37 PROGNOSIS IN SYSTEMIC LUPUS ERYTHEMATOSUS Negative Impact of Increasing Age at Onset, Black Race, and Thrombocytopenia, as well as Causes of Death JOHN D. REVEILLE, ALFRED BARTOLUCCI, and GRACIELA S. ALARCdN To assess the impact of demographic and clinical factors on prognosis in patients with systemic lupus erythematosus (SLE), we examined survivorship by Life-table analysis in 389 patients. There were approximately equal numbers of Caucasian patients and American black patients in this study group. On both univariate and multivariate analyses, we found that both American black race and increasing age at SLE onset independently worsened the probability of survival. Of all the clinical factors we analyzed, thrombocytopenia emerged as the only independent risk factor for a worse prognosis in SLE. In all clinical and demographic groups considered, the leading cause of death was infection. Systemic lupus erythematosus (SLE) is a chronic, multisystem autoimmune disease that predominantly affects women of childbearing age. The extensive cutaneous, musculoskeletal, and visceral manifestations of this disease, especially in younger patients, are often associated with considerable limiFrom The Departments of Medicine (Division of Clinical Immunology and Rheumatology and the Clinical Information Systems), Biostatistics and Biomathematics, and Epidemiology, School of Medicine and School of Public Health, The University of Alabama at Birmingham. John D. Reveille, MD: Department of Medicine (current address: Division of Rheumatology and Clinical Immunogenetics, University of Texas Health Science Center, Houston); Alfred Bartolucci, PhD: Department of Biostatistics and Biomathematics; Graciela S. Alarcon, MD, MPH: Department of Medicine. Address reprint requests to John D. Reveille, MD, Division of Rheumatology and Clinical Immunogenetics, University of Texas Health Science Center, PO Box 20708, Houston, TX 77225. Submitted for publication December 20, 1988; accepted in revised form August 7, 1989. Arthritis and Rheumatism, Vol. 33, No. 1 (January 1990) tation of activities, both social and occupational, as well as with a decreased life expectancy. Since the initial, 1955 report of a markedly decreased probability of survival of patients with SLE (l), prognosis in this disease has been the subject of a number of studies (2-16). The results of these studies show that the probability of survival has significantly improved over the ensuing 35 years, although it is debatable whether this is due to increased awareness and earlier diagnosis in less severely affected individuals, or to better treatment. Aside from the negative impact of renal and neuropsychiatric manifestations on outcome in SLE (10,l l), few studies have identified a role for other clinical features of the disease in the prognosis. Demographic characteristics, particularly race (5,9,15-18), sex (19), and young age at disease onset (17,18,20-26), have also been shown to affect the clinical presentation of SLE. Moreover, this disease has been shown to be more common among the American black population (9,27), and some studies have found a worse prognosis for American black patients with SLE than for Caucasian SLE patients (5,15,16). However, the reasons for this difference, whether due to socioeconomic or clinical factors (or a combination of these), are not clear. To further address these issues, we studied a large, geographically stable, and clinically well-defined group of SLE patients to determine the relative contributions of demdgraphic and clinical factors to disease outcome, and to causes of death. The results of our epidemiologic analyses are reported here. PATIENTS AND METHODS Patients in this study were seen by members of the Division of Clinical Immunology and Rheumatology or the 38 Division of Nephrology at The University of Alabama at Birmingham (UAB) affiliated hospitals, as either outpatients or inpatients, between 1975 and 1984. This included patients seen at the UAB hospital and outpatient clinic, the Birmingham Veterans Administration Hospital, and the Birmingham Children’s Hospital. International Classification of Disease codes 734. I (before 1978) and 710.0 (after 1978) were used to perform a computer search for all inpatients seen during the period of study. In addition, all medical records from the rheumatology outpatient clinic (covering the period 1979 to 1984) were reviewed for those with the diagnosis of SLE who were seen as outpatients only. Outpatients seen by members of the Division of Clinical Immunology and Rheumatology between 1975 and 1979 were identified by reviewing laboratory serum log books, since sera from nearly all SLE outpatients during this period had been stored. Although outpatient records from the Division of Nephrology and the Birmingham Children’s Hospital were not reviewed, the names of all those with SLE who were seen as outpatients between July 1983 and July 1985 were provided by their respective physicians. The charts of all patients seen in the rheumatology outpatient clinic at the VA Hospital between July 1982 and July 1985 were also reviewed for the diagnosis of SLE (lists of patients seen at