Recently, a prospective study was done in 410 patients with early undifferentiated or early defined connective tissue disease [6]. Selecting 48 patients with early scleroderma from this cohort, we analyzed short-term outcomes and identified some features occurring within the first year of disease that may be useful in distinguishing patients at high risk for an unfavorable outcome.

Methods

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The Cooperative Systematic Studies of the Rheumatic Diseases Program is funded under a National Institute of Arthritis and Musculoskeletal Diseases contract through the Coordinating Center at the University of Utah, Salt Lake City, Utah, and includes 10 centers participating in the study of early undifferentiated connective tissue disease. Outpatients and inpatients seen at participating centers were eligible for the study if they met diagnostic criteria for rheumatoid arthritis, scleroderma, systemic lupus erythematosus, or poly/dermatomyositis [7-10] and had experienced symptoms for less than 1 year. Patients who had features of a connective tissue disease, including Raynaud phenomenon, unexplained polyarthritis, or 3 of 11 findings characteristic of connective tissue disease, but who did not meet established criteria for a specific connective tissue disease were classified as having undifferentiated connective tissue disease. Patients were evaluated at baseline and at follow-up intervals of 1, 3, and 5 years. Details on data collection and on the clinical and laboratory features of the patients with early undifferentiated connective tissue disease have been described previously [6, 11].

Enrollment for the study began in July 1982 and was completed in June 1987. Survival status was confirmed through at least 5 years after symptom onset in all cases except one (patient lost to follow-up after 1.6 years). A diagnosis of scleroderma was made in 52 patients (in 46 within 1 year of symptom onset and in 6 within 4 years of symptom onset). Four of these patients (including 2 of 6 diagnosed after the baseline evaluation) developed overlap syndromes during the 5-year follow-up period and were excluded from the study, leaving 48 patients for analysis. Deaths and causes of death were reported to the Coordinating Center; every possible effort was made to confirm the cause of death through hospital records and autopsy reports from the participating centers. Five patients died at home, on the way to the hospital, or shortly after arrival at the hospital.

Sclerodermatous skin findings on physical examination were categorized as follows: sclerodactyly (involvement distal to the metacarpophalangeal joints); acrosclerosis (involvement distal to elbows and knees); or generalized or diffuse scleroderma. A skin score was not determined. Physical findings for each organ system were recorded as a "yes" or "no" response to a list of abnormal findings. Twelve cardiorespiratory signs were assessed on the baseline physical examination: These included the presence or absence of rales, wheezes, pleural or pericardial rubs, pleural effusion, systolic or diastolic murmurs, abnormal second heart sounds, cardiomegaly, arrhythmia, dependent edema, and tachycardia (pulse 100 beats/min).

All patients had routine hematology and biochemical laboratory tests. Many patients also had a determination of erythrocyte sedimentation rate (Westergren method) (n = 47), pulmonary function tests (n = 43), an electrocardiogram (n = 40), a chest radiograph (n = 40), and the Schirmer test. Serum specimens from all patients were analyzed for serologic markers of rheumatic disease at the Centers for Disease Control [11]. In addition, frozen serum specimens from 45 of the 48 patients with scleroderma were analyzed at Specialty Laboratories, Inc. (Santa Monica, California): Interleukin-2 levels were assessed by enzyme-linked immunosorbent assay (ELISA); soluble interleukin-2 receptor levels by ELISA; and neopterin levels by radioimmunoassay; anti-Scl-70 antibody levels by ELISA; and anticentromere antibody titer by immunofluorescence assay.

Lung diffusing capacity was considered to be abnormal if it was less than 70% of the predicted diffusing capacity. Chest radiographs were considered to be abnormal if infiltrates, effusions, pleural thickening, or heart enlargement was present. Electrocardiograms were considered to be abnormal if evidence of arrhythmia, heart block, ventricular enlargement, repolarization abnormalities, significant shift in axis, or infarction was found. For the purposes of our study, nonspecific ST or T-wave abnormalities were not considered to be abnormal.

