arthritis and rheumatism

Official journal of t h e American Rheumatism Association Section of t h e Arthritis Foundation

A MULTICENTER STUDY OF OUTCOME IN SYSTEMIC LUPUS ERYTHEMATOSUS

I. Entry Variables as Predictors of Prognosis

ELLEN M. GINZLER, HERBERT S. DIAMOND, MAX WEINER, MICHAEL SCHLESINGER, JAMES F. FRIES, CODY WASNER, THOMAS A. MEDSGER, JR., GAYLE ZIEGLER,

JOHN H. KLIPPEL, NORTIN M. HADLER, DANIEL A. ALBERT, EVELYN V. HESS,

and EUGENE V. BARNETT GEORGE SPENCER-GREEN, ARTHUR GRAYZEL, DAVID WORTH, BEVRA H. HAHN,

A retrospective study of factors influencing sur- vival in 1,103 patients with systemic lupus erythemato-

During the course of this work, Dr. Diamond was an Irma T. Hirschl Scholar, Mr. Schlesinger was an Arthritis Health Profes- sions Fellow, Dr. Hadler was the recipient of an Established Investigatorship from the American Heart Association, Dr. Albert was a Robert Wood Johnson Clinical Scholar, and Dr. Spencer- Green received a fellowship from the Arthritis Care and Education Program of the Ohio Department of Health. This investigation was supported in part by grants from the Manhattan chapter of the Lupus Foundation of America, Aramis (NIAMDD Grant 20615), and a Health Sciences Technology Grant PR 2125.

Ellen M. Ginzler, MD, Herbert S. Diamond, MD, Max Weiner, PhD, Michael Schlesinger, MS: Department of Medicine, Downstate Medical Center, State University of New York; James F. Fries, MD, Cody Wasner, MD: Stanford University School of Medicine; Thomas A. Medsger, Jr., MD, Gayle Ziegler, RN.: University of Pittsburgh School of Medicine; John H. Klippel, MD: The National Institutes of Health, Arthritis and Rheumatism Branch; Nortin M. Hadler, MD, Daniel A. Albert, MD: University of North Carolina School of Medicine; Evelyn V. Hess, MD, George Spencer-Green, MD: University of Cincinnati Medical Cen- ter; Arthur Grayzel, MD, David Worth, MD: Montefiore Hospital and Medical Center, Albert Einstein College of Medicine; Bevra H. Hahn, MD: Washington University School of Medicine; Eugene V. Barnett, MD: University of California at Los Angeles School of Medicine.

Participants in the Lupus Survival Study Group: The Na- tional Institutes of Health, Arthritis and Rheumatism Branch, Bethesda, MD: Montefiore Hospital and Medical Center, Albert Einstein College of Medicine, Bronx, NY: State University of New York, Downstate Medical Center, Brooklyn, NY; University of North Carolina School of Medicine, Chapel Hill, NC; University of Cincinnati Medical Center, Cincinnati, OH; University of California at Los Angeles, Los Angeles, CA; Stanford University School of Medicine, Stanford, CA; University of Pittsburgh School of Medi- cine, Pittsburgh, PA; Washington University School of Medicine, St. Louis, MO.

Address reprint requests to Dr. Ellen M. Ginzler, Box 42, Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203.

Submitted for publication December 17, 1980; accepted in revised form December 22, 1981.

sus (SLE) was carried out at 9 university centers diverse in geographic, socioeconomic, and racial characteris- tics. The mortality and disease characteristics of the patients at study entry varied widely among centers. The survival rates from the time patients with a diagno- sis of SLE were first evaluated at the participating center was 90% at 1 year, 77% at 5 years, and 71% at 10 years. Patients with a serum creatinine >3 mg/dl at study entry had the lowest survival rates: 48%, 29%, and 12% at 1, 5, and 10 years, respectively. Survival rate also correlated independently with the entry hemat- ocrit, degree of proteinuria, number of preliminary American Rheumatism Association criteria for SLE satisfied, and source of funding of medical care. When data were corrected for socioeconomic status, race1 ethnic origin did not significantly influence survival. Survival rates varied widely at different participating institutions, generally due to differences in disease sever- ity. Place of treatment was independently associated with survival only in the second year after study entry. Disease duration before study entry did not account for the differences in disease severity.

Reports of prognosis in systemic lupus erythe- matosus (SLE) from single medical centers are often not comparable because of differences in the charac- teristics of patient populations. Because of these dif- ferences, there has been disagreement about the natu- ral history and clinical course of SLE. Attempts to analyze literature trends (1) and to pool data from several centers (2) have provided some insights. In order to test the reliability of these insights and to assess more accurately which factors determine sur-

60 1 Arthritis and Rheumatism, Vol. 25, No. 6 (June 1982)

602 GINZLER ET AL

viva1 in SLE, the Lupus Survival Study Group was established. We analyzed data about disease manifes- tations and outcome for a large number of patients treated at institutions with varied geographic, socio- economic, and racial composition. This report is con- cerned with identifying those features observed at the time of first evaluation for SLE at the participating center which correlated with survival. In the accompa- nying report, we examine the causes of death (3).