this facility before July 1982 were not available). Only those patients whose SLE met 4 or more of the American Rheumatism Association (ARA) revised criteria for the classification of SLE (28) were included in this study. Patients referred for renal transplant or for hemodialysis alone were studied only if their referring physician had included records of their disease course. The medical records of each patient were abstracted for the following information: race, sex, date of birth, age at SLE onset, date of onset of SLE (defined as the onset of multisystem disease), insurance status at the first visit to our medical system (private insurance versus public insurance, which was defined as Medicare a n d o r Medicaid only, or no insurance), and absence or presence (at any time in the SLE course) of the following disease features: arthritis, neuropsychiatric manifestations (including seizures, psychosis, longtract signs, coma, transverse myelitis, cranial nerve signs, chorea, organic brain syndromes, or other central nervous system [CNS] lesions directly attributable to SLE and not to metabolic, drug, or other causes, and excluding headache and peripheral neuropathy), renal disease (defined as 1 or more of the following: 3 0 0 mg of proteinuria in 24 hours, >2+ proteinuria on 2 occasions, or cellular casts [not attributable to infection], or abnormal renal biopsy findings), mucocutaneous disease (and type), serositis (including pericarditis, as documented by echocardiogram, or pleurisy, as documented by the presence of pleuritic chest pain or pleural effusion believed by the physician of record to be due to SLE and not to infection), or cytopenia (either as autoimmune hemolytic anemia, leukopenia of 54,000 white blood cells [WBC]/mm3, or moderate-to-severe thrombocytopenia defined as 5100,000 platelets/mm3). The maximum level of anti-DNA antibodies that had been detected was entered and subcategorized as high titer (250% binding by the Farr technique [29] or 2 1:80 by Crithidia luciliae [30]), low titer REVEILLE ET AL (10-50% binding on Farr assay or <1:80 on C luciliae substrate), or absent. To analyze the impact of clinical parameters of SLE present at the time of, or within 6 months of, the diagnosis, we further examined a subset of patients whose medical care from the time of diagnosis had been at our system or whose complete medical records since diagnosis were available for our review. The following data were obtained at entry into the medical system for those patients seen at, or within 6 months of, the SLE diagnosis: age at diagnosis, date of diagnosis, serum creatinine level (elevated levels defined as 2 1.5 mg/dl), amount of proteinuria, blood pressure value, hematocrit value, platelet count (moderate-to-severe thrombocytopenia defined as 5 100,000/mm3), DNA antibody levels, and serum hemolytic complement (CH50) levels (hypocomplementemia defined as depressed CH50), as well as the presence of neuropsychiatric manifestations, myositis, and pulmonary involvement (defined as a chest radiograph showing interstitial fibrosis or pulmonary function tests demonstrating restrictive lung disease). Causes of death were determined on the basis of the clinical data, death certificates, and when available, on autopsy findings. For SLE patients who died at the UAB affiliated hospitals, the following laboratory values were obtained from the medical records at the time of the last hospital admission: blood glucose, serum creatinine, hematocrit, WBC count, differential cell count, and platelet count. We also recorded the dosage of prednisone the patient had been taking prior to admission, as well as any use of immunosuppressive agents, either at or after the last hospital admission. In the fall of 1985, we contacted all of the patients, their family members, or their referring physicians if the family members were not available, to ascertain the patient’s current status. Death certificates were sought from the Alabama Bureau of Vital Statistics for those patients who could not be located. The duration of followup was defined as the interval from onset of multisystem disease. In the subset of patients with medical records available from the time of SLE diagnosis, the duration of followup began at the time the diagnosis of SLE was established. For those whose current status could not be ascertained, followup was calculated as the interval from the onset or diagnosis of SLE to the last contact with the system. Life-table analysis was performed by the method of Merrell and Shulman ( I ) . The method proposed by Greenwood (31) was used to determine difFerences between survival curves. We also utilized Cox’s proportional hazards general linear model procedure (32), with the dependent variable being survival, to determine which of the many potentially important parameters had the greatest impact on prognosis in SLE. For life-table and multivariate analyses, P values less than or equal to 0.05 were considered significant. RESULTS Demographic characteristics of patients studied. A total of 525 medical records with a listed diagnosis of SLE were reviewed. Of these, 67 patients were found 39 FACTORS AFFECTING SLE