eosinophils became more numerous during treatment. After hormone administration was stopped the counts returned to pretreatment values in most instances. In eight patients, whose counts were low, they rose to within the normal range after therapy. The L.E. cell phenomenon. Dubois (59) noted the complete disappearance of L.E. cells in some patients within six weeks after the induction of a remission by ACTH or cortisone He postulated a direct correlation between the number of cells and evidence of activity of disease, especially fever, Haserick (107) observed the disappearance of L.E. cells in five of 16 treated patients and Shearn and Pirofsky (234), in four of 20. Soffer and Bader (240), on the other hand, reported that L.E. cells persisted during both drug-induced and spontaneous remissions. The effects of ACTH or cortisone on the L.E phenomenon were observed in 21 of our patients. In five the abnormal cells disappeared during treatment, but in each instance they were described as "rare" before treatment. In eight they became less numerous and in six no change Occurred. In two patients a few more cells were seen during hormone administration than before After prolonged hormone treatment the L E. cells became less numerous, but were still present in four patients. In another, however, in whom L.E cells had ·BYSTE UIC LUPUS ERYTHENATOSUS 409 boen seen in moderato numbers before, only one rag scen after seven months on cortisone, but after a second seven months they were found in abundance. There was no correlation between the perustencc of L.E. cells and the completeness of the clinical remission, 1. OTHER PROTEIN ABNORMALITIES. The serologic test for syptiis. At the time of treatment, 11 patients had positive scrologic tests. The TPI Test *as negative in eight of these. During hormono administration the serologic test became negative in only one patient The positive STS in the other three patients, all colored females, were presumably due to syphils on the basis of a positive TPI Test in all three altor penicillin therapy. No significant change in these serologic tests occurred during hormone therapy. Sedimentation rale. In 57 patients the corrected sedimentation mato was elevated. The range was 16 to 47 mm./hr, the mean, 30 and in 30 patients it was 30 or higher. The sedimentation rate fell during therapy to less than 15 in 29 of the 57 patients, to less than 10 in 17. In ninc the rate was mduced by at least 10 but was never less than 15 No significant change occurred in 13 patients The return to normal levels took place from three days to six rocks after starting the hormone; the average timo being 17 days of the 15 patients in whom the rate fell to normal and was measured during the first two weeks after treatment, it returned in all to elevated values in only one of theso did it then fall to within normal limits without further therapy. There was no direct correla tion between the dose of hormone and the degree of reduction of sedimentation rate. Morcover, changes in the rate during treatment did not correlate well with changes in scrum globulin concentration, cephalin flocculation or thymol turbidity, When tho sedimentation rato returned to normal there was always a satis. factory clinical remission. However, in many instances the patient had a goox! remission from the clinical point of view while the rato remained elerated. Scrum protena and liver function {ests In Soffer and Bader's series (240). 15 of 18 patients had a low serum albumin, which during therapy increased in zinc, was unaltered in three, and decreased in three The scrum globulin was high in 16 patients and with therapy there was a reduction in ten, no change in two and an increase in four. From Borial electrophoretic patterns Reiner (212) JA depression of gamma globulin during treatment and coincident with this a rise la the non-specific complement citer. Similar changes were also odkrred by Carey (39) Thirty of our patients at tho time of treatment had serum albumin concra. Lestions lower than 30 mm. per 100 ml. With therapy there were increase in nino of 0.7-1.8 gm., averaging 1.1; an increase during como courses of hormone administration and no change during others in tro patients; no change in fiftecn; and in tournal determinations are not arailable of the filtera patients ·410 A. MCGEHEE HARVEY ET AL. in whom no change occurred, ten had proteinuria, and two bad hepatic disease Of twenty-four with serum albumin concentrations of 3.5 gm. or higher there were increases in six of 06-1.2 gm., averaging 08, varying responses during different courses in two; and no change in sixteen. Maximal elevation of the albumin did not occur until the end of the second or more frequently the third week. Of the thirty-nine patients with serum globulin concentrations of 3 0 or more gm. per 100 ml. at the start of treatment, there were reductions in twenty-five of 06-2 8 gm , averaging 1.3; variable responses in three; no change in five, and no subsequent determinations in sıx. Furthermore, seven of twelve with globulin concentrations of 25-2,9 had reductions of 06-1.2 gm., the average being 0.9. In general, the change was greater in those with the higher initial concentrations and was not maximal until the second or third week of therapy. O! twenty-nine patients with positive cephalın-cholesterol flocculation before treatment, the test became negative in twelve It was less positive in five, the response was variable in two, there was no change in eight, and more flocculation developed in one during an allergic reaction to ACTH. All but one of the twelve in whom the flocculation disappeared during therapy had a concomitant fall in serum globulin. The thymol turbidity was elevated, greater than 55 units, at the start of hormone administration in twenty-one patients in whom serial observations were made. It returned to normal in six, was reduced in six, improved during one course and was unchanged during another course in two, was unchanged in sıx and increased in the patient with ACTH hypersensitivity. In most patients various protein abnormalities recurred promptly after treatment was discontinued. 