Introduction

The co-occurrence of inflammatory bowel disease (IBD) and type 1 diabetes (T1D) has been linked to poor clinical outcomes. However, few longitudinal studies have explored their temporal relationships.

Aims & Methods

This study aimed to investigate the bidirectional association between IBD and T1D. In this nationwide cohort and case-control study, patients with biopsy-confirmed IBD were identified between 1987 and 2017. The cohort included 20,314 patients with IBD (≤28 years; Crohn’s disease [CD, n=7,277], ulcerative colitis [UC, n=10,112], and IBD-unclassified [IBD-U, n=2,925]) and individually matched reference individuals from the general population (n=99,200). The case-control study enrolled 87,001 patients with IBD and 431,054 matched controls. We estimated adjusted hazard ratios (aHRs) of incident T1D by IBD status with flexible parametric survival models and adjusted odds ratios (aORs) of IBD by history of T1D with conditional logistic regression, with 95% confidence intervals (CIs). The familial factors from genetics and early environmental factors were additionally accounted for via sibling comparisons.

Results

In the cohort, during a median follow-up of 14 years, 116 patients with IBD and 353 reference individuals developed T1D. Patients with IBD had a higher incidence of T1D than reference individuals (incidence rate:3.7 vs. 2.3 per 10,000 person-years; aHR=1.58[95%CI=1.27 to 1.95]). The HR was increased in patients with UC (aHR=2.02[1.51 to 2.70]) but not in those with CD (aHR=1.11[0.76 to 1.64]) or IBD-unclassified (aHR=1.48[0.82 to 2.69]). In the case-control study, a total of 1,018 IBD patients and 3,496 controls had been diagnosed with T1D. Compared with controls, patients with IBD tend to have higher odds of having previous T1D (aOR=1.36[95%CI=1.26 to 1.46]). Such positive association was observed in all IBD subtypes. Comparisons with siblings showed similar associations (aHR=1.44 [0.97 to 2.15] and aOR=1.32 [1.18 to 1.49]).

Conclusion

Patients with IBD had a moderately increased incidence of developing T1D and higher odds of having a previous diagnosis of T1D. These findings demonstrate a bidirectional association between IBD and T1D independent of shared genetics and early environmental factors.

Disclosure

All authors have completed the ICMJE uniform disclosure form and declare:
OO has been PI on projects at Karolinska Institutet financed by grants from Janssen, Pfizer, AbbVie, Takeda, Bristol Myer Squibb and Ferring, and Karolinska Institutet has received fees for lectures and participation on advisory boards from Janssen, Ferring, Galapagos, Bristol Myer Squibb, Takeda, and Pfizer. OO also reports grants from Pfizer, Janssen, Galapagos, and AbbVie in the context of a national safety monitoring programs.

JH served as speaker and/or advisory board member for AbbVie, Aqilion, BMS, Celgene, Celltrion, Dr Falk Pharma and the Falk Foundation, Eli Lilly, Ferring, Galapagos, Gilead, Hospira, Index Pharma, Janssen, MEDA, Medivir, MSD, Novartis, Pfizer, Prometheus Laboratories Inc., Sandoz, Shire, STADA, Takeda, Thermo Fisher Scientific, Tillotts Pharma, Vifor Pharma, UCB and received grant support from Janssen, MSD and Takeda.

FE has served as an advisory board member for Boehringer Ingelheim.

JFL has coordinated a study on behalf of the Swedish IBD quality register (SWIBREG). That study received funding from Janssen Corporation. JFL has also received financial support from MSD developing a paper reviewing national healthcare registers in China. JFL has a research collaboration on celiac disease with Takeda.

The other authors report no disclosures relevant to the manuscript.

Introduction

Mirikizumab (miri), an anti-IL-23p19 antibody, has shown efficacy in patients with moderately-to-severely active Crohn’s disease (CD) to Week (W)52. We explored the potential relationship between early histologic and endoscopic responses on long term clinical outcomes after 2 years of miri treatment in a double-blind, placebo (PBO)-controlled Phase 2 trial (NCT02891226) in patients with CD.

