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Conventional systemic and biologic agents are the mainstay of inflammatory bowel disease (IBD) management; however, many of these agents are associated with loss of clinical response, highlighting the need for effective, novel targeted therapies. Janus kinase (JAK) 1-3 and tyrosine kinase 2 (TYK2) mediate signal transduction events downstream of multiple cytokine receptors that regulate targeted gene transcription, including the interleukin-12, interleukin-23, and type I interferon receptors for TYK2. This review summarizes the role of TYK2 signaling in IBD pathogenesis, the differential selectivity of TYK2 inhibitors, and the potential clinical implications of TYK2 inhibition in IBD. A PubMed literature review was conducted to identify studies of JAK1-3 and TYK2 inhibitors in IBD and other immune-mediated inflammatory diseases. Key efficacy and safety information was extracted and summarized. Pan-JAK inhibitors provide inconsistent efficacy in patients with IBD and are associated with toxicities resulting from a lack of selectivity at therapeutic dosages. Selective inhibition of TYK2 signaling via an allosteric mechanism, with an agent that binds to the regulatory (pseudokinase) domain, may reduce potential toxicities typically associated with JAK1-3 inhibitors. Deucravacitinib, a novel, oral, selective TYK2 inhibitor, and brepocitinib and PF-06826647, TYK2 inhibitors that bind to the active site in the catalytic domain, are in development for IBD and other immune-mediated inflammatory diseases. Allosteric TYK2 inhibition is more selective than JAK1-3 inhibition and has the potential to limit toxicities typically associated with JAK1-3 inhibitors. Future studies will be important in establishing the role of selective, allosteric TYK2 inhibition in the management of IBD.

Background Janus kinase (JAK) inhibition shows promise for treatment of patients with moderate to severe Crohn’s disease. We aimed to provide mechanistic insights into the JAK1-selective inhibitor upadacitinib through a transcriptomics substudy on biopsies from patients with Crohn's disease from CELEST. Methods Seventy-four patients consented to this optional substudy. Ileal and colonic biopsies were collected during endoscopy at screening and week 12 or 16. RNA isolated from 226 samples was analyzed by RNAseq, with additional qPCR analysis. Additional biopsies from patients with Crohn's disease receiving anti-tumor necrosis factor (anti-TNF; n = 34) and healthy controls (n = 10) were used for qPCR. Single-cell RNAseq public profiles were used to evaluate treatment effects on specific cellular subsets, associations with endoscopic improvement, and indirect comparisons with the anti-TNF-treated cohort. Results In involved areas of mucosa with endoscopic remission after upadacitinib treatment, 1156 and 76 protein-coding genes were significantly regulated (false discovery rate < 0.05) at week 12/16 in colonic and ileal biopsies, respectively (60 overlapped), compared with baseline. Upadacitinib did not significantly affect transcriptomes of noninvolved intestinal areas. CELEST patients (mostly anti-TNF-refractory) showed baseline differences in gene expression compared with a separate cohort of biologic-naïve patients. Notably, upadacitinib reversed overexpression of inflammatory fibroblast and interferon-γ effector signature markers. Conclusions Upadacitinib modulates inflammatory pathways in mucosal lesions of patients with anti-TNF-refractory Crohn's disease, including inflammatory fibroblast and interferon-γ-expressing cytotoxic T cell compartments. This substudy is the first to describe the molecular response to JAK1 inhibition in inflammatory bowel disease and differential effects relative to anti-TNF treatment. (Clinical trial identifier: NCT02365649)

