Extraintestinal manifestations in inflammatory bowel disease – epidemiology, genetics, and pathogenesis

ABSTRACT

Introduction: Inflammatory bowel disease (IBD) is a chronic inflammatory disorder, primarily of, but not restricted to the gut. Extraintestinal manifestations (EIMs) are frequently observed and involve the joints, eyes, hepatobiliary tract, and skin.

Areas covered: In this review, we discuss classical EIM focusing on epidemiology, genetics, and pathogenesis, highlighting recent advances in the understanding of EIM. We further discuss treatment-induced immunological phenomena, which are increasingly recognized and might challenge IBD-treating physicians in the era of biological treatment.

Expert opinion: EIM considerably contributes to morbidity and mortality. Genetic studies have revealed a common genetic background between EIM and IBD and among specific EIM. Identified protein interactions have been shown to cluster in shared biological pathways. However – despite these recent advances – pathogenesis of EIM is at best partially understood. Several pathogenic mechanisms have been proposed such as upregulation of tumor necrosis factor, aberrant lymphocyte homing, and cross-reactive antigen presentation. It still remains unclear whether EIM is a direct result of the inflammatory process in the gut or rather a consequence of a shared genetic background leading to dysfunctional immune responses to environmental stimuli. Exploration and understanding of EIM genetics and pathophysiology will pave the road for better and more efficacious treatment options in the future.

KEYWORDS:

• Extraintestinal manifestations
• inflammatory bowel disease
• Crohn’s disease
• ulcerative colitis
• uveitis
• episcleritis
• erythema nodosum
• pyoderma gangrenosum
• stomatitis
• arthritis
• spondylarthritis
• primary sclerosing cholangitis
• genetics
• epidemiology
• pathomechanisms

Article highlights

• EIMs are frequent and considerably affect morbidity and mortality in IBD patients.

• EIMs have a strong genetic background.

• Pathogenesis of EIM is at best partially understood. Several not mutually exclusive mechanisms are involved, such as cross-reactivity, cytokine imbalance, and aberrant lymphocyte homing.

Declaration of interest

T. Greuter has declared associations with Sanofi, Falk, Vifor and Novartis. S.R. Vavricka has declared associations with Abbott, Fering, Merk, Pfizer, Takeda, Tillots, Union Chimique Belge, Vifor and Falk. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This work was supported by a grant from the Swiss National Science Foundation to TG (grant no. P2ZHP3_168561).