Introduction

Inflammatory bowel disease is a chronic, relapsing condition influenced by genetic, microbial, and environmental factors. This study evaluated the therapeutic potential of multi-strain probiotics in mitigating the severity of experimentally induced colitis in rats, focusing on clinical outcomes, histopathological changes, inflammatory markers, and microbiota changes.

Aims & Methods

Thirty six-week-old male Sprague-Dawley rats were randomly assigned to three groups: Control, Acute Colitis (AC), and Probiotic Treatment (RP; receiving Lactobacillus rhamnosus and Lactobacillus paracasei). Probiotics were administered orally once daily, beginning three days prior to colitis induction with rectal DNBS and continued for seven days post-induction. On day eight, colon tissues and blood samples were collected for histological and biochemical analysis, and fecal samples were analyzed to assess gut microbiota composition.

Results

The AC group showed significantly elevated TNF-α levels compared to the Control and RP groups (p < 0.001), while probiotic treatment significantly reduced TNF-α levels compared to the AC group (p = 0.002, p < 0.001, respectively). Although the RP group demonstrated increased IL-10 levels and decreased MDA levels, these changes were not statistically significant. Histopathological analysis revealed a lower median Ameho’s score in the RP group compared to the AC group, though without statistical significance.

Microbiota analysis showed no significant differences in alpha diversity across groups. However, beta diversity significantly differed in the AC group compared to Control, and after probiotic treatment, the RP group’s beta diversity showed a partial shift toward the Control group. Distinct microbial species characterized each group: Akkermansia spp. and Parasutterella spp. were predominant in distinguishing the Control group from others; Romboutsia spp. and Turicibacter spp. differentiated the AC group; and Roseburia spp. and Anaerotruncus spp. were the key species distinguishing the RP group from the others.

Conclusion

Multi-strain probiotics reduced TNF-α levels and modulated gut microbiota composition in DNBS-induced colitis. Although changes in IL-10, MDA, and histopathology were not statistically significant, trends favored the probiotic group. Microbial analysis revealed distinct species profiles across groups, with partial restoration of beta diversity and enrichment of beneficial taxa like Roseburia spp. in the probiotic group. These findings support the potential of probiotics as a therapeutic adjunct in IBD, highlighting the need for further studies to confirm efficacy and explore underlying mechanisms.

Introduction

Endoscopic healing is an important treatment goal for patients (pts) with Crohn’s disease (CD).¹ Herein, the relationships between endoscopic healing and achievement of long-term patient reported outcomes (PROs) and occurrence of CD-related hospitalization were assessed in pts with moderate to severe CD treated with risankizumab (RZB) maintenance therapy from the FORTIFY trial.

Aims & Methods

In FORTIFY, pts who had clinical response to RZB induction² received 52 weeks (wks) of maintenance therapy (subcutaneous 180mg or 360mg every 8wks) in substudy 1³ and continued receiving RZB as per their treatment assignment in the open-label extension (OLE) substudy 3. This analysis included pts who completed 2 years (y) of RZB in the OLE (cumulative RZB treatment of 3 years including 52wks in substudy 1) (cutoff date: 01MAR2024). Clinically meaningful improvements in PROs were assessed, including Inflammatory Bowel Disease Questionnaire (IBDQ) response (≥16-point increase in total score), IBDQ remission (total score ≥170-points), improvement in 36-Item Short Survey (SF-36) physical component score (PCS, ≥4.1-points) and mental component summary (MCS, ≥3.9-points), EuroQol-5D questionnaire visual analog scale (EQ-5D-5L VAS; ≥9.2-points), and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) response (≥9-points). Exposure-adjusted occurrence of CD-related hospitalizations was also assessed as incidence rates (events/100 patient-y) from OLE wk52 to wk152. The proportion of pts who achieved each outcome at wk152 were compared based on their achievement of wk52 endoscopic response, endoscopic remission, or ulcer-free endoscopy vs not (endpoint definitions in Table footnote) using chi-square testing. Pts with missing outcomes were considered nonresponders. Endoscopies were scored by a central reviewer. Long-term safety of RZB has been reported.²

Results

Of the 257 pts included in the analysis, 134 (52.1%), 99 (38.5%), and 79 (30.7%) pts achieved wk52 endoscopic response, endoscopic remission, and ulcer-free endoscopy, respectively. Significantly more pts who achieved wk52 endoscopic response also achieved IBDQ response and remission, SF36 PCS and MCS response, and improvement in FACIT-F and EQ-5D-5L VAS scores at wk152 (P≤.0001 for all comparisons) vs pts who did not achieve wk52 endoscopic response (Table). Similar results were observed for pts who achieved wk52 endoscopic remission (P≤.01) and pts who achieved wk52 ulcer-free endoscopy (P≤.02, except for SF36 MCS response) at wk152. CD-related hospitalizations from wk56 to wk152 were significantly lower for pts who achieved wk52 endoscopic remission and endoscopic response and numerically lower for pts who achieved wk52 ulcer-free endoscopy, vs not.