PATIENTS AND METHODS Nine university-affiliated medical centers that have

published SLE survival studies agreed to participate in the Lupus Survival Study Group. The centers are listed in a footnote in alphabetic order by city. The diagnosis of SLE was made independently at each center, according to clinical judgment, Data were submitted on all patients seen for the first time with a diagnosis of SLE at the participating center between January 1965 and January 1976, or any consecutive segment of that period. Patient followup extended to early 1978.

The following dates were defined for the purpose of this study: 1) onset of multisystem disease: the date of the appearance of recognizable symptoms or signs of SLE, according to the medical record, not necessarily confined to American Rheumatism Association (ARA) preliminary crite- ria (4); 2) first diagnosis of SLE: the date that SLE was first diagnosed by any physician, regardless of location; 3) study entry: the date of first diagnosis of SLE at the participating center (the patient may have been seen at the center before this time, or the diagnosis of SLE may have been made previously elsewhere); 4) last visit: the date of last recorded visit or, if the patient died, the date of death.

Additional information was requested about each patient, including sex, age at study entry, source of funding of medical care (public or private), entry visit location (hospital or outpatient), and date offirst dialysis and/or renal transplantation. Measures of disease severity included the most abnormal laboratory values recorded before or at the time of study entry, including the highest serum creatinine, lowest hematocrit, highest qualitative and quantitative urine protein excretion, and the total number of ARA preliminary criteria fulfilled for SLE. Measures of the clinical course included the most recent serum creatinine in surviving patients, the highest corticosteroid dose prescribed at the participating institution, a list of other immunosuppressive drugs received, and the cause of death.

Data analysis. The BMDP Biomedical Program was used to construct life tables and survival rates (5). This program provides proportions of individuals surviving, sur- vival rates, and standard errors for time from study entry to termination of study, and a plot of the cumulative proportion surviving. In calculating survival rates, the date of study entry, as defined above, was used as the starting date. The terminal date was the last visit (date last seen or date of death). Patients not known to be dead and last seen alive more than 1 year before the end of the study period were classified as lost to followup. These individuals were includ- ed, with the terminal date being the date last seen. The unit

of time used was months. For the purpose of calculation, survival to any point in a given month was considered to be to the midpoint of the month.

A large proportion of patients were lost to followup before the end of the study. It is neither wholly appropriate to exclude them from analysis nor to include them as if they had survived to the end of the study. By definition, a censored observation is one in which the terminal event, in this case death, has not occurred by the end of the study, since the precise survival time cannot be known exactly but is known to be of at least a certain duration. Data about patients lost to followup are therefore also considered cen- sored data. There is no single method of statistical analysis that is entirely satisfactory to deal with such censored data. To determine whether survival curves for specific subsets of patients were statistically different from each other, we therefore employed two tests: 1) the Mantel test assumes that the temporal distributions of censored observations are the same for both groups being compared (5); 2 ) the Breslow test gives greater weight to terminal events occurring early and allows for differing distributions of censored observa- tions for different populations (6). Unless specifically noted, P values were significant by both tests employed, with the more conservative value given.

A stepwise linear regression was used to determine the specific characteristics at study entry that had the highest correlation with mortality (7). These independent variables included the duration of multisystem disease to first diagnosis of SLE and to study entry, age at study entry, sex, race, source of funding of medical care, location of referral, the presence of seizures, organic brain syndrome, number of ARA criteria satisfied, place of treatment, and the worst values for serum creatinine, hematocrit, and urine protein excretion at any time up to and including study entry. The dependent variable was death.

The degree of the relationship of entry variables to one another was determined by calculating correlation coef- ficients by the Spearman method (5).

RESULTS Data were obtained on 1,103 patients; there was

a range of 30-229 patients per center. The mean age at study entry was 32.3 ? 13.9 years (mean ? standard deviation) (range 3-89). Nine hundred sixty-nine pa- tients, or 88%, were female. The raciallethnic compo- sition of the population included 642 (58%) whites, 356 (32%) blacks, 42 (4%) Puerto Ricans, 27 (3%) Orien- tals, 17 (2%) Mexicans, 5 (1%) American Indians, and 14 (1%) others. Public funding of medical care, a crude measure of socioeconomic status, was required by 623 patients (57%), while 465 patients funded their medical care through private sources. The mean duration of SLE from the onset of multisystem disease to study entry was 36.7 & 52.2 months, with a median of 14 months. The mean duration of multisystem disease before the first diagnosis of SLE was 16.8 5 36.5 months, with a median of 3 months. The mean length

OUTCOME IN SLE 603

of followup from study entry to the last visit or death was 43.5 2 35.2 months. Two hundred twenty-two patients (20%) died during the followup period. The causes of death, including both primary and contribut- ing causes, are the subject of the following report (3).

