Management of Refractory and Difficult‐To‐Treat Inflammatory Bowel Disease: An Expert Opinion Review

ABSTRACT

The management of refractory and difficult‐to‐treat inflammatory bowel disease (IBD) poses significant challenges, requiring a personalized, treat‐to‐target approach. Refractory IBD is defined as persistent or worsening disease despite all classes of licensed immunosuppressive and biologic agents, with additional criteria for Crohn's disease (CD) and ulcerative colitis (UC). Because studies restricted to strictly patients refractory are scarce for several treatment modalities, evidence from difficult‐to‐treat populations is also considered here. A multidisciplinary evaluation, including adherence, dose optimization, disease phenotype, smoking cessation, genetic factors, and exclusion of mimicking conditions, is essential before introducing unlicensed therapies. Comprehensive strategies encompass screening, combination therapy, surgical interventions, and nutritional support. Emerging therapies focus on targeting inflammation and immune pathways, including Janus kinase (JAK) inhibitors (e.g., tofacitinib and upadacitinib), IL‐23 antagonists (e.g., risankizumab), and TL1A inhibitors (e.g., PF‐06480605). Novel approaches, such as mesenchymal stem cell therapy and hyperbaric oxygen therapy, have been reported mainly in perianal fistulizing CD, although the supporting evidence remains limited. Nutritional therapies, especially exclusive enteral nutrition, are effective in managing pediatric CD, whereas partial enteral nutrition may provide long‐term benefits. Future strategies may incorporate combination or sequential therapies during induction and maintenance phases to optimize outcomes. Despite these advancements, significant unmet needs persist, emphasizing the necessity for personalized, evidence‐based interventions. Here, we tried to outline current insights, diagnostic considerations, and therapeutic innovations, providing a comprehensive resource for improving the management of refractory IBD. For several of these questions, the evidence is limited to case series, so the statements have not been graded, and expert opinion is identified as such in the text.