Introduction

Owing to the multiplication of therapeutic options in ulcerative colitis (UC), how sequencing the drugs is a burning question. For chosing the best treatment, efficacy is a key point. However, only one head-to-head randomized controlled trial is available (VARSITY) and network meta-analyses are difficult to interpret. Then, real-world data are necessary to help ranking the treatment in UC.

Aims & Methods

We aimed to compare the effectiveness of tofacitinib and ustekinumab in patients with ulcerative colitis (UC) previously exposed to at least one anti-TNF agent.
In this multicenter study, we retrospectively included consecutive UC adult patients previously exposed to at least one anti-TNF agent, with partial Mayo score (pMS) > 2, having who started tofacitinib or ustekinumab between January 2019 and June 2022.
The primary endpoint was steroid-free clinical remission (pMS ≤ 2) (CFREM) at week 16 (W16). Secondary endpoints were endoscopic remission (CFREM + Mayo endoscopic score (MES) ≤ 1), and histological remission (CFREM + MES ≤ 1 + Nancy index ≤ 1).
Comparisons were performed using propensity score analyses adjusted on potential confounders.

Results

Overall, 289 patients were included (tofacitinib = 124 patients, ustekinumab = 165 patients). The groups were comparable (tofacitinib vs vedolizumab) for male gender (50.8% vs 43.3%), mean age (40.7 vs 42.9 years), median UC duration (8.6 vs 9.3 years), concomitant use of 5-ASA (13.7% vs 9.7%), steroids (25.0% vs 29.7%), immunosuppressants (7.3% vs 5.5%), and ≥ 2 prior biologics (85.5% vs 82.4%). Tofacitinib group had more pancolitis (55.6% vs 42.4%, p = 0.026) and UC with pMS > 6 (64.5% vs 50.3%, p = 0.016). In our study, 42.1 % of the patients treated with tofacitinib continued using a dose of 10 mgx2/day until W16 while 47.3% of the patients on ustekinumab required dose escalation to 90 mg/4 weeks before W16.
After propensity score analysis, the rate of CFREM at W16 was 37.8% and 35.6% in the tofacitinib and ustekinumab arms, respectively arm (p=0.75). CFREM at W16 was achieved in 43.3% vs 57.1% (p = 0.48) after failure of one biologic, 20.7% vs 37.9% (p=0.16) two biologics and 46.7% vs 23.2% (p=0.047) if ≥ 3 biologics, in tofacitinib and ustekinumab arms, respectively. After primary failure to at least one biologic, the rate of CFREM at W16 was 46.3% on tofacitinib vs 25.9% on ustekinumab (p = 0.13). CFREM at W16 was similar with tofacitinib and ustekinumab in case of more severe UC such as pMS ≥ 6 (40.6% vs 41.5%) and CRP > 30 (27.2% vs 33.0%).
No predictor of tofacitinib effectiveness has been identified. Factors associated with no CFREM at W16 on ustekinumab were male gender (p=0.035), ≥ 3 prior biologics (p=0.013), prior use of tofacitinib (p=0.03), primary failure to at least one biologic (p=0.013).
After propensity score analysis, endoscopic remission was achieved in 17.0% vs 11.7% (p =0.47) and histological remission in 4.4% vs 7.8% (p=0.32) of the patients treated with tofacitinib and ustekinumab, respectively.
At last follow-up, we did not observe any difference between the two groups regarding the time to drug discontinuation, time to hospitalization and time to colectomy.

Conclusion

Tofacitinib and ustekinumab have similar effectiveness at short and long-term in UC after anti-TNF failure. However, the efficacy of ustekinumab could be more impacted by prior therapeutic failures but not by UC severity.

