Current paradigms in the management of inflammatory bowel disease

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INTRODUCTION Advances in therapeutic strategies, molecular understanding and patient-centered approaches have reshaped the management of inflammatory bowel disease (IBD). This article explores current paradigms in the management of IBD, focusing on emerging treatments, safety considerations, novel pathophysiological insights, and the role of digital technologies and patient-reported outcomes. ADVANCED THERAPY AT DIAGNOSIS OF CROHN’S DISEASE Historically, treatment for Crohn’s disease (CD) followed an accelerated step-up approach — beginning with corticosteroids, early introduction of immunosuppressants and a low threshold for starting biological therapy. Then came PRedicting Outcomes For Crohn’s disease using a moLecular biomarker (PROFILE; 2024).[1] PROFILE was a UK, multicentre, randomised controlled trial evaluating the use of a prognostic biomarker to guide therapy by comparing the impact of anti-TNF therapy at diagnosis with conventional standard of care. The results were remarkable. Sustained steroid- and surgery-free remission was achieved in 79% (149/189) of patients in the top-down group versus 15% (29/190) of patients receiving accelerated step-up therapy (absolute difference: 64 percentage points; 95% confidence interval 57–72; P < 0.0001). As if this were not impressive enough, there were fewer complications requiring abdominal surgery in the top-down group (1/189 vs. 10/190). Additionally, there was no biomarker–treatment interaction effect. This suggests that advanced therapy is best initiated at the time of diagnosis of CD. Although the study used anti-TNF therapy — administered within a median of 12 days from diagnosis — it is likely that other advanced therapies could be similarly effective, although this remains to be established. Clearly, the pharmacoeconomic implications are substantial; however, the societal cost of CD is likely to favour this approach, owing to savings on hospitalisation, major abdominal surgery, reduced relapse rates and fewer complications requiring medical care. Whether advanced combination therapies may be more effective than monotherapy remains the focus of ongoing trials, although anecdotal reports are abundant.[2] The choice, dose, timing, duration and safety of these therapies have yet to be fully elucidated. SAFETY CONSIDERATIONS IN ADVANCED THERAPY While the safety of advanced therapy continues to be debated, there is little contest when compared with the adverse effects of conventional steroids and immunosuppressants.[3] Returning to the PROFILE study, fewer adverse events (including disease flares) were observed in the top-down group (adverse events: 168 vs. 315; serious adverse events: 15 vs. 42), with no difference in serious infections (3 vs. 8). Anti-integrin therapy (vedolizumab) and anti-interleukin (IL)-23 therapies (mirikizumab, risankizumab and ustekinumab) are particularly safe. Janus-activated kinase inhibitors have been associated with an increased risk of herpes zoster reactivation (shingles), occurring in approximately one event per 100 patient-years of treatment; however, this is preventable through vaccination.[4] Furthermore, a systematic review and meta-analysis of small-molecule therapies found no evidence of an increased rate of infection or venous thromboembolism in patients with IBD during either induction or maintenance phases.[5] The adverse consequences of under-treated CD or ulcerative colitis warrant greater attention and clearer communication with patients. NEW CONCEPTS IN PATHOGENESIS There is a complex interplay of genetic predisposition, environmental factors, microbiome dysbiosis and immune dysregulation in IBD. Two concepts are particularly noteworthy. Emerging research suggests that IL-10 autoantibodies may contribute to immune dysregulation in IBD. As IL-10 is an essential anti-inflammatory cytokine, the loss of its function due to neutralising autoantibodies promotes intestinal inflammation, creating a phenocopy of IL-10 receptor mutations seen in very early onset IBD.[6] It is likely that this mechanism also applies to adults. The second concept relates to ETS2, a transcription factor involved in immune cell regulation. Convincing evidence has identified ETS2 as the causal gene in immune-mediated diseases, including CD, as it serves as a central regulator of human inflammatory macrophages.[7] The mechanism leading to ETS2 overexpression is currently being elucidated, illustrating the power of functional genomics as opposed to genome-wide association studies. Both mechanisms present opportunities for entirely new therapeutic approaches. ENDPOINTS IN CLINICAL TRIALS Mucosal healing has become a key target in the management of IBD, as it correlates with reduced relapse rates and a decreased need for surgery. The challenge, however, is that there is no internationally agreed definition of mucosal healing — although this is being addressed by the Foundation for the National Institutes of Health (https://fnih.org/our-programs/biomarkers-consortium-mucosal-healing-in-uc-definition-treatment-target-and-clinical-endpoints/). There are three areas to consider. The first is histological remission, defined as the absence of neutrophils in colonic mucosal biopsies. When this is achieved in conjunction with normalisation of endoscopic activity (Mayo Endoscopic Subscore [MES] = 0), the 12-month relapse rate is just 5%, compared with 14% if there is active microscopic inflammation and MES = 0, or 29% for MES = 1.