4. Some generalizations concerning hormone therapy. We have been particularly concerned tvith the enteria of adequacy of treatment. As previously stated, there was at the beginning an attempt to revert all abnormalities, including those indicated by laboratory tests, to normal We found, however, that in several patients who became asymptomatic during hormone therapy, and had no signs of active SLE except a persistent elevation of the sedimentation rate, positive STS and L E. cells, continuation of treatment for one or two weeks longer resulted in no further improvement. Dubois (59) believed that "the obvinohan's stata untha than stereotyped dosage termine the effectiveness of our patients have enthout the induction of a Cushing's state, even with the most liberal definition of this condition. What is really needed is a reliable index of disease activity which is currently not available. Even more perplexing is the evaluation and desirability of long-term treatment with these hormones. Does treatment, no matter what the details of sdministration, influence the overall course of the disease? Is continuous treatment, which has now been adopted by most groups of investigators su- ·61 STEVIC LUTC'S ERYTIZATOSC5 411 perior or inferior to intermittent courses of treatment, which we have used in many of our patients? Because of the chronic and relapsing course of the disease and the variable results of treatment, answers to these questions will only be realed through observations over long periods of time. Analyzing the results of treatment in patients, year by year after the discovery of the L.E. cell, Ilaserick believed that mortality had been reduced by hormone administration (101). Dubois recommended continuous treatment and stated that such treatment had prolonged life. Flowever, whereas the incidence of spontancous remissions in his untreated patients during the 15 years prior to 1930 was 20 to 30 per cent, only two of 21 patients in the continuous treatment group maintained their remission when treatment was stopped We concluded from statistically incon- (clusive data that the frequency of occurrence of spontaneous remissions seems to be lowered by therapyand it is suggested that "milder cases be observed during a rest period of several weeks pror to starting treatment" This has been our practice both before inutial treatment and after therapy when exacerbs. tion following a remission has taken place However, that constitutes sufficient activity for treatment or retreatment is difficult to ascertain Generally, this is determined by the severity of symptoms and signs of activity as well as the importance of the organs involved It is possible that continuous treatment may prevent or minimize further damage in 8 ntal organ in which some irreversible alteration has already occurreri. In our experience there 19 little, u any, diference betwech the suppressiro effects obtained with ACTII and those with cortisone There may be less danger of adrenocortical insufficiency after a course of ACTII, but oral cortisone is casic to administer. Cortisone produces less salt retention and 29 usually preferable in patients with cardiac or renal disease With cortisone one does not run the risk of inducing an allergic reaction Nowever, thero are unusual mith currently available preparations of ACTII These hormones do not constituto a specific treatment for tho baric disease llowever, as Sofier and Bader (210) stated: "Despite the risks attendant on V the use of these hormones, they constituto the most effectivo agents yet availabin for the treatment of this disease It raust be emphasized, homever, that no curcs result It is possible that some patients may bo maintained in a state of remiason for an indefinitely prolongea period of time with judicious treatment". With this to concur. Moro effective therapy may be expected to result from a clearer understanding of the pathogenesis of the disease flowever, until that time, we would find that ACTII or cortisone treatment u indicated in most na. trents with clinically active SLE. 5. Complications of hormone therapy in patients with SLE tho mantestations of the discase and the complications resulting from treatment with ACTII or cortzone may simulate one another Such complications as heart failure of convulsions may deselop either as a consequence of betare SLE o asa "side-reartim" ta harmone administration. These various complications are summarized in Table XVII. Approximately one-half of our patients (3) of (2) developed some type of ·412 A, BICGENEE HARVEY ET AL. TABLE XVII Complications of steroid therapy in systemic lupus erythematosus: hormone- or disease-induced Compikation Patients Complication Paueats Patients trested Cardiovascular Excessive weight gain (7+ lb) Manifest edema Congestive heart failure Ilypertension Nervous system Restlessness Psycho918 Euphoria Depression Convulsiong Paresthesias Confusion only Paranoia, mild 62 32 20 11 2 16 31 12 10 7 5 5 3 Infection.... Focal only.. Systemic Gastrointestinal Abdominal pain. Diarrhea. Kypersensitivity ACTII most likely Other agents Thrombophlebitis Amenorrhea 30 15 5 12 8 4 11 8 5 5 4 cardiovascular complication. Twenty gained an ercessive amount of weight ranging between 7 and 22 pounds, the average being 13. In 12 of these there was no evidence of cardiac or renal disease, and in two no salt restriction had been instituted Two patients developed congestive heart failure which responded to further salt restriction and digitalization without drastic reduction in ACTH dosage. Significant elevation of blood pressure occurred during therapy in 17 patients of the nine with normal blood pressure at onset of treatment, three had renal disease, and of the eight with hypertension four had renal disease. The blood pressure elevations in all seven with renal involvement occurred Bo abruptly and were accompanied by such rapid accumulations of fluids that in five it as thought advisable to stop the hormone. The presence of cardiovascular-renal discase, however, is not an absolute contraindication to hormone therapy. In contrast to seven patients with cardiac disease who gained an average of 13 pounds during treatment, there were seven others who diuresed, losing between eight and 27 pounds. In most of these latter cases the cardiac manifestations were probably due to SLE. In such patients the salt intake was restricted to a maximum of 0 5 gm. daily and cortisone was administered at full dosage. The patient was usually digitalized and if fluid retention developed diuretics were used. Convulsive seizures and behavior disturbances of various types occur during semir ---------.. dann in nationte during hor. 3, when ermine jis (56) --- -- after the A ·BISTEMIC LUPUS ERYTIESLATOSTS 113 recent exacerbation of the illness, is febrilc, normotensiic and without recent