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RHEUMATISM OFFICIAL JOURNAL OF T H E AMERICAN RHEUMXTISM ASSOCIATION SECTION OF T H E ARTHRI TI S FOUNDATION

DOES CORTICOSTEROID THERAPY AFFECT THE SURVIVAL OF PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS? DANIEL A. ALBERT, NORTIN M. HADLER, and MARIAN W. ROPES The hypothesis that corticosteroid therapy is responsible for the striking improvement in survival of patients with systemic lupus erythematosus (SLE) was investigated with two approachks: Of 250 published papers on SLE, 52 were chosen for the first analysis because they included sufficient information on diagnostic criteria and survival but were not limited to patients selected for a particular target organ. From each article percent survival by series, average duration to death, and 1 and 5 year survival curves were abstracted. Each statistic showed linear improvement in survival since the 1930s without a significant change (P> 0.10) in slope for the time period following the introduction of corticosteroids. The second analysis examined the effect of From the Robert Wood Johnson Clinical Scholars Program, the Departments of Medicine and Bacteriology (Immunology), University of North Carolina School of Medicine, Chapel Hill, North Carolina; the Department of Medicine, Harvard Medical School and the Medical Services (Arthritis Unit), Massachusetts General Hospital. Supported in part by the Robert Wood Johnson Foundation and the American Heart Association. Daniel A. Albert, MD: Robert Wood Johnson Clinical Scholar, University of North Carolina; Nortin M. Hadler, MD: Associate Professor of Medicine and Bacteriology (Immunology), University of North Carolina School of Medicine, recipient of an Established Investigatorship from the American Heart Association; Marian W. Ropes, MD: Clinical Associate Professor of Medicine Emerita, Department of Medicine, Harvard Medical School and the Medical Services (Arthritis Unit), Massachusetts General Hospital, Boston, Massachusetts. Address reprint requests to Dr. Hadler, Department of Medicine, Division of Rheumatology, 938 Faculty Laboratory Office Building-23 IH, UNC School of Medicine, Chapel Hill, NC 27514. Submitted for publication February 15, 1979; accepted in revised form April 23, 1979. Arthritis and Rheumatism, Vol. 22, No. 9 (September 1979)

corticosteroid therapy on 142 patients with SLE followed at the Massachusetts General Hospital between 1922 and 1966. Although the steroid use was conservative, the patients’ survival, from year of entry, was comparable to the 52 abstracted series. A prognostic index was used to stratify patients admitted in the steroid era (after 1950) for life table analysis of survival with and without steroids. Steroids had no discernible effect on overall survival in low and medium risk groups. Use of steroids was associated with improved survival among high risk patients (P< 0.05).

Although corticosteroid therapy has a clearly beneficial effect on the severity of many clinical features of systemic lupus erythematosus (SLE) (1,2), there has been little documentation of its effect on survival (3). The remarkable improvement in survival of SLE patients from a 90% 2-year mortality before World War I1 (4) to a current 90% 10-year survival ( 5 ) is often attributed to the introduction and widespread use of steroids (6). Further, the effects of steroids are so strikingly palliative that randomized clinical trials have been considered unnecessary, unethical, or impractical (7). Ideally, the question of whether steroids affect survival of patients with SLE should be answered by a randomized controlled trial, but this is currently not feasible. In lieu of a trial we developed two retrospective methodologies in an attempt to answer this question. These techniques do not depend on unique features of SLE and could be adopted to other therapeutic or diagnostic questions where trials are not possible. We first

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reviewed the literature to extract quantitative data from each article for statistical analysis. This method allows us to quantify the changing survivorship in SLE over the past four decades. Improvement in survival might be expected to coincide temporally with the introduction of dramatically effective intervention, such as corticosteroids. Our second approach was to study the survival experience of a single well characterized series of SLE patients followed personally by one of us (MWR)at the Massachusetts General Hospital (MGH) since 1922. The MGH survivorship was found to be strikingly similar to that described by the literature. Using a stratified analysis we ascertained which subgroups of SLE patients within this series survived longer when treated with corticosteroids.

