Singh, S

Abstract Introduction Despite regulatory mandates for advanced therapy (AT) washout periods of up to 5 drug half-lives before enrolling patients in inflammatory bowel disease (IBD) trials, the evidence base for these requirements is largely empirical, and whether shorter intervals independently increase the risk of serious infections in real-world practice remains unknown. Methods Using the OptumLabs Data Warehouse, we identified adult patients with IBD who initiated a new AT (tumor necrosis factor antagonists, vedolizumab, interleukin (IL)-12/23 or IL-23 antagonists, or Janus kinase inhibitors) between 2018 and 2023 using a class-specific new-user design. We examined whether exposure to AT within the preceding 12 months (vs no exposure to AT within that window) and timing of discontinuation (≤1 month, 1-<3 months, or 3-12 months) were associated with risk of serious infections using multivariable Cox proportional hazards regression. Results Among 21 564 AT initiators (47 ± 18 years; 52% female; 57% Crohn’s disease), 7490 (34.7%) had AT exposure within the preceding 12 months. Over a mean follow-up of 1.6 ± 0.9 y, 1955 (9.1%) experienced a serious infection. Prior AT exposure was associated with higher infection risk (hazard ratio [HR]: 1.19, 95% confidence interval [CI]: 1.07-1.33), consistent in inverse probability of treatment-weighted analyses (HR, 1.20 [1.06-1.37]). Among patients with prior exposure, timing of discontinuation was not associated with infection risk (HR, 1.17 [0.95-1.43] for ≤1 month vs 3-12 months; HR, 1.01 [0.83-1.22] for 1-<3 months), with no dose–response relationship on continuous modeling. Discussion AT exposure within the preceding 12 months is associated with modestly higher risk of serious infection after initiating a new AT in IBD, but timing of discontinuation does not independently influence this risk.

Abstract Introduction Despite progress in understanding placebo effects in clinical trials of inflammatory bowel disease (IBD), there is a limited understanding of how socioeconomic factors of recruiting countries impact placebo rates. We investigated the association of socioeconomic factors across recruitment sites on placebo rates in IBD randomized controlled trials. Methods We examined the association of clinical and endoscopic remission and response to the weighted Gross National Index (GNI) per capita, Human Development Index (HDI), and out-of-pocket health expenditures as a percentage of current health expenditures (OOP_CHE) of identified trials using mixed effects linear regression. Results Across 76 trials (Crohn’s disease [CD]: n = 32; ulcerative colitis [UC]: n = 44), placebo response rates over time were largely stable, with a small increase across time in clinical remission for CD trials (β = 0.4% per increase in study year, 95% CI: 0.3%-0.84%, P = .04) and a small decrease across time in endoscopic response for UC trials (β = −1.39% per increase in study year, 95% CI: −1.79, −0.99, P < .001). Clinical response was most susceptible to changes in socioeconomic factors in IBD trials (β = −2.96% per 10 000 USD increase in study GNI, 95% CI: −4.98, −0.95%, P = .004; P < .05 for HDI and OOP_CHE). Across both conditions, decreases in clinical response were associated with increases in HDI and OOP_CHE (CD HDI: β = −1.15% per 0.01 increase in study HDI, 95% CI: −2.24, −0.06%, P = .04; UC HDI: β = −0.66% per 0.01 increase in study HDI, 95% CI: −1.19, −0.12%, P = .02). Discussion We found that placebo clinical response was most susceptible to influences of site-level socioeconomic wellbeing. These findings highlight that estimation of placebo rates in trial planning should account for geographic location of recruiting sites.

INTRODUCTION: Safety and effectiveness of treating to target mucosal healing in older patients with Crohn's disease (CD) is unknown. METHODS: We analyzed CD-related complications by 24 months in the randomized evaluation of an algorithm for Crohn's treatment—study 2-2 trial that randomized practices to an enhanced-care or step-care algorithm to determine whether patient age modifies the effect of treatment. Data were analyzed using marginal Cox regression and modified Poisson regression. RESULTS: There was no difference in treatment between younger and older patients in at 24 months. DISCUSSION: Enhanced-care was effective and not associated with increased risk compared with step-care in older patients with CD.