Background Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We present integrated analyses of nonmelanoma skin cancer (NMSC) incidence in the tofacitinib UC clinical program. Methods Nonmelanoma skin cancer events were evaluated from 3 randomized, placebo-controlled studies: 2 identical, 8-week induction studies (NCT01465763, NCT01458951), a 52-week maintenance study (NCT01458574), and an open-label, long-term extension study (NCT01470612). Cohorts analyzed were: Induction, Maintenance, and Overall (patients receiving ≥1 dose of tofacitinib 5 mg or 10 mg twice daily [BID]). An independent adjudication committee reviewed potential NMSC. Proportions and incidence rates (IRs; unique patients with events per 100 patient-years of exposure) for NMSC were evaluated. A Cox proportional hazards model was used for risk factor analysis. Results Nonmelanoma skin cancer was evaluated for 1124 patients (2576.4 patient-years of tofacitinib exposure; ≤6.8 years’ treatment). In the Induction Cohort, NMSC IR was 0.00 for placebo and 1.26 for 10 mg BID. Nonmelanoma skin cancer IR was 0.97 for placebo, 0.00 for 5 mg BID and 1.91 for 10 mg BID in the Maintenance Cohort, and 0.73 (n = 19) in the Overall Cohort. No NMSC was metastatic or led to discontinuation. In the Overall Cohort, Cox regression identified prior NMSC (hazard ratio [HR], 9.09; P = 0.0001), tumor necrosis factor inhibitor (TNFi) failure (3.32; P = 0.0363), and age (HR per 10-year increase, 2.03; P = 0.0004) as significant independent NMSC risk factors. Conclusions For patients receiving tofacitinib, NMSC occurred infrequently. Older age, prior NMSC, and TNFi failure, which are previously reported NMSC risk factors in patients with UC, were associated with increased NMSC risk.

Background In ulcerative colitis, a pouchitis is the most common long-term adverse effect after proctocolectomy and ileal pouch-anal anastomosis. Approximately 5% of patients develop chronic antibiotic-dependent or antibiotic-refractory pouchitis without any effective treatment. The aim of this trial was to investigate the efficacy and safety of fecal microbiota transplantation in the treatment of chronic pouchitis. Methods This was a single-center, double-blinded, parallel group trial comparing donor fecal microbiota transplantation with placebo (autologous transplant) in chronic pouchitis. Twenty-six patients were recruited at the Helsinki University Hospital between December 2017 and August 2018 and were randomly allocated a 1:1 ratio to either donor fecal microbiota transplantation or placebo. The protocol included 2 transplantations into the pouch on weeks 0 and 4, and patients were followed up for 52 weeks. Results Nine patients in the intervention group and 8 patients in the placebo group relapsed during the 52-week follow-up, and the relapse-free survival did not differ between the groups (P = 0.183, log-rank; hazard ratio, 1.90 [95% confidence interval, 0.73-4.98; P = 0.190]). In the subgroup analysis of patients using continuous antibiotics before the study, the relapse-free survival was shorter in the intervention group (P = 0.004, log-rank; hazard ratio, 13.08 [95% confidence interval, 1.47-116.60; P = 0.021]). No major adverse effects were reported. Conclusions The fecal microbiota transplantation treatment regime used in our study was not effective in the treatment of chronic pouchitis. The safety profile of fecal microbiota transplantation was good. ClinicalTrials.gov identifier NCT03378921.

Background Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We examined the effect of tofacitinib induction treatment on Inflammatory Bowel Disease Questionnaire (IBDQ) items in adults with moderate to severe UC. Methods Data were pooled from the randomized, 8‑week, double-blind, phase 3 OCTAVE Induction 1 and 2 studies. The IBDQ was self-administered by patients at baseline, week 4, and week 8, with higher scores indicating better health-related quality of life (HRQoL). Change from baseline in IBDQ items was analyzed for 10 mg of tofacitinib twice daily (BID) vs placebo using a linear mixed-effects model, with no multiplicity adjustment performed. Effect sizes were calculated. Subgroup analyses by tumor necrosis factor inhibitor (TNFi) experience were performed. Results Significant improvements (nominal P < 0.05) were observed in all IBDQ items with 10 mg of tofacitinib BID vs placebo at weeks 4 and 8. For the overall population, the largest treatment differences across all items were reported for “bowel movements been loose” at weeks 4 and 8, and “problem with rectal bleeding” at week 8 (mean treatment differences all 1.1; both in bowel symptoms domain). These items also showed the largest effect sizes. Treatment benefits were generally slightly numerically higher in TNFi-experienced vs TNFi-naïve patients. Conclusions Tofacitinib induction therapy improved all IBDQ items vs placebo in patients with UC, reflecting improvements in HRQoL, with greatest benefits reported in bowel symptoms domain items (Funded by Pfizer Inc; OCTAVE Induction 1 and OCTAVE Induction 2; ClinicalTrials.gov, NCT01465763 and NCT01458951, respectively).