A AVERAGE DURATION TO DEATH

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MATERIALS AND METHODS Quantitative literature review. Over two hundred and fifty published papers on SLE were considered. Fifty-two of these were not limited to patients selected for a particular target organ and contained usable survival data on patients with systemic disease defined by criteria which approximated that of the American Rheumatism Association for the diagnosis of SLE.These papers are cited in the Appendix. From each the following data were obtained 1) average duration of disease until death, 2) percent of patients who survived in each series, and 3) percent of patients surviving 1 and 5 years of disease by l i e table analysis (8). When available, disease onset was used as the starting point in calculating these statistiks. Otherwise entry or time of diagnosis was used. We examined the trend in each of these survival statistics plotted against the calendar year of the article’s publication. Our hypothesis was that there would be a continuous improvement in survival without a change in slope corresponding to any event such as corticosteroid introduction. MGH series. We examined survival data on 142 lupus patients followed at the Massachusetts General Hospital between 1922 and 1966. A detailed clinical summary of these patients has been published as a monograph (9). Their clinical characteristics are similar to large series of patients reported from other institutions. The patients met any three of the following diagnostic criteria, or both one and two: 1) characteristic skin rash, 2) characteristic renal involvement, 3) serositis, 4) characteristic arthritis. These diagnostic criteria are similar to the British Medical Research Council‘s criteria for SLE (see reference 33 in the Appendix). Activity was measured at each clinic or hospital visit on a semiquantitative clinical scale. This scoring technique has been detailed in the previously mentioned monograph (9). Patients are scored for 0 4 + based on the clinical and laboratory assessment of intensity of involvement and number of target organs. The diagnosis of nephritis is based on the clinical recording of urinary sediment abnormality, L 2+ proteinuria, or azotemia on two or more successive visits. No systematic assessment of renal function or histopathology was undertaken.

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1950

DATE

1960

1970

1900

OF PUBLICATION

Figure 1. Analysis of survival statistics culled from the literature. A, The average duration of disease until death in each series is plotted against the publication date of that series. The regression line is drawn by the method of least squares and has a correlationcoefficient (r) of 0.64. B is a plot of the percent survival in each paper against the publication date (r = 0.76). C, The survival at 1 (r = 0.83) and 5 (r = 0.86) years of disease is plotted against the date of publication of the series. For convenienceC also depicts the percent of patients receiving high dose steroids in each of the respective series against the publication date.

CORTICOSTEROID THERAPY IN SLE

In a manner analogous to that of the quantitative literature review, we examined patient survival by year of entrance in 5-year segments using the same survival statistics: average duration of disease from entry until death, percent survival by 5-year entrant groups, and percent survival at 1 and 5 years of disease by the life table method. Again our hypothesis was that the improvement in survival was essentially linear without significant alteration during the time periods corresponding to improvements in management. This linearity hypothesis was also examined with standardized rates by using United States census data for age, sex, race, year of entry, and duration of disease (10). Because the survival of patients in the MGH series varied dramatically between 1922 and 1966, we chose to examine the effect of steroids on survival only within that group of patients admitted in the steroid era (after 1950). Within this group entrance data did not measurably affect survival (Table 1). We divided the patients entering our series after 1950 into prognostic strata by high, medium, and low risk subgroups (1 1,12). We then assessed within each stratum whether survival was better for those who received high dose corticosteroids than for those who did not. Stratified survival analysis was performed utilizing the computer program NHLIFE. High dose corticosteroid treatment is defined as greater than 30 mg prednisone/day or its equivalent for 30 days or longer. In the untreated group greater than 90% never received steroids (80 of 88) and the remainder received an average of less than 5 mg of prednisone/day for the duration of their illness. Our hypothesis was that even within prognostically similar subgroups of SLE patients, we would not find a difference in survival related to steroid treatment.

RESULTS The results of the quantitative literature review are depicted in Figure 1. All three of the statistics indicate survival has improved for lupus patients. The linearity of this improvement is reflected by their respective r values. Adding terms to the regression equation (i.e., bending the curve) did not improve the “fit.” If corticosteroid therapy had a major effect on survival, one might expect an upward shift in the slope of these curves after 1950. Using the technique of piece-wise regression (13), we found no statistically significant change in slope after 1950 for any of these three survival curves (P> 0.10). The same statistics-average duration of disease to death, percent survival, and survival curves at 1 and 5 years-were calculated for the 142 patients followed at MGH against 5 year entrance periods (Figure 2). One might expect shorter survival in patients seen more recently because their length of followup was shorter; however, this was not observed. Again linear improvement in survival over the past four decades is apparent. These patients were treated “conservatively7’compared

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Figure 2. Comparison of the MGH series to the cumulated 52 studies. The lines in each frame are the regression lines calculated from the data in Figure I . The MGH data are plotted in the presence of these regression lines and appear to be comparable to the experience at other institutions.