PROGNOSIS Table 1. Impact of demographic and clinical parameters, present at any time during the course of systemic lupus erythematosus, on survival* Probability of survival (%) n year 5 years years 15 years 85 304 96.0 96.0 89.1 88.8 82.8 83.8 80.2 79.0 NS 151 97 95.2 93.5 92.5 84.7 86.2 80.2 - <0.01 33 106 95.5 96.1 90.0 78.9 81.9 74.8 - NS 215 174 95.3 95.4 86.5 91.2 78.5 89.4 71.6 87.6 <0.01 68 86 95.6 92.9 83.3 82.3 81.7 72.7 - <0.05 101 288 90.2 97.2 83.0 89.1 74.8 84.7 71’7 80.7 <0.05 79 309 85.9 97.7 74.0 90.6 65.2 85.3 81.7 c0.005 1 Males Females Insurance statust Private insurance Caucasians American blacks Public o r no insurance Caucasians American blacks Renal disease Present Absent ProteinuriaS 0.5-3 g d 2 4 hours >3 g d 2 4 hours Neuropsychiatric disease Present Absent Thromboc ytopenia8 Present (5100,000 plateletslmm’) Absent 10 P C0.03 * Total patient population was 389. Time interval from the onset of multisystem autoimmune disease to either fall 1985, death, or last followup. NS = not significant; - = number too small for meaningful analysis. t Insurance status was not available for 2 patients; the 12 patients from the VA hospital were included in the group with public or no insurance. $ Compared with patients without proteinuria (<0.5 g d 2 4 hours). No significant difference was seen in the probability of survival when the survival curve of those with 0.5-3 gm of protein in 24 hours was compared with those with >3 grn/24 hours. No 24-hour urine protein collections were available from 61 patients with renal involvement. 8 Platelet count was not available for I patient. to have diagnoses other than SLE (including 10 with drug-induced lupus), 14 had been referred for renal transplant evaluation or hemodialysis but without the records of their disease course, and 15 had incomplete data available to evaluate the SLE diagnosis. Forty patients had a listed diagnosis of SLE and complete clinical and serologic data, but their symptoms did not meet 4 of the ARA revised criteria for the classification of SLE; they were therefore not included in this study (19 were American black and 21 were Caucasian). In all, 389 patients who met 4 or more ARA revised criteria for the classification of SLE and were seen at UAB between 1975 and 1984 (including 12 referred for hemodialysis or transplant alone and I2 who were seen only at the VA hospital) were identified. Of these, 184 were Caucasian, 203 were American black, and 2 were Asian. There were 85 male and 304 female patients. Caucasian males were significantly older at SLE onset than were Caucasian fe- $ 1 P< 0.05 3 5 0 ‘0 2 4 6 8 10 12 14 33 38 25 Years Since Disease Onset Caucasians-184 AmericanBlacks ....2 0 3 149 161 121 125 96 86 70 66 47 53 32 Figure 1. Cumulative probability of survival at disease onset for 387 patients with systemic lupus erythematosus, according to race (184 Caucasians and 203 American blacks; 2 Asians excluded). Differences between survival curves were determined by the method of Greenwood (31). REVEILLE ET AL 40 * males (mean ? SD age 47.8 +- 17.6years versus 36.8 16.7 years; P < 0.001). Caucasian males and females as a group were significantly older at disease onset than were American black females (27.2 13.1 years) (P < 0.001) or males (27.6 17.5 years) (P < 0.001). There was an increased frequency of SLE in females compared with males, which was much more significant among the American blacks than among the Caucasians (ratio of fema1es:males 6.1: 1 in American blacks versus 2.2:l in Caucasians; P < 0.001). The mean duration of followup was 8.8 years. The fall 1985 * * status was obtained for 363 of the original 389 patients (93%), including 6 whose death certificates were obtained from the Alabama Bureau of Vital Statistics. A total of 89 patients (25%) had died. Impact of demographic parameters on survival. Univariate analysis demonstrated no difference in the probability of survival of males compared with females with SLE (Table 1). When race alone was considered, however, American black SLE patients fared worse than Caucasian SLE patients (P < 0.05) (Figure 1). Those patients with SLE onset before the age of 20 n F Y .02 r 0 t 6o 40. .- 20. -a .I- 3 5 2 0 4 6 10 8 Years Since Disease Onset Years Since Disease Onset SLE Patients-94 U.S. Population ---- 85 66 49 40 SLEPatients-218 30 202 162 135 104 84 US. Population.--- B A h z# Y 100- Figure 2. Cumulative probability of survival at disease onset for 389 patients with systemic lupus erythematosus (SLE), according to age at disease onset, as compared with the US population. A. Age 0-19 years (94 patients). B. Age 2 0 4 9 years (218 patients). C. Age 2 5 0 years (77 patients). Differences between survival curves were determined by the method of Greenwood (31). Years Since Disease Onset SLEPatients-77 52 68 US. Population---- C 35 21 15 41 FACTORS AFFECTING SLE PROGNOSIS appeared to do worse than those with later onset (between ages 20 and 49), and the probability of survival in the group with young age at SLE onset approximated that of the group with onset at age 50 or after. Compared with the estimated survival of the age-matched segment of the US population (33) (data