Conclusion

A significantly greater proportion of pts achieved 3y sustained improvement in PROs when they achieved endoscopic outcomes at 52wks of RZB maintenance treatment. Achievement of endoscopic outcomes at 52wks also resulted in fewer CD-related hospitalizations through 152wks when continuing active therapy, pointing to favorable long-term outcomes of disease.

References

Turner D, et al. Gastroenterology. 2021;160:1570-83.
Ferrante M, et al. J Crohns Colitis. 2021; 15(12):2001-2010.

Disclosure

Christopher Ma has received consulting fees from AbbVie, Alimentiv, Amgen, AVIR Pharma Inc, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Fresenius Kabi, Janssen, McKesson, Mylan, Pendopharm, Pfizer, Prometheus Biosciences Inc., Roche, Sanofi, Takeda, Tillotts Pharma; speaker's fees from AbbVie, Amgen, AVIR Pharma Inc, Alimentiv, Bristol Myers Squibb, Eli Lilly, Ferring, Fresenius Kabi, Janssen, Organon, Pendopharm, Pfizer, Sanofi, Takeda, Tillotts Pharma; royalties from Springer Publishing; research support from AbbVie, Ferring, Pfizer.
Brian G Feagan has served as a consultant or received speaker’s fees from Abbott/AbbVie, ActoGeniX, Akros, Albireo Pharma, Amgen, AstraZeneca, Avaxia Biologics, Avir Pharma, Axcan, Baxter Healthcare, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Calypso Biotech, Celgene, Elan/Biogen, enGene, Ferring Pharmaceuticals, gIcare Pharma, Gilead, Given Imaging, GSK, Ironwood Pharmaceuticals, Janssen Biotech (Centocor), Johnson & Johnson/Janssen, Kyowa Hakko Kirin Co, Lexicon, Lilly, Lycera, Merck, Mesoblast, Millennium, Nektar, Nestlé, Novartis, Novo Nordisk, Pfizer, Prometheus Therapeutics and Diagnostics, Protagonist Therapeutics, Receptos, Roche/Genentech, Salix Pharmaceuticals, Serono, Shire, Sigmoid Pharma, Synergy Pharmaceuticals, Takeda, Teva Pharmaceuticals, TiGenix, Tillotts, UCB, Vertex Pharmaceuticals, VHsquared, Warner Chilcott, Wyeth, Zealand Pharma, and Zyngenia, and has received research support from Abbott/AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Janssen Biotech (Centocor), Johnson & Johnson/Janssen, Millennium, Pfizer, Receptos, Roche/Genentech, Sanofi, Santarus, Tillotts, and UCB.
Peter Bossuyt received financial support for research from AbbVie, Amgen, Celltrion, Mylan, Pfizer, and Takeda; lecture fees from AbbVie, Celltrion, Janssen, Lilly, and Takeda; and advisory board fees from AbbVie, Arena Pharmaceuticals, BMS, Celltrion, Dr Falk, Galapagos, Janssen, Lilly, Pentax, PSI-CRO, Roche, Takeda, and Tetrameros.
Vipul Jairath has received has received consulting/advisory board fees from AbbVie, Alimentiv Inc, Arena Pharmaceuticals, Asahi Kasei Pharma, Asieris, Astra Zeneca, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, GlaxoSmithKline, Genentech, Gilead, Janssen, Merck, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Reistone Biopharma, Roche, Sandoz, Second Genome, Takeda, Teva, Topivert, Ventyx, and Vividion; and speaker’s fees from, AbbVie, Ferring, Galapagos, Janssen Pfizer Shire, Takeda, and Fresenius Kabi.
Namita Joshi, Nidhi Shukla, Kristina Kligys, Ari Stromberg,andJameson Crowley are full-time employees/contractor of AbbVie and may own AbbVie stock or options.
Acknowledgments
AbbVie funded this study (NCT03105102) and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the abstract. All authors had access to relevant data and participated in the drafting, review, and approval of this abstract. No honoraria or payments were made for authorship. AbbVie and authors thank all the trial investigators and the patients who participated in this clinical trial.
Medical writing support was provided by Stephanie Parsons, PhD, an employee of AbbVie. Editorial support was provided by Amy Kuang, an employee of AbbVie.

