Published estimates of the prevalence and incidence of systemic sclerosis (SSc; scleroderma) vary widely depending on the period of observation, methods of case ascertainment, and the geographic area of study (1–6; for review, see ref.7). Reported US incidence rates vary between 2.7 cases per million per year for the time period 1947–1968 (2) and 18.7 cases per million per year for the time period 1972–1982 (6). Similarly, US prevalence estimates have varied from 138 cases per million for the period 1950–1979 (4) to 286 cases per million in 1985 (5). These discrepancies may reflect true variation in disease occurrence among different populations or may be related to methodologic differences, such as the degree of scrutiny applied or the classification of disease.
Although survival in patients with SSc has improved in the past several decades, it remains considerably diminished compared with that in age- and sex-matched populations (8–18; for review, see ref.19). Reliable estimates of overall survival as well as survival by disease subtypes are important in order to gauge effects of new treatment modalities or to document the changing natural history of this disease. Dependable incidence, prevalence, and mortality statistics are necessary to evaluate the health impact of this disease on the population.
The aim of this study was to determine the prevalence and incidence of SSc and survival rates in patients with SSc by conducting a census of all patients with SSc in the Detroit tricounty metropolitan area for the years 1989–1991. This metropolitan area, consisting of the counties of Wayne, Oakland, and Macomb, has a large overall population with a substantial black component (2.917 million adults, of whom 75.0% are white, 21.9% are black, and 3.1% are of other races [according to 1990 US census data]).
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- PATIENTS AND METHODS
This study of prevalence and incidence is based on the largest SSc population in the US assembled to date. Multiple methods of case ascertainment were used, and cases included both inpatients and outpatients identified from university referral sources, community physicians, and patient support groups. The observed prevalence (based on the 706 identified and verified cases) is 242.0 cases per million adults. The estimated prevalence, using capture-recapture analysis of 809 presumed cases, is 276 cases per million adults. A major assumption of this method is that the sources of case ascertainment are independent; that is, that identification by one source (e.g., hospital discharge database) is not related to identification by another source (e.g., physician office). Although this assumption frequently is not valid, correction for dependency results in a larger estimate of total cases was not done for this study (30, 31).
Large population studies are necessary to provide reliable estimates of the prevalence and incidence of rare diseases. This approach, however, relies on available medical records, which frequently lack documentation of key clinical, laboratory, or other diagnostic testing. In clinical practice, a description of SSc features such as digital pitting scars or scars of old ulcers may not be documented in the physical findings but contribute to the diagnostic impression. As noted above, this study included probable as well as definite cases: probable cases included patients in whom SSc was diagnosed by a rheumatologist and who had documented sclerodactyly plus at least 2 additional features of the CREST syndrome.
Even using this approach, an additional source of potential underestimation was involved in case ascertainment. Among the 1,596 unique individuals identified as potentially eligible, medical records for 441 of these patients (27.6%) were unavailable for review. Assuming that the proportion of eligible individuals in this nonreviewed group would be the same as that in the group whose medical records were reviewed (61.1% of patients whose records were reviewed were eligible), an additional 265 cases would be added to our total. The 103 additional cases predicted by the capture-recapture analysis may be included in this group but would not account for the entire number of potentially eligible nonreviewed cases. Had the capture-recapture analysis used less stringent assumptions, the predicted number of cases would be greater but unlikely to increase by more than double. The prevalence estimate reported here should be interpreted as a conservative value.
Our estimate of an annual incidence of 19.3 new cases per million adults per year (95% CI 12.4–30.2) is similar to the incidence estimate of 18.2 per million reported by Steen et al (6) for the period 1978–1982 in Allegheny County, Pennsylvania. For the earliest study period (1963–1967) in the same area of Pennsylvania, these investigators reported a lower incidence of only 9.7 cases per million but speculated that the apparent increase in SSc may have been attributable to improved case detection rather than a true increase in incidence. Our data would suggest that the annual incidence of SSc has not increased but has been relatively stable, at least during the period 1978–1991.
Our predicted prevalence of 242.0 cases per million adults based on our 706 verified cases is similar to the prevalence estimate of 286 cases per million reported by Maricq et al (5), based on 2 cases of definite SSc in a South Carolina population. However, the small number of cases in the Maricq study precludes much confidence in this estimate. Our capture-recapture analysis suggests that the true population prevalence is at least 276 cases per million adults (95% CI 245–310), with an annual incidence of 21 new cases per million adults per year.