for age-matched segment of the Alabama population not available), SLE patients fared significantly worse in all age groups (Figures 2A-C). The most striking difference was in the group whose SLE began when they were young. However, when compared with each other, the differences in probability of survival between the 3 age groups considered did not reach statistical significance. Insurance status (as a proxy for economic status) indicated a slight difference in the probability of survival between those with private insurance compared with those with public insurance or no insurance, although these differences did not achieve statistical significance. Moreover, Caucasian SLE patients with private insurance fared better than American black SLE patients with private insurance (P < 0.01). The number of Caucasian patients who had public insurance or no insurance (n = 33) was too small to perform conclusive life-table analysis. When American black patients with private insurance (n = 97) were compared with those with public insurance or no insurance (n = lM), the differences did not reach statistical significance. Impact of clinical parameters, occurring at any time during the course of SLE, on survival. Because arthritis, serositis, autoimmune hemolytic anemia, leukopenia, and cutaneous disease were equally present in those who died and those who did not die (data not shown), life-table analysis was not performed for those parameters. Patients with renal involvement at any time in the disease course (n = 215) fared worse than those with no renal involvement (n = 174) (P< 0.01). Furthermore, the maximum level of proteinuria at any time in the disease course (>3 gm/24 hours and 0.5-3 g d 2 4 hours versus <0.5 g d 2 4 hours) also adversely affected prognosis (Table 1). Similarly, neuropsychiatric manifestations negatively impacted survival probability (P < 0.05). Because there were only 13 patients with only psychiatric symptoms, statistical analysis of this group versus those with neurolokic involvement would not be meaningful. However, the most striking negative effect on survival, more than either renal or neuropsychiatric involvement, was qignificant thrombocytopenia (platelet count 5100,000!mm3, n = 79) (Figure 3), with only - 100 c 0 0 Thrombocylopenia Presenl Absent ____ - 2 4 6 8 10 12 14 18 12 58 12 45 8 30 Years Since Disease Onset 78 61 309 253 50 109 30 156 23 116 17 82 Figure 3. Cumulative probability of survival at disease onset for 79 systemic lupus erythematosus (SLE) patients who had thrombocytopenia at any time in the disease course, compared with 309 SLE patients without thrombocytopenia (1 patient in whom platelet counts were not available was excluded). Differences between survival curves were determined by the method of Greenwood (31). an 85.9% probability of survival 1 year after disease onset (P < 0.005). After 2 years, the slope of the survival curve leveled off, and paralleled the slopes of the renal and neuropsychiatric involvement curves. This suggests that the major impact of moderateto-severe thrombocytopenia on SLE prognosis occurs in the first 2 years of disease. Multivariate analysis showed that American black race, increasing age at SLE onset, and moderate-to-severe thrombocytopenia, were independent factors that adversely affected survival in SLE (Table 2). When adjusted for other variables in the model, including sex, insurance status, neuropsychiatric involvement, DNA antibodies, proteinuria, renal disease, and serositis, none of the clinical parameters considered (present at any time in the course of SLE) affected the probability of survival. Table 2. Cox multivariate analysis of the impact of demographic and clinical parameters occumng at any time during the course of systemic lupus erythematosus on survival* Variable Increasing age at disease onset American black race Thrombocytopenia J P 12.33 O.OOO4 9.93 4.42 0.0016 0.035 * Total patient population was 389. Only those parameters found to have a statistically significant impact are shown. Insurance status, neuropsychiatric involvement, presence of DNA antibody, proteinuria, renal involvement, and serositis showed no significant impact on prognosis by multivariate analysis. 42 REVEILLE ET AL Impact of clinical parameters, at diagnosis, on survival. For the 277 patients on whom extensive clinical data were available either at or within 6 months of SLE diagnosis, there were significant differences in the results of univariate life-table analysis from the time of diagnosis (Table 3). When present at the time of diagnosis, proteinuria, diastolic or systolic hypertension, anemia, and thrombocytopenia all negatively impacted survival probability. Of the 79 patients who had a platelet count 5100,000/mm3 at any time in the disease course, platelet counts done at or within 6 months of SLE diagnosis were available in 61. Qf these 61 patients, 37 (61%) had a platelet count s100,000/mm3at diagnosis. It should be noted that for the analysis shown in Table 3, thrombocytopenia was defined as a platelet count of <150,000/mm3. The probability of survival was the same for those with a platelet count of I100,W/mm3(data not