Disclosure

Anthony Buisson: Consulting fees for Abbvie, Amgen, Arena, Biogen, Celtrion, CTMA, Fresenius-Kabi, Galapagos, Janssen, MSD, Nexbiome, Pfizer, Roche, Takeda and Tillotts. Lecture fees for Abbvie, Amgen, Biogen, Fresenius-Kabi Galapagos, Janssen, Mayoli-Spindler, MSD, Norgine, Pfizer, Roche, Takeda, Tillotts and Vifor Pharma. Research grants from Abbvie, Celltrion, Janssen, Pfizer, Takeda.
Maria Nachury: MN received board membership, consultancy, or lecture fees from Abbvie, Adacyte, Amgen, Arena, Biogen, CTMA, Celltrion, Ferring, Fresenius-Kabi, Janssen, Mayoli-Spindler, MSD, Pfizer, Takeda
Thomas Guilmoteau: None
Romain Altwegg: Received lecture and consulting fees from Abbvie, Janssen, MSD, Pfizer, Takeda.
Xavier Treton: Received honoraria from Abbvie, MSD, Takeda, Ferring, Norgine and Janssen.
Mathurin Fumery: Consulting/lecture fees for Abbvie, Amgen, Arena, Biogen, Celtrion, CTMA, Galapagos, Janssen, MSD, Pfizer, Takeda, Tillotts. MSD, Gilead, Celgene, Sandoz and Ferring.
Mélanie Serrero: Declared fees from Pfizer, Abbvie, Takeda, Janssen, MSD, Amgen, Ferring, Tillotts, Celltrion
Ludovic Caillo: Declared fees from Janssen, abbvie, Takeda, amgen, Pfizer, norgine
Bruno Pereira: None
Aurélien Amiot: Has served as a consultant, served on the advisory board, received lecture fees, and received travel fees from AbbVie, Hospira, Takeda, Gilead, Biocodex, Janssen, Ferring, and MSD.
Guillaume Bouguen: Received lecture fees from Abbvie, Ferring, MSD, Takeda and Pfizer and consultant fees from Takeda, Janssen.

Introduction

Inflammatory bowel disease (IBD) is a growing global health concern, especially in industrializing nations where westernized lifestyles drive rising incidence. Its etiology involves genetic, immune, and environmental factors. ^[1]. Plastics are extensively used in industry and daily life, and global plastic production is projected to exceed 34 billion tonnes by 2050^[2]. After release into the environment, plastic waste degrade into micro- (0.1 µm–5 mm) and nanoplastics (<0.1 µm)^[3]. These emerging pollutants are persistent, bioaccumulative, and the gastrointestinal tract is the primary interface for NPs exposure. The gut is the primary exposure route: adults ingest 0.1–5 g/week of micro-/nanoplastics^[4]. Fecal microplastic levels correlate with IBD severity^[5]; animal studies show these particles disrupt microbiota, alter short-chain fatty acids, impair the barrier, and trigger inflammation^[6]. However, most existing research is limited to histopathological observations; the cellular and molecular mechanisms underlying NP toxicity in the small intestine remain poorly understood, hindering systematic risk assessment and development of IBD prevention strategies.

Aims & Methods

To elucidate the dynamics of NP distribution and toxicity, we established a fluorescent-tracking system and reared mice in a plastic-free environment. Mice were orally exposed to 100 nm polystyrene nanospheres for or 3 or 6 weeks. We used fluorescent imaging, histology (H&E, PAS), immunofluorescence, electron microscopy, targeted metabolomics, and 16S rRNA sequencing to assess toxicity across small-intestinal regions. We tested succinate supplementation and compared effects in germ-free mice and small-intestinal organoids to distinguish microbiota-dependent from direct epithelial toxicity.

Results

Fluorescent imaging provided in vivo evidence for an enterohepatic–gallbladder circulation of NPs: following intestinal absorption, NPs first accumulate in the liver, are secreted into the gallbladder with bile acids, become concentrated between meals, and are released back into the gut upon gallbladder contraction after feeding. Prolonged NPs exposure induced chronic inflammatory cell infiltration in the small intestine, with significant reductions in crypt density, Tuft cell, goblet cell, and Paneth cell numbers, accompanied by neutrophil infiltration and decreased group 2 innate lymphoid cells (ILC2s). These changes were most pronounced in the ileum. NPs exposure also significantly reduced succinate levels in cecal contents—without altering tissue succinate—and markedly decreased the relative abundance of succinate-producing bacterial taxa. Succinate supplementation effectively reversed all of these alterations. Under germ-free conditions, NP-induced toxicity was abolished, and no direct toxic effect on Tuft cells was observed in intestinal organoids.