Baseline clinical, laboratory, and other features of patients with early death were compared with those of survivors. Mean values were compared using the Student t-test. Comparisons between dichotomous variables were done using chi-square distribution with Yate's correction. Life-table analyses using Kaplan-Meier survival estimation [12] and Mantel-Haenszel statistics [13] were done to predict survival rates for the group of patients with early scleroderma and the various subgroups generated by stratification based on selected variables. Variables were evaluated using univariate Cox proportional-hazards analysis for their ability to predict survival [14]. The variables found to be most significant, as determined by univariate Cox proportional-hazards analysis, and for which less than 10% of data were missing, were then evaluated by multivariate Cox analysis with stepwise regression modeling. We did not apply the Bonferroni correction to our results; however, because of the many variables compared, we defined statistical significance by a probability level of 0.01.

Results

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Forty-eight patients with scleroderma were enrolled in the study. One patient was lost to follow-up 1.6 years after symptom onset, and the data gathered on her were used only in the survival and Cox analyses. During the 5-year follow-up period, 15 of the 47 evaluable patients with early scleroderma died. Kaplan-Meier estimation yielded overall survival rates at 1, 3, and 5 years after symptom onset of 92%, 75%, and 68%, respectively (Figure 1). Five patients died within 1 year of symptom onset. The cohort of patients with scleroderma accounted for 41% of all early deaths recorded for the entire study population of 410 patients. The causes of death are summarized in Table 1. Multiorgan involvement was frequently observed at the time of death, although pulmonary or cardiac system failure (or both) was thought to be the immediate cause of death in 8 of the 15 patients who died. Renal crisis was substantiated or suspected in 4 of the patients who died. The time from symptom onset to death was similar for those dying of renal causes (21 ± 11 months) and those dying of cardiopulmonary causes (25 ± 17 months).

View larger version (17K): [in this window] [in a new window]   Figure 1. Cumulative survival probabilities: Kaplan-Meier survival curve with Greenwood confidence limits from onset of symptoms for the 48 early scleroderma patients. Number of patients at risk listed below curve at yearly intervals.

Clinical Features

In Table 2, baseline characteristics of patients who died within 5 years after symptom onset are compared with those of the survivors. Twelve of the 15 (80%) patients who died had at least one abnormal cardiopulmonary sign at baseline compared with 13 of 32 (41%) survivors (P = 0.03). Among individual cardiopulmonary findings, resting heart rate was significantly different between survivors (79 ± 13 beats/min; range, 50 to 110 beats/min) and patients who died (93 ± 12 beats/min; range, 70 to 120 beats/min) (P = 0.001). Baseline blood pressure was similar in the subgroups (survivors: 120 ± 17/76 ± 12 mm Hg; patients who died: 127 ± 27/78 ± 16 mm Hg; P > 0.3), as was the frequency of chest radiographic, pulmonary function, and electrocardiographic abnormalities (P = 0.09).

Chest pain, dyspnea, orthopnea, dependent edema, cough, and wheezing were common complaints; 57% of the entire group had at least one symptom. Dyspnea was the most common single cardiorespiratory complaint (36%). No significant difference in frequency of cardiopulmonary symptoms was detected between those who died and those who survived.

Ninety-two percent of our patients developed skin involvement within 1 year of symptom onset, implying that patients with gradual-onset scleroderma were not included in our study. Four of the 48 patients did not have diagnosable scleroderma at their first visit, but they did develop skin disease within 3 years of follow-up (or within 4 years of disease onset). At entry, two patients had Raynaud phenomenon only and two were diagnosed with undifferentiated connective tissue disease. When baseline variables for these 4 patients with intermediate-onset scleroderma were compared with those of the remaining 44 patients with earlier-onset disease, no significant differences were found (data not presented), although this comparison was limited by the small group numbers. Patients who survived and those who died did not differ regarding the time from onset of symptoms to the first skin manifestation. Subsequent analysis in this article will not attempt to differentiate outcome on the basis of the rate of cutaneous sclerosis.

Patients who survived and those who died did not differ regarding the baseline pattern of skin involvement, (based on either a classification of "limited" or "diffuse" [1, 15] or on a classification of "sclerodactyly," "acrosclerosis," or "diffuse scleroderma" [4]). Although nailfold analysis and various methods for scoring skin involvement have been validated over the past 10 years, they were not uniformly accepted when we began our study in 1982 and thus were not part of the study protocol. The frequency of Raynaud phenomenon, digital ulcers, joint symptoms or signs, and gastrointestinal symptoms were similar in both groups. Only 18 patients had esophageal manometry, a barium-swallow study, or a cine-esophagram, and thus no conclusions could be drawn regarding objective esophageal dysfunction.