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to patients seen in the same era (Figure 1, C) in that less than one-third of all the patients received high dose steroids and less than one-half of those entering after 1950 received high dose steroids. Nonetheless they survived comparably to temporally equivalent patients in the cumulated 52 studies. Again tests for change in slope after 1950 in the MGH group were not significant (P > 0.10). Linearity of survival over the steroid introduction period was also observed when the mortality of the 142 MGH patients was corrected by sex, race, and age at entry (Figure 3, A). This linearity persisted with further correction for length of survival (Figure 3, B) eliminating the possibility that the improved survival was due to acquisition of a clinic population of stable long-term survivors.

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In order to assess whether steroids differentially affected survival in particular types of patients, we examined the prognostic significance of several characteristics in the MGH patients who entered after 1950 (Table 1). The prognostic variables were chosen for face validity and possible predictive value. Only three of these variables predicted death in our series (P< 0.05): nephritis, total average severity > 2+, and the presence, at any time, of 4+ severity. After these prognostic variables were identified, the MGH series was stratified as to risk: low risk-patients without any poor prognosticators; medium risk-patients with one poor prognostic variable; and high risk-patients with two or more poor prognostic variables. The strength of this risk index is reflected in the proportion of patients in each category who died: low (1/ 15), medium (14/32), and high (21/23). The list of risk factors was not intended to be exhaustive but only to identify patients with different prognoses. The survival curves of steroid treated and untreated patients with nephritis and in medium and high risk strata are shown in Figure 4. Only in the high risk stratum can we discern improved survival in patients treated with high dose steroids (P< 0.05).

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YEAR OF ENTRY Figure 3. A, The mortality by year of entry is corrected for age at entry, sex, and race. Correction was obtained by dividing the observed mortality by the expected mortality from census data for white females of the same age during the same time period (O/E). The mortality by year of entry was further corrected for years of disease (B) by dividing the difference between the observed and expected mortality by the person-years of illness (0-E/P year). Neither correction alters the linear improvement in survival over the time period denoted.

The impressive improvement in survival of lupus patients begins with the first recorded survival statistics and has proceeded unabated to the present day. The trend clearly predates the introduction of corticosteroid therapy and antedates their generalized use in patients with systemic lupus. From these data it seems reasonable to conclude that while steroids may be making a contribution to improved survival they are only one of many factors doing so. Likely contributions to this improvement come from other therapeutic advances such as antibiotics and dialysis. Better diagnostic tests also improve survival by increasing the pool of patients with individuals who, for the most part, have mild disease and thus a better chance of surviving. A rough guide to disease severity is the average number of ARA criteria fulfilled by the patients. When this guide was used, early studies averaged almost twice the number of criteria as later studies, suggesting that the current series are composed of less severely ill patients. Better diagnostic tests that have been developed for lupus include the LE prep, the antinuclear antibody test (ANA), and serum complement determinations. Survival data are difficult to interpret except when the disorder is of short duration with a high case

CORTICOSTEROID THERAPY IN SLE

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Table 1. Prognostic value of selected clinical features

Clinical feature

Correlation with (Pvalue) mortality (after 1950).

Sex

0.6205

Age

0.4253

Categorization of feature Male Female 10-20 21-30 31 4 0 41-50 51+

Severity at presentation

0.2026

Average severity during 1st year of disease

0.3866

Total average severity

0.0025

Number of flarest

0.4265

II+ I+ -2+ 2+ - 3+ 5 I+ I+ - 2+ 2+ - 3+ 0- I+ I + - 2+ 2+ - 3+ 0 I 2 3 4

Nephritis

0.0308

CerebritisS

0.9501

4+ severity at any time

O.oo00

Year of entry

0.4510

No Yes No Yes No Yes Yes in 1st year 1950-54 1955-59 1960-64

Total group

After

20 I22 44

6 64 18 19 16

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9 8 38 27

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39

31 70

20 38 12 I26 23

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3 56

53 24 6 58 84

13 I II 98

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21 43 66 4

42 21 7 19 21 24

* The clinical features of patients at Massachusetts General Hospital are examined for their ability to prognosticate a poor outcome. Each feature is examined against death (yes or no). P values are simple 2 tests of statistical significance in the post-1950 entrant group only. t A flare is defined as a change of 2 1.5 severity units between successivevisits to the physician. $Cerebritis is defined as an episode of psychosis or seizures without an alternative etiologic explanation.