Conclusion

Oral NP exposure undergoes enterohepatic–gallbladder recirculation, resulting in sustained high NPs concentrations in the intestinal mucosa. The ileum is the most susceptible region, and NP toxicity depends on the gut microbiota: NP-induced dysbiosis impairs luminal succinate production, leading to depletion of ileal Tuft cells, which in turn diminishes proliferation and activation of goblet cells, Paneth cells, and ILC2s. Succinate supplementation rescues NP-induced ileal immune dysfunction. While plastic products have provided immense convenience, their uncontrolled use may contribute to the rising incidence of IBD. Our study delineates the mechanism by which NPs exacerbate ileal inflammation and proposes a feasible intervention strategy.

References

1. Ng SC, Shi HY, Hamidi N, Underwood FE, Tang W, Benchimol EI, et al. Lancet. 2017;390(10114):2769-78.
2. Luo D, Chu X, Wu Y, Wang Z, Liao Z, Ji X, et al. J Hazard Mater. 2024;465:133412.
3. Kumar M, Chen H, Sarsaiya S, Qin S, Liu H, Awasthi MK, et al. J Hazard Mater. 2021;409:124967.
4. Senathirajah K, Attwood S, Bhagwat G, Carbery M, Wilson S, Palanisami T. J Hazard Mater. 2021;404(Pt B):124004.
5. Yan Z, Liu Y, Zhang T, Zhang F, Ren H, Zhang Y. Environ Sci Technol. 2022;56(1):414-21.
6. Zhang Z, Xu M, Wang L, Gu W, Li X, Han Z, et al. Environ Int. 2023;182:108353.

Introduction

Upadacitinib (UPA) is an oral, selective JAK inhibitor that demonstrated efficacy compared to placebo (PBO) in two induction (U-EXCEED and U-EXCEL) and one maintenance (U-ENDURE) phase 3 studies.^1-3 UPA is approved for patients with moderate to severely active Crohn’s disease (CD).^4,5 Symptom improvement was seen as early as Day 5-6 with UPA 45 mg (UPA45) compared with PBO, an important treatment target.^6,7 Here, we evaluated the effect of achieving early response to UPA45 on clinical and endoscopic outcomes at the end of the induction and maintenance studies.

Aims & Methods

In U-EXCEED and U-EXCEL, patients were randomized (2:1) to UPA45 or PBO for 12 weeks (wks); results from the induction studies were pooled for this post hoc analysis. Clinical responders to 12-wk induction treatment were randomized (1:1:1) to receive UPA 15 mg (UPA15), UPA 30 mg QD (UPA30) or PBO maintenance treatment for 52 wks. Early clinical responders were defined as those patients who achieved a daily very soft/liquid stool frequency (SF) < 3 and daily abdominal pain score (APS) ≤ 1 within the first 15 days and maintained this status for >5 consecutive days until Day 19 (inclusive). Endpoints were assessed at Wk 12 of induction and Wk 52 of maintenance (Table 1). Due to unbalanced patient numbers between PBO and UPA45 in induction, only descriptive analyses were performed.

Results

Of the overall study population^1,2, 17.1% (n=115) of UPA-treated and 6.3% (n=22) of PBO-treated patients were early responders. Baseline demographics and characteristics were similar for both populations. Early responders to UPA45 (84.0%) or PBO (81.8%) had higher rates of SF/APS clinical remission at Wk 12 compared with the overall population (45.5% UPA45; 18.2% PBO). At Wk 52, greater SF/APS clinical remission rates were observed during maintenance for early responders treated with UPA15 (54.8%) or UPA30 (71.1%) vs PBO (25.9%); these rates were higher than what was observed for the overall population (33.9% UPA15; 49.3% UPA30, 15.2% PBO). For endoscopic outcomes, early clinical responders treated UPA45 achieved higher rates of endoscopic response (54.1% vs 40.3%), endoscopic remission (36.6% vs 24.2%), and mucosal healing (34.0% vs 21.1%) vs the overall population at Wk 12; this was also seen for PBO-treated early responders (see Table). These high rates of endoscopic remission (36.8%), response (50.0%), and mucosal healing (28.9%) were maintained with UPA30 for early responders at Wk 52 and were numerically greater than the overall population rates or PBO (see Table). When compared to the overall study population,the treatment effects at Wk 52 across clinical and endoscopic outcomes for both doses were generally higher for the early responder population evaluated here.