Laboratory Features

The laboratory characteristics of the two groups are shown in Table 3. Patients who survived and those who died differed regarding the mean peripheral leukocyte count (P = 0.006); 6 of 32 survivors (19%) had leukocyte counts greater than 10.0 x 10⁹/L compared with 7 of 15 patients who died (47%) (P = 0.1). Differences were not related to corticosteroid use. The mean blood hemoglobin level for patients who died was modestly lower than the level found in survivors (P = 0.1). No patient had evidence of hemolysis. Thirteen of 32 survivors (41%) had elevated erythrocyte sedimentation rates ( 25 mm/h) at baseline compared with 10 of 14 patients who died (71%; data were missing for 1 patient). The mean rates were 25 mm/h and 42 mm/h, respectively (P = 0.02). An elevated erythrocyte sedimentation rate did not correlate with the age or sex of the patient.

Renal abnormalities were observed in 5 of 32 survivors (16%) and in 6 of 15 patients who died (40%). Abnormalities included a history or presence of abnormal urine sediment (>2 erythrocytes/high-power field or >5 leukocytes/high-power field), proteinuria ( 1+ dipstick protein), a blood urea nitrogen level greater than 7 mmol/L, and a serum creatinine level greater than 110 µmol/L at baseline (P = 0.1). Three of 32 survivors (9%) and 6 of 15 patients who died (40%) had abnormal urine sediment (P = 0.04). Only two of four patients who died of renal causes had renal abnormalities at baseline.

The mean baseline levels of serum soluble interleukin-2 receptor and neopterin in surviving patients with scleroderma was lower (856 ± 362 U/mL and 7.8 ± 4.5 mmol/L, respectively) than those seen in patients with scleroderma who died (1245 ± 657 U/mL and 11.9 ± 5.8 mmol/L, respectively) (P = 0.02). The two subgroups showed no significant differences in serum interleukin-2, anti-Scl-70 antibody, and anticentromere antibody levels. One patient had a low antiribonuclear protein titer (1:800), and four patients had positive assay results for rheumatoid factor (range, 1:160 to 1:640).

Predictors of Survival

A univariate Cox proportional-hazards model was used to test each variable for its ability to predict survival. Abnormalities of the cardiopulmonary system on physical examination, blood leukocyte count, abnormal urine sediment, serum soluble interleukin-2 receptor level, Westergren erythrocyte sedimentation rate, platelet count, serum neopterin level, and abnormal electrocardiographic findings were identified in the univariate analysis as potentially important predictors of survival (P 0.01); however, serum neopterin level and abnormal electrocardiographic findings were excluded from multivariate analysis because data on each variable were missing in seven cases, which together would have reduced the total number of observations in the analysis from 48 to 33. The other six variables were entered in a multivariate, stepwise Cox proportional-hazards regression model. The presence of abnormal cardiopulmonary signs and abnormal urine sediment, as measured within 1 year of symptom onset, were significant prognostic indicators of survival by multivariate analysis (Table 4).

Survival Curve Analyses

To show the predictive value of some important baseline variables, we plotted the survival curves for subgroups of patients with scleroderma that were defined by dichotomizing selected variables. Cut-off values were chosen to maximize subgroup differences, maintaining, where possible, at least 20% of cases in each subgroup. Life-table analyses of subgroups created for abnormal cardiopulmonary signs, abnormal urine sediment, elevated soluble interleukin-2 receptor level, and Westergren erythrocyte sedimentation rate are presented in Figures 2 and 3.

View larger version (22K): [in this window] [in a new window]   Figure 2. Cumulative survival probabilities [Kaplan-Meier] for subgroups of early scleroderma patients: A) patients with baseline cardiopulmonary abnormalities on examination compared with those without abnormalities [P = 0.01]; B) patients with abnormal urine sediment compared with those with normal sediment (P = 0.002). Number of patients at risk listed below curves at yearly intervals.

View larger version (22K): [in this window] [in a new window]   Figure 3. Cumulative survival probabilities [Kaplan-Meier] for subgroups of early scleroderma patients: A) patients with serum soluble interleukin-2 receptor (s-IL2-R) levels 1200 U/mL compared with those with <1200 U/mL [P = 0.0006]; B) patients with Westergren erythrocyte sedimentation rates (ESR) 39 mm/hr compared with those with ESR <39 mm/hr (P = 0.005). Number of patients at risk listed below curves at yearly intervals.