fatality rate. In contrast, lupus has enormous variability in both the nature of the clinical findings and the temporal course. Clearly, each one of our statistics has limited precision. All three statistics vary with the convention for establishing a starting point. Percent mortality by series varies with both the nature of the patient population and the length of followup. Survival curves vary with age and sex distribution and the severity of disease in the patient population, although they are probably the best single statistical representation of survival (8). We have therefore used several statistical approaches, each with its own assumptions and imprecisions. However, trends in the first segment of the analysis, the literature review, must be interpreted with caution and should be viewed as no more than suggestive.

At the very least, undertaking a literature review in this format yields considerable insight into the nature and evolution of the medical concept of SLE. Clearly SLE,as defined in each consecutive decade since 1930, is a disease of increasing benignity. The slope of this improvement in the survival statistics is constant, although there is considerable scatter of points reflecting the variability between institutions. This constancy of slope argues that the improvement in survival of the published medical concept of SLE cannot be ascribed to any single intervention. Although it is conceivable that the curve would have plateaued early had not steroids been introduced, we think not. If that were the case, survival should have declined during the recent trend to moderation in steroid use. Also one would predict that an in-

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YEAR Figure 4. Stratified survival curve analysis of the MGH patients who entered after 1950. A, The subgroup of patients with nephritis were examined. Steroid treated patients (0)were compared to untreated patients 0 and found not to be significantly different in survival ( P = 0.247). B, The difference in survival between steroid treated and untreated patients within the medium risk stratum was examined and also found not to be significantly different ( P = 0.766). C, The difference in survival between steroid treated and untreated patients within the high risk category was examined and found to be significantly different (P= 0.015) with improved survival in the steroid treated group. Pvalues are strata specific Mantel-Hansel1 2 tests of association. Relative risk of death in untreated versus treated patients in the high risk group is 3.76 at 1 year of disease, 1.75 at 2 years, 1.87 at 3 years, and 1.77 overall. The number of steroid treated patients alive and under observation at entry and annually thereafter in A was 23, 22, 18, 17, 17, 15, 13, 11, 10,9, 8,4,4,4, 3. The untreated patients in A were 20, 17, 17, 15, 15, 14, 13, 12, 12, 11, 10,9,9, 8, 8. In B the treated were 14, 14, 14, 13, 13, 13, 12, 10, 10, 10, 8, 8, 8, 5, 5,4 and untreated were 18, 16, 16, 16, 16, 16, 14, 14, 14, 12, 12, 12, 10, 8. In C the steroid treated were 15, 14, 10,9,9,7,6,5,5,4,3 and the untreated were 8,5,4,3, 3, 1, 0.

stitution, such as the MGH, that used steroids sparingly would have a poorer outcome but this is not the case. Furthermore, the experience in any single series is better appreciated in the context of this evolution of improved survival. The MGH series also refleck the evolution of the concept in SLE in that survivorship is improving since 1930 at a rate indistinguishable from that defined by the literature. This analysis of the MGH patients is a historical cohort or historical followup study which has analogies to prospective randomized clinical trials where survival

is assessed with various therapeutic agents (12). There are two major differences: The patients were entered over a period of time considerably longer (1950-1964) than the usual I to 5 years and the therapeutic intervention was not randomized. The bias of not having the intervention randomized is real and significant. However, it is a bias in a direction away from our hypothesis; that is, in all likelihood the patients who received steroids were sicker rather than healthier and therefore should have poorer survival. Thus, when the survival of treated and nontreated patients is the same, as in the