Conclusion

Early clinical responders to upadacitinib therapy had high rates for clinical and endoscopic endpoints at Weeks 12 and 52, suggesting that early symptom improvement with upadacitinib may indicate promising durability in outcomes for patients with CD.

References

1. Colombel, JF et al. Abstract 867f. Gastroenterology [Abstract] 162(7): 2022; S-1394.
2. Loftus, EV Jr. et al. Abstract. United European Gastroenterology Journal. [Abstract] 10: 2022; 103.
3. Panes, J. et al. American Journal of Gastroenterology. [Abstract] 117: 2022. S11.
4. Medicines & Healthcare Products Regulatory Agency. RINVOQ 45 mg prolonged-release tablets (Great Britain). 09 Feb 2023. Retrieved 15 March 2023 from https://www.medicines.org.uk/emc/product/13935/smpc.
5. Annex I: Summary of Product Characteristics (RINVOQ). European Medicines Agency.
24 April 2023. Retrieved 25 April 2023 from https://www.ema.europa.eu/en/documents /product-information/rinvoq-epar-product-information_en.pdf
6. Turner D, et al. Gastroenterology 2021;160:1570–1583.
7. J F Colombel et al, Journal of Crohn's and Colitis. [Abstract] 17: S1 2023; i102–i103.

Disclosure

Jean-Frederic Colombel reports receiving research grants from AbbVie, Janssen Pharmaceuticals and Takeda; receiving payment for lectures from AbbVie, Amgen, Allergan, Inc. Ferring Pharmaceuticals, Shire, and Takeda; receiving consulting fees from AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, BMS, Celgene Corporation, Eli Lilly, Ferring Pharmaceuticals, Galmed Research, Genentech, Glaxo Smith Kline, Janssen Pharmaceuticals, Kaleido Biosciences, Imedex, Immunic, Iterative Scopes, Merck, Microbia, Novartis, PBM Capital, Pfizer, Protagonist Therapeutics, Sanofi, Takeda, TiGenix, Vifor; and hold stock options in Intestinal Biotech Development
Tadakazu Hisamatsu has received research grants from AbbVie, Alfresa Pharma, Daiichi Sankyo, EA Pharma, JIMRO, Kyorin Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nippon Kayaku, Pfizer, Takeda, and Zeria Pharmaceutical; consulting fees from AbbVie, Celgene, EA Pharma, Janssen, Nichi-Iko, and Pfizer; and lecture fees from AbbVie, EA Pharma, Janssen, JIMRO, Kyorin Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Pfizer, and Takeda.
Raja Atreya has been a consultant and/or speaker for AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion Healthcare, DrFalk Pharma, Ferring, Fresenius Kabi, Galapagos, Gilead, GlaxoSmithKline plc, InDex Pharmaceuticals, Janssen-Cilag, Kliniksa Pharmaceuticals, Lilly, MSD Sharp & Dohme, Novartis, Pandion Therapeutics, Pfizer, Roche Pharma, Samsung Bioepsis, Stelic Institute, Takeda Pharma, Tillotts Pharma AG, Viatris and has received research/educational support from AbbVie, Biogen, InDex Pharmaceuticals, Takeda Pharma, Tillotts Pharma AG.
Lena Thin is an advisory board member for AbbVie; receives advisory board/steering committees fees for education from AbbVie, Takeda, Janssen, Ferring, BMS, Pfizer, Celltrion, Chiesi; receives research grants from Celltrion, Takeda, Pfizer; and is an executive member of the Australian New Zealand IBD consortium.
Rogerio S. Parra has served as a consultant, speaker, and advisory board member for AbbVie, Janssen, Takeda, Ferring, and Pfizer.
Sharanya Ford, Valencia Remple, Ana Paula Lacerda,Samuel I. Anyanwu,Madhuja Mallick, and AndrewGarrisonare employees of AbbVie and may own stock options.
Miguel Regueiro has served as a consultant, speaker, and advisory board member for AbbVie.
Funding: AbbVie funded this study 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.
Acknowledgments: AbbVie and authors thank all the trial investigators and the patients who participated in this clinical trial. Paulette Krishack, PhD of AbbVie Inc., provided medical writing assistance for the development of this publication.