shown), but fewer patients in this group meant less meaningful statistical analysis. Thrombocytopenia was present with approximately equal frequency in patients with and patients without renal disease (23% versus 19%), although it was slightly more frequent in patients with neuropsychiatric disease than in those without this manifestation (30% versus 19%; P = 0.02). The presence of hypocomplementemia, elevated serum creatinine levels, DNA antibodies (either low or high titer), neuropsychiatric manifestations, and interstitial lung disease did not adversely affect prognosis in this subgroup of patients. The negative influence of some parameters, such as thrombocytopenia (even when mild) and hypertension, were apparent early in the disease course, whereas other parameters, such as Table 3. Impact of clinical parameters, present at or within 6 months of diagnosis of systemic lupus erythematosus, on survival* Probability of survivial (%) 1 year 5 years years P 170 92 93 81 86 72 82 0.02 225 52 94 87 85 77 79 - NS 60 217 88 94 80 85 81 0.04 n Proteinuriat 20.5 g d 2 4 hours <0.5 gm/24 hours Serum creatinine 5 1 . 5 gm/dl >1.5 gm/dl Systolic blood pressure >I50 mm Hg 5150 mm Hg Diastolic blood pressure >90 m m Hg 590 mm Hg Hematocritt <30% 2 30% Platelet countt <150,000/mm3 2150,000/mm3 Neuropsychiatric disease Present Absent Interstitial lung disease Present Absent DNA antibodiest Absent Present at low titer Present at high titer Hypocomplementemiat Present Absent 106 10 50 86 80 227 94 84 80 0.01 88 188 89 94 75 87 70 81 0.05 61 21 1 82 96 72 92 67 83 0.005 47 230 90 93 87 83 49 228 90 93 81 84 54 I08 40 98 94 93 95 86 83 80 151 82 91 93 79 88 74 80 NS NS * Total patient population was 277. Time interval from the diagnosis to either fall 1985, death, or last followup. NS = not significant; - = number too small for meaningful analysis. t Parameter was not measured at diagnosis in all patients. FACTORS AFFECTING SLE PROGNOSIS Table 4. Cox multivariate analysis of the impact of demographic and clinical parameters present at or within 6 months of the diagnosis of systemic lupus erythematosus on survival* Variable 2 P American black race Thrornboc ytopenia Increasing age at disease onset 9.45 8.82 4.52 0.002 0.003 0.034 * Total patient population was 277. Only those parameters found to have a statistically significant impact are shown. Hypocomplementemia, neuropsychiatric involvement, elevated diastolic or systolic blood pressure, decreased hematwrit, presence of DNA antibody, pulmonary disease, insurance status, elevated creatinine level, and proteinuria showed no significant impact on prognosis by multivariate analysis. proteinuria, appeared to produce their greatest effect later. Multivariate analysis of demographic and clinical factors present at or within 6 months of disease diagnosis showed that American black race, thrombocytopenia (defined, as in the previous multivariate analysis, as a platelet count %100,000/mm3),and increasing age at SLE onset were independent risk factors for a decreased probability of survival (Table 4). Regardless of their effect on SLE outcome as shown by univariate analysis, neither proteinuria, anemia, hypertension, hypocomplementemia, DNA antibodies, neuropsychiatric involvement, interstitial lung disease, elevated creatinine level, nor insurance status at diagnosis independently affected the prognosis in SLE as shown by multivariate analysis. Causes of death in the study population. Eightynine patients died between 1975 and the end of 1985 (26% of the American black SLE patients and 20% of the Caucasian SLE patients studied). The circumstances and/or cause of death were known in 74 study patients (83%). In this group, infection was the leading primary cause of death (Table 5 ) , followed by bleeding (gastrointestinal or CNS hemorrhage), cardiovascular disease, and active SLE. The proportions of those who died of infection compared with those who died of other causes were equivalent in Caucasian patients and American black patients, as well as in all patients with and all patients without thrombocytopenia (data not shown). Infection as a primary cause of death was more frequent in the early-onset SLE group (46%, age 519) and in the “mid-onset’’ group (61%, ages 2049) than in the group with late-onset SLE (26%, age ?SO) (P= 0.03). In this latter group, cardiovascular disease and neoplasms, respectively, accounted for 26% and 21% of the deaths, compared with 8% and 4% of the 43 Table 5. Causes of death of patients with systemic lupus erythematosus (SLE). according to age at disease onset* Age at onset of SLE 5 1 9 years (n = 24) 2 0 4 9 years (n = 31) 2 5 0 years Cause of death Infection Gram-positive Gram-negative Mixed bacterial Fungal Unspecified Bleeding Active SLE Renal failure7 Neoplasm Cardiovascular disease Other 46t 4 21 4 4 13 13t 17 8 4 8 17 61$ 16 26 0 13 7 10 1O$ 3 0 3 20 265 0 5 5 0 16 5 11 0 21 26 11 (n = 19) * A total of 89 patients died during the period of study; cause of death was ascertained for 74 of them. Values shown are percentages. t Includes 2 patients who died of sepsis and bleeding, and 1 who died of sepsis in the setting of uremia. $ Includes 2 