CORTICOSTEROID THERAPY IN SLE

medium risk group, no conclusion can be drawn-either they were truly the same or the steroid treated patients were actually sicker and did improve with treatment. However, in the high risk group the steroid treated patients, whether they were sicker or not, clearly did better than the nontreated group. This improvement in survival is best demonstrated by the survival curves (Figure 4). From both the literature analysis and the MGH experience it is clear that the survival of patients with systemic lupus has improved dramatically over the last four decades. This improvement has been continuous with no significant breaks corresponding to individual improvements in diagnosis or therapy. Our data suggest that steroids have little effect on the survival of the majority of lupus patients with mild disease. The MGH data do not allow us to discern small differences in survival in milder cases. However, steroid use in patients with nephritis appears to have effects on life span only when the nephritis is present in the setting of a patient who is otherwise seriously ill. We were able to demonstrate improved survival with steroid use in the very sickest one-third of our patient population. Since our patient survival was comparable to other published series of the same era, we have no reason to believe, although we cannot be certain, that still higher doses of corticosteroids, as was the practice at other institutions (Figure lC), would have increased the effects observed. We conclude that steroids are efficaciousin promoting survival among very ill (high risk) patients, but have not been shown to extend the lives of less severely afflicted patients with systemic lupus erythematosus.

ACKNOWLEDGMENTS We are indebted to Drs. Dennis Gillings, Steve Samuels, and Regina Johnson for biostatistical advice, Carol Porter for computer assistance, and David McKay for critical review of the manuscript.

REFERENCES Carey RA, Harvey AM, Howard JE: The effect of adrenocorticotropic hormone (ACTH) and cortisone on the course of disseminated lupus erythematosus and periarteritis nodosa. Bull Johns Hopkins Hosp 87:425460, 19SO Pickering G, Bywaters EGL, Danielli JF, Gell PG, Kellgren JH, Long DA, Neuberger A, Nicholson H, Prunty FTG, Robb-Smith AHT, Wright GP, Conybeare ET, Duthie JJR: Treatment of systemic lupus erythematosus with steroids. Report to the Medical Research Council by

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the Collagen Diseases and Hypersensitivity Panel. Br Med J 2:9 15-920,196 1 3. Kaplan D: Treatment of systemic lupus erythematosus. Arthritis Rheum 20:S175-S179, 1977 4. Cluxton HE, Krause LAM: Acute lupus erythematosus disseminatus. Ann Intern Med 19:843-872, 1943 5. Fries JF, Weyl S, Holman H R Estimating prognosis in systemic lupus erythematosus. Am J Med 57561-565, 1974 6. Ektes D, Christian CL: The natural history of systemic lupus erythematosus by prospective analysis. Medicine 50~85-95,197I 7. Dornfeld L, Bluestone R: Therapy of diffuse lupus glomerulonephritis. Arthritis Rheum 19:833-834, 1976 8. Colton T: Statistics in Medicine. Boston, Little Brown, 1974, pp 237-250 9. Ropes M W Systemic Lupus Erythematosus. Cambridge, Massachusetts, Harvard University Press, 1976, p 173 10. Monson RR: Analysis of relative survival and proportional mortality. Comput.Biomed Res 7:325-332, 1974 11. Feinstein AR: Clinical Biostatistics. St. Louis, C. V. Mosby Company, 1977, pp 385-443 12. Pet0 R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV,Mantel N, McPherson K, Pet0 J, Smith PG: Design and analysis of randomized clinical trials requiring’prolonged observation of each patient. Br J Cancer (I. Introduction and design) 34:585-612, 1976; (11. Analysis and examples) 351-39, 1977 13. Neter J, Wasserman W: Applied Linear Statistical Models. Homewood, Illinois, Richard D. Irwin, Inc., 1974, pp 3 13-3 17

APPENDIX Two hundred and fifty papers were identified that describe the clinical course of patients with SLE who were not selected by principal target organ. The 52 series, listed here chronologically, were utilized in the retrospective analysis because they include sufficient information on diagnostic criteria and survival. When more than one chroriologically separate series is included in a single paper, that paper is cited for each series in order. The statistics culled from each series are indicated in parentheses after each citation with the following code: average duration to death (l), total mortality (2), survival curves (3). 1. Madden JF: Acute disseminated lupus erythematosus. Arch Dermatol Syph 25:854-875, 1932 (1) (2) (3) 2. Friedberg CK, Gross L, Wallach K Nonbacterial thrombotic endocarditis associated with prolonged fever, arthritis, inflammation of serous membranes and widespread vascular lesions. Arch Intern Med 58:662-684, 1936 (1)