Introduction

Ulcerative colitis (UC) occurs in genetically predisposed individuals. The influence of environmental factors and the gastrointestinal microbiome is thought to be of particular importance in this disorder. Proton pump inhibitors (PPIs) affect the microbiome along the entire GI tract and PPI use is the single factor that influences fecal microbial composition to the largest extent at a population level. Only few studies have previously investigated the association between PPI use and UC, but these suggest that PPIs may increase the risk of UC and possibly also affect the disease course. The objective of the study was to examine how PPI exposure is associated with disease course in a large national cohort of newly diagnosed UC patients.

Aims & Methods

Nationwide data from the Norwegian Patient Registry (NPR) and the Norwegian Prescription Database (NorPD) were linked and a study cohort including all newly diagnosed UC patients in Norway between 2010 and 2020 was drawn based on predefined case definitions. PPI exposure was included as a time dependent variable and defined as PPI dispensal of at least 0.5 defined daily doses for 28 days. A 30 day time lag from dispensal was added and the exposure period extended 60 days after the duration of the prescription. Outcomes were classed by use of advanced therapies (adalimumab, infliximab, golimumab, vedolizumab, ustekinumab and tofacitinib), systemic glucocorticoids, and starting any additional systemic anti-inflammatory medication and colectomy during follow-up. Time-dependent Cox regressions included the variables PPI use (time-dependent), first systemic glucocorticoid prescription (time-dependent), first UC hospitalization (time-dependent), age-groups 0-19, 20-39, 40-59, 60+ years and sex. In the multivariate analyses using systemic glucocorticoids and colectomy as outcomes, advanced therapies was also included as a variable. Patients were followed from time of diagnosis until the outcome of interest, death or December 2020, whichever came first.

Results

There were 10149 patients in the study cohort. The median age was 40 years (IQR 27-56) and 56% were males. PPI use independently increased the risk of starting glucocorticoids (HR 1.20, 95% CI 1.07-1.34), advanced therapies (HR 1.54, 95% CI 1.36-1.73), any additional anti-inflammatory treatment (HR 1.18, 95%CI 1.05-1.32) and undergoing colon surgery (HR 1.52, 95%CI 1.17-1.98). The strongest risk factor for starting glucocorticoids were hospitalization (HR 4.35 95%CI 3.96-4.77), while young age also was a significant risk factor. Use of glucocorticoids was the strongest risk factor for starting treatment advanced therapies (HR 13.19, 95%CI 11.12-15.63) and younger age was also a significant risk factor in this analysis. In the sensitivity analysis using outcomes occurring without time lag and with 60 days lag, the HR of PPI use were similar. In analyses where patients exposed to NSAID were excluded, PPI use remained a significant risk factor for starting advanced therapies HR 1.66 (1.47-1.88) and undergoing colectomy HR 1.64 (1.25-2.15), but PPI use was no longer a risk factor for starting glucocorticoids or starting any anti-inflammatory treatment.

Conclusion

In this national cohort of newly diagnosed patients with UC, PPI use was a risk factor for unfavorable outcomes including advanced therapy initiation, additional anti-inflammatory medications and undergoing colectomy. Although further studies are needed, the evidence suggests that PPIs could affect the course of UC and should be used cautiously in UC patients.

Disclosure

The project was funded by Takeda. The author SSL reports research funding from Takeda during the conduct of the study. RF has received lecture fee from Takeda. MLH reports investigator research grants from Takeda, Pfizer, Tillotts and Ferring, and speaker fees from Tillotts, Ferring, Galapagos, BMS, MSD and AbbVie as well as Advisory board honoraria from Takeda and AbbVie.