Pharmacotherapy of Inflammatory Bowel Disease

Introduction & pathogenesis

• Inflammatory bowel disease (IBD) is a spectrum of chronic, idiopathic, remitting-relapsing intestinal inflammation causing diarrhoea, abdominal pain, bleeding, anaemia and weight loss — classically two subtypes: ulcerative colitis (UC) and Crohn's disease (CD); an unclassifiable minority is termed indeterminate colitis.
• UC = confluent, continuous mucosal/submucosal inflammation starting at the rectum/anal verge and extending proximally (proctitis → left-sided → pancolitis); hallmark crypt abscesses; curable by colectomy. CD = transmural inflammation of any gut segment (mouth-to-anus, classically ileocaecal), discontinuous "skip lesions", granulomas, cobblestoning → fibrosis, strictures and fistulae; not cured by surgery (post-op recurrence up to 80%).
• Pathogenesis: aberrant mucosal immune response to commensal gut microbiota (dysbiosis) in a genetically susceptible host. Cytokine polarity drives drug targeting — CD is T_H1/T_H17-mediated (IL-12, IL-23, IFN-γ, TNF-α) and UC is T_H2-mediated (IL-4, IL-13). TNF-α is the pivotal proinflammatory cytokine.
• Druggable targets mapped onto pathogenesis: general immunosuppressants (steroids, thiopurines, MTX, ciclosporin), anti-TNF, anti-IL-12/23 and anti-IL-23(p19), anti-integrin (anti-α4β7), JAK inhibitors, S1P-receptor modulators, and microbiome manipulation.
• Genetics/environment: first-degree relatives ~20× risk; NOD2 is the major CD gene; smoking is protective in UC but worsens CD; NSAIDs and appendectomy modify risk. Therapeutic goals have shifted from symptom relief to "treat-to-target" mucosal healing: induce remission, maintain remission, treat extraintestinal manifestations (joints/skin/eyes ~50%; PSC; ↑colorectal-cancer risk).