weight gain. IA our experience these features are not always sharply defined. The most common servous system manifestation among our treated patients was byperirritability which occurred in 12. This was variously descnbed as locking "nervous", "restless", "jumpy", "shaky inside or having "a funny feeling in the head". It occurred only in patients receiving large doses of horpope. Nine patients became psychotic during treatment. Another became psychotic two weeks after an 11-day course of cortisonc during which no improvement had taken place. All these reactions took the form of severe paranoid delusions. of these ten patients three had had similar psychotic episodes before hormone administration, such an episode during hormone therapy was the prelude to convulsions in two patients. In two others the abnormal behaszor appeared in relation to an acute flare-up of SLE coincident with the development of hypersensitivity to ACTH. Ransohoff and co-workers (206) noted rapid cleaning of a psychosi, in a paticnt given potassium intravenously In none of our patients was the serum potansium concentration losy durog the abnormal behavior nor did the ad. ministration of potassium intravenously have any immediate effect That ACTII and cortisone may play & eignificant role is supported by tho rapidity with which the psychosis clcared after treatment was discontinued in most patients the reaction disappeared within one week, the longest period being one month Ilowever, in one, cortisono #29 continued because of high lever, and the psychosis cleared after ton days A mild euphora appeared in most patients after the initial symptomatic mom Sic induced by therapy. However, in sovca it was greater in degree than would be cxpected to result from elation over improvement in the basic disease On the other hand, five patients becamo depressed in two thus was pre-terminal The other thro mero relatively resistant to treatment, munng high donny of hormone over a period of several weeks. ACTII and cortisone have been reported to induce status epilepticus, un. wwally rocistant to anti-consulsive therapy, in patients with asthma, acuto rheumatic fever, periarteritia nodoss and dermatomyositis (51, 161) Tha frequency with which convulsivo sigures appear during the course of SLE, exprecially preterminally, has been discussed the differential demostic features astlined by Dubois (56) may be helpful if the clinical picture at the time of the convulsions clearly falls into one of his to groups which it often dors not. Rus. all and his colleagues (21) noted improvement during ACTII and cortinas włministration in tro patients who had had repeated epilepulotto scirurea of beveral years durstion. Ilowever, in three patients in whom the convulsions were asociated with acute fulminating SLC, cortisono srned to exert no effect. In (Fo patients abpontaal electroencephalographic pattere disappeared during treatment. In Dubois' scries of patients with rritures, 19 were thought to ling due to disrese and tirea to treatment. Only five of our patients had grand-msi sricums Ol then, tro had consul ning when not on tratment, and the other thren were preterminal mith lui.

·A. MCGEHEE HARVEY ET AL. minating SLE, one in advanced uremia. All five had active nephritis and four had fluid retention and hypertension. Convulsions did not appear in any of several patients receiving very large doses of hormone. In our experience convulsions occuring during treatment are likely to be the result of active disease, but if there has not been adequate restriction of sodium intake during intensive therapy, the hormones certainly may play a role There is no convincing evidence that hormone administration can significantly alter the convulsive state due to active SLE. Seven of 12 patients studied in our series had abnormally slow electroencephalographic patterns before treatment and one had low voltage as well. Five of these had serial records and in three the traciags became normal during therapy; in one, less abnormal, and no change took place in the other. There is evidence to support the concept that ACTH or cortisone may inhibit the host's ability to cope with infectious agents. In the first 662 courses of ACTH given in this hospital 13 generalized infections developed. In almost every instance, however, the patient had an illness, such as a blood dyscrasia, a severe burn, severe ulcerative colitis or a connective tissue disease, in which the predisposition to a superimposed infection was high. All patients should be investigated for infection before instituting hormone therapy. Moreover, any patient in whom fever recurs during ACTH or cortisone administration should be considered to have an infection until proven otherwise. Among our treated patients 20 developed one or more localized infections during therapy. The most common site was the urinary tract (six). In two patients pre-treatment urinary tract infections became more severe during ACTH administration Paronychiae appeared in three patients during treatment, two had the characteristic periungual erythema of lupus and had had similar episodes previously. Two with alopecia developed staphylococcal scalp infections. One of these was particularly prone to infections for during three courses of treatment she developed, in addition to the scalp infection, a cellulitís of the face, axillary impetigo, and a lung abscess with a Pseudomonas aeruginosa bacteremia. An abscess on the buttock at an ACTH injection site appeared in one patient. One developed an acute sinusitis and another oral moniliasis, Generalized infections developed in three patients and tuberculosis was made worse in two others One was the patient with the Pseudomonas bacteremua probably arising from a lung abscess Cryptococcal meningitis was the cause of death in another. One had two episodes of staphylococcal septicemia from a focus in the urinary tract. There are several isolated case reports of either the appearance of miliary tuberculosis following hormone therapy in patients with SLE (51, 99, 263) or the reactivation with lymphatic spread of an old, healed tuberculous lesion (203). Soffer and Bader (240) gave each of their 18 patients a routine trial on an antibiotic before starting treatment and reported no complicating infections. We have not elected to use prophylactic chemotherapy because it may interfere with the detection of an infection, and also because of the high incidence of drug reactions in patients with this disease.