Aims & Methods

Patients were randomized 2:1:1:2 to 4 treatment arms: miri 1000mg, 600mg, 200mg, and PBO administered intravenously (IV) at W0, W4, and W8. Patients who received miri and achieved ≥1 point improvement at W12 in Simple Endoscopic Score for Crohn’s disease score were re-randomized to either continue their induction IV dose or receive miri 300mg subcutaneously (SC) every 4 weeks up to W52. Subjects reported to experience clinical benefit received 300mg SC from W52 to W104. Biopsies were obtained during endoscopy at W0, W12 and W52 from the edges of any ulcers or from the most inflamed mucosa in the terminal ileum and 4 colonic segments and were scored by blinded central readers. Endpoints were defined post-hoc and prior to analyses (see Table 1). Among patients receiving miri with active histological disease at baseline, we determined the relationship between histologic and/or endoscopic response or remission at W12 and W52 and with clinical remission based on the Crohn’s Disease Activity Index (CDAI), patient-reported outcomes (PRO), and hospitalization rates at W104. Non-responder imputation for CDAI or PRO at W104 was used for patients who have observed histologic and endoscopic outcome value at W52 or W12. Hospitalizations were summarized by observed value. P-values for categorical values were determined with Fisher’s exact test.

Results

At W104, 56.9% patients (N=137) achieved CDAI remission compared to 41.5% of 176 patients at W52. We observed no association between early (W12) histologic, endoscopic, or combined (histo-endo) response and clinical remission (CDAI & PRO) at 2 years. After 2 years, the percentage of patients achieving remission based on CDAI varied according to their response at W52 by histology (60%), endoscopy (25.9%), both histo-endo (56.3%), or neither (10.5%, p=0.006; Table 1). Similarly, the proportion of patients who achieved 2-year clinical remission (by CDAI) varied according to W52 remission by histology (72.7%), endoscopy (40%), both histo-endo (40%) or neither (19.5%, p=0.007). Hospitalization rates during this period were low and varied according to W52 response by histology (16.7%), endoscopy (0%), both (0%) or neither (3.9%, p=0.021).

Table 1. Week 104 clinical remission and hospitalization rates by histologic and endoscopic response at Week 12 and Week 52, and by histologic and endoscopic remission at Week 52

Conclusion

In CD patients treated with miri for 2 years, long term clinical remission (CDAI, PRO) was significantly correlated with histologic response alone as well as combined histologic-endoscopic response at Week 52, but not at Week 12. The small sample size was likely a limitation. This data will be further studied in Phase 3 trials.

Disclosure

VJ reports consulting/advisory board fees from AbbVie, Alimentiv Inc (formerly Robarts Clinical Trials), Arena pharmaceuticals, Asahi Kasei Pharma, Asieris, 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, Vividion; speaker’s fees from, Abbvie, Ferring, Galapagos, Janssen, Pfizer, Shire, Takeda, Fresenius Kabi. 
WR reports lecture fees from AbbVie, Actelion, Alpha Wasserman, AstraZeneca, Cellerix, Cosmo Pharmaceuticals, Ferring, Genentech, Grunenthal, Johnson & Johnson, Millennium, Merck, NovoNordisk, Nycomed, Pfizer, Pharmacosmos, Schering-Plough, Salix, Takeda, UCB Pharma, and Vifor; consultant fees from AbbVie, Actelion, Alpha Wasserman, AstraZeneca, Cellerix, Cosmo Pharmaceuticals, Ferring, Genentech, Grunenthal, Johnson & Johnson, Millennium, Merck, NovoNordisk, Nycomed, Pfizer, Pharmacosmos, Schering-Plough, Salix, Takeda, UCB Pharma, and Vifor; and serves as an advisory board member for AbbVie, Actelion, Alpha Wasserman, AstraZeneca, Cellerix, Cosmo Pharmaceuticals, Ferring, Genentech, Grunenthal, Johnson & Johnson, Millennium, Merck, NovoNordisk, Nycomed, Pfizer, Pharmacosmos, Schering-Plough, Salix, Takeda, UCB Pharma, and Vifor.
GDH reports that his institution has received fees for his clinical trial activities with Centocor J&J.
NH has served as an advisory board member or consultant for Eli Lilly and Company, Abbvie Inc., Bristol Meyer Squibb, Inc., and PathAI, Inc.
RP reports consulting fees from Seres Therapeutics, Eli Lilly, Protagonist, Genentech, and Robarts Clinical Trials.
MP, ZL, RH, HC are employees and minor shareholders of Eli Lilly and company. 
FM served as speaker for Abbvie, Arena, Biogen, Bristol-Myers Squibb, Falk, Ferring, Hospira, Janssen, Laboratórios Vitoria, Pfizer, Lilly, Merck Sharp & Dohme, Sandoz, Takeda, UCB, Vifor.

