This population-based study examines the familiality of SSc in the setting of a family history of vasculopathy (RP), autoimmune inflammatory diseases (SLE, SjS, DM, UCTD, and RA), and fibrosis (ILD) in order to examine the relative genetic influence of these components of SSc pathophysiology. In the UPDB, which is linked to over 7 million individuals, 1316 distinct SSc patients and 50 SSc families with the highest FSIR were examined in detail. These families were 2 to 17 times as affected with SSc as would be predicted by a uniform distribution corrected for age, sex, and demographics and had excess RP, autoimmunity (as represented by AD) and fibrosis (as represented by ILD). The PAR, a measure of the familial predisposition to SSc, appears to be 8%. This study is genetically representative of northern Europe with low inbreeding levels (22
). This has important implication when counseling SSc patients about familial risk. The cumulative incidence rate was 3.3 per 100,000 person-years in the inpatient data and 2.8 per 100,000 person-years in the UUHSC group which is higher, but close to the confidence interval of 1.9 per 100,000/yr (95% CI 1.24-3.02) previously reported in the large cohort study done in the Detroit tri-county area (5
). Our reported higher incidence could be due to the fact that localized scleroderma (morphea and linear disease), were excluded in the Mayes study, but these entities could have possibly been coded in our data sources under ICD-9 710.1.
The exact genetic contribution to vasculopathy, inflammation, and fibrosis in SSc remains unknown. When KAT was used to find the relative risks to SSc families for RP (to represent vasculopathy), ILD (fibrosis), and overlapping autoimmune diseases (inflammatory diseases; SLE, SjS, DM, UCTD, RA), the risk for each of these conditions was increased in first degree relatives. First degree relatives were 6 times more likely to have RP than controls. Risk for RP was also significantly increased in second degree relatives, through the risk tended to decrease with more distant relationship as expected for heritable conditions. The presence of RP in a SSc family member seems to imply that there may by increased risk for SSc, consistent with the hypothesis that places vascular injury at the center of the pathogenesis SSc (13
). Additionally, this supports the importance of the clinical finding of capillaroscopy, which examines the vascular nailbed changes in the setting of RP, as an important diagnostic test for SSc, which has a reported sensitivity of 100%, specificity of 81%, and a positive predictive value of 90% (28
). This is an important tool for screening for and diagnosing SSc (29
Only first and second degree relatives of SSc patients had a statistically significant increase in risk for other autoimmune diseases. First degree relatives were 3 times more likely to have an AD than first degree relatives of the controls. Second degree relatives were 1.8 times more at risk for an overlapping condition. This finding is consistent with other data that immune dysregulation, possibly related to highly pleiotropic cytokines, also has a heritable component (30
With exception of second degree relatives, the relative risk of ILD to the other kinship classes also follows the expected decreasing trend for inherited risk. First degree relatives were 1.5 times more likely to have ILD. These results suggest that in the clinical setting, screening questions for the presence of RP, ILD, or another autoimmune condition in a first degree relative is important when considering the diagnosis of SSc. Additionally, these results attest to the important role of RP in the pathophysiology of SSc. Improved inpatient coding for RP may be warranted. Institution of potent therapies aimed at patients with RP could lower the risk for development of systemic sclerosis a proposition that remains untested.
There are limitations to this population database approach. The study population was primarily of Northern European descent and should be generalized to only other populations of similar origin. Nonetheless this study does suggest a genetic contribution to vasculopathy, immune dysfunction, and fibrosis, and provides the background for additional studies. The identification of the cases is based on billing codes which may include some misclassification. Due to the de-identified nature of the data we were unable to validate the diagnoses. However, this approach allows the estimates of familial risk to be more valid as they are not based on self reports by patients. Every patient with SSc did not have RP as a co-diagnosis although it is almost universally present in this condition (31
). This suggests that perhaps only the most severe aspect of the disease was recorded. There may have been biases of ascertainment for each disease that was captured. It is possible that a relative of someone with SSc is more likely to be evaluated if they have RP or pulmonary complaints. The ICD-9 code for post-inflammatory disease/pulmonary fibrosis may not capture all cases of ILD. Additionally, we could have looked at other fibrotic and vasculopathy aspects of SSc, such as primary biliary cirrhosis or pulmonary hypertension. Similarly, we could have looked at other more common autoimmune inflammatory conditions, such as thyroid disease. It is likely that the cases with SSc were accurately diagnosed based on its unique physical properties, while less accuracy is expected with the autoimmune disorders. We pooled them in order to mitigate any effect this lower accuracy of specific diagnosis might have instilled. Analysis of each autoimmune disease separately may have better characterize the genetic component of each disease, but was not done to allow large enough numbers for calculation of RR.
In summary, this study uses the unique UPDB resource to examine the familial nature of SSc. Through its use, we have estimated RRs in SSc relatives, with a focus on RP, ILD, and other autoimmune diseases. We have shown that the presence of SSc in a first degree relative confers a significantly increased risk of SSc, RP, ILD, and other autoimmune diseases. Further, it suggests vasculopathy is the most important heritable component and fibrosis is less polygenic. This finding warrants attention for screening strategies aimed at early identification of SSc, with a focus on a personal and family history of RP and ILD. Further, studies performed on the high-risk pedigrees that have been identified in the UPDB could allow increased understanding of the specifics of these three components to SSc predisposition. Additionally, studying outpatient records for the presence of RP and subsequently examining cases of SSc might better clarify the risk that RP imparts on familial risk of developing SSc.