Introduction

Ulcerative colitis (UC) is a chronic inflammatory bowel disease marked by relapsing symptoms and significant impact on quality of life, with current therapies often limited by suboptimal efficacy or adverse effects. Interleukin-12/23p40 (IL-12/23p40) antagonists have emerged as targeted treatments due to their role in modulating key inflammatory pathways, yet the class-wide efficacy and safety of these agents remain uncertain.

Aims & Methods

To evaluate the effectiveness and safety of IL-12/23p40 antagonists in moderate to severe UC, a systematic review, meta-analysis, and trial sequential analysis were conducted. Databases including PubMed, Embase, Cochrane Central, and ClinicalTrials.gov were searched in December 2024 to identify randomized controlled trials (RCTs) comparing IL-12/23p40 antagonists to placebo. Outcomes included clinical and endoscopic remission and response, adverse events, and additional endpoints such as histologic healing, symptomatic relief, and glucocorticoid-free remission. Risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI) were pooled using a random-effects model in R software.

Results

Nine RCTs enrolling 3,808 patients in the induction phase and 1,734 in the maintenance phase were included [1–6]. IL-12/23p40 antagonists significantly improved clinical remission during induction (21.8% vs. 8%; RR 2.63, 95% CI 2.05–3.36, p < 0.001) and maintenance (46.8% vs. 23%; RR 1.99, 95% CI 1.63–2.44, p < 0.001), and clinical response (induction: RR 1.94, 95% CI 1.70–2.20, p < 0.001; maintenance: RR 1.51, 95% CI 1.34–1.69, p < 0.001). Endoscopic remission (induction: RR 2.36, 95% CI 1.63–3.41, p < 0.001; maintenance: RR 1.96, 95% CI 1.63–2.37, p < 0.001) and endoscopic response were also significantly improved. Notably, prior biologic or JAK inhibitor failure was linked to higher induction remission rates (RR 3.74, 95% CI 1.60–8.76, p = 0.002), with meta-regression confirming this association (p = 0.008), suggesting enhanced remission in previously treatment-resistant patients. Additionally, IL-12/23p40 antagonists improved histologic, endoscopic, and mucosal healing (RR 2.49; 95% CI 2.01–3.08, p < 0.001), symptomatic remission (RR 2.16, 95% CI 1.66–2.82, p < 0.001), and quality of life as measured by the IBDQ score (MD 16.3, 95% CI 12.2–20.4, p < 0.001). Moreover, IL-12/23p40 antagonists demonstrated a favorable safety profile in both the induction and maintenance phases. During induction, they were associated with a significantly lower risk of serious adverse events (RR 0.40, 95% CI 0.27–0.69, p < 0.001). No significant differences were observed compared to placebo in the overall incidence of adverse events (induction: RR 0.97, 95% CI 0.90–1.04, p = 0.38; maintenance: RR 0.95, 95% CI 0.87–1.03, p = 0.22), headache (induction: RR 1.17, 95% CI 0.82–1.68, p = 0.39; maintenance: RR 1.29, 95% CI 0.60–2.78, p = 0.51), or nasopharyngitis (induction: RR 1.09, 95% CI 0.67–1.76, p = 0.73; maintenance: RR 1.07, 95% CI 0.77–1.50, p = 0.68).

Conclusion

IL-12/23p40 antagonists demonstrate superior efficacy compared to placebo in inducing and maintaining clinical and endoscopic remission in patients with moderate to severe UC, with a favorable safety profile and potential benefits even among biologic-experienced populations. These results support the use of IL-12/23p40 antagonists as an effective and well-tolerated treatment option in the management of UC.

References

1. Louis E, Schreiber S, Panaccione R, Bossuyt P, Biedermann L, Colombel JF, et al. Risankizumab for Ulcerative Colitis: Two Randomized Clinical Trials. JAMA. 2024 Sep 17;332(11):881–97.
2. D’Haens G, Dubinsky M, Kobayashi T, Irving PM, Howaldt S, Pokrotnieks J, et al. Mirikizumab as Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med. 2023 Jun 29;388(26):2444–55.
3. Rubin DT, Allegretti JR, Panés J, Shipitofsky N, Yarandi SS, Huang KHG, et al. Guselkumab in patients with moderately to severely active ulcerative colitis (QUASAR): phase 3 double-blind, randomised, placebo-controlled induction and maintenance studies. Lancet. 2024 Dec 17;S0140-6736(24)01927-5.
4. Peyrin-Biroulet L, Allegretti JR, Rubin DT, Bressler B, Germinaro M, Huang KHG, et al. Guselkumab in Patients With Moderately to Severely Active Ulcerative Colitis: QUASAR Phase 2b Induction Study. Gastroenterology. 2023 Dec;165(6):1443–57.
5. Sandborn WJ, Ferrante M, Bhandari BR, Berliba E, Feagan BG, Hibi T, et al. Efficacy and Safety of Mirikizumab in a Randomized Phase 2 Study of Patients With Ulcerative Colitis. Gastroenterology. 2020 Feb;158(3):537-549.e10.
6. Sands BE, Sandborn WJ, Panaccione R, O’Brien CD, Zhang H, Johanns J, et al. Ustekinumab as Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med. 2019 Sep 26;381(13):1201–14.