patients who died of infection in the setting of active SLE. § P = 0.03 versus all patients under age 50 at SLE onset. fl Includes those with complications of either uremia or dialysis. deaths in the early-onset SLE group and 3% and 0% in the mid-onset group (P = 0.0003, relative risk [RR] = 13). Of the 29 SLE patients with moderate-to-severe thrombocytopenia ( I l00,00O/mm~at any time in the disease course) whose cause of death was known, only 5 (17%) died from hemorrhage or complications thereof, compared with 3 (7%) of the 45 patients without thrombocytopenia whose cause of death was known. Of the 28 patients with thrombocytopenia who died (and for whom clinical data were available; in 1 patient, the cause of death was recorded, but no other clinical data were available), 14% were taking immunosuppressive drugs in the month prior to death, compared with 40% of patients without thrombocytopenia who died. Among the 50 patients whose prednisone dosage at the time of the last hospital admission (before death) was known, the mean SD dosage varied widely, from 32.0 f 35.8 mg/day in the 23 patients with thrombocytopenia to 24.4 ? 25.0 mg/day in the 27 patients without (Pnot significant). Similarly, there were no significant differences in the mean prednisone dosage at the time of the last hospital admission in the 30 patients with SLE who died of infection (28.5 25.4 mg/day) compared with the 20 who diqd of other causes (20.3 2 36.4 mg/day). Likewise, the frequency of recent immunosuppressive * * REVEILLE ET AL 44 therapy did not differ between the 2 groups (24% versus 17%). It is noteworthy that renal insufficiency was frequently present on the first day of the final hospital admission both in those who died of infection (mean ? SD serum creatinine 3.5 ? 3.5 mg/dl) and in those who died of other causes (5.0 4.9 mg/dl). * DISCUSSION We have examined the impact of specific clinical and demographic characteristics on the probability of survival in a well-defined group of 389 SLE patients. The numbers of American black patients and Caucasian patients were equally well represented (n = 203 and n = 184, respectively). The parameters were examined for their effects when present at SLE diagnosis, as well as when present at any time in the course of the disease. Knowing what clinical features are present at diagnosis is important to such analyses because of their predictive value; moreover, it is less likely that such features are the result of progressive disease. For example, proteinuria could be the result of longstanding hypertension, or the hypertension could itself be the result of longstanding lupus nephritis. The disease features that emerge later in the course of SLE also require analysis, because they may be markers of more severe SLE and may require more aggressive therapy. Since medical records at or within 6 months of diagnosis were not available for 112 SLE patients, the parameters present at diagnosis were analyzed in the smaller group of SLE patients whose records were available (n = 277). On both univariate and multivariate analyses, we found that American black race acts as a risk factor for a worse prognosis; that is, American black patients with SLE have a lower life expectancy than Caucasian patients with SLE, regardless of the other demographic and clinical features present. In a previously published multicenter study of outcome in SLE (UAB not included) (15)-an analysis of 642 Caucasian patients and 356 black patients (including American and Caribbean blacks )-this difference in prognosis was also noted, with black patients having more severe disease at study entry (as evidenced by a higher mean serum creatinine level, lower mean hematocrit value, and higher frequency of CNS lupus). It should be noted that, although we did not analyze place of birth data for all subjects in this study, of the 100 black SLE study patients currently followed by us, 92 were born in Alabama, 6 were born elsewhere in the southeastern US, and 4 were born elsewhere in the US. We are not aware of any black SLE patients in this study who were born outside the US. Studenski et a1 (16), who studied SLE patients seen at another Southern US medical center, found a decreased probability of survival among nonwhites. Other, earlier reports suggesting that Caucasians and American blacks have a similar probability of survival (4,6,13) are complicated by the fairly small numbers of non-Caucasians studied. Thrombocytopenia, whose presence at diagnosis was the only clinical feature that was an independent risk factor for a poorer outcome, was present in this study in equal frequency in Caucasians (30%) and American blacks (29%), except in the group with late-onset SLE, in whom severe thrombocytopenia was slightly more common in American blacks (40%) (data not shown). Results of a multicenter study by Ginzler et a1 ( 1 3 , as well as the recent study by Studenski et al(16), suggested socioeconomic factors (using insurance status as a proxy) to explain at least part of the dif€erences in mortality rates between blacks and Caucasians. However, even in the multicenter study, the correlation of a worse prognosis with public funding