Progress Continues in Systemic Sclerosis

Over the past several years, there have been significant advances in our understanding of the biology and treatment of systemic sclerosis (SSc). In this article, we will review a few areas of particular interest, including the genetics of SSc, pulmonary hypertension, and evolving therapies including stem cell transplantation.

Genetics

Systemic sclerosis is a rare disease, and familial SSc is observed for only a small number of cases.1 Therefore, it is unlikely for most rheumatologists to see a multicase family. That said, a large SSc population study has identified familial cases at a rate that is considerably greater than that expected by chance alone. The findings of this study indicated a 13-fold increase in the relative risk for a first-degree family member to also have SSc.¹ A separate study of multicase SSc families found that affected family members tended to have the same autoantibody pattern, clinical disease, and human leukocyte antigen (HLA) Class II susceptibility genotype.²

In 2009, two reports of genome-wide association studies (GWAS) in SSc, one involving American cases and the other involving European subjects, were presented at the annual meeting of the ACR in Philadelphia.^3,4 Both studies found a strong association with the HLA Class II region on chromosome 6, firmly establishing that SSc is an autoimmune disease. The specific HLA Class II genes have been identified in a separate study.⁵ These were found to be different according to the SSc-specific autoantibody subgroup. In addition, several non-HLA candidate gene regions were found in the GWAS, but the exact identification of these genes has not yet been established.

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FIGURE 1: Pathogenesis and treatment targets of systemic sclerosis.

There have been multiple reports of associations of non-HLA candidate genes with SSc, and the most likely candidates include those in pathways that regulate interferon production, such as interferon regulatory factor 5 (IRF5), as well as genes that regulate immunological responses such as signal transducer and activator 4 (STAT4). Gene variants in these pathways have been identified in systemic lupus erythematosus and in some populations of individuals with rheumatoid arthritis.^6,7 This suggests that these genes may contribute to an increased susceptibility to autoimmunity in general. Future studies of candidate genes will identify functionally relevant disease pathways which may provide modifiable targets for therapy and provide a better classification schema with prognostic implications.

Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a progressive disease that leads to increased pulmonary vascular resistance, compromised vasoreactivity, and eventual right-heart failure and death. This condition is an increasingly recognized cause of morbidity and mortality in SSc.^8,9 Pulmonary hypertension (PH) is defined as a resting mean pulmonary arterial pressure >25mmHg at right-heart catheterization (RHC). PAH is defined as PH in addition to pulmonary capillary wedge <15mmHg.¹⁰ Based on RHC, the prevalence of resting PAH in SSc may be as high as 20%.^11,12 However, histopathological evidence of pulmonary arteriopathy has been documented in up to 72% of patients with limited scleroderma, suggesting discordance between resting hemodynamics, clinical symptoms, and pathologic diagnosis.¹³