# Systemic Sclerosis and Primary Biliary Cholangitis: A Comprehensive Review of Two Overlapping Rare Entities With Insights on Diagnostics and Management

## TL;DR

This review explores the connection between two rare autoimmune diseases, PBC and SSc, focusing on their overlapping symptoms, shared genetic factors, and challenges in diagnosis and treatment.

## Contribution

The paper provides a comprehensive review of the overlap between PBC and SSc, highlighting shared genetic and pathogenic mechanisms and their clinical implications.

## Key findings

- PBC and SSc frequently coexist, especially with the limited cutaneous subtype of SSc.
- Shared genetic factors like HLA-DRB1, DQA1, STAT4, and IRF5 are implicated in both diseases.
- Overlapping cases have altered prognosis, with reduced liver-related mortality but increased non-liver-related mortality.

## Abstract

Primary biliary cholangitis (PBC) is an autoimmune liver disease of a chronic nature that can lead to liver cirrhosis, predominantly in females. PBC frequently coexists with other autoimmune diseases, such as systemic sclerosis (SSc), rheumatoid arthritis, systemic lupus erythematosus, and Sjögren’s syndrome. Despite variations in the literature, most studies have reported that a few PBC patients have SSc, especially the limited cutaneous subtype. Pathology of SSc includes microvascular affection and widespread fibrotic changes along with the autoimmune process. This narrative review aims to provide a comprehensive overview of the existing literature up to December 2024 regarding PBC, SSc, and overlap syndrome with emphasis on diagnostic points. Clinical manifestations can be significantly overlapping for both conditions. Thus, laboratory and histopathological investigations are necessary. The antibody profile is a cornerstone in such autoimmune diseases. While the antimitochondrial antibody (AMA) is considered specific for PBC, the presence of anticentromere antibody (ACA) highly suggests the concomitant presence of SSc. Several common pathologic mechanisms and triggers have been suggested for both diseases, and genes like HLA-DRB1, DQA1, STAT4, and IRF5 are shared between the two conditions. It is noteworthy that the prognosis and outcome of PBC cases are affected by the presence of SSc; for instance, the high liver-related PBC mortality decreases with the presence of SSc, although overlapping cases are at high risk of non-liver-related mortality. The overlapping cases comprise a clinical challenge for diagnosis and tailored management, although some promising medications are being investigated for both conditions, possibly due to common pathogenic mechanisms. Herein, we comprehensively review the available literature on PBC-SSc overlapping syndrome in terms of epidemiology, underlying pathophysiology, and clinical aspects.