Singh, S

Importance With the availability of multiple classes of advanced therapies for the treatment of Crohn disease (CD), understanding the comparative safety of different therapies can inform treatment positioning. Objective To compare the risk of serious infections, venous thromboembolism (VTE), and major adverse cardiovascular events (MACE) with different advanced therapies in patients with CD. Design, Setting, and Participants This retrospective comparative effectiveness research study was conducted between January 1, 2016, and December 31, 2022, with a mean (SD) follow-up of 26.9 (2.4) months until July 1, 2024. Using an administrative claims database (OptumLabs Data Warehouse), commercially insured patients with CD, who initiated treatment with tumor necrosis factor-α (TNF) antagonists, anti-integrin agents (vedolizumab), interleukin (IL)-12/23p40 antagonists (ustekinumab), IL-23p19 antagonists (primarily risankizumab), or Janus kinase inhibitors (upadacitinib) between 2016 and 2022 and had follow-up for at least 1 year before and after treatment initiation, were included. Exposure TNF antagonists vs anti-integrin agents (vedolizumab) vs IL-12/23p40 antagonists (ustekinumab) vs IL-23p19 antagonists (risankizumab) vs Janus kinase inhibitors (upadacitinib). Main Outcomes and Measures The risk of serious infections, VTE, and MACE was compared with various advanced therapies through multinomial propensity score-based inverse probability treatment weighting, with propensity scores estimated through generalized boosted models, accounting for disease characteristics, health care utilization, comorbidities, and prior and concomitant medications, and through competing risk of mortality. Cause-specific hazard ratios (HRs) and 95% CIs for multiple treatment comparisons were calculated. Results This study included 12 245 patients with CD (mean [SD] age, 46.5 [17.5] years; 6642 females [54.2%]), who were treated with TNF antagonists (n = 5274), vedolizumab (n = 2716), ustekinumab (n = 3544), risankizumab (n = 559), or upadacitinib (n = 152). Serious infection incidence rates ranged from 5.46 (95% CI, 4.86-6.07) to 9.02 (95% CI, 6.38-11.89) per 100 person-years across therapies. After adjusting for confounding variables, there were no statistically significant differences in the risk of serious infections across different agents, including between risankizumab and ustekinumab (HR, 1.14 [95% CI, 0.78-1.67]), risankizumab and TNF antagonists (HR, 1.00 [95% CI, 0.68-1.47]), or ustekinumab and TNF antagonists (HR, 0.88 [95% CI, 0.74-1.04]). The incidence of VTE (incidence rate, 0.90 [95% CI, 0.71-1.10] to 2.33 [95% CI, 1.06-3.82] per 100 person-years) and MACE (0.68 [95% CI, 0.51-0.85] to 1.49 [95% CI, 0.43-2.76] per 100 person-years) was low, without any significant differences across agents. Conclusions and Relevance In this comparative effectiveness research study of patients with CD, no significant differences in the risks of serious infections, VTE, or MACE across various advanced therapies were found. These findings support clinical decision-making on choice of advanced therapies for most individual patients with CD to be driven primarily by comparative treatment effectiveness rather than driven by concerns of serious adverse events.