Entry characteristics. Seven hundred thirty-one patients (66%) satisfied 4 or more ARA classification criteria for SLE at study entry; 126 of these fulfilled more than 6 criteria. Of the 372 patients who satisfied fewer than 4 ARA criteria at study entry, 324 eventual- ly fulfilled 4 or more criteria; thus, by the end of the study period, 96% of patients had satisfied at least 4 criteria.

The mean highest serum creatinine before or at study entry was I .5 ? 2.0 mg/dl. Seven hundred sixty- three of the 1,046 patients (73%) tested had a serum creatinine less than 1.3 mg/dl. Mild to moderate azote- mia (serum creatinine 1.3-3.0 mg/dl) was observed in 202 patients (19%); severe azotemia (serum creatinine > 3.0 mg/dl) was seen in 81 (8%). Proteinuria was documented in 702 of 1,085 patients (65%) tested; moderate proteinuria (2-3 +) was observed in 285 patients (26%), and severe proteinuria (4+) was noted in 208 patients (19%). Twenty-four-hour urine protein excretion was measured in only 587 patients (53%), and the distribution of values was skewed toward those with overt renal disease. Among these individ- uals, the mean protein excretion was 2.2 gm/24 hours. One hundred ninety-seven patients had proteinuria in excess of 3 gm/24 hours.

Two measures of central nervous system (CNS) disease were used. Seizures were reported in 75 of 1,100 patients (7%) for whom data were available, and organic brain syndrome was diagnosed in 93 of 1,094 patients (8%).

The mean lowest hematocrit by the time of study entry was 32.9 & 32.5%. Anemia (hematocrit 537%) from any cause was present in 787 of 1,089 patients (72%), of whom 330 (30%) had severe anemia (hematocrit <30%).

Survival rates. Life table analysis of projected survival for all patients was calculated, with time zero as the date of study entry; this curve is represented by the square symbols in Figure 1. Cumulative survival was 86% at 2 years, 77% at 5 years, and 71% at 10 years. For purposes of comparison with other pub- lished series ( l ) , the curve with the closed circles illustrates survival rates, with time zero being the onset of multisystem disease. Survival was 96% at 1 year, 93% at 2 years, 86% at 5 years, and 76% at 10 years. For all subsequent calculations of survival rates, time zero is the time of study entry.

- FROM ONSET OF MULTISYSTEM DISEASE

w - FROM STUDY ENTRY n

‘“1 YEARS

Figure 1. Survival by life table analysis of all patients in the multicenter Lupus Survival Study Group; the starting time is either onset of multisystem disease or the time of study entry at the participating center. For the survival curve based on onset of multisystem disease, 1,016 patients were alive at I-year followup, 953 at 2 years, 608 at 5 years, and 222 at 10 years. For the survival curve based on time of study entry, there were 859,762,321, and 42 patients alive at 1, 2, 5, and 10 years of followup, respectively.

When patients who entered the study during the earlier years (1965-1970) were compared with those entering during later years (1971-1976), there were no significant differences in the cumulative survival rates, which were 85% and 76% versus 87% and 78%, respectively, at 2 and 5 years.

Predictive value of entry variables to prognosis. To assess the specific contribution of each entry variable to the prognosis for survival, the data were analyzed by stepwise linear regression. All entry vari- ables were considered, except for quantitative protein- uria, which was not used because of the relatively small number of values submitted and the skewed distribution toward severe disease. When the depen- dent variable of death occurred at any time during the followup period, the significant entry predictors of death were (in decreasing order of significance) the qualitative urine protein excretion, highest serum cre- atinine, lowest hematocrit, source of funding of medi- cal care, and place of treatment. When other indepen- dent variables associated with hematocrit (sex, race, payment status, serum creatinine, number of ARA criteria) were “forced” into the stepwise linear regres- sion before entering hematocrit, hematocrit remained a significant independent predictor of mortality ( P <

604 GINZLER ET AL

Table 1. Survival based on the greatest amount of qualitative urine protein up to study entry ~

% survival* Urine No. of

protein patients 1 year 2 years 5 years 10 years

Trace-1 + 209 96 f 1.4 92 -t 2.0 82 f 3.3 75 f 5.1 2-3 + 285 80 -t 2.4 76 f 2.6 68 2 3.1 54 2 6.7 4+ 208 85 f 2.5 79 f 3.0 65 2 3.7 54 f 6.9

* Mean f standard error of mean.