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3. Rose E, Pillsbury DM: Acute disseminated lupus erythematosus-a systemic disease. AM Intern Med 12:951963, 1939 (2) (3) 4. Reifenstein EC, Reifenstein EC Jr, Reifenstein GH: A variable symptom complex of undetermined etiology with fatal termination. Arch Intern Med 6333-574, 1939 (1) 5. Bywaters E, Bauer W: Series included in reference 33 (2) 6. Kierland RR, Montgomery H, Stickney JM: Symposium on lupus erythematosus. Mayo Clinic Proc 15:675-688, 1940 (2) 7. Stickney JM, Keith NM: Renal involvement ii~disseminated lupus erythematosus. Arch Intern Med 66:643-660, 1940 (2) 8. Klemperer P, Pollack AD, Baehr G: Pathology of disseminated lupus erythematosus. Arch Pathol 32:569-63 1, 1941 (1) (3) 9. Cluxton HE, Krause LAM: Acute lupus erythematosus disseminatus. Ann Intern Med 19:843-872, 1943 (1) (2) 10. Montgomery H, McCreight WG: Disseminated lupus erythematosus. Arch Dermatol Syph 60:356-372, 1949 (2) 11. Tumulty PA, Harvey AM: The clinical course of disseminated lupus erythematosus. Bull Johns Hopkins Hosp 85:47-73, 1949 (I) (2) 12. Dubois EL: Series included in reference 25 (1) (2) 13. McCombs RP, Patterson J R Series included in reference 29 (3) 14. Posnick J: Series included in reference 34 (3) 15. Ropes MW: Series included in reference 38 (2) (3) 16. Carey RA, Harvey AM, Howard JE: The effect of adrenocorticotropic hormone (ACTH) and cortisone on the source of disseminated lupus erythematosus and periarteritis nodosa. Bull Johns Hopkins Hosp 87:425-460, 1950 (1) (2) 17. Dubois EL, Commons RR, Starr P, Stein CS, Morrison R: Corticotropin and cortisone treatment for systemic lupus erythematosus. JAMA 149:995-1002, 1952 (1) (2) (3) 18. Soffer LJ, Bader R: Corticotropin and cortisone in acute disseminated lupus erythematosus. Results of long-term use. JAMA 149:1002-1008, 1952 (2) 19. Shearn MA, Pirofsky B: Disseminated lupus erythematosus. Arch Intern Med 90790-807, 1952 (1) (2) 20. Jessar RA, Lamont-Havers RW, Ragan C: Natural history of lupus erythematosus disseminatus. Ann Intern Med 38:717-731, 1953 (1) (2) (3) 21. Haserick J R Effect of cortisone and corticotropin on prognosis of systemic lupus erythematosus. Arch Dermato1 Syph 68:714-725, 1953 (1) (2) 22. Soffer LJ, Elster SK, Hammerman DJ: Treatment of acute disseminated lupus erythematosus with corticotropin and cortisone. Arch Intern Med 93503-5 14, 1954 (2) 23. Merrell M, Shulman L E Determination of prognosis in chronic disease, illustrated by systemic lupus erythematosus. J Chronic Dis 1:12-32, 1955 (2) (3) 24. Zetterstrom R, Berglund G: Systemic lupus erythema-

