Oral Gut-Restricted Targeted Therapy for IBD: A Pipeline Review.

Defining Endpoints and Biomarkers in Inflammatory Bowel Disease: Moving the Needle Through Clinical Trial Design

Background Ustekinumab is an effective biologic therapy for inflammatory bowel disease (IBD), yet many patients experience loss of response requiring dose escalation (1). Predictors of ustekinumab dose escalation remain poorly defined, particularly across Crohn’s disease (CD) and ulcerative colitis (UC) (2). Current literature demonstrates variable approaches to managing loss of response to ustekinumab, with limited standardized guidance on dose optimization strategies (3). This study aims to evaluate clinical outcomes and predictive factors supporting ustekinumab dose escalation strategies in IBD patients with loss of response or suboptimal outcomes. Methods We conducted a retrospective cohort study between 2019 and 2024. Study included adult patients with IBD initiated on ustekinumab. The primary outcome was factors associated with dose escalation, defined as shortening ustekinumab maintenance interval to every 4 weeks, analyzed separately for CD and UC via multivariable logistic regression. The secondary outcome assessed predictors of time to escalation among CD patients using multivariable linear regression. Results A total of 206 patients were included (CD: 165, UC: 41). Dose escalation occurred in 69 41.8% of CD and 14 (34.1%) of UC patients. In CD, prior biologic use (OR 3.05; 95% CI: 1.31–7.14; p = 0.01) and prior immunomodulator use (OR 2.07; 95% CI: 1.00–4.29; p = 0.05) were significantly associated with escalation (figure 1). Longer disease duration was also observed in escalated patients (median 6 vs. 4 years, p = 0.003). In UC, none of the evaluated variables predicted escalation. Median time to escalation was 9 months (IQR 3–18) in CD and 4.5 months (IQR 2–12.8) in UC. No predictors were significantly associated with time to escalation in CD subgroup analysis (figure 1). Conclusion Prior biologic exposure, immunomodulator use, and longer disease duration predict ustekinumab dose escalation in CD but not in UC, highlighting disease-specific differences in therapeutic needs. These findings support tailored dose optimization strategies in IBD and underscore the need for prospective studies incorporating therapeutic drug monitoring and standardized escalation protocols.

Interferon-β-1a for the Treatment of Steroid-Refractory Ulcerative Colitis: A Randomized, Double-Blind, Placebo-Controlled Trial

Cell-Specific Inhibition of p38α as a Therapeutic Strategy for Inflammatory Bowel Disease

Corticosteroid Therapy in the Age of Infliximab: Acute and 1-Year Outcomes in Newly Diagnosed Children With Crohn’s Disease

Future Therapeutic Approaches for Inflammatory Bowel Diseases

Chronic inflammatory bowel diseases (IBD), such as Crohn’s disease and ulcerative colitis, are recurrent and aggressive inflammatory disorders that are most likely the result of an overly aggressive immune response to ubiquitous intestinal antigens in a genetically susceptible host. Despite decades of intense research, our knowledge of factors causing IBD remains incomplete and, therefore, conventional therapy to induce and maintain remission works in a symptomatic fashion, merely suppressing the immune response. Probiotic bacteria have long been known to confer health benefits, especially with regard to intestinal disorders. Although there is mounting evidence from in vitro and animal experiments supporting the use of probiotics in IBD, clinical trials have not provided definite evidence for the therapeutic effect of probiotic therapy in IBD to date. This is with the notable exception of pouchitis and the maintenance of remission in ulcerative colitis, whereas Crohn’s disease and active ulcerative colitis do not seem amenable to probiotic intervention. The next 5 years will see more trials targeting specific clinical settings using tailor-made probiotic combinations, taking into account our increasing knowledge of individual probiotic properties and the diversity of these microorganisms.

Systematic review on failure to adhere to IBD therapies during the COVID-19 pandemic: Correct information is crucial

AGA Clinical Practice Update on Management of Inflammatory Bowel Disease in Elderly Patients: Expert Review

Fecal Microbiota Transplantation for Ulcerative Colitis: Not Just Yet

Beyond Gene Discovery in Inflammatory Bowel Disease: The Emerging Role of Epigenetics

Immune Response to Influenza Vaccine in Pediatric Patients With Inflammatory Bowel Disease

Despite the development of novel small molecules and antibody-based therapies targeting pro-inflammatory immune pathways, the clinical management of inflammatory bowel disease (IBD) remains challenging. In this Perspective, we highlight emerging treatment strategies with a focus on engineered cellular immunotherapies, including stem cell-based approaches, regulatory T cell and type 1 regulatory T cell therapies, as well as chimeric antigen receptor (CAR) T cell platforms(CAR T cells, CAR Treg cells). Early-stage studies using haematopoietic and mesenchymal stem cells have yielded promising clinical results, although the safety and efficacy of such therapies require further careful validation. Moreover, efforts in immune cell engineering are now directed towards the expansion and adoptive transfer of allogeneic IL-10-producing type 1 regulatory T cells and autologous transforming growth factor-β-secreting regulatory T cells, which are currently being evaluated in early-stage clinical trials. Notably, a recent case report demonstrated that CD19-targeted CAR T cell therapy can induce long-term remission of intestinal inflammation in ulcerative colitis, highlighting a potential pathogenic role of mucosal B cells and plasmablasts in ulcerative colitis and underscoring the transformative therapeutic potential of CAR T cell strategies in IBD. Although these approaches offer exciting therapeutic prospects in IBD, rigorous prospective and controlled clinical trials are essential to fully assess their safety and efficacy.