0 383 97 f 0.8 94 f 1.3 91 f 1.8 90 f 2.2

0.05). The most significant entry variables to deter- mine death in the first year of followup after study entry were the highest serum creatinine, lowest hemat- ocrit, and the highest qualitative urine protein excre- tion. Variables most significant to prediction of mor- tality in the second year after study entry were serum creatinine, hematocrit, and the participating institu- tion. In the fifth year after study entry, the significant predictors of death were serum creatinine, hematocrit, urine protein, the number of ARA criteria fulfilled at entry, age at entry, and duration of multisystem dis- ease. By the tenth year, among the entry variables studied, only the highest qualitative urine protein excretion at entry remained a significant predictor of mortality.

Qualitative urine protein excretion had the greatest influence on overall survival among the entry variables examined. Survival rates based on the great- est amount of qualitative proteinuria before or at study entry are shown in Table 1. The presence of protein- uria at a level of 2+ or greater was associated with a significant decrease in survival; survival rates of pa- tients with high proteinuria were 82%, 78%, 66%, and 56% at 1, 2, 5 , and 10 years, respectively, compared with survival rates of 97%, 92%, 86%, and 81% among patients with 0-1 + proteinuria (P < 0.001). The differ- ence in survival between patients having 0 and 1+ proteinuria at entry was significant only at the second year of followup (P < 0.05). Marked proteinuria (4+) was associated with a diminished survival of 85% at 1 year to 54% at 10 years, compared to 97% I-year and 90% 10-year survival among patients with no protein- uria at entry ( P < 0.001).

The highest serum creatinine up to the time of study entry was also associated with survival. The upper limit of “normal” renal function was defined as a serum creatinine of 1.2 mg/dl. In Figure 2 are the survival curves among the subsets of patients with normal renal function, mild to moderate azotemia, and severe azotemia. Patients with any degree of azotemia

had significantly diminished survival when compared with nonazotemic patients ( P < 0.001). Patients with a serum creatinine > 3 mg/dl at any time before or at study entry had a 56% mortality in the first year and a somewhat slower death rate during subsequent years. The 10-year survival for this subset was 12%. Survival in this subset was significantly poorer than for patients with mild to moderate azotemia (P < 0.001). As observed in patients with severe proteinuria, the pres- ence of severe azotemia was associated with the greatest mortality in the first year after study entry. The highest serum creatinine and qualitiative urine

100

80 -I s 5 - CREAT~NINC <I

YEARS OF FOLLOW-UP Figure 2. Survival rates based on the highest level of serum creati- nine recorded before or at the time of study entry. There was normal renal function (serum creatinine <1.3 mg/dl) in 763 patients at study entry, of whom 633 were available for followup at 1 year, 573 at 2 years, 250 at 5 years, 84 at 8 years, and 26 at 10 years. Mild to moderate azotemia (serum creatinine 1.3-3.0 mgidl) was present in 202 patients at study entry of whom 164, 149, 58, 23, and 8 patients were alive at 1, 2, 5, 8, and 10 years of followup, respectively. Severe azotemia (creatinine >3.0 mgidl) was present in 81 patients at study entry, of whom 37, 21, 6, 2, and 1 were alive at 1, 2, 5, 8, and 10 years of followup, respectively.

OUTCOME IN SLE 605

Table 2. Survival based on the lowest hematocrit UP to studv entry

% survival*

No. of 10 Hematocrit patients 1 year 2 years 5 years years

1 3 7 % 302 96 2 1 93 ? 2 9 0 2 2 8 0 2 6 451 93 2 1 88 2 2 7 9 2 2 1 2 2 4

<30% 330 77 2 2 72 5 3 5 9 2 3 5 0 2 6

All patients:

30-37%

Patients with serum creatinine 5 1.2 mg/dl:

>37% 252 98 2 1 94 ? 2 9 1 2 2 8 8 2 3 30-37% 352 95 2 1 91 5 2 8 2 2 3 1 3 2 4 <30% 151 96 2 2 92 5 2 8 2 2 4 7 5 2 5

Patients with serum creatinine 1.3-3.0 mg/dl:

>37% 29 93 2 5 88 5 7 80 2 8 71 2 1 1 30-37% 73 88 2 4 86 5 5 74 C 6 -

<30% 99 82 2 4 76 5 5 6 6 2 5 4 8 2 1 1

* Mean 2 standard error of mean.

protein excretion before or at entry had a correlation coefficient of 0.43.