The recent emergency use authorization of a third COVID-19 vaccine means that most patients with inflammatory bowel disease (IBD) will soon be eligible to be vaccinated. Gastroenterology clinicians should be prepared to address patients’ concerns regarding safety and efficacy of vaccines. They should also strongly recommend that all their patients be vaccinated with a COVID-19 vaccine. Additionally, they should be prepared to educate patients about logistics that will result in successful vaccination completion. All these measures will be crucial to ensure high uptake among their patients with IBD.

This study quantifies the wide-ranging health care costs affecting patients living with IBD, including the annualized direct and indirect costs of care for patients with IBD, the longitudinal drivers of these costs, and the cost of care for newly diagnosed patients., Background The Crohn’s & Colitis Foundation’s Cost of Inflammatory Bowel Disease (IBD) Care Initiative seeks to quantify the wide-ranging health care costs affecting patients living with IBD. We aimed to (1) describe the annualized direct and indirect costs of care for patients with Crohn’s disease (CD) or ulcerative colitis (UC), (2) determine the longitudinal drivers of these costs, and (3) characterize the cost of care for newly diagnosed patients. Methods We analyzed the Optum Research Database from the years 2007 to 2016, representing commercially insured and Medicare Advantage–insured patients in the United States. Inclusion for the study was limited to those who had continuous enrollment with medical and pharmacy benefit coverage for at least 24 months (12 months before through 12 months after the index date of diagnosis). The value of patient time spent on health care was calculated as number of workplace hours lost due to health care encounters multiplied by the patients’ estimated average wage derived from the Bureau of Labor Statistics. Comparisons between IBD patients and non-IBD patients were analyzed based on demographics, health plan type, and length of follow-up. We used generalized linear models to estimate the association between total annual costs and various patient variables. Results There were 52,782 IBD patients (29,062 UC; 23,720 CD) included in the analysis (54.1% females). On a per-annual basis, patients with IBD incurred a greater than 3-fold higher direct cost of care compared with non-IBD controls ($22,987 vs $6956 per-member per-year paid claims) and more than twice the out-of-pocket costs ($2213 vs $979 per-year reported costs), with all-cause IBD costs rising after 2013. Patients with IBD also experienced significantly higher costs associated with time spent on health care as compared with controls. The burden of costs was most notable in the first year after initial IBD diagnosis (mean = $26,555). The study identified several key drivers of cost for IBD patients: treatment with specific therapeutics (biologics, opioids, or steroids); ED use; and health care services associated with relapsing disease, anemia, or mental health comorbidity. Conclusion The costs of care for IBD have increased in the last 5 years and are driven by specific therapeutics and disease features. In addition, compared with non-IBD controls, IBD patients are increasingly incurring higher costs associated with health care utilization, out-of-pocket expenditures, and workplace productivity losses. There is a pressing need for cost-effective strategies to address these burdens on patients and families affected by IBD.