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.

Abstract Background We examined real-world utilization of treat-to-target (TTT) strategies and conducted a quality improvement (QI) project to improve uptake of TTT strategies in a learning health system, IBD Qorus. Methods We implemented a structured QI intervention to increase uptake of TTT in 41 gastroenterology practices in the United States, over a 13-month intervention period (November 2020 to November 2021; modified breakthrough series [BTS] collaborative), and a 10-month post-BTS observation period (December 2021 to October 2022). Through encounter-level surveys, we examined providers’ “intention to TTT” based on discussion of TTT with patients, documentation of inflammation, and intention to change therapy to TTT. We examined changes in rates of “intention to TTT,” and whether improvement in intention to TTT influenced site-level rates of remission. Results Over 13 months, there were 7932 patient visits (55% with Crohn’s disease; 47% in clinical remission); patients in 2160 visits (27%) were not in endoscopic remission. Overall, rates of intention to TTT increased from 31% to 54% (P = .06) with considerable site-to-site variability and was maintained at 49% in the post-BTS observation period. The increased rate was attributable to higher rates of testing for inflammation. Despite an increase in the rate of intention to TTT, there was no significant change in site-level achievement of remission over the same time. Conclusions Through a QI initiative in a learning health system, rates of intention to TTT increased significantly over 12-months, though overall rates remained low. Assessing patient-, provider- and practice-level barriers and facilitators for successful implementation of a TTT strategy is warranted to improve clinical outcomes.

ABSTRACT We conducted a USA claims‐based cohort study in 20,705 patients with inflammatory bowel diseases (IBD) on advanced therapies to estimate the overall and comparative risk of tuberculosis between advanced therapies using inverse probability of treatment weighted Cox proportional hazards model. The incidence rate (IR, per 100,000 person‐years) of tuberculosis with TNF antagonists ( n = 9378) and non‐TNF‐targeting biologics (anti‐integrins [ n = 5877], anti‐interleukins [ n = 5450]) was similar (38 [95% CI, 8–69] vs. 33[7–59]). Adjusting for covariates, risk of tuberculosis was similar (HR, 1.16 [0.41–3.31]). In low incidence regions like USA, the incidence of tuberculosis after starting advanced therapies for IBD is very low, and comparable across advanced therapies.

ABSTRACT Background Advanced therapies increase the risk of shingles in inflammatory bowel diseases (IBD). Aim To compare the risk of shingles with different advanced therapies in patients with IBD. Methods We identified patients with IBD who initiated treatment with tumour necrosis factor (TNF) antagonists, anti‐integrins, anti‐interleukins, Janus kinase (JAK) inhibitors, or sphingosine‐1 phosphate receptor (S1PR) modulators between 2016 and 2022 and had follow‐up for at least 1 year before and after treatment initiation. We estimated the incidence rate (IR per 100 person‐year [PY]) of shingles (overall and complicated) and compared the risk with different advanced therapies through multinomial propensity score‐based inverse probability of treatment weighting (IPTW), with propensity scores estimated through generalised boosted models, accounting for disease characteristics, healthcare utilisation, comorbidities and prior and concomitant medications. Weighted Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for multiple treatment comparisons. Results We included 21,675 patients followed over 27 months. IRs per 100 PY of shingles and complicated shingles were: TNF antagonists 1.0/0.3, anti‐integrin agents 1.4/0.4, anti‐interleukins 1.2/0.5, JAK inhibitors 3.3/0.9 and S1PR modulators 2.0/1.0. After adjusting for confounding variables, JAK inhibitors were associated with higher risks of shingles than TNF antagonists (HR 2.19; 1.28–3.75), anti‐integrins (HR 1.87; 1.12–3.14) and anti‐interleukins (HR 1.70; 0.98–2.96). Conclusions JAK inhibitors were associated with 1.7–2.2‐fold higher risk of shingles than other advanced therapies.