Sixty-eight patients underwent hemodialysis at some time during the course of the study. Of these, 11 were lost to followup within 1 month. Thirty of the remaining 57 patients died. Possible prognostic factors were examined that might be predictive of survival on hemodialysis, despite the development of renal failure in the remaining 57 patients. There were no significant differences when the subsets of patients on dialysis who lived or died were compared with regard to disease severity variables (serum creatinine, qualita- tive urine protein, hematocrit, CNS involvement, or number of fulfilled ARA criteria) at study entry. Nor were there differences in the duration of multisystem disease to first SLE diagnosis or study entry, age at entry, or socioeconomic status. Data were not avail- able on the clinical status at the start of dialysis. The duration of followup from study entry to the first dialysis was significantly greater among the 27 surviv- ing hemodialysis patients (34.1 & 21.8 months) than for the 21 hemodialysis patients with active SLE who died (15.1 & 19.1 months) ( P < 0.005). This duration was not significantly different when surviving patients were compared with all 30 hemodialysis patients who died (24.2 k 28.4 months).

The lowest hematocrit to the time of study entry was the third most significant variable as an independent predictor of survival as determined by stepwise linear regression. When data from patients were placed in subsets based only on the lowest hematocrit, survival was significantly reduced in pa-

tients with mild anemia (P < 0.005) or severe anemia ( P < 0.001) compared with patients with hematocrit >37% (Table 2). Survival rates in patients with severe anemia were significantly lower than those for patients with mild anemia ( P < 0.001).

Because the highest serum creatinine at entry was inversely correlated with the lowest hematocrit (r = -0.35), and because 68 of the 81 patients with a serum creatinine >3 mg/dl were severely anemic, we analyzed separately the association of anemia with survival among patients in each of the creatinine subsets (Table 2). Among patients with normal renal function, anemia of any degree was associated with a significant decrease in survival ( P < 0.02). When data from patients with severe azotemia were excluded, the survival rates of 90%, 71%, and 63% at 1 , 5 , and 10 years among the patients with hematocrit <30% re- mained significantly decreased, compared with surviv- al rates in patients with hematocrit 230% (P C0.005). However, the difference in survival between patients with and without severe azotemia was not significant when the patients with normal renal function and mild to moderate azotemia were analyzed separately.

Rate of survival decreased in patients with CNS features of seizures (P < 0.05) and organic psychosis ( P < 0.05) (Figure 3). Diminished survival rates associ- ated with either of these features of CNS disease were accounted for primarily by an increased death rate during the first year after study entry. However, neither seizures nor organic brain syndrome were independent predictors of survival, as determined by stepwise linear regression. The possibility that sei-

606 GINZLER ET AL

- I- z 8 40- U w - a

20 - -

0 -

I00

U NO PSYCHOSIS - NOSEIZURES

PSYCHOSIS

U SEIZURES

I I I I , I I I , I

80

zures may have resulted from the effects of active nephritis and renal dysfunction rather than from “lu- pus cerebritis” was considered. When patients were further classified by entry creatinine, the survival rate among the patients with and without seizures was not different for those with normal renal function or those with severe azotemia. Among the patients with mild to moderate azotemia, the presence of seizures at entry was associated with a significantly decreased survival rate compared with that in patients without seizures (P<0.02).

Although the number of ARA criteria fulfilled for SLE at study entry was not a significant indepen- dent predictor of survival throughout the entire study period, survival to the end of the fifth year was influenced by the number of ARA criteria at entry, The survival rates were significantly different among patients based upon this entry variable ( P <0.001) (Figure 4). The subset of patients with less than 4 criteria at entry did well throughout the followup period, achieving a 10-year survival of 82% (P <0.001 versus all other patients). By the time of their last visit, 87% of the patients in this subset had satisfied at least 4 ARA criteria. Patients with 7 or more ARA criteria at

entry had a progressive decline in cumulative survival rate to 37% at 10 years ( P <0.001 versus all other patients). These differences remain significant (P <0.005) when the data from patients with entry creati- nine > I .2 mg/dl and/or 4+ proteinuria (an estimate of nephrotic syndrome) were excluded from analysis. The contribution of urinary cellular casts as an ARA criterion could not be evaluated because this informa- tion was not obtained. The number of ARA criteria was only weakly correlated with other entry predictors of survival, with correlation coefficients of 0.27 for highest urine protein, -0.25 for lowest hematocrit, and 0.12 for highest serum creatinine.