Introduction

Upadacitinib (UPA) is an oral Janus kinase inhibitor approved for treating moderately to severely active Crohn’s disease (CD).^1-3 Sustained efficacy and safety were reported after 2 years (yrs) of UPA therapy in the U-ENDURE maintenance and long-term extension (LTE) studies.⁴ Here, we evaluated the long-term efficacy and safety of up to 3 yrs of total UPA maintenance therapy in patients with moderately to severely active CD in the ongoing U-ENDURE LTE study.

Aims & Methods

Patients who completed the U-ENDURE 52-week (wk) maintenance study were eligible for the subsequent LTE study and continued their previously assigned treatment (UPA 15 mg [UPA15] once-daily [QD] or UPA 30 mg [UPA30] QD). This analysis included all patients who completed 52 wks of maintenance treatment followed by an additional 96 wks in the LTE study (total of 3 yrs of maintenance therapy), with efficacy assessed from LTE wk 0 to wk 96. Inadequate responders were eligible to receive rescue therapy (open-label UPA30 or protocol-approved CD-related medications); patients who received rescue therapy were analysed separately. Clinical and endoscopic endpoints were evaluated using both as-observed (AO) (in text and Table) and nonresponder imputation (NRI) methods (Table); mean change from baseline of induction in high-sensitivity C-reactive protein (hs-CRP) and faecal calprotectin (FCP) were evaluated using AO analysis (in text). Safety was assessed from maintenance wk 0, with up to 292 wks of cumulative maintenance and LTE treatment exposure (cut-off date: 19 Nov 2024).

Results

Baseline (wk 0 of induction) demographics and clinical characteristics were generally well-balanced among UPA15- or UPA30-treated patients enrolled in the LTE. From LTE wk 0 to wk 96, AO efficacy rates remained stable in each treatment group for clinical remission per stool frequency (SF)/abdominal pain score (APS) (UPA15: 78.3% to 83.1%; UPA30: 84.7% to 84.3%; Table) or Crohn’s Disease Activity Index (CDAI) (UPA15: 81.3% to 83.1%; UPA30: 86.1% to 88.6%; Table); similar results were observed in corticosteroid-free clinical remission. From LTE wk 0 to wk 96, efficacy rates remained stable for endoscopic response (UPA15: 59.6% to 70.8%; UPA30: 71.2% to 70.1%; Table), and endoscopic remission (UPA15: 42.4% to 50.8%; UPA30: 53.0% to 56.7%; Table). Clinical or endoscopic remission was sustained through LTE wk 96. Mean change from induction baseline was stable from LTE wk 0 through wk 96 for inflammatory markers, hs-CRP (UPA15: -12.4, -12.0; UPA30: -12.7, -10.1) and FCP (UPA15: -2752, -3263; UPA30: -1850, -2055) (AO). Across efficacy endpoints, similar results were found per NRI. No new safety signals were identified in this safety analysis among UPA15- or UPA30-treated patients.⁴ The safety profile was consistent with the known safety profile of UPA in CD.^1
​

Conclusion

Sustained efficacy for clinical, endoscopic, and inflammatory markers was observed in patients who completed up to 3 yrs of UPA maintenance therapy, with no new safety signals identified.¹

References

1. Loftus EV, Jr. and Panés J et al. N Engl J Med. 2023;88:1966-80.
2. AbbVie Inc. RINVOQ (Upadacitinib) [package insert] U.S. Food and Drug Administration website. https://www.rxabbvie.com/pdf/rinvoq_pi.pdf. Revised May 2023.
3. AbbVie DG& CoK. RINVOQ. (Upadacitinib) [package insert] Summary of Product Characteristics. European Medicine Agency website. https://www.ema.europa.eu/en/documents/product-information/rinvoq-epar-product-information_en.pdf. Revised Feb 2025.
4. G D'Haens, et al. J Crohn's Colitis. (Abstract). 2024;18:i17–i18.