ALBERT ET AL tosus in childhood. A clinical study. Acta Paeditr 45:189204, 1956 (1) (2) 25. Dubois EL: Systemic lupus erythematosus: recent advances in its diagnosis and treatment. AM Intern Med 45: 163-184, 1956 (1) (2) 26. Hill LC: Systemic lupus erythematosus. Br Med J 2:655660, 1957 (1) (2) 27. Ziff M, Esserman P, McEwen C: Observations on the course and treatment of systemic lupus erythematosus. Arthritis Rheum 1:332-350, 1958 (1) (2) (3) 28. Gribetz D, Henley WL: Systemic lupus erythematosus in childhood. J Mt Sinai Hosp 26:289-296, 1959 (1) (2) 29. McCombs RP, Patterson JF: Factors influencing the course and prognosis of systemic lupus erythematosus. N Engl J Med 260 1195-1204, 1959 (1) (2) (3) 30. Rupe CE, Nickel SN: New clinical concept of systemic lupus erythematosus. JAMA 171:1055-1061, 1959 (1) (2) (3) 31. Cook CD, Wedgwood RJP, Craig JM, Hartmann JR, Janeway CA: Systemic lupus erythematosus. Description of 37 cases in children and a discussion of endocrine therapy in 32 of the cases. Pediatrics 26570-585, 1960 (2) 32. SoKer LJ, Southren AL, Weiner HE, Wolf R L Renal manifestations of systemic lupus erythematosus: a clinical and pathologic study of 90 cases. Ann Intern Med 54215228, 1961 (2) 33. Pickering G, Bywaters EGL, Danielli JF, Gell PO, Kellgren JH, Long DA, Neuberger A, Nicholson H, Prunty FTG, Robb-Smith AHT, Wright GP, Conybeare ET, Duthie J J R Treatment of systemic lupus erythematosus with steroids. Report to the Medical Research Council by the Collagen Diseases and Hypersensitivity Panel. Br Med J 2:915-920, 1961 (1) (2) 34. Posnick J: Systemic lupus erythematosus. The effect of corticotropin and adrenocorticoid therapy on survival rate. Calif Med 98:308-3 12, 1963 (I) (2) 35. Dubois EL, Tuffanelli DL: Clinical manifestations of systemic lupus erythematosus. JAMA 190 104-1 11, 1964 (2) (3) 36. Kellum RE, Haserik, JR: Systemic lupus erythematosus. Arch Intern Med I13:200-207, 1964 (2) (3) 37. Bencze G, Lakatos L: “Benign” form of systemic lupus erythematosus-a clinical study. Acta Rheum Scand k65-69, 1964 (1) (2) (3) 38. Ropes M W Observations on the natural course of disseminated lupus erythematosus. Medicine 43:387-39 I, 1964 (2) (3) 39. Leonhardt T: Long-term prognosis of systemic lupus erythematosus. Acta Med Scand (suppl) 445:44M3, 1966 (2) (3) 40. Carpenter RR, Sturgill BC: The course of systemic lupus erythematosus. J Chron Dis 19:117-131, 1966 (1) (2) 41. Meislin AG, Rothfield N: Systemic lupus erythematosus in childhood. Analysis of 42 cases, with comparative data

CORTICOSTEROID THERAPY IN SLE

on 200 adult cases followed concurrently. Pediatrics 42:3749, 1968 (1) (2) (3) 42. Siege1 M, Gwon N, Lee SL,Rivero I, Wong W Survivorship in systemic lupus erythematosus. Relationship to race and pregnancy. Arthritis Rheum 12117-125, 1969 (2) (3) 43. Rothfield NR: Series included in reference 52 (3) 44. Estes D, Christian CL: The natural history of systemic lupus erythematosus by prospective analysis. Medicine 5085-95, 1971 (3) 45. Caperton E, Mullin G, Dick FR, Michael A Successful results with aggressive approach to systemic lupus erythematosus (SLE). Arthritis Rheum 15432, 1972 (2) 46. Dubois EL, Wierzchowiecki M, Cox MB, Weiner JM: Duration and death in systemic lupus erythematosus. An analysis of 249 cases. JAMA 227:1399-1402, 1974 (1) (2) 47. Fries JR, Weyl S, Holman HR: Estimating prognosis in

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48. 49.

50.

51.

52.

systemic lupus erythematosus. Am J Med 57561-565. 1974 (2) (3) Fessel WJ: Systemic lupus erythematosus in the community. Arch Intern Med 134:1027-1035, 1974 (2) Bulkley BH, Roberts WC: The heart in systemic lupus erythematosus and the changes induced in it by corticosteroid therapy. A study of 36 necropsy patients. Am J Med 58:243-264, 1975 (1) Urowitz MB, Bookman AAM, Koehler BE, Gordon DA, Smythe HA, Ogryzlo MA: The bimodal mortality pattern of systemic lupus erythematosus. Am J Med 60221-225, 1976 (1) (2) (3) Lee P, Urowitz MB, Bookman AAM, Koehler BE, Smythe HA, Gordon DA, Ogryzlo MA: Systemic lupus erythematosus. Quart J Med &:I-32, 1977 (2) (3) Urman JD, Rothfield NF: Corticosteroid treatment in systemic lupus erythematosus. JAMA 238:2272-2276, 1977 (2) (3)

Does corticosteroid therapy affect the survival of patients with systemic lupus erythematosus?

ARTHRITIS 945 82 RHEUMATISM OFFICIAL JOURNAL OF T H E AMERICAN RHEUMXTISM ASSOCIATION SECTION OF T H E ARTHRI TI S FOUNDATION DOES CORTICOSTEROID...
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