Three hundred seventy-five patients entered the study with normal renal function, proteinuria 5 I +, hematocrit ?30%, and no CNS involvement. Among these patients with mild SLE, there was a 98% surviv- al in the first year, compared with an 88% survival among all other patients. In the subsequent 9 years, incremental mortality among the mild subset ranged from 1-2% per year, with 5- and 10-year survival rates of 90% and 78% respectively, compared with 5- and

3 +:;;; 0

YEARS OF FOLLOW-UP Figure 4. Survival rate based on the number of preliminary Ameri- can Rheumatism Association (ARA) criteria for systemic lupus erythematosus fulfilled by the time of study entry. Less than 4 ARA criteria were satisfied by 372 patients, 605 satisfied 4-6 criteria, and 126 satisfied 7 or more criteria. Among patients who satisfied 3 ARA criteria at study entry, 290, 260, 114, 32, and 9 were alive at 1 , 2, 5, 8, and 10 years after study entry, respectively. For patients who fulfilled 4-6 criteria at study entry, there were 461. 31 I , 165, 61, and 25 patients alive at 1, 2, 5, 8, and 10 years after study entry, respectively. Among patients who fulfilled 7 or more criteria at study entry, 99, 80, 35, 10, and 4 were alive at I , 2, 5, 8, and 10 years after study entry, respectively.

OUTCOME IN SLE 607

Table 3. Differences in entry characteristics between patient populations at the center with the highest survival rate and the center with the lowest survival rate*

Entry characteristic Highest survival Lowest survival P value

Number of patients 206 229 Age at study entry 34.4 +- 14.2t 30.2 +- 12.3 <0.002 % female 84.0 93.9 <0.002 % public funding 21.9 64.2 <0.001 % white/black 85.017.3 22.3161.1 <0.001 % inpatient referral 22.5 65.5 <0.001 Duration multisystem disease

to SLE diagnosis (mo) 32.6 5 59.7 7.2 2 15.5 <0.001 Duration multisystem disease

to study entry (mo) 56.8 2 66.5 24.7 ? 43.6 <0.001 Highest serum creatinine

% with serum creatinine (mg/dl) 1.2 ? 1.5 1.6 t 2.6 NS

>3.0 mg/dl 3.3 8.2 NS Lowest hematocrit (%) 36.2 2 6.7 32.6 2 7.0 <0.001 % with hematocrit <30% 15.9 29.7 <0.002 % with central nervous

system disease 2.9 17.9 <0.001 Number of ARA criteria

satisfied 2.8 +- 1.7 4.9 2 1.9 <O.OOl % with <4/>7 ARA criteria 66.5123 22.3118.8 <0.001

* SLE = systemic lupus erythematosus; mo = month; NS = not significant; ARA = American Rheumatism Association. t Mean ? standard deviation.

10-year survival rates of 72% and 60% among all other patients (P < 0.001).

In addition to parameters of disease severity at entry, survival rate also correlated with other entry characteristics. Among these was the specific center at which the patient was treated. At individual centers, there was a wide variation in mean survival from entry (P < 0.001). Survival rates ranged from 83-100% at 1 year, 79-93% at 2 years, 68-93% at 5 years, and 52- 93% at 10 years. The patient populations at each of 4 centers had survival rates similar to those calculated for all other patients, excluding the specific center in question, while 3 centers had significantly higher sur- vival rates and 2 centers significantly lower survival rates. The center with the highest and the center with the lowest survival rates were among those that con- tributed the largest number of patients to the study. Sixty percent of patients at the center with the highest survival rates had mild disease at entry, compared with only 37% of patients at the center with the lowest survival rates ( P < 0.01). Other features of the patient populations at each center varied widely, not only with regard to racial composition, socioeconomic status, and duration of disease before diagnosis of SLE and treatment at the participating center. These differences are shown in Table 3, in which the entry status of

patients is compared at the two centers with the extremes of survival.

Treatment received before a patient came to the participating center might have influenced the subse- quent disease course. To eliminate this possible influ- ence, we examined survival rates for the 373 patients with multisystem disease of only 6 months or less duration before study entry. The prognosis for the patients in this subset was not significantly different from that of all other patients in the study; survival at 1 , 2, 5 , and 10 years was 90%, 87%, 79%, and 72%, respectively.

In this retrospective study, no specific data for socioeconomic status were available. Payment for medical care through public funding versus private sources, including private insurance and Medicare, was therefore used as a crude measure of socioeco- nomic status. Data from the National Institutes of Health, where all patients are treated without charge, were excluded from this analysis. Four hundred sixty- two privately funded patients had a projected survival rate of 92% at 1 year, 85% at 5 years, and 71% at 10 years. In contrast, public funding of medical care was provided for 415 patients, in whom survival was significantly decreased (P < 0.001) to 86% at 1 year, 68% at 5 years, and 53% at 10 years.

GINZLER ET AL

Table 4. Survival based on race/ethnic origin

% survival* No. of

Race/ethnic origin patients 1 year 2 years 5 years 10 years

White 642 92 2 1.1 89 ? 1.3 80 ? 2.2 82 ? 3.4 68 2 5.9 Black 356 86 2 1.9 81 2 2.4 73 t 2.7

Puerto Rican 42 93 2 4.2 82 2 6.2 71 t 7.8 51 t 14.4 Oriental 27 81 ? 717 81 2 7.7 81 2 7.7 81 ? 7.7 Mexican 17 94 t 5.9 87 2 8.8 87 2 8.8 87 2 8.8 American Indian 5 100 100 100 100 Other 14 73 ? 1.3 73 t 1.3 36 t 2.7 36 +- 2.7

* Standard error of mean.