varied from center to center. We found the probability of survival for American blacks with private medical insurance was not significantly better than that for American blacks with public or no medical insurance. Moreover, multivariate analysis did not demonstrate insurance status as producing a negative impact on prognosis, which contrasts with Studenski and coworkers’ findings (16). Since both groups were composed of American blacks from the Southern US, there is no apparent reason for the discrepant findings. Perhaps either insurance status does not correlate with socioeconomic status, and therefore cannot be used to represent this feature, or socioeconomic status does not truly act as a significant factor in the diminished probability of survival of American blacks compared with Caucasians. A study examining socioeconomic status in more detail, such as one using the “Hollingshead index” (34), which is widely used among social and behavioral scientists, may help to further address this issue by analyzing the impact of educational status and occupation (among many other variables). Esdaile et al (35) found no correlation between socioeconomic status (as determined from educational and occupational status) and outcome (as measured not by survival but by health status, which was determined by the Arthritis Impact Measurement Scales scores) in 78 Canadian SLE patients. On the other hand, Hochberg and Sutton (36) reported that educational status was FACTORS AFFECTING SLE PROGNOSIS associated with poor psychosocial adjustment to SLE; thus, it appears that at least some socioeconomic factors may be important in the impact of SLE. At least 2 interrelated factors are more likely to be present in American blacks with SLE, and these may contribute to their lowered expected survival. These patients had a higher frequency of renal involvement (a%, versus 46% in Caucasians; data not shown), a finding that has been reported by others (18), and more aggressive disease at onset (indicated by the shorter mean interval between the diagnosis of SLE and the onset of multisystem disease). It is noteworthy that, despite the results of the univariate analysis, neither the presence of renal disease nor the presence of an elevated serum creatinine level at diagnosis independently affected prognosis; this contrasts with the findings of the previous multicenter study (15). Whether this is due to differences in treatment or in compliance is not clear, and the finding merits further study. Sixty-one patients with renal involvement did not have 24-hour protein excretion determinations. These patients might represent a group with transient or milder renal involvement. The possible effect this might have on the data would be to falsely increase the impact of proteinuria on prognosis in SLE, but multivariate analysis demonstrated no association of proteinuria with a worse prognosis. In patients who died (regardless of cause), the elevated serum creatinine level noted on the first day of the last hospital admission (before death),could have been due to a variety of causes, including lupus nephritis, hypertension, heart failure, or sepsis, or combinations thereof. Age at SLE onset proved to be an important determinant in prognosis. On univariate analysis, both early-onset and late-onset SLE groups appeared to fare worse, whereas on the multivariate analysis, only increasing age at SLE onset independently worsened the probability of survival. The higher proportion of American blacks (this being another independent risk factor) in the young age at onset group (69%) partly explains the former finding, and this is underscored by the fact that American black patients whose disease onset occurred befdre age 20 fared worse than Caucasians in the same group (data not shown). In the late-onset SLE group, the probability of survival was equivalent in Caucasians and American bIacks, and the worse prognosis can be partly explained by the higher frequency of atherosclerotic cardiovascular disease and neoplasia (37). This is especially important to note, because other features of SLE that are classi- 45 cally associated with worse prognosis (e.g., renal disease) were much less frequent in this group. In all clinical and demographic groups considered, infection emerged as a leading cause of death; this finding has also been seen in other recent studies (3840). The major impact of thrombocytopenia, another independent factor in SLE prognosis, occurred during the first 1-2 years after disease onset. However, bleeding (and complications thereof) was an uncommon cause of death in this group, in whom infection emerged as the most immediate factor contributing to death. We could not demonstrate significant differences in either the prednisone dosage at the last hospital admission or the use of immunosuppressive therapy in those with or without thrombocytopenia that might account for this; thus, thrombocytopenia may, instead, be a marker of more aggressive and severe disease, as has been suggested by other investigators (41). Thrornbocytopenia was present with equal frequency in those with and those without renal involvement, although it was slightly