·STSTEMIC LUPUS ERITIIEVATOsts 113 Eight of our patients experienced abdominal pain during treatment Three had mild to moderate cpigastric discomfort which responded readily to antiacids. One who had a known duodenal ulcer, developed melens and anemia. One patient, while on low doses of cortisone, developed hematenesis and melens, shown to be due to an acute gastric ulcer. Six patients had allergic reactions thought to be due to ACTH (23G). These occurred during the first course of treatment in five of the bux; during the third course in the other. In two the animal source of the hormone was the pig; in one, the sheep, and in three, 4 mixture of pig, sheep and cattle. It is of interest that, as with other sensitizing agents, reactions to ACTII bave been more numerous in patients with SLE than in other discese groups In this hospital 13 ACTII reactions have been observed among more than 1000 patients given this hormone and six of these occurred in the 62 patients with SLE c. Olker Jeasures Aside from the usual supportive measures other agents have been used in patients with SLE Only a few ment brief discussion. 1. Acetylsalicylic acid (ASA), Perhaps the most useful drug other than the bormones in the management of SLE 18 ASA In many instances there is rapid defervescence (Chart 3) and the patient feels greatly improved, as in the follor. ing case Care 43 SD (COSO52), 21-year old white female, was admitted in June, 1952 with a three year bratory of episodes of fever, chilly sensations, weight loss, butterfly erythema, migratory polyarthritis and pleuntic pain. She bad received several courts of ASA or cortione, each ni which had induced partial symptomatic relief On admiraion the temperature range DISTMIWATED LUDUS TATTNEMATOSU$ RESPONSE TO ASN AND COATONE 104 AD 27 601407 *CCTRL-100 hou) LU Post avanti wan CORTOAC 100) DATI . CHART 3 Comparative effrets of acetylsalicyle acid and optimor Os the lurts sod white cel munt in patient with SLE.

·416 A. MCGEHEE HARVEY ET AL. between 102 and 104°F. The elbows could not be fully extended. There was a "butterfly" eruption and erythema over the neck Subcutaneoga rodules were felt in the occipital reg100 And there was generalized lymphadenopathy One cytoid body was geen. Laboratory ab. normalities included anemia, leucopenia, elevated sedimentation rate, hyperglobulinemia, positive cephalin flocculation, and LE cells in the peripheral blood. On the fourth hospital day, after a single dose of 0 6 gr. of ASA the temperature fell from 103 8°F. to 97.6°F. within four hours and she felt better Over the next week ASA was con. tinued at 24 got daily She remained afebrile and the occipital nodules disappeared. How. ever, nausea and joint pains continued and the aspira was stopped. Two days later the temperature rose to 104.8°F , occipital nodules reappeared, Daurea increased and vomiting ensued HP Acthar-gel, 40 units daily, was started Defervescence was slower than with ASA, but on the second treatment day, although the temperature was still 101°F, she felt better than on the second day on ASA with no nausea, good appetite and no joint pain Such a rapid defervescence following the administration of ASA does not always occur. Of 19 patients in whom there was adequate documentation of treatment with this drug, eight had no response, even with as much as 60 gm. daily. Four patients experienced a prompt remission of fever but joint pains persisted and conversely, in one patient joint pains were controlled but fever continued. In the six other patients striking responses, similar to those which occurred in the patient whose case history was described above, took place. Four had Alamat of atabrine (quinaerine hydrochloride) in most patients with chronic discoid lupus erythematosus, has now been repeatedly confirmed (47, 142, 226, 243, 269), His treatment schedule consisted of 100 mg. three times daily for the first week, 100 mg twice daily for the second week; and then 100 mg. daily. Kierland and co-workers (142) point out that improvement in discoid lupus during atabrine was first reported by Prokoptchauk as early as 1910. Of 65 patients in Kierland's series, 17 had complete arrest of the disease and 15 had "more than 75 per cent" improvement. After stopping the drug, recurrences were frequent and during maintenance treatment (50 to 100 mg daily) several patients noted reactivation of skin lesions following exposure to sunlight Goldman et al. (86) noted "great improvement" in discoid lupus in 14 of 21 patients given chloroqun diphosphate. The improvement occurred more slowly than with atabrine in some patients. Severe side effects occurred in five of Kierland's (142) patients who had SLE, six weeks to six months after starting treatment although in three the skin had improved before the untoward effects appeared. The side effects included a "lichenoid" eruption in three, & pityriasis rosea-like eruption in one and in the fifth patient, fever, leucopenia, thrombocytopenis, and an increased Redimentation rate. These reactions cleared one to four months after discontinuing the drug. Fatal aplastic anemia following quinacrine therapy in chronic discoid LE has been reported (193). 3) Nitrogen mustards. Following reports of beneficial effects of nitrogen mustards in various diseases of hypersensitivity, trials in SLE have been described ·STSTELIC LUFTS ERSTWENTOSIS 417 by several observers. Plaza de los Reyes noted beneficial effects in two patients (200). Rohn and Bond (219) treated fire and were able to compaso the effects of nitrogea mustard with ACTH) in four One patient with pulmonary tuberculosis as well 29 SLE obtained remissions of 41, 217, and 21+ days, respectively, after ach of three courses of nitrogen mustards, and the tuberculosis did not spread. In two patienta, horever, only briel remission of 17 and 20 days, to spectively, took place and in the other two there was no response of the two patients with the brief remissions, one had also a brief remission (14 days) on ACTI and the otaer a long period of improvement (210 days) Similarly, of the two patients with no response, one had no response to ACTU, but the other Asd two remissions of 300 and 205+ days, respectively Dubois (58) gave nitrogen mustard and trethylene saelamine (TEST) to 20 patients who were not responding to dormono therapy of 11 with a nephrotic picture, muide vero