In calculating survival rates based on racial subsets, only whites and blacks were represented in sufficient numbers to analyze differences. Survival among black patients was significantly reduced com- pared with all other patients ( P < 0.02) and specifically when compared with whites ( P < 0.02) (Table 4). Blacks had more severe disease than white patients at study entry, as shown by a significantly higher mean serum creatinine, lower mean hematocrit, and greater frequency of CNS lupus (Table 5). Although blacks had more severe disease at study entry, the duration of multisystem disease from onset to the time of first diagnosis of SLE and from onset to study entry was shorter among black than among white patients. Public funding of medical care was significantly more fre- quent among blacks than among whites. When pa- tients were divided into subsets by race and socioeco- nomic status, the survival rates were not significantly different between publicly funded white and publicly funded black patients nor between white private and black private patients. The survival rate was signifi- cantly better, however, among white private versus white public patients ( P < 0.02) and among black private versus black public patients (P < 0.02).

DISCUSSION This study describes survival in a large series of

SLE patients who were treated at university-affiliated centers throughout the United States from 1965 to 1978. Survival is further assessed in subsets of patients with specific disease features at the time of study entry, and an attempt has been made to define the prognostic significance of these features. We have not evaluated the influence of later changes in the patients’ course or the treatment received after study entry.

The reported survival rates among large groups of SLE patients with diverse disease manifestations

have increased from less than 50% after 4 years at Johns Hopkins Hospital in 1954 (8), to 50% at 10 years at the Cleveland Clinic in 1964 (9), and finally to approximately 60% at 10 years at Columbia University in 1969 (10). The improvement in prognosis observed in the Columbia study may reflect in part a difference in the starting point for calculation of survival times; this was defined as the time of recognition of onset of multisystem disease (at least 4 manifestations of SLE), whereas the starting point in the 2 earlier studies was the date of diagnosis. A recent study by Fessel in San Francisco ( 1 1 ) , in which a group of patients with generally mild disease was described, yielded the most promising results; Fessel showed a projected 10-year survival rate of greater than 90% (the apparent starting time was the development of the fourth ARA criterion for SLE). The present study supports the concept of a more favorable prognosis in SLE, with a mortality of less than 3% per year and a projected l0-year survival rate of 76% from the time of onset of multisystem disease manifestations.

These previous reports describe survival rates at a single institution. In the present study, the com- bined survival rates of the 9 centers are undoubtedly more representative of the prognosis for SLE patients treated at university centers in the United States. Survival varied widely among the 9 centers, due in part to the differences in patient characteristics at study entry. Prognosis at the center with the best statistics in our study was similar to that of Fessel’s series (1 1). The wide range of survival rates at individ- ual centers is indicative of the limitations of attempts to recognize changes in survival rates by comparing data from different centers collected at different times.

One of our aims in the present report is to identify specific disease features and other patient characteristics at the time of first evaluation at a

OUTCOME IN SLE 609

Table 5. Differences in entry characteristics between black and white oatients'

Entry characteristic Black White P value

Number of patients Age at study entry % female % public funding % inpatient referral Duration multisystem disease

to SLE diagnosis (mo) Duration multisystem disease

to study entry (mo) Highest serum creatinine

(mddl) % with serum creatinine

>3.0 mg/dl Lowest hematocrit ("6) % with hematocrit <30% % with central nervous

Number of AKA criteria

"6 with <4/>7 AKA criteria

system disease

satisfied

356 31.6 t 13.0t

92.4 81.4 76.9

11.0 t 22.9

25.0 * 41.1

1.7 2 2.6

9.9 30.9 t 6.8

39.7

18.5

4.4 f 1.7 28.0112.4

642 33.3 t 14.8

83.9 41.H 56.4

20.6 t 43.8

44.8 5 57.8

1.4 * 1.5

6.4 34.0 2 6.9

25.3

10.5

4.2 * 1.9 36.0110.0

<0.001

<0.05 NS

* N S = not significant; SLE = systemic lupus erythernatosus; mo = months; AKA = American Rheumatism Association. t Standard deviation.

university center that are predictive of the subsequent disease course. Some selection bias is inherent in such a study, in that patients who become severely ill very early in their disease course may not live to be referred to a university center. Likewise, patients with mild disease may never require referral.