[8] A 95% chance of being relapse-free over the next 12 months is an important message for eligible patients, although historical remission is not yet considered a formal treatment target. The second area is multi-omic profiling and single-cell RNA sequencing analysis, which define the cellular mechanisms of response or non-response to therapy such as anti-TNF agents.[9] This approach is expected to revolutionise precision medicine in IBD.[10] The third area — more prosaic but of significant interest to patients — concerns neglected symptoms in IBD. NEGLECTED SYMPTOMS IN IBD Urgency, fatigue, pain and psychological correlates are experienced by most patients with IBD, yet these symptoms are often neglected by physicians and not typically included as outcome measures in therapeutic trials. This, however, is beginning to change. There are potentially modifiable cognitive behavioural factors that contribute to persistent symptoms, which — if recognised and addressed — can allow for more precisely tailored treatment plans.[11] Consequently, therapeutic trials are increasingly incorporating a ‘basket’ of such features as exploratory endpoints, as these symptoms often matter more to patients than traditional measures such as mucosal healing or inflammation control.[12] AI-ASSISTED DIGITAL PATHOLOGY AND ENDOSCOPY Artificial intelligence (AI) is transforming diagnostics in IBD through automated histopathological analysis and AI-assisted endoscopic assessments. Moreover, AI algorithms have shown high accuracy in detecting inflammation and dysplasia, as well as in predicting treatment response, thereby enhancing clinical decision-making.[13] The impact of these technologies will be evident at the local level, even as they are integrated into clinical trials. This is largely due to the increasing adoption of AI-assisted digital pathology and endoscopy to address the shortage of specialist gastrointestinal pathologists and endoscopists. Clinicians are likely to welcome the support offered by AI-generated estimates of cumulative damage and disease activity, which can inform more confident clinical decisions. Nevertheless, a note of caution is warranted: AI algorithms are only as good as their training sets. Cumulative bias may arise when certain ethnic groups, such as Asian, Black or other under-represented populations, are excluded from development or validation cohorts, which are often based on predominantly Caucasian populations. Therefore, AI has the potential to amplify such bias. DIET AND MICROBIAL THERAPY Dietary interventions and microbial therapies are emerging as adjunctive treatments to support a healthy microbiome in patients with IBD. Although it is too early to draw definitive conclusions, most patients do seek dietary guidance. The Mediterranean diet and IBD anti-inflammatory diet (IBD-AID) show promise in controlling symptoms and reducing inflammation.[14] However, ‘natural foods’ are not without risk, particularly beyond the well-known issue of dietary fibre exacerbating obstructive symptoms in patients with small bowel strictures. Unfermented β-fructans (such as inulin or fructo-oligosaccharides) may promote inflammation, potentially explaining the intolerance to dietary fibre reported by some patients with IBD.[15] Microbiome manipulation is an appealing concept for patients, and personalised regimens based on individual microbial profiles are on the horizon.[16] This approach extends beyond faecal microbiota transplantation as a method of modulating gut dysbiosis. Indeed, if IBD specialists and scientists readily acknowledge the pivotal role of the gut microbiota in the pathogenesis of ulcerative colitis and CD, then microbial manipulation should be welcomed, rather than dismissed solely because its clinical benefit has not yet been firmly established. This area warrants close attention. CONCLUSION The management of IBD is evolving rapidly, with advanced therapy from the time of CD diagnosis, AI-driven diagnostics and patient-centred care increasingly becoming the standard. In the next 12 months, it is likely that causal mechanisms will be identified in a subset of patients — offering the potential for transformative, novel treatments. The majority of patients will have to wait for access to precision medicine through molecular classification. However, they can already benefit from personalised medicine that utilises multiple safe, advanced therapies. The optimal sequencing of these therapies will only be established through multi-omic analysis of the cellular basis of individual diseases. Future research should focus on integrating molecular and clinical biomarkers, optimizing safety profiles, and addressing neglected symptoms to improve long-term patient outcomes. Acknowledgement Generative AI (ChatGPT) was used as an experiment for this article. However, the content, headings and references generated bear no relation to the submitted paper. Nevertheless, it is important to acknowledge that generative AI promoted creative thinking. Financial support and sponsorship Nil. Conflicts of interest Travis S received the following: grants/research support (AbbVie, Celgene, Celsius, ECCO, Galapagos, GSK, Helmsley Trust, IOIBD, Janssen, Lilly, Pfizer, Takeda, UKIERI, Vifor, and Norman Collisson Foundation), consulting fees (Alimentiv; Apexian; Apollo; Arcturis; AstraZeneca; BMS; Clario; Cosmo; Endpoint Health; EQrX; Equillium; Ferring; Galapagos; Genentech/Roche; Gilead; GSK; Janssen; Iterative Health; Lilly; Mestag; Microbiotica; ONO; Pfizer; Phesi; Protagonist; Sanofi; Satisfai; Sensyne Health; Spyre; Takeda; Teva; Theravance; Tr1X Bio), speaker fees (BMS, Ferring, GSK, Janssen, Lilly, Pfizer, Sun Pharma, Takeda) and share options (Satisfai Health Inc).