Introduction

Advances in non-celiac wheat sensitivity (NCWS) have proved that it should be considered a protean condition in which several potential triggers [e.g. gluten, wheat amylase-trypsin inhibitors, etc.] might determine an intestinal mucosal damage with increased permeability and exposure of foods/microbial peptides to immune cells (1,2), resulting in both a local and systemic inflammatory activation responsible for its gastrointestinal and extraintestinal manifestations (3,4). Up to 75% of NCWS subjects complain of multiple foods hypersensitivities (MFH) (5). These patients usually have clinical, immunological and histological features similar to wheat allergy patients, although without positive gluten/wheat IgE assays, allowing to hypothesize the existence of a non-IgE mediated hypersensitivity. In addition, several studies have reported an association between atopic diseases and NCWS.

Aims & Methods

This study aimed to define the presence and features of atopic diseases and other hypersensitivities (primarily food allergies/intolerances) in NCWS compared with celiac disease (CD) and irritable bowel syndrome/functional dyspepsia (IBS/FD) and to analyze a possible correlation between these diseases and NCWS clinical manifestations. This retrospective, multicenter study included NCWS patients diagnosed by double-blind placebo-controlled challenge with wheat. Their clinical, laboratory and histology data at diagnosis (i.e. before the start of a wheat-free diet) were analyzed and compared to control subjects with CD and IBS/FD. Specific allergology data, other than clinical/laboratory features typical of NCWS, were collected and analyzed: family and personal history of atopic diseases, type of allergens responsible, positivity of skin prick tests (SPT), patch tests and total and food-specific IgE.

Results

Atopic disease prevalence was higher in NCWS (32.8%) than in CD (19.3%) and IBS/FD (21.5%) (P=.001 for both). Similarly, NCWS subjects had a higher frequency of MFH (39.8%) and self-reported milk intolerance (SRMI) (65.9%) compared to the controls (P <.001 for both). Allergic asthma, either alone (P=.03) or associated with allergic rhinitis (P=.005), was more prevalent in NCWS compared to IBS/FD, which was more often associated with allergic conjunctivitis (P=.004) or allergic rhinitis alone (P=.02). Graminaceae hypersensitivity and nickel allergic contact dermatitis (Ni-ACD) were more frequent in patients with NCWS (70.1% and 17.8%) vs both CD (48.7% and 9.4%, P=.03 and P=.01, respectively) and IBS/FD (50.8% and 6.7%, P=.01 and P<.001, respectively). On multiple logistic regression analysis, a coexistent atopic disease (OR 1.481), MFH (OR 3.882) and SRMI (OR 2.259) were associated with the NCWS diagnosis. NCWS subjects with atopy compared to those without more frequently had Ni-ACD (P<.001) and SRMI (P=.03), positive patch test (P<.001), SPT for foods (P=0.001) and both total and food-specific serum IgE (P=.02 and P=.002, respectively). On multiple logistic regression analysis, positivity to patch test (OR 2.955), SPT for foods (OR 5.799), and food-specific serum IgE (OR 3.101) were confirmed as differentiating the 2 subgroups.

Conclusion

NCWS subjects have a higher frequency of atopic disease, MFH and SRMI compared to both CD and IBS/FD ones. These conditions could be expression of an underlying hypersensitivity milieu characterizing NCWS and might be of support in the differential diagnosis between NCWS and functional gastrointestinal disorders, if inserted into a broader diagnostic panel.

References

1) Zevallos VF, Raker V, Tenzer S, Jimenez-Calvente C, Ashfaq-Khan M, Rüssel N, et al. Nutritional Wheat Amylase-Trypsin Inhibitors Promote Intestinal Inflammation via Activation of Myeloid Cells. Gastroenterology. 2017;152:1100-1113.e12.
2) Uhde M, Ajamian M, Caio G, De Giorgio R, Indart A, Green PH, et al. Intestinal cell damage and systemic immune activation in individuals reporting sensitivity to wheat in the absence of coeliac disease. Gut. 2016;65:1930–7.
3) Volta U, De Giorgio R, Caio G, Uhde M, Manfredini R, Alaedini A. Nonceliac Wheat Sensitivity. Gastroenterol Clin North Am. 2019;48:165–82.
4) Catassi C, Elli L, Bonaz B, Bouma G, Carroccio A, Castillejo G, et al. Diagnosis of Non-Celiac Gluten Sensitivity (NCGS): The Salerno Experts’ Criteria. Nutrients. 2015;7:4966–77.
5) Carroccio A, Mansueto P, Iacono G, Soresi M, D’Alcamo A, Cavataio F, et al. Non-Celiac Wheat Sensitivity Diagnosed by Double-Blind Placebo-Controlled Challenge: Exploring a New Clinical Entity. American Journal of Gastroenterology. 2012;107:1898–906.

Disclosure

This study is funded by the European Union - Next Generation EU, Mission 4, Component 1 CUP B53D23031860001, Project Code: P2022Z9RZY_001.