The correlation of a variable with survival may mean that the variable has a direct influence on survival, or it may indicate that the feature is associat- ed with other factors which directly affect survival. The technique of stepwise linear regression allows assessment of the specific prognostic contribution of individual features independently of the influence of other measured variables. By such analysis, it is apparent that measures of disease severity are the most important entry predictors of prognosis in the SLE patients studied here. Although these variables frequently correlate with each other, stepwise linear regression shows some of them have independent significance.

As would be expected, patients with evidence of severe renal dysfunction at study entry had a poor prognosis. However, few patients with severe renal dysfunction survived beyond the first 5 years. Entry serum creatinine is thus a poor predictor of late mortality in individuals who survive longer than 5 years. In this situation, qualitative urine protein excre-

tion at entry, which has less influence on early mortal- i ty, is a significant predictor of late survival.

Although there is a strong association between the development of azotemia and anemia, according to the stepwise linear regression the entry hematocrit had an independent association with mortality among our SLE patients. This is consistent with the findings of Fries (2). Similarly, fullfillment of 7 or more ARA criteria for SLE at entry seemed to correlate well with severe disease and was associated with a poor progno- sis, even among patients who did not have azotemia of 4+ proteinuria. Stepwise linear regression showed the number of ARA criteria at entry was a significant independent predictor of survival to the end of 5 years.

According to our data, features of CNS involve- ment at entry did not independently influence survival, as determined by stepwise linear regression. This finding is in agreement with the observation of Estes and Christian (10).

Demographic features such as race and sdcio- economic status seemed to be associated with survival rates. By stepwise linear regression. however, only the source of payment of medical care had a significant influence on prognosis. Racial differences correlated with differences in disease severity and method of payment for medical care. These correlations may reflect an inherent difference in the patterns of entry

610 GINZLER ET AL

into the health care system or differences in care after entry. Siegel, Holley, and Lee (12) reported that the incidence, morbidity, and mortality of SLE were con- sistently highest for black women in both New York City and Jefferson County, Alabama during the period from 1956 to 1965. Kaslow and Masi (13) similarly found an increased mortality from SLE among black women, according to nationwide data from the Nation- al Center for Health Statistics, during the period from 1968 to 1972. Conversely, Dubois (14) concluded that black patients seen from 1950 to 1973 did not have a more malignant course than other patients; however, he noted only a 48% 3-year survival among patients first seen at a county hospital, compared with a 71% survival among patients seen privately or in consulta- tion. These observations were confirmed in a subse- quent report (15), in which Dubois’ patients were followed until 1980.

Fessel(l1) reported data about patients homog- enous in their ability to pay for medical care, in that all were members of the prepaid Kaiser Permanente Medical Plan. Nevertheless, he found a considerable difference in disease features among black and non- black patients; blacks had a greater frequency of serologic abnormalities (84% versus 42%) and serositis (58% versus 24%) and a lower frequency of CNS disease (0% versus 18%). Our experience in the multi- center study was somewhat different; black patients had a higher frequency of both seizures and organic brain syndrome by the time of study entry. The apparent development of more severe renal, hemato- logic, and central nervous system disease over a shorter period of time, as reflected by the shorter duration of multisystem disease to diagnosis and study entry, might be indicative of a more virulent form of the disease in blacks. Alternatively, the stepwise lin- ear regression analysis supports the hypothesis that the observed association of mortality and race is related to selection factors in presentation for medical care.

Neither disease severity at entry nor ultimate survival were related directly to duration from onset of multisystem disease to study entry or to duration of multisystem disease before the first diagnosis of SLE. In fact, these time intervals, at least as recorded in the medical records, were shorter at the centers with lower survival rates. A number of explanations for this finding are possible: patients at these centers might have a more virulent form of disease, their perception of the actual time of onset of disease symptoms might be inaccurate, and/or treatment received before study

entry might have positively influenced survival and retarded disease progression among patients at the centers with significantly increased survival rates.

This report deals only with characteristics of patients at study entry as predictors of prognosis. Neither the development of additional disease features nor the specific details of treatment after study entry have been considered here, in part because the retro- spective nature of this multicenter study prevented access to all of the data that would have been desir- able. Furthermore, it has been shown in another large multicenter study (16) in which treatment regimens for coronary heart disease were evaluated, that statistical analyses that place patient data into subsets by post- entry criteria may be unreliable and misleading.

We have described survival rates for a large number of SLE patients who had diverse clinical manifestations and widespread geographic distribu- tion. The results of the study indicate a relatively favorable prognosis for prolonged survival in SLE. These data support the belief that features of disease severity (namely, serum creatinine, degree of protein- uria, and hematocrit) are major determinants of life expectancy. Future studies should be designed to better characterize the differences in patient popula- tions and ultimate prognosis at different institutions and to investigate the contribution of socioeconomic factors to mortality.

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OUTCOME IN SLE 61 1

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