helped, but in ttro frith non-edematoug nephritis and seven without renal involvement no improvement occurred Two of the fire given TEMI developed agranulocytosis and one a fatal aplastic anMNI. All were continued on cortisotic or ACTI and a no caso was a full remission caduced One of our patients (Case 20) received two courses of putrogen mustard, when ac es errorcously thought to have a lymphoma It is difficult to interpret the course of events ia this patient There were virtually no immediato beneficia) elechar but tro periods of symptomatic relief ensucd Orer the two-year period the SLE progressed to involve both the joints and the kidneys The use of nitrogen mustards in SLE dong not appear to be therapeutically promising and 18 potentially bazardous (4) Vitamin B, The evidenco that Vitamin But may benefit patients with SLE is meagre. Goldblatt (85) gave the substance to 17 patients with various forms of LE and reported improvement in all Only two had acuto SLE at the time Ono patient became alebnilo on the fourth treatment day and a 60 per cent decrease in the rash was observed after the third reek The other had been on treatment for 53 weeks, had "80 per cent long" of the dermatitis after {ve Werks, but did not become symptom-free until the SIst treek Para-aminobencosc acid since light sensitization may accur both in pa. lienta with lupus erytheraatosus and in those given sulfonamidea, and ance para-aminobenzoic acid (PABA) 1 metabolic antagonist to sulfonamide, Larsfonetis (274, 275) treated patients with ranous forms of lupus with PADI. Most of tho patients (27 of 33) bod disease largely confined to the skin and rar, ing degrees of improvement occurred in the majonty Ilometr, of the su clasa fied 44 acute SLE four were unchanged, one had a "poor" te pongo and one had "Ok" response Furthermore, the author, who liat administrred this drug in a wido variety of disease plates, indicated that reactions to PIBA Atre more Iragaent in patients with lupus than in any other group One of our patients had a severe exaceration of renal manufestations coincident fth Pass ad. ministrstina Johnson and Seycz (131) obeessai ruhjectite and objective im. provement in four of fire patients giren PABA but in each instance this was not sustained to demonstmble change was ert in the filth All Babaxuendy ·418 4. MGEKEE HARYEY ET AL. received cortisone and in each instance the response was more rapid than that following PABA. XKY PROGNOSIS a. Introduction Data as to the duration of this disease in patients receiving no specific treatment are important as a background for the evaluation of therapy. SLE may make its appearance with dramatic suddenness, or so insidiously that its presence is unsuspected for a long period. The frequency with which the discase develops obscurely, and the long interval of time elapsing before its recognition has lead to a false impression regarding its usuel duration. The dramatic events of the acute phases of the disease may detract attention from more subtle events that have gone before. For this reason, also, de must be cautious in depicting various phenomena such as idiopathic thrombocytopedia, epilepsy, and biological false positive tests for syphilis as commonly being the earliest manifestations of SLE. In many patients in our series in whom such events at first appeared to be the earliest evidence of the disease, careful analysis showed that other changes kad been present antecedently, sometimes by many years. The determination of survivorship figures in SLE presents several problems. The first of these is the definition of the cases included: the type of patients presenting themselves at a given institution, the diagnostic criteria, the chronicity of the disease, its variable pattern, and treatment. Secondly, there are different points of reference from which survivorship might be stated. Finally, there is the problem of coping with the variable length of follow-up for the patients coming under observation The literature on prognosis in this disease is very limited and fails to deal satisfactorily with the problems of starting point and variable follow-up (104, 120, 129, 258) The most complete data on survivorship were presented by Jessar and his co-workers (129) on 103 patients, but the analysis of the observations may be misleading with regard to the handling of persons still alive who had been followed for variable times. In their final assessment the authors stated that while the prognosis in SLE is unfavorable, it is liketrise apparent that in some 20 per cent à duration of illness greater than five years may be expected" (p 728) Yet, on the same page they give a five-year death rate of 70 per cent, obtained by a different procedure. This inconsistency results from two di known tients years from onset. Only four of these 26 were lost to observation and tol LLU AU maining 22 their fifth anniversary bad not yet arrived. The 20 per cent sursival figure was obtained by implicitly assuming tbat the four lost cases survived five years but that none of the 22 did. The 30 per cent survival rate was obtained by limiting the analysis to those cases that had an opportunity to be AND Tare ·SYSTE31C LUPUS ERTTUEILATOSC followed five years This result agrees with the results obtained by applying the analytical method used in this paper to all of Jesear's patients, taking duc account of their length of follow-up. The estimate means that 12 of the 26 living capes will survive to their filth anniversary. Thero are scrious difficulties in the interpretation of such currivorship figures As giving the natural history of the disease when the onset of the discase is chosen as the starting point in the first place, as stated previously, the onset way bo frequently vague in terms of both the Assignment of the precisc time of onect and the validity of the compisint as part of the disease Horrorer, fisce the cases were not seen at onset but at some later stage they must leave been pre-dated and the survivorship figures arc based in part on a backward look at the history of the case and in part on follow-up after diagnosis The falscy of considering such estimates as prognosis from onset may be clarified by an exampic. Congder an estimate of infant mortalty from birth to one year obtained by Arlecting babics brought in for vaccination, prodatiog them to birth, and following