Abstract Background Inflammatory bowel disease (IBD) is associated with increased risk of major adverse cardiovascular events (MACE), likely driven by systemic inflammation. Treating inflammation may reduce this risk. We aimed to investigate MACE across different therapies in patients with IBD. Methods We used Swedish nationwide registers (2007–2023) to describe MACE rates (ischemic heart disease, stroke, heart failure, and cardiovascular mortality) in patients with IBD receiving different therapies. For contextualization, we compared MACE rates during therapy exposure periods in patients with IBD with matched (by age, sex, and residence) general population comparators without IBD. Comparisons included exposure periods naïve to immunomodulators/advanced therapies and periods of different treatments (immunomodulators, TNF-α inhibitors (TNFi), vedolizumab, ustekinumab, and Janus kinase inhibitors). Each patient could contribute with multiple periods, with a new period starting upon switch of therapy. Incidence rates (IRs) and adjusted hazard ratios (aHRs) were estimated by using Cox regression (Model 1: conditioned on matching variables; Model 2: additional adjustment for Charlson Comorbidity Index). Among patients with IBD, we performed 1:1 propensity score (PS)-matched analysis, with exposure periods of TNFi or vedolizumab as the reference, to compare MACE rates between advanced therapies. In these comparisons, we adjusted for demographics, disease characteristics, healthcare utilization, prior treatment, and cardiovascular risk factors. Results We included 106,894 patients with IBD with 99,661 exposure periods naïve to immunomodulators/advanced therapy, 60,573 exposure periods of immunomodulators, and 71,551 of advanced therapies. Distribution of age, sex and disease duration differed substantially across therapy exposures (data not shown). Compared with the general population, MACE rates in patients with IBD were similar across therapies (IRs=3.0-13.0/1,000 person-years; aHRs=1.02-1.49) (Table 1), and significantly increased only for exposure periods naïve to immunomodulators/advanced therapy, immunomodulators, or ustekinumab. In PS-matched comparisons, no significant differences were found between periods of TNFi, vedolizumab and other advanced therapies (Table 2). Conclusion Therapy exposure periods in patients with IBD showed only slightly increased MACE rates compared to corresponding periods in the general population, and significantly so only for periods naïve to immunomodulators/advanced therapy and exposure to immunomodulators or ustekinumab. In PS-matched analyses of patients with IBD, no significant differences in MACE rates were observed when comparing exposure periods of different advanced therapies. Conflict of interest: Eriksson, Carl: Served as speaker/advisory board member for Janssen Cilag AB and Tillotts Pharma. Forss, Anders: Served as speaker/advisory board member for Janssen Cilag AB and Tillotts Pharma. Singh, Siddharth: Dr. Singh has research grants from Pfizer. Halfvarson, Jonas: Grant support: Swedish Foundation for Strategic Research (RB13-0160 to J.H.), the Swedish Research Council (2020-02021 to J.H.), the Örebro University Hospital research foundation (OLL-890291 to J.H.), NordForsk (90569 to J.H.) and Vinnova ( 2019-01185 to JH and 2024-01155 co-applicant), IHI, EU, INTERCEPT (Grant agreement number 101194780, co-applicant), miGut-Health, HORIZON-HLTH-2022, EU (Grant Agreement 101095470, Co-applicant), 3TR, IMI 2, EU, (Grant agreement number 831434, Co-applicant), Janssen, MSD, and Takeda. Consulting and/or advisory board fees from: AbbVie, Alfasigma, Aqilion, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly, Ferring, Galapagos, Gilead Sciences, Hospira, Index Pharmaceuticals, Janssen, Johnson &amp Johnson, MEDA, Medivir, Medtronic, Merck, Merck Sharp &amp Dohme, Novartis, Pfizer, Prometheus Laboratories Inc., Sandoz, Shire, STADA, Takeda, Thermo Fisher Scientific, Tillotts Pharma, Vifor Pharma, UCB and speaker’s fees from: AbbVie, Alfasigma, Bristol Myers Squibb, Celgene, Eli Lilly, Ferring, Galapagos, Gilead, Hospira, Janssen, Johnson &amp Johnson, Merck Sharp &amp Dohme, Novartis, Pfizer, Shire, Takeda, Thermo Fisher Scientific, Tillotts Pharma and research grant support from Janssen, Merck Sharp &amp Dohme and Takeda. Sun, Jiangwei: No conflicts Söderling, Jonas: Dr. Söderling has worked on projects at Karolinska Institutet and SWIBREG partly financed by grants from Ferring and Janssen. Everhov, Åsa H: Dr Everhov has worked on projects at Karolinska Institutet and SWIBREG, partly financed by grants from Ferring and Janssen. Bröms, Gabriella: Dr. Bröms has served as a speaker for Takeda and Janssen and worked on projects at Karolinska Institutet, partly financed by Janssen, UCB and Pfizer. James, Stefan: Dr. James reports institutional research grants from Novo Nordisk, Astra Zeneca, Amgen, Jansen, Alnylam and proctor fees from Medtronic. Ludvigsson, Jonas: Dr. Ludvigsson has coordinated an unrelated study for the Swedish IBD Quality Register (SWIBREG). That study received funding from Jansen Corporation. Ludvigsson has also received financial support from MSD/Merck for unrelated research on inflammatory bowel disease, and for developing a paper reviewing national healthcare registers in China. Ludvigsson has an ongoing research collaboration with Takeda about celiac disease and is discussing additional collaboration on chronic liver disease with this company. Olen, Ola: Karolinska Institutet has received research grants from Pfizer, Janssen, AbbVie, Takeda, Ferring, Bristol Myers Squibb, and Alfasigma for projects led by Olén. Ola Olén has also received fees for lectures from Pfizer, Janssen, Bristol Myers Squibb, and Takeda.