The advent of biological therapies for inflammatory bowel disease (IBD) began in 1998 with the approval of infliximab for the treatment of refractory (to conventional agents) Crohn's disease (CD). Since then, the indications for anti-tumor necrosis factor-α (anti-TNFα) therapy have increased to include induction and maintenance of clinical responses and remissions for luminal and fistulizing CD, the treatment of children with CD, and the treatment of adults with ulcerative colitis. Additional utilities of biological therapies have included demonstrable mucosal healing, improvement in quality of life, reduction in surgeries and hospitalizations, and the treatment of extraintestinal manifestations of IBD including central and peripheral arthritis and pyoderma gangrenosum. Natalizumab has also been approved for the treatment of refractory Crohn's in patients who have failed conventional agents and anti-TNFα therapies. Unfortunately, despite the overall effectiveness of biological agents in a spectrum of indications for IBD, a significant proportion of patients do not respond or lose response over time. In this review, we intend to appraise the latest evolution in treatment strategies in IBD and to suggest an evidence-based approach and risk stratification while coping with cases of non-responders or loss of response to biological therapies. We conducted a literature search of English publications listed in the electronic databases of MEDLINE (source PUBMED) and constructed an analytical review based on definitions of response and loss of response, considering potential responsible mechanisms, clinical assessment tools, and finally recommending a practical approach for its prevention and management. Favorable clinical outcome appears to be the consequence of sustained therapeutic drug levels, and the current literature supports a practice of dose adjustments. When immunogenicity develops to a single biological agent, response can be regained by introduction of an alternative biological agent of the same or different class. Efficacy is reduced with second-line agents either within or across classes compared with naive patients. In the absence of direct measurement of drug levels and anti-drug antibodies, clinical judgment is necessary to assess the mechanisms of loss of response, and more empiric decision making may be necessary to determine the choice of second-line biological agents. Optimal treatment strategies are still controversial. It is essential to recognize the spectrum of mechanisms affecting response and loss of response to form a logical and efficient management algorithm, and, perhaps, it is time to incorporate the measurement of trough levels and anti-drug antibodies in the strategy of such an assessment. Prospective controlled trials are direly needed to investigate the optimal tailored management in individual patients who lose response.

Background Biologic and small molecule therapies have revolutionised the treatment of inflammatory bowel disease (IBD). Despite these advances, there appears to be a therapeutic ceiling with single agent therapy with up to 50% of patients failing to achieve long term remission. Combination of two biologic therapies or a biologic therapy and small molecule agent, with differing mechanisms of action, has the potential to improve IBD therapy outcomes. Information on the effectiveness and safety of this treatment strategy in IBD remains limited. Methods A retrospective, multicentre study was carried out at five Irish Academic Centres within the Initiative Network. Combination biologic or small molecule use was defined as concomitant use of two biologics or one biologic and small molecule therapy licenced or undergoing clinical trial assessment for treatment of IBD. Patients who had received combination therapy were identified from institutional databases. Review of clinical records was performed and demographic data collected. Combination therapy persistence was considered a proxy for successful therapy outcome. Adverse events were documented. P values < 0.05 were considered significant in analyses. Results The study cohort included 85 patients; 70% Crohn’s disease (CD), 30% ulcerative colitis (UC); median (IQR) number of prior biologic therapies 3 (2 – 3); median (IQR) study follow up 40.71 weeks (13.68 – 82.86). Further baseline characteristics are described in Figure 1. 97 combination therapy trials were undertaken in 85 patients. 13 different combination therapy regimes were utilised with ustekinumab & vedolizumab being the most common regimen. 76.5% (n=65 patients) remained on combination therapy at last follow up. Higher rates of combination therapy discontinuation (p=0.04) and shorter time to combination therapy discontinuation were observed in UC compared with with CD (HR 0.48 [95% CI 0.21-1.11], p<0.05). 3.1% of the study cohort developed a serious or opportunistic infection. No deaths or intensive care unit admissions occurred during study follow up. Conclusion Combination therapy is an effective therapeutic strategy with an acceptable safety profile in refractory IBD patients. Randomised controlled trials are required to clearly define the role of combination therapy in the management of IBD.