them to their first birthday Infant mortalty estimated in this way will be erroneous because it fasis to include all babies who bave died during the first year of life before being presented for vaccination Similarly thoso patients with BLE surviving to and pnwending themselve for diagnosus usually represent a brased group of thoso baving an onset of the disease, Apother approach to prognons has born to get the averago duration of life from ansct, by averaging the length of file of those who have died to the cur. rent date Excluding tho living cases and determining an average duration of hfe th those who here died almost always results in an under-estimate of bilo expectancy which may bo substantial Dubois and colleagues (59) quoted their own experience in the terms for the pre-treatment dazt, Alating that they hnu no living patients in the pre-treatment kerics, but they compared their liguny terth those of other authors without the assurance that the latter also hal na living patients If this procedure were used in the cases included in our on analy 813 it would give a median dutstion of uſe after diagnost of ssen months whereas a correct analysis gives approtimately four years Ono analysis dealing explicitly trith all the observations, living and dead, and taking account of the variable lengths of follow-up, results in a "lle table", which gives among other things the percentage surviving to ymous points of time from the selected starting point if retake the diagnosis or "omo other point in the management of the case as the starting wint from *kueli cztem are follosed, no retrospective pbersations are involved, and so can arvo at prognosis from this point We are reporting here the ruits of such an analytis for patient dugno at the John: Ifopkin tropisal, prognosis txing etated from date of disonoris Thens teulu art atsiment from a more extensire discusion dealing with the problems and methods of analysis of progno64 in long time follow-up, achet. tim to appear elsewhere (170).

·422 A. MICGEHEE HARVEY ET AL. tion of therapy. Therefore, no further breakdown, beyond the question of whether the patient received treatment or not, was performed. On the basis of the history, an attempt was made to date the onset. When there was a question of validity of symptoms or signs we have selected the more definite and recent ones. The duration of time between the estimated onset of the disease and the date of diagnosis varied from less than a month to 25 years, but the distribution of these intervals is piled up toward the short intervals, as shown in Chart 5. One-fourth of the intervals are less than 1.1 years, one-half less than 2.6 years and three-fourths less than 6.8 years. The remaining fourth is scattered with diminishing frequency up to 25 years. There is a slight tendency for the persons with shorter durations of disease at the time of diagnosis to be younger but this relationship is less pronounced than might have been anticipated. Of the cases with onset less than 2 years PERCENTAGE PER HALF-YEAR 25 0 1 2 3 4 5 10 15 20 YEARS FROM ONSET TO DIAGNOSIS CHART 5. The interval from onset to diagnosis in 99 cases of SLE seen from 1949 through 1953 prior to diagnosis, 17 per cent were under age 20 compared with 5 per cent under this age for persons with longer durations prior to diagnosis. The median ages of the two distributions are almost identical, however, being 36.1 years and 36.8 years, respectively c. Prognosis From Time of Diagnosis The life table based on the total experience of the 99 cases yields the survivor. ship curve shown in Chart 6. The x-scale gives years measured from diagnosis, the origin being date of diagnosis; the ordinate is the percentage surviving to the various times. The deaths occur most rapidly within the first three months after diagnosis, 13 per cent of the cases dying within this time. Of patients diagnosed, 78 per cent survive to their first anniversary, 52 per cent to their fourth. The drop in this curve between any two points represents the percentage of the original group of diagnosed patients who die in the interval. It is also of interest to consider the death rates during the different intervals ·SYSTFSIC LETES EGITTESLATOSCS 423 relative to the survivors at the beginning of the interval. The rapid death rate in the first three months is followed by a lower and virtually constant rate of 10 per cent per year. That is, of the survivors to any point, about 10 per cent will die in the following year. Tbo eurvivorship observed for this series of patients is very much morc farorable than that cited from the literature. Jessar's series (loc. cit.) showed only 38 per cent surviving four years after onset, wheress our Berics had 60 per cent surviving four years after diagnosis. This difference in percentages is in the opposite direction from that which would be expected to result from the difference in the sclected starting points and, therefore, the discrepancy betneen the two is greater than that between the percentages quoted Jessar's scrieg was composed of 41 of their own patients observed during the 15 years prior to 1932 and 59, among the 279 gathered from the literature in the years 1918-1932, in whom eo to PERCENTAGE SURVIVING + YEARS 20 . YEARS TROM DIAGNOSTI) CHART 6 Purvivorship alter diagnosis in 09 cases of &LE seen from 1917 throuch 1953 there was sufficient information to estimate duration of illness from onset. The moro favorable survivorship in our patients when compared with Jessar's series may be tho result of several factors: 1) tho possibility that on the average our patients were les severely all than theirs. This might be due to the inclusion in our scries of ander, or earlier, cases, discovernd cither by tho L E. cell test or by the carlice recognition of this disease by physicians in general, so that earlier diagnoses are mado 2) This may result from beneficial effects of hormone ther. apy. Roughly thre-fourths (75 of 19) of our patients terred such therapy, in ono form or another, whereas theirs received nonc. 3) Thus may be a consoquence of one or more of the several factors which make one hapital's casos unlike another's I diagnosis was made on clinical grounds (and confirmed by the LL. cell test) and those in whom the dispnoeg was in varying degrees nuected clinically, but established by the demonstration of these cells.