Introduction

The QUASAR program (NCT04033445) evaluated guselkumab (GUS), a dual-acting interleukin (IL)-23p19 subunit inhibitor that potently neutralizes IL-23 and binds to CD64 (a receptor on cells that produce IL-23), in patients (pts) with moderately to severely active ulcerative colitis (UC). Induction Week 12 (Week I-12) nonresponders to intravenous (IV) GUS received subcutaneous (SC) GUS through Week I-24.¹ Week I‑24 responders were eligible for maintenance therapy. Here, we present the efficacy and safety of maintenance SC GUS among GUS Week I-24 responders.

Aims & Methods

Pts who were not in clinical response (see Table for definition) at Week I-12 after IV GUS 200 mg or 400 mg received SC GUS 200 mg at Weeks I-12, I-16, and I-20. Those who were in clinical response at Week I-24 (GUS Week I-24 responders) received SC GUS 200 mg every 4 weeks during the maintenance study in a blinded fashion and were evaluated as part of the nonrandomized study population. Clinical, symptomatic, endoscopic, histologic, and patient-reported outcome measures at maintenance Week 44 (Week M-44) and safety throughout the maintenance study are reported for GUS Week I-24 responders.

Results

Overall, 123 of 203 (60.6%) Week I-12 nonresponders to IV GUS achieved clinical response at Week I-24 and entered the maintenance study phase. Induction baseline characteristics of GUS Week I-24 responders were: 74.8% had severe disease (modified Mayo score 7-9), 77.2% had a Mayo endoscopy subscore of 3, median C-reactive protein was 5.0 mg/L (upper limit of normal, 3 mg/L), and 59.3% had a history of inadequate response or intolerance to biologic or Janus kinase inhibitor therapy for UC. At Week M‑44, 67.5% of the pts maintained clinical response and 30.1% were in clinical remission. Additional efficacy outcomes are shown in the Table. The proportion of GUS Week I-24 responders in symptomatic remission (defined as a stool frequency subscore of 0 or 1 and not increased from induction baseline, and a rectal bleeding subscore of 0) at maintenance baseline (58.5%) was sustained through Week M‑44 (56.9%). Adverse events (AEs) were reported for 78.0% of GUS Week I-24 responders, serious AEs for 5.7%, and serious infections for 1.6%. No opportunistic infections or deaths occurred. No new safety concerns were identified.

Conclusion

In this refractory population of GUS Week I-24 responders, maintenance treatment with GUS provided clinical benefit across a range of clinically relevant efficacy endpoints. Safety results were consistent with the overall population and safety profile of GUS in its approved indications.