more frequent in those with neuropsychiatric disease, as has been shown in other studies (10). Two other groups of investigators (42,43) studying fairly small numbers of patients with thrombocytopenia (n = 24 and n = 21, respectively), could not confirm an association between this complication and more aggressive disease. Whether the differences between these 2 studies and our findings are due to the differences in numbers of patients evaluated, to treatment, or to other factors cannot be determined. In clinical studies like the one presented here, there are a number of sources of possible bias (44).A study such as this might miss patients with rapidly fatal or short disease courses, as well as those with mild cases. We limited study inclusion to those who met 4 or more ARA criteria for SLE, and those with milder disease may therefore have been excluded. Furthermore, we did not obtain followup status on most of the 40 patients who did not meet our study inclusion criteria (4 or more SLE classification criteria). However, the numbers of American blacks and Caucasians who did not meet the disease criteria were nearly the same and were fairly low (19 American blacks and 21 Caucasians), so any small impact this source of bias might have would be approximately the same in both races. SLE is usually not a rapidly fatal disease, and in this study spanning 10 years, only 3 patients died within 1 month of disease onset. Thus, it is unlikely that a significant number of cases were missed in this way. 46 To avoid bias toward patients with more severe disease, we examined rheumatology outpatient records over most of this period and outpatient nephrology division records after 1982, as well as the inpatient records. While the different methods of identifying SLE outpatients (see Patients and Methods) might raise concerns about confounding effects of different sources of care and different methods of identification, nearly all of the SLE patients in this study, regardless of which UAB affiliated hospitals they attended, were either directly cared for or were seen in consultation by UAB faculty rheumatologists or nephrologists. Only a fairly small proportion of cases were seen only once or twice, receiving most of their medical care elsewhere. We therefore believe that significant differences in treatment were not a major factor here. With the different methods we used to identify outpatients, we attempted to include all outpatients with SLE seen at UAB over the study period. For example, a serum bank was kept of all SLE outpatients seen at UAB by the rheumatology division between 1975 and 1979. The diagnoses were reviewed thereafter, and only those meeting 4 or more classification criteria for SLE were included in this study. We were able to ascertain fall 1985 status in all but 7% of our SLE patients, and we believe that no significant nonresponse bias has affected our results. A number of clinical features that were demonstrated by univariate analysis as significantly impacting prognosis, such as renal disease and neuropsychiatric disease and, at diagnosis, proteinuria, hypertension, and anemia, were not significant by multivariate analysis. These variables could have been dependent on other factors, such as black race and age at onset of SLE. Alternatively, since the P values found for these variables did not maintain significance when corrected for the number of statistical tests performed, we cannot rule out a multiple-testing bias. Some of those parameters that were significant both on univariate and multivariate analysis, such as black race, might also lose significance when corrected for the number of tests performed. However, since these were significant on both univariate and multivariate analyses, both at diagnosis as well as at any time in the disease course, we believe that correction for the number of tests performed is not necessary in this setting. Last, our calculations measured the impact of the presence or absence of hypocomplementemia (at diagnosis) on survival. We did not examine the relative impact of severe versus mild depressions of total hemolytic REVEILLE ET AL complement, and we cannot exclude a relative difference between these two in the impact on prognosis. Thus, our analyses of the impact of such demographic factors as race and age at onset on the clinical presentation and prognosis in SLE showed that American black race and increasing age at SLE onset were independent risk factors for a worse prognosis. Thrombocytopenia, whether present at SLE diagnosis or at any other time in the disease course, emerged as the sole clinical parameter that independently impacted survival probability. Future studies should thus be aimed at defining features not examined here that contribute to a younger mean age at SLE onset in American blacks (such as genetic or hormonal factors), as well as other confounding variables (such as compliance and educational status) that might affect disease outcome, so that public health measures (such as patient education about SLE) could be taken to improve the probability of survival in this ethnic group. 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