·424 A. MOGEHEE HARVEY ET AL It is, thus, tempting to entertain the possibility that the effects of hormone treatment, begun in mid-1919, were largely responsible for the enhanced survivorship in our patients when compared with that of Jessar's series. However, such a conclusion would not be sound because of the limited experience to date, and absence of an acceptable group of untreated patients in the years 1949 through 1953 to serve as a control. Haserick (101) attempted a comparison of hormone-treated with non-hormone-treated patients, the diagnosis in all being confirmed by the presence of L.E. cells, and assigned to the treatment of lengthening of life. However, of his 83 patients only ten were in the untreated series and these antedated the treated cases, thus not constituting a concurrent untreated control. The data from his study would seem to be, therefore, insufficient to allow any firm conclusions to be drawn. In order to assess with accuracy the value of any specific therapy in this disease, it is essential to carry out a planned study having some sort of random assignment of patients to different treatment ONSET TO DIAGNOSIS - 2 YEARS 2+ YEARS PERCENTAGE SURVIVING + YEARS 20 0 YEARS FROM DIAGNOSIS (X) CHART 7. Survivorship after diagnosis, by interval from onset to diagnosis, in 99 cases of SLE seen from 1919 through 1953 schedules. With the evidence suggesting that hormone therapy may be ad- 1 1. ffect on progoosis, ime from onset to diagnosis The numbers were too small to permit detailed break-downs into sub-groups and age was considered in the two broad groups; 'under and over age 40. No significant difference was found in the two survivorship curves. With regard to interval between onset and diagnosis, the patients were again divided into two groups, under and over two years. Forty-one patients were diagnosed less than two years after onset of symptoms, and 58 patients two or more years after onset. The numbers are so small that the life tables are not carried beyond the third anniversary and even over this interval the standard errors are large Nevertheless, there is a significant difference in survivorship at the second and third anniversaries (at the 5 per cent level of significance), in ·SYSTEMIC LCPLS ERITIESLATOSTS favor of the cases with longer intervals. Chart 7 shows that within the first year after diagnosis the survivorship curves aro identical, but after tho first year the cases with more recent onset, die off moro rapidly. The actual size of the difference is substantial at the 3rd anniversary, 72 per cent compared with 46 per cent but as noted above these percentages have a large sampling varistion and the size of the difference is not well established. Tho interpretation of this difference seems most likely to be in the selection of the cases, since it is unlikely that carly diagnosis per se should be a disad. vantage. The type of case that presents senous enough symptoms carly in its course to bring the patient to the atteation of the doctor and enable him to make a diagnosis, may well be the type that progresses more rapidly thereafter. XIV SUDART Incrcasing familianty with the varied clirucal manifestations of SLE, together with improved methods of definitive diagnosis, have led to an altered concept of the character of this disease It has become apparent that the courgo is frequently chronic, associated with cxacerbations and remissions over a period of many years The disease is often characterized by recurrent mild illnesses, Hemingly unrelated, with prolonged asymptomatic intervals Even when severo manifestations appear, they may be followed by spontaneous improvement or complete remissions. In some patients, serologic abnormalities antedata by years other ovidences of SLE, indicating that the disease may remain clinically inactive for indefinite periods of time after the onset Our present knowlcgo is based largely on retrospective study al cases of full blown LE, for only recently has it been possible to recognize the discuto in its mild or carly forms. It is well known that fulminating or fatal illness may occur abruptly or alter many years of mild symptoms Iforever, it remains to bo de termined whether all cases must necessarily terminate in this fashion. I'rolonged observations will be required to establish the course of the disease in the mild mases now being recognized. It is entirely possible that some patients may free cover, or that the disease will fail to progress Tho possibility cannot be orcelooked that even now we are failing to recognize mung mild cases of SLE bocause of the lack of an adequate diagnostic test It should be emphasized that the negative L, E. ccll test does not crclude the existence of this discec. Tho cau of SLF remains obscure, but two ſeatures have attracted mpecial Attention. One is the almost constant presence of abnormalities of the serum proteins, and the other is the evidence of discs of collagen. The manner in *hich the phenomena arc interrelated and tho mechanism of their production have not been elucidated Whilo manifestations of hypersensitivity are common in patients with $1.E, it has not been established that hypersantire risetions and of ctio!ogic significance Definitive treatment will have to atrat a better understanding of the patho neis of SLE.. Stnking suppression of many of the signs and symptoms of tho die maag be obtained with hormone therapy, but others are una.fected, and