References

1. Bressler B, et al. Am J Gastroenterol. 2023;118(10S):806-807.

Disclosure

D. T. Rubin: research funding from Takeda; consultant to AbbVie, Altrubio, Allergan, Arena, Aslan, Athos, Bellatrix, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Corp/Syneos, Connect, GalenPharma/Atlantica, Genentech/Roche, InDex, Ironwood, Iterative Scopes, Janssen, Lilly, Pfizer, Prometheus, Reistone, Takeda, and Techlab; and co-founder of Cornerstones Health.
A. Dignass: fees for participation in clinical trials, review activities (data monitoring boards, statistical analysis, endpoint committees) from Abivax, AbbVie, Bristol Myers Squibb, Dr Falk Foundation, Galapagos, Gilead, Janssen, and Pfizer; consultancy fees from AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Dr Falk Foundation, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos, Janssen, Lilly, MSD, Pfizer, Pharmacosmos, Roche, Sandoz, Stada, Takeda, Tillotts, and Vifor Pharma; payment for lectures/speaker’s bureaus from AbbVie, Biogen, CED Service GmbH, Celltrion, Falk Foundation, Ferring, Galapagos, Gilead, High5MD, Janssen, Materia Prima, MedToday, MSD, Pfizer, Sandoz, Takeda, Tillotts, and Vifor Pharma; payment for manuscript preparation from Abbvie, Falk Foundation, Janssen, Takeda, Thieme, and UniMed Verlag.
J. R. Allegretti: consultant for AbbVie, Adiso, Ferring, Finch, Iterative Scopes, Janssen, Merck, Pfizer, Roivant, and Seres Therapeutics; speaker for AbbVie, Bristol Myer Squibb, and Janssen; and research support from Janssen, Merck, and Pfizer.
Y. Rayyan: fees for participating in clinical trials for Janssen as principal investigator and payment from lectures including service on speaker’s bureaus from Janssen, AbbVie, and Amgen.
M. Saruta: grants or contracts from Mochida, Zeria Pharma, EA Pharma, Kissei, and EPS Corporation; and payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events from AbbVie GK, Janssen, Mitsubishi Tanabe Pharma, Takeda, EA Pharma, Gilead Sciences, and Kissei.
D. Balderramo: advisor/speaker fees from AbbVie, Janssen, Pfizer, Takeda, and Amgen; and travel/congress support from AbbVie, Janssen, Takeda, and Ferring.
B. Bressler: advisor/speaker for AbbVie, Bristol Myers Squibb, Ferring, Janssen, Merck, Novartis, Organon, Pfizer, Sandoz, and Takeda; advisor for Alimentiv, Allergan, Amgen, AMT, Bausch Health, Bristol Myers Squibb, Celgene, Celltrion, Eupraxia Fresenius Kabi, Genentech/Roche, Gilead, Iterative Scopes, Jamp, Merck, Microbiome Insights, Mylan, Pendopharm, Protagonist, and Viatris; research support from AbbVie, Amgen, Business Intelligence, Bristol Myers Squibb, Genentech/Roche, GlaxoSmithKline, Janssen, Merck, and Qu Biologic; and holds stock options in Qu Biologic.
L. Peyrin-Biroulet: consultant for AbbVie, Abivax, Alimentiv, Alma, Amgen, Applied Molecular Transport, Arena, Biogen, Bristol Myers Squibb, Celltrion, Connect, Cytoki, Lilly, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech/Roche, Gilead, Gossamer Bio, GlaxoSmithKline, HAC-Pharma, IAG, InDex, Inotrem, Janssen, Medac, Mopac, Morphic, MSD, Norgine, Novartis, OM, ONO, OSE, Pandion, Par’Immune, Pfizer, Prometheus, Protagonist, Roche, Sandoz, Takeda, Theravance, Thermo Fisher, Tigenix, Tillots, Viatris, Vifor, and Ysopia; grants from Celltrion, Fresenius Kabi, and Takeda; honorarium for lectures from AbbVie, Amgen, Arena, Biogen, Celltrion, Lilly, Ferring, Galapagos, Genentech/Roche, Gilead, Janssen, Medac, MSD, Pfizer, Sandoz, Takeda, Tillots, Viatris, and Vifor; and fees from AbbVie, Adacyte, Alimentiv, Alma Bio Therapeutics, Amgen, Applied Molecular Transport, Arena, Biogen, BMS, Celltrion, CONNECT Biopharm, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer Bio, GSK, HAC-Pharma, IAG Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Lilly, Medac, Mopac, Morphic, MSD, Norgine, Nordic Pharma, Novartis, OM Pharma, ONO Pharma, OSE Immunotherapeutics, Pandion Therapeutics, Par’Immune, Pfizer, Prometheus, Protagonist, Roche, Sanofi, Sandoz, Takeda, Theravance, Thermo Fisher, Tigenix, Tillots, Viatris, Vifor, Ysopia, Abivax, Samsung, Ventyx, Roivant, and Vectivbio.
T. Hisamatsu: grant support from AbbVie, Daiichi-Sankyo, EA Pharma, JIMRO, Mitsubishi Tanabe Pharma, Mochida, Nippon Kayaku, Pfizer, and Takeda; consulting fees from EA Pharma, Janssen Research & Development, Gilead Sciences, Lilly, and Bristol Myers Squibb; and lecture fees from AbbVie, EA Pharma, Mitsubishi Tanabe Pharma, Takeda, Mochida, and Kissei.
S. Yarandi, K.-H. G. Huang, M. Germinaro, J. Zhan, and H. Zhang: employees of Johnson & Johnson and own company stock/stock options.

