IgG4-related sclerosing cholangitis: navigating diagnostic dilemmas and the challenge of relapse

Background: Immunoglobulin G4-related sclerosing cholangitis (IgG4-SC), also termed IgG4-related cholangitis (IRC), is a challenging immune-mediated biliary disease, frequently mimicking malignancies such as cholangiocarcinoma (CCA) or other sclerosing cholangitides like primary sclerosing cholangitis (PSC). Accurate diagnosis is critical to avoid unnecessary surgical interventions. Objective: This mini-review aims to synthesize the most current evidence on the pathogenesis, diagnostic pitfalls, and management strategies for IgG4-SC, with a focused discussion on overcoming diagnostic dilemmas and addressing the significant challenge of disease relapse. Key findings: The pathogenesis of IgG4-SC involves a complex interplay of genetic predisposition, environmental triggers (e.g., industrial vapors, dust, gases, fumes, and asbestos), and dysregulated adaptive immunity. A distinctive CD4+ T-cell response, dominated by T-helper 2 (Th2), follicular helper T (Tfh) cells, and regulatory T cells (Tregs), drives B-cell activation, oligoclonal expansion of IgG4+ plasmablasts, and progressive fibrosis. Notably, the discovery of IgG4/IgG1 autoantibodies against annexin A11 and laminin 511-E8 has provided insight into potential direct pathogenic mechanisms. Diagnosis relies on a multimodal approach integrating clinical presentation, characteristic imaging findings, elevated serum IgG4 levels (with levels >2× ULN being suggestive, and >4× ULN being highly specific), the IgG4/IgG1 ratio (>0.24), other organ involvement (notably type 1 autoimmune pancreatitis, AIP), supportive histopathology, and a rapid response to corticosteroid therapy. Despite high initial response rates to steroids, relapse occurs in 30%-50% of patients. Maintenance therapy with steroid-sparing immunomodulators (e.g., azathioprine, mycophenolate mofetil) or B-cell depleting agents such as rituximab is often required. The anti-CD19 monoclonal antibody inebilizumab has emerged as a potent new option for maintaining remission. Conclusion: Maintaining a high index of clinical suspicion for IgG4-SC is essential in patients with obstructive jaundice and biliary strictures. Future efforts should focus on validating specific biomarkers (e.g., circulating plasmablasts, autoantibody profiles) and developing evidence-based protocols for long-term management to prevent fibrotic complications and reduce the relapse rate.