Discussion

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The goal of the early undifferentiated connective tissue disease study was to begin surveillance of patients with rheumatic disease within the first year of disease and to follow them prospectively to assess fully the natural early course of disease. Forty-eight patients in the incipient stages of scleroderma were identified. Fifteen of 47 evaluable patients (32%) died within the first 5 years of the study, yielding a 5-year estimated cumulative survival rate of 68%. The high rate of mortality in our short-term prospective study emphasizes that scleroderma can lead to early death in a significant number of patients.

The study of patients who had experienced symptoms for less than 1 year provided a new perspective on a progressive disease with devastating sequelae. In addition to a high early mortality rate, we found that some patients destined to die of rapidly progressive disease could be identified within 1 year of symptom onset by the following: the presence of cardiopulmonary abnormalities (abnormal cardiopulmonary signs on physical examination, tachycardia, and possibly an abnormal electrocardiogram); renal abnormalities (hematuria or pyuria); evidence of an ongoing inflammatory response (elevated erythrocyte sedimentation rate, leukocytosis, and thrombocytosis); and evidence of immunologic activation (an elevated soluble interleukin-2 receptor level and possibly an elevated neopterin level).

The findings of our inception cohort study generally support those of previous retrospective or cross-sectional studies, although a sample of only 48 patients and the occurrence of only 15 deaths limits the power of our univariate analyses. In a retrospective analysis, Lally and colleagues [3] found that patients with rapidly progressive disease had a significantly higher rate of renal and cardiac involvement at the time of death compared with those with slower disease progression. Early studies suggested that renal disease was the most significant predictor of poor outcome [1, 2, 16], but death due to this complication is decreasing, in part because of both the use of angiotensin-converting enzyme inhibitors [17] and the more cautious use of systemic corticosteroids, which may be associated with increased mortality rates [18]. Our study did not address the role of treatment.

Previous studies suggest that the risk for death is greatest during the first few years of disease and may be associated with older age [1, 2, 16, 18, 19]; male sex [1, 19, 20]; black race [19]; cigarette smoking [19]; and early renal [16, 19, 21], cardiac [16, 19, 21], pulmonary [19, 21], gastrointestinal [19, 22], or diffuse or truncal cutaneous involvement [2, 4, 15, 23]. Poor outcome may also be linked to an elevated erythrocyte sedimentation rate [16, 19, 21], a reduced hemoglobin concentration [16, 22], an increased blood urea nitrogen level [2, 22], proteinuria [19], hematuria [22], a reduced lung diffusing capacity [22, 24], a diminished forced vital capacity [22], an abnormal electrocardiogram result [25], a decreased total serum protein level [22], and an elevated level of soluble interleukin-2 receptor [26-28].

The correlation of early cardiac and pulmonary system abnormalities with decreased survival observed in our study is consistent with findings of previous studies, as well as with the finding that patients who develop significant cardiopulmonary disease generally do so within the first several years of disease [21]. Other investigators have reported that electrocardiographic abnormalities and cardiac arrhythmia are predictive of poor outcome [25]. Our data suggested a similar association for electrocardiographic findings, but missing data prevented us from drawing this conclusion.

Baseline microscopic urine abnormalities (>2 erythrocytes/high-power field or >5 leukocytes/high-power field, or both) indicated a poor prognosis in our study; this finding is consistent with the results of a recent study by Altman and colleagues [22] but differs from those of earlier retrospective studies [29, 30]. Proteinuria and an elevated serum creatinine level, although suggestive, were not statistically significant prognostic indicators. Although renal failure carries a poor prognosis [16, 19, 21], only 2 of our 48 patients with early scleroderma had an elevated serum creatinine level. As in more recent studies, renal abnormalities at entry correlated poorly with the subsequent development of renal crisis [3, 31]: Only two of four patients who died of renal causes had baseline urine or creatinine abnormalities.

We could not confirm the reported association of abnormal lung diffusing capacity with diminished survival [24]. In our study, 50% of survivors and 64% of patients who died had abnormal lung diffusing capacity at baseline (P > 0.3). Pulmonary function tests were difficult to do in the more critically ill patients. The four patients who did not have diffusing capacity measurements had cardiopulmonary dysfunction evident on chest radiograph, electrocardiogram, or physical examination, and two patients were extremely ill at their first evaluation. However, even when patients with missing values were included as "abnormal" in the statistical analysis, the resultant 73% abnormality rate among patients who died was still not statistically different from the rate among survivors (P = 0.2).