In contrast to this relative agreement among recent US reports, similar epidemiology studies in other countries suggest far lower SSc prevalence and incidence estimates. In England, the prevalence of SSc has been reported as 30.8 cases per million (based on 156 cases) (34), in Japan the prevalence estimate is 38 cases per million (based on 357 cases) (35), and in Iceland the prevalence estimate is 71 cases per million (based on 37 cases) (36). These studies included both limited and diffuse forms of SSc. Although methods of case ascertainment and verification and the length of the study period vary among these reports, it is unlikely that methodologic differences alone account for this considerable disparity. For example, the difference in point prevalence between the British study and the current report is 8-fold (30 cases per million versus 242 cases per million). It would therefore appear that SSc occurs more commonly in the US than in other countries in which it has been systematically investigated.
Estimates of SSc occurrence similar to those in our study were reported among residents of the Australian state of South Australia, by Roberts-Thomson et al (37). Those investigators estimated the point prevalence of SSc to be 233 cases per million (based on 348 cases), with an annual incidence of 16 cases per million. In contrast, a lower prevalence of SSc was reported in the Australian city of Sydney (state of New South Wales) (86 cases per million for 1988) (38). Reasons for the difference between these 2 adjacent regions are not clear. Similar female-to-male ratios and similar proportions of limited and diffuse disease were reported in both studies. The racial and ethnic backgrounds of patients were not described in either report.
The highest prevalence of SSc has been reported in a Choctaw Native American group in Oklahoma (660 cases per million, based on 14 cases) (39). Genetic influences have been proposed to account for this increase but have not yet been definitively identified (39; for review, see ref.40). In addition, no specific environmental factors have been recognized (39).
In terms of serology, ACAs were found more frequently in women than in men, a finding that has not been reported previously. As in other studies, ACAs were less frequent in black patients than in non-black patients (32, 33). Of the 20 prevalent cases involving black men (5 of whom had limited disease), no individual had ACA positivity. Due to the retrospective nature of this study and the fact that individuals were seen by various physicians, a complete autoantibody profile was not available for all patients, nor was the designation in the medical record regarding the extent of skin involvement always clear enough to permit classification of the disease as limited or diffuse.
For patients in this cohort, median survival from the time of diagnosis was ∼11 years. This represents an improvement in survival compared with the 35% survival at ∼10 years from diagnosis reported by Medsger and Masi in 1971 (2). The survival rates reported in different studies vary widely, depending to a large extent on the proportion of limited and diffuse disease in the cohort (for review, see ref.19). In the current study, survival from the time of diagnosis was 77.9% at 5 years, 55.1% at 10 years, 37.4% at 15 years, and 26.8% at 20 years. Observed survival was substantially less than expected for the case population overall as well as for all subgroups. The deleterious effect of renal involvement on long-term survival likely does not reflect the new onset of renal crisis late in the course of the disease, but rather the fact that individuals who have experienced renal crisis, most of whom are left with impaired renal function, have a poorer prognosis.
It should be noted that the mean age at diagnosis for the prevalent case patients was 46.1 years (Table 2), which is younger than that for the incident case patients (52.2 years) (Table 3). This apparent discrepancy in age at diagnosis between incident cases and prevalent cases may be attributable to the survival advantage of younger individuals in terms of all-cause mortality; that is, patients diagnosed at an earlier age have a greater likelihood of surviving to be counted in the prevalence period. Alternatively, older prevalent case patients might have been systematically excluded if they were no longer being followed up by rheumatologists or were not hospitalized.
Both the prevalence and incidence of SSc were higher in blacks than in whites, although the comparison for incidence did not reach statistical significance. Incident cases in black patients may have been missed more frequently than were incident cases in white patients if there was a longer delay before diagnosis or a delay before specialist referral for black patients compared with patients of other races. Also, and as noted above, because the mean age at diagnosis was younger among black patients than among white patients, more black patients may have survived to be counted in the prevalence group.
We found a rather marked difference in the proportion of diffuse and limited disease between racial groups (black patients were 1.86 times more likely than non-black patients to have diffuse disease), suggesting that disease expression is different between racial groups. Alternatively, we could have missed cases of limited disease among black patients due to a delayed diagnosis or specialist referral compared with that in other racial groups. If this were the case, then the black/white differential in prevalence and incidence is even higher than we report here. Although our data do not permit us to resolve this issue, it is an important consideration, because it affects our interpretation of the role of genetic influences on disease occurrence and expression.
In summary, both sex and race appear to have a strong influence on the incidence (i.e., disease susceptibility) of SSc, whereas race additionally influences disease expression, particularly age at onset and extent of skin involvement. This implies that sex-related risk factors (e.g., hormonal, reproductive, sex-specific environmental exposures and the like) may serve as or amplify the initiating trigger for the disease, whereas genetic factors may exert a stronger influence on disease severity.
This study firmly establishes baseline estimates of SSc disease occurrence and expression in a large US population consisting primarily of black adults and white adults residing in a metropolitan area. These data should facilitate research regarding the role of geographic, ethnic, racial, genetic, and environmental factors in SSc susceptibility and disease expression in comparison populations.