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

To observe the long-term efficacy and complications of FMT in the treatment of diseases related to intestinal dysbiosis in China.

Aims & Methods

Collect clinical data of 15000 patients who received FMT treatment and were followed up for more than 3 months from May 2017 to September 2024; The inclusion criteria for cases are patients who meet the indications for FMT treatment; Among them, there were 8258 cases of constipation, 684 cases of CDI, 1730 cases of chronic diarrhea, 510 cases of inflammatory bowel disease, 432 cases of radiation enteritis, 1940 cases of irritable bowel syndrome, 365 cases of autism, 870 cases of postoperative gastrointestinal dysfunction, and 211 cases of neurodegenerative diseases. The treatment methods for intestinal microbiota transplantation include receiving continuous infusion of intestinal microbiota solution through the nasointestinal tube (into the jejunum) for 6 days after placement (upper gastrointestinal tract transplantation group), continuous oral administration of intestinal microbiota capsules for 6 days (oral capsule transplantation), and one-time injection of microbiota solution into the colon through colonoscopy (lower gastrointestinal tract transplantation group);The main observation indicators are the efficacy of intestinal microbiota transplantation treatment at 3, 12, and 36 months. The secondary outcome measures were the occurrence of short-term (within 2 weeks after treatment) and long-term (within 36 months after treatment) adverse reactions.

Results

A total of 15000 patients in the group were treated with upper gastrointestinal route in 11125 cases, oral capsule transplantation (oral capsule group) in 3597 cases, and lower gastrointestinal route in 278 cases. At 3, 12, and 36 months after treatment, the overall treatment efficacy rates were 71.8% (10763/15000), 64.4% (7600/11808), and 58.8% (3659/6218), respectively. The clinical improvement rates for constipation were 70.3% (5805/8258), 60.8% (3858/6345), and 56.5% (1894/3352), respectively. The clinical improvement rates for CDI were 85.8% (587/684), 72.3% (408/564), and 67.3% (218/324), respectively. The clinical improvement rates for chronic diarrhea were 81.0% (1401/1730), 78.1% (1198/1534), and 72.3% (633/876), respectively. The clinical improvement rates of intestinal diseases were 64.3% (328/510), 52.3% (249/476), and 46.6% (97/208), respectively. The clinical improvement rates of radiation enteritis were 77.3%, 65.4%, and 53.6%, respectively; The clinical improvement rates of the oral capsule group were 57.3% (2062/3597), 53.6% (1115/2081), and 45.0% (453/1006), respectively; The clinical improvement rates of the lower gastrointestinal pathway group in three time periods were 43.5% (121/278), 36.4% (48/132), and 14.9% (10/67), respectively. No serious adverse reactions occurred during treatment and follow-up. The most common adverse reactions in the upper gastrointestinal route group, oral capsule group, and lower gastrointestinal route group were respiratory discomfort (20.4%, 2269/11 125), nausea and vomiting during capsule swallowing (7.6%, 273/3597), and diarrhea (47.5%, 132/278), respectively; The above symptoms disappeared after the end of treatment. During a follow-up period of 36 months, 19 patients reported worsening of their pre-existing disease symptoms, 16 deaths were not directly related to FMT, and no abnormal systemic diseases were found after FMT.

Conclusion

FMT is effective in treating intestinal dysfunction and related extraintestinal diseases related to gut microbiota disorders in the long term, with no serious adverse events

References

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• [5] Paramsothy S, Kamm MA, Kaakoush NO, et al. Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial[J]. Lancet, 2017, 389(10075):1218-1228. DOI: 10.1016/S0140-6736(17)30182-4.
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Disclosure

None

Clinical Case Summary

A 57 years-old patient with a history of active smoking, moderate body overweight (BMI 29 Kg/mq) and mild systolic hypertension in treatment with Olmesartan complained history of chronic diarrea and abdominal pain since 2006, rarely associated with hematochezia. After replacement of antihypertensive therapy to eliminate a potential confouding factor, he underwent multiple colonoscopies through the years with nonspecific findings until 2017, when moderated discontinuos inflammation with multiple erosions was seen in the transverse colon and in the rectum. Histologic examination described presence of chronic inflammation with cryptic microabscesses and cryptitis suggetive for Crohn's disease, while intestinal ultrasound revealed no small bowel localizations. He was treated with 2.4 daily grams of oral mesalamine with benefit until the end of 2023, when he came up to our clinic complaining resumption of bloody diarrhoea and abdominal pain, with 3-4 liquid stools per day. Addition of topic mesalamine was not of benefit. The patient underwent another colonoscopy which confirmed presence of hyperemic mucosa with diffuse erosions in the rectum, with histology confirming active Inflammatory Bowel Disease. In march 2024, after neurological investigations for recurrent paresthesias and strength deficits, the patient was diagnosed with relapsing-remitting Multiple Sclerosis. After multidisciplinary consultation, negative cardiologic evaluation, chest X-ray and blood screening exams, in October 2024 the patient started the anti sphingosine-1 phosphate Ozanimod, which was well-tolerated at maintenance dose of 0.92 milligrams per day. Three months after, he came back for scheduled follow-up reporting 1 or 2 daily evacuations in absence of abdominal pain and rectal bleeding. Calprotectin levels droped up to 17 ug/g. He also described complete neurological remission and complete absence of drug side effects.

References

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2) Pérez-Jeldres T, Alvarez-Lobos M, Rivera-Nieves J. Targeting Sphingosine-1-Phosphate Signaling in Immune-Mediated Diseases: Beyond Multiple Sclerosis. Drugs. 2021 Jun;81(9):985-1002. Erratum in: Drugs. 2021 Aug;81(12):1451.
3) Harris S, Feagan BG, Hanauer S, Vermeire S, Ghosh S, Yan J, Wu C, Hu Y, Maddux R, Wolf DC, D'Haens G. Ozanimod Differentially Impacts Circulating Lymphocyte Subsets in Patients with Moderately to Severely Active Crohn's Disease. Dig Dis Sci. 2024 Jun;69(6):2044-2054.
4) Sands BE. Positioning Sphingosine-1 Phosphate Receptor Modulators in Inflammatory Bowel Disease. Gastroenterol Hepatol (N Y). 2024 Jul;20(7):417-420.
5) Cree BA, Selmaj KW, Steinman L, Comi G, Bar-Or A, Arnold DL, Hartung HP, Montalbán X, Havrdová EK, Sheffield JK, Minton N, Cheng CY, Silva D, Kappos L, Cohen JA. Long-term safety and efficacy of ozanimod in relapsing multiple sclerosis: Up to 5 years of follow-up in the DAYBREAK open-label extension trial. Mult Scler. 2022 Oct;28(12):1944-1962. doi: 10.1177/13524585221102584. Epub 2022 Jun 28. Erratum in: Mult Scler. 2022.