Disclosure

Edward V. Loftus Jr. has served as a consultant for AbbVie, Abivax Astellas, Avalo, Biocon, Bristol Myers Squibb, Celltrion, Eli Lilly, Fresenius Kabi, Genentech, Gilead, Iota Biosciences, Iterative Health, Janssen, Merck, Morphic Therapeutics, Ono Pharma, Takeda, and TR1X Bio; has received research grants from AbbVie, Genentech, Gilead, Janssen, Merck, and Takeda; and is a shareowner of Exact Sciences and Moderna.
Geert D’Haens has served as advisor and/or speaker for AbbVie, Abivax, Agomab, Akros, Alimentiv, Anaptys Bio, Bristol Meiers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Galapagos, Glaxo Smith Kline, Index Pharmaceuticals, Johnson and Johnson, Merck, Polpharm, Prometheus Biosciences, Sanofi, Spyre, Takeda, and Tillotts.
Edouard Louis has received research grants from Janssen, Pfizer, and Takeda; received educational grants from AbbVie, Janssen, MSD, and Takeda; received speaker fees from AbbVie, Falk, Ferring, Hospira, Janssen, MSD, Pfizer, and Takeda; served on advisory boards for AbbVie, Arena, Celgene, Ferring, Galapagos, Gilead, Hospira, Janssen, MSD, Pfizer, and Takeda; and served as a consultant for AbbVie.
Miguel Regueiro has served as a consultant, speaker, and is an advisory board member for AbbVie.
Vipul Jairath has received consulting/advisory board fees from AbbVie, Alimentiv, Arena, Asahi Kasei Pharma, Asieris, Astra Zeneca, Avoro Capital, Bristol Myers Squibb, Celltrion, Eli Lilly, Endpoint Health, Enthera, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, Gilde Healthcare, GlaxoSmithKline, Genentech, Gilead, Innomar, JAMP, Janssen, Merck, Metacrine, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Prometheus Biosciences, Reistone Biopharma, Roche, Roivant, Sandoz, Scope Eyecare, Second Genome, Sorriso, Takeda, TD Securities, Teva, TopiVert, Ventyx, Vividion; received speaker’s fees from AbbVie, Ferring, Bristol Myers Squibb, Galapagos, Janssen, Pfizer, Takeda, and Fresenius Kabi.
Fernando Magro has been a speaker and has received honoraria for services from AbbVie, Biogen, Falk, Ferring, Hospira, Laboratorios Vitoria, Merck, and Vifor.
Hiroshi Nakase reports receiving personal fees from AbbVie, Kissei Pharmaceutical, KYORIN Pharmaceutical, Mitsubishi Tanabe Pharma Corporation, Janssen Pharmaceutical K.K., Takeda, Pfizer Japan, EA Pharma, Zeria Pharmaceutical, Mochida Pharmaceutical, Nippon Kayaku, Daiichi Sankyo, Gilead, Viatris, JIMRO, and grants for commissioned/joint research from Hoya Group Pentax Medical, Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical, AbbVie.
Elena Dubcenco, Irina Fish, Kimmie Kim,Yibo Wang,Samuel I. Anyanwu, Fernando Aponte, and Sina Ogholikhan are employees of AbbVie and may own stock options.
Irina Blumenstein has received consultant honoraria from AbbVie Deutschland, Amgen GmbH, Bristol Myers Squibb, Janssen-Cilag GmbH, Fresenius Kabi Deutschland, Pharmacosmos GmbH, Pfizer GmbH, Shire Deutschland GmbH, Takeda Pharma GmbH; honoraria from AbbVie Deutschland, Biogen GmbH, DGVS, Dr. Falk Pharma GmbH, EndoAkademie, Ferring Arzneimittel, Fraunhofer, Fresenius Kabi Deutschland, Kompetenznetz Darmerkrankungen, MSD Sharp Dohme, Mylan GmbH, Pfizer GmbH, Janssen-Cilag GmbH, Shire Deutschland GmbH, Takeda Pharma GmbH.
Funding: AbbVie funded this study (U-ENDURE; NCT03345823) and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the publication. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship.
Acknowledgements: AbbVie and the authors thank the participants, study sites, and investigators who participated in this clinical trial. Paulette A. Krishack, PhD, of AbbVie, provided medical writing support, and S. Michael Austin, of AbbVie, provided editorial support.