Background and Aims Persons with inflammatory bowel disease (IBD) may be particularly vulnerable to COVID-19 either because of their underlying disease or its management. Guidance has been presented on the management of persons with IBD in the time of this pandemic by different groups. We aimed to determine how gastroenterologists around the world were approaching the management of IBD. Methods Members of the World Gastroenterology Organization (WGO) IBD Task Force contacted colleagues in countries largely beyond North America and Europe, inviting them to review the WGO website for IBD and COVID-19 introduction, with links to guideline documents, and then to respond to 9 ancillary open-ended management questions. Results Fifty-two gastroenterologists from 33 countries across 6 continents completed the survey (April 14 to May 16, 2020). They were all adhering for the most part to published guidelines on IBD management in the COVID-19 era. Some differences and reductions in services related to access, and some related to approach within their communities in terms of limiting virus spread. In particular, most gastroenterologists reduced in-person clinics (43 of 52), limited steroid use (47 of 51), limited elective endoscopy (45 of 52), and limited elective surgeries (48 of 51). If a patient was diagnosed with COVID-19, immunomodulatory therapy was mostly held. Conclusions In most countries, the COVID-19 pandemic significantly altered the approach to persons with IBD. The few exceptions were mostly based on low burden of COVID-19 in individual communities. Regardless of resources or health care systems, gastroenterologists around the world took a similar approach to the management of IBD.

Background Ustekinumab is currently approved globally in Crohn’s disease (CD) and psoriatic diseases. Recent phase 3 data demonstrate safety/efficacy in ulcerative colitis (UC). Crohn’s disease and UC phase 3 programs had similar study designs, facilitating integrated safety analyses. Methods Data from 6 ustekinumab phase 2/3 CD and UC studies were pooled, and safety was evaluated through 1 year. Patients received 1 placebo or ustekinumab (generally 130 mg or ~6 mg/kg) intravenous induction, then subcutaneous (90 mg) maintenance every 8/12 weeks. Analyses incorporated all patients who received ≥1 ustekinumab dose. Safety outcomes are presented as percentages of patients (induction) and as number of patients with events per 100 patient-years of follow-up (through 1 year). For key safety events, 95% confidence intervals (CIs) are provided, as appropriate. Hazard ratios with 95% CIs from time-to-event analyses for serious adverse events and serious infections were also performed. Results Through 1 year, 2574 patients received ustekinumab (1733 patient-years of follow-up). The number of patients with adverse events per 100 patient-years (placebo 165.99 [95% CI, 155.81–176.67] vs ustekinumab 118.32 [95% CI, 113.25–123.55]), serious AEs (27.50 [95% CI, 23.45–32.04] vs 21.23 [95% CI, 19.12–23.51]), infections (80.31 [95% CI, 73.28–87.84] vs 64.32 [95% CI, 60.60–68.21]), serious infections (5.53 [95% CI, 3.81–7.77] vs 5.02 [95% CI, 4.02–6.19]), and malignancies excluding nonmelanoma skin cancer (0.17 [95% CI, 0.00–0.93] vs 0.40 [95% CI, 0.16–0.83]) were similar between placebo and ustekinumab. Conclusions The safety profile of ustekinumab across the pooled inflammatory bowel disease population through 1 year was favorable and generally comparable to placebo. These data are consistent with the established safety profile of ustekinumab across indications. ClinicalTrials.gov numbers NCT00265122; NCT00771667; NCT01369329; NCT01369342; NCT01369355; NCT02407236.