Univariate analysis indicated that several laboratory abnormalities associated with ongoing inflammatory and immunologic activity appeared to be important prognostic indicators of survival in patients with early rapidly progressive scleroderma. An elevated erythrocyte sedimentation rate was a marker of poor outcome in our patients with scleroderma (see Figure 3); other studies have had similar findings [16, 19, 21] but some have not [2]. Our patients' mean leukocyte and platelet counts were only marginally above the normal range; thus, these measures may not be clinically useful as prognostic indicators.

In our study, univariate analysis showed a correlation between the baseline soluble interleukin-2 receptor level and survival prognosis in patients with early scleroderma (see Figure 3). The serum soluble interleukin-2 receptor level is related to lymphocyte cell-surface expression of interleukin-2 receptor and is therefore a putative marker of lymphocyte activation [32]. The reported relations between the level of soluble interleukin-2 receptor and the duration of disease, extent of skin disease [26-28], and shortened survival [26] support the hypothesized role of cell-mediated immunologic responses in patients with scleroderma. The baseline neopterin level, a marker for macrophage and monocyte activation, was a possible prognostic indicator of survival, but values were not available for seven patients. Because only one patient in our study had a positive assay result for anticentromere antibodies, the reported association of an elevated anticentromere antibody level with limited skin disease and a better outcome could not be addressed [3, 33, 34]. The association of anti-Scl-70 antibodies with diffuse scleroderma and pulmonary fibrosis [34, 35] was not observed in our study.

Although it is generally recognized that diffuse cutaneous involvement carries a worse prognosis than limited skin disease [4, 15, 16], we found that the development of diffuse skin disease within 1 year of onset did not correlate with prognosis. This somewhat surprising finding may be related to one of our criteria for entry into the study. Many patients with limited cutaneous involvement who may have had only Raynaud phenomenon for years before the onset of skin disease were excluded because we prohibited the entry of patients who had had any disease-related symptom for more than 1 year. The use of this criterion is reflected in the low frequency of anticentromere antibodies among patients in our study and the high rate of diffuse scleroderma (73%) when compared with the previously reported frequency of approximately 50% [36].

Some of our recruiting centers are tertiary referral institutions, and the tendency for such institutions to see patients with more serious forms of scleroderma may have also contributed to the high rate of diffuse disease in our study; patients with limited scleroderma are rarely referred to tertiary centers early in their illness. Perhaps a single observation of skin pattern within 1 year of symptom onset is not as useful in predicting survival as the rate of progression or the more fully developed pattern of skin involvement after several years of disease.

Patients with scleroderma who do not have Raynaud phenomenon reportedly have a worse prognosis than those with Raynaud phenomenon [37]. We observed a similar, although not statistically significant, trend. Our inability to link Raynaud phenomenon with outcome was probably affected by the same factors discussed above in relation to skin pattern.

We conclude that patients with early, rapidly progressive scleroderma should be recruited for future therapeutic trials. Early, aggressive, and higher-risk treatment interventions appear to be justified in this subset of patients with scleroderma.

Appendix

Participating clinics and laboratories included the following: the University of California, Los Angeles (Drs. Bulpitt, Clements, Lachenbruch, and Paulus); Specialty Laboratories, Inc., Santa Monica, California (Dr. Peter and Mr. Agopian); the State University of New York, Brooklyn, New York (Dr. Singer); the University of Pittsburgh, Pittsburgh, Pennsylvania (Dr. Steen); the University of Utah, Salt Lake City, Utah (Drs. Clegg, Reading, Williams, and Ward); the Johns Hopkins University, Baltimore, Maryland (Dr. Ziminski); the University of Alabama, Birmingham, Alabama (Dr. Alarcon); the University of Cincinnati, Ohio (Dr. Luggen); Duke University (Dr. Polisson); the University of Washington, Seattle, Washington (Dr. Willkens); and the National Institutes of Health, Bethesda, Maryland.

This study was presented in abstract form at the American College of Rheumatology Scientific meetings in Seattle, Washington, in 1990.

Acknowledgments: The authors thank Kevin Nechodom, data manager for the Cooperative Systematic Studies of the Rheumatic Diseases Program database at the University of Utah, Salt Lake City, Utah, for assistance with data acquisition.