Introduction

While the effect of anti-TNFs on postoperative outcomes in patients with Crohn's disease (CD) has been widely studied, the impact of vedolizumab and ustekinumab on the risk of postoperative complications remains poorly known.

Aims & Methods

All consecutive patients who underwent intestinal resection for CD between July 2014 and April 2022 within 22 French centers were included in a retrospective cohort. The risk of early post-operative complications (≤ 30 days) in patients exposed to biologics was compared to patients not exposed by logistic regression and propensity score-matched analysis adjusted for age, previous intestinal resection, corticosteroids or immunosuppressants exposure, disease activity, presence of abscess, urgent surgery and initial stoma (preoperative contra-indication to anastomosis).

Results

Among the 1201 patients included, respectively 491 (41%), 76 (6.3%) and 57 (4.7%) were exposed to anti-TNFs, ustekinumab, or vedolizumab within six months before surgery. A total of 317 (26.4%) patients had at least one complication of which 123 (38%) were considered as severe (DINDO III/IV). New surgery was necessary in 69 (5.7%) patients and secondary stoma in 23 (1.9%). Three deaths were observed (0.25%). The rates of overall complications in patients not exposed to biologics, exposed to anti-TNFs, ustekinumab or vedolizumab were respectively 26.1%, 25.1%, 34.7% and 29.8%. The risks of intra-abdominal infectious complications in these four groups were respectively 13.5%, 11.1%, 13.3% and 8.8%. In multivariate analysis, age [OR, 1.02 (1.01-1.04); p=0.004], disease activity [OR, 8.36 (1.79 – 149); p=0.037], the presence of an abscess [OR, 2.01 (1.25-3.20); p=0.004] and initial stoma [OR, 1.70 (1.10 –2.61); p=0.016] were significantly associated with intra-abdominal infectious complications. Conversely, preoperative enteral nutrition [OR, 0.12 (0.01 -0.59); p=0.040] was associated with a reduction in this risk. Exposure to anti-TNFs [OR, 0.80 (0.51-1.24); p=0.31], ustekinumab [OR, 1.17 (0.39-3.51); p=0.78] and vedolizumab [OR, 1.28 (0.32-5.17); p=0.72] within the 3 months before surgery were not associated with the risk of intra-abdominal infectious complications. Similar results were observed in patients exposed to these treatments in the month before surgery.

Conclusion

In this large cohort, a quarter of patients operated on for CD presented an early postoperative complication and 10% a severe complication. Preoperative exposure to anti-TNFs, vedolizumab or ustekinumab was not associated with an increased risk of early postoperative complications. Preoperative enteral nutrition was associated with a reduced risk of intra-abdominal infectious complication.

Disclosure

AbbVie, Ferring, Janssen, MSD, Takeda, Pfizer, Celgene, Biogen, Amgen, Boehringer Ingelheim, Biogen, Sandoz, Hospira et Celltrion