Background Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We aimed to estimate the overall incidence of safety events in patients with UC in a real-life population cohort for comparison with the tofacitinib UC clinical trial program. Methods Clinical trial-like criteria were applied to an IBM MarketScan® claims database population-based cohort (n = 22,967) of patients with UC (October 2010 to September 2015) to identify a UC trial-like cohort treated with tumor necrosis factor inhibitors (TNFi; n = 6366) to compare with the tofacitinib UC clinical trial cohort (n = 1157). Results Incidence rates (events per 100 patient-years; [95% confidence interval]) in the UC trial-like cohort were as follows: serious infections, 3.33 (2.73–4.02); opportunistic infections (OIs; excluding herpes zoster [HZ]), 1.45 (1.06–1.93); HZ, 1.77 (1.34–2.29); malignancies (excluding nonmelanoma skin cancer [NMSC]), 0.63 (0.43–0.90); NMSC, 1.69 (1.35–2.10); major adverse cardiovascular events (MACE), 0.51 (0.31–0.79); pulmonary embolism (PE), 0.54 (0.30–0.89); deep vein thrombosis (DVT), 1.41 (1.00–1.93); and gastrointestinal perforations, 0.31 (0.16–0.54). Compared with the UC trial-like cohort, tofacitinib-treated patients had numerically lower incidence rates for serious infections (1.75 [1.27–2.36]), OIs (excluding HZ; 0.16 [0.04–0.42]), NMSC (0.78 [0.47–1.22]), PE (0.16 [0.04–0.41]), and DVT (0.04 [0.00–0.23]), and a higher rate for HZ (3.57 [2.84–4.43]); rates for malignancies (excluding NMSC), MACE, and gastrointestinal perforations were similar. Conclusions When acknowledging limitations of comparing claims data with controlled clinical trial data, incidence rates for HZ among TNFi-treated patients in the UC trial-like cohort were lower than in the tofacitinib UC clinical trial cohort; rates for serious infections, OIs, NMSC, PE, and DVT were numerically higher. ClinicalTrials.gov NCT00787202, NCT01465763, NCT01458951, NCT01458574, NCT01470612.

Background Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Here, we performed an integrated analysis of malignancy events from the tofacitinib phase 3 UC clinical development program (excluding nonmelanoma skin cancer [NMSC]). Methods Data (up to May 2019) were pooled from two phase 3 induction studies, a phase 3 maintenance study, and an ongoing, open-label, long-term extension (OLE) study, and analyzed as 3 cohorts: induction (N = 1139), maintenance (N = 592), and overall (induction, maintenance, and ongoing OLE study; N = 1124). Proportions and incidence rates (IRs; unique patients with events per 100 patient-years [PY] of exposure) for malignancies confirmed by adjudication were calculated. Results The overall cohort consisted of patients who received at least 1 dose of tofacitinib at 5 or 10 mg twice daily, for up to 6.8 years, with an exposure of 2576.4 PY. Of the 1124 overall cohort tofacitinib-treated patients, 20 developed a malignancy (excluding NMSC; IR, 0.75; 95% confidence interval, 0.46–1.16), of which 17 occurred in patients treated with tofacitinib 10 mg twice daily; importantly, more than 80% of patients predominantly received this dose. Furthermore, there was no apparent clustering of malignancy types, and IRs were stable over time. Conclusions In the tofacitinib UC clinical development program, malignancy events were infrequent, and rates were comparable with those in the tofacitinib rheumatoid arthritis and psoriatic arthritis clinical development programs, and for biologic UC treatments. ClinicalTrials.gov: NCT01465763, NCT01458951, NCT01458574, and NCT01470612.

Background CALM was a randomized phase 3 trial in patients with Crohn’s disease (CD) that demonstrated improved endoscopic outcomes when treatment was escalated based on cutoffs for inflammatory biomarkers, fecal calprotectin (FC), C-reactive protein (CRP), and CD Activity Index (CDAI) remission vs CDAI response alone. The purpose of this post hoc analysis of CALM was to identify drivers of treatment escalation and evaluate the association between biomarker cutoff concentrations and endoscopic end points. Methods The proportion of patients achieving CD Endoscopic Index of Severity (CDEIS), A post hoc analysis of a phase 3 trial in Crohn’s disease showed that a fecal calprotectin cutoff of

Background Patients with ulcerative colitis (UC) are at elevated risk of cardiovascular disease vs the general population, despite a lower prevalence of traditional risk factors, including hyperlipidemia. Mechanistic studies in patients with rheumatoid arthritis and psoriasis suggest that tofacitinib restores serum lipids to preinