A comprehensive review of systemic sclerosis–primary biliary cholangitis overlap: emerging evidence for a distinct clinical subtype

Purpose of review To synthesize current knowledge on the genetic, immunopathogenic, and clinical presentations of systemic sclerosis (SSc) and primary biliary cholangitis (PBC) with a focus on their co-occurrence as a clinically relevant overlap syndrome. This narrative review summarizes preclinical and clinical studies addressing SSc-PBC overlap. Recent findings Genomic studies highlight shared susceptibility loci between SSc and PBC. Furthermore, SSc–PBC overlap patient sera reveals anticentromere antibodies which cross-react with an antigenic motif on pyruvate dehydrogenase-E2 (structural core of pyruvate dehydrogenase complex catalyzing formation of acetyl coA), the most common target of antimitochondrial antibodies in PBC. Similar profibrotic cytokines and T regulatory cell profiles are identified in sera and skin and liver biopsies of patients with SSc and PBC respectively. Analysis of clinical phenotypes reveals that SSc–PBC overlap patients have reduced incidence of pulmonary fibrosis and pulmonary arterial hypertension compared to SSc alone, and less severe hepatic involvement compared to PBC alone. Summary SSc–PBC overlap remains an understudied disease process. This review summarizes current knowledge and outlines future directions to guide research and improve care for patients with this distinct clinical overlap.