mmplications occur frequently. Whether or not lưe is prolonged by ruch therapy ·424 A. MOGEEEE HARVEY ET AL. It is, thus, tempting to entertain the possibility that the effects of hormone treatment, begun in mid-1949, were largely responsible for the enhanced survivorship in our patients when compared with that of Jessar's series. However, such a conclusion would not be sound because of the limited experience to date, and absence of an acceptable group of untreated patients in the years 1949 through 1953 to serve as a control. Haserick (104) attempted a comparison of hormone-treated with non-hormone-treated patients, the diagnosis in all being confirmed by the presence of L.E. cells, and assigned to the treatment of lengthening of life. However, of his 83 patients only ten were in the untreated series and these antedated the treated cases, thus not constituting a concurrent untreated control. The data from his study would seem to be, therefore, insufficient to allow any firm conclusions to be drawn. In order to assess with accuracy the value of any specific therapy in this disease, it is essential to carry out a planned study having some sort of random assignment of patients to different treatment ONSET TO DIAGNOSIS -C2 YEARS 60 2+ YEARS 60 PERCENTAGE SURVIVING * YEARS 40 0 2 YEARS FROM DIAGNOSIS () CHART 7. Survivorship after diagnosis, by interval from onset to diagnosis, in 99 cases of SLE seen from 1949 through 1953 schedules With the evidence suggesting that hormone therapy may be advantageous in SLE, this would be exceedingly difficult to do. Two specific factors were studied in our cases as to their effect on prognosis, namely: age at the time of diagnosis, and the duration of time from onset to diagnosis The numbers were too small to permit detailed break-downs into sub-groups and age was considered in the two broad groups; "under and over age 40. No significant difference was found in the two survivorship curves. With regard to interval between onset and diagnosis, the patients were again divided into two groups, under and over two years. Forty-one patients were TM - inntato O not dard errors are large. Nevertheless, there is a signihcant difference in su vivunwip at the second and third anniversaries (at the 5 per cent level of significance), in C I ·BTSTEMIC LUPTS FRITHEXATOSS 427 14. BARONDESS, J. A. Thrombotic thrombocytopenic purpura. Review of the literature and report of three cases Am J. Med , 13, 174, 1952 15. BARR, D P., READER, G.G, AND THEELER, C II. Cryoglobulinemia. I. 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A, SLOCT MR, C II , AND Discret, JW Feels of cortimine on acuto dikecmiasted lupus en thematorus 'roe Stall dret, Mayo Clin . 15:479, 1950 34 BENDICE, 1 R , Axp Fun, FA Lepus en thematneus, claxifications, diante and promote talue of topeies fouth M 3,41: DI, 1951 33 Rt vix, JJ I upus erythematosus diesemnatus Ann Int Hel. 13.17, 1910 36 CALLEDIN, ST, A5 Tharr, R R A Prological and practical study of maluisie antidien lommello responr lo bloof transfusioa brmatient with lopus erythrom. Atewus duluxur fon Turnica, 13:102, 1946 ·426 A, BICGEHEE HARVEY ET AL. cannot at this time be accurately ascertained, but the evidence to date is in the affirmative. ACKNOWLEDGEMENTS We wish to express our appreciation to the various members of the staff who have allowed us to utilize data on patients under their care; to Dr. Morgan Berthrong and Dr. Stanton L. Eversole for their help in editing the section on Pathology and in the preparation of the photomicrographs; to Dr. David M. Gould for bis help in the selection and interpretation of the roentgenograms; to Dr. Margaret Merrell for analysis of the data in the section on Prognosis, and to Dr. Ivan L Bennett, Jr and Dr. J. Earle Moore for help in preparation of the manuscript Part of the cortisone and ACTH used in these studies was purchased through a grant from the Division of Research Grants and Fellowships, National Instatutes of Health, U. S Public Health Service. Part of the cortisone and ACTH was supplied through the courtesy of the Medical Divisions of Merck and Company, G. D Searle and Company, and the Armour Laboratories We gratefully acknowledge financial support from Merck and Company for the reproduction in color of figure 17. BIBLIOGRAPHY 1 AEGERTER, E , AND LONG,J H The collagen diseases Am. J M. Sc., 218: 324, 1949 2 ALLEN, A C The Kidney Medical and Surgical Diseases Ed 1, New York, Grune and Stratton, 1951, 583 PP 3 ARNOLD, K L , Je Systemic lupus erythematosus Areb. 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·SYSTEMIC LUPUS ERYTEELLATOSUS 433 159. Lewis, T. The blood sessels of the human skia sod their responses London, Shaw and Sons, Ltd, 1977. 130. LET, A.B, READER, G G, SORENSON, C. W, AND OVERMAN, R. 8. Idiopathic hypoprothrombudemia 888ociated with hemorragie diatbeals, and the effect of vitamin K. Blood, 6:740, 1951 60. LIBUAN, E, AND SACES, B. A lutherto undesenbed form of valvular and mural endocarditis. Arch Int. fed , $3: 701, 1924. 181. LOWELL, F. C., FRANKLIN, W., DEALE, D, AND ScalLLIR, I W. Occurrence of convalaire seizures dunng treatment of asthma with cortisone acetate New Englaod J. Med. 844:49, 1951 162. LOWAN, E. W Muscle, serve, sad synovial changes in lupus erythematosus Ann. Rheumat Dis , 10:18, 1951 163 LTON, J.M. Acuta lupus erythematosus Am J Dua Child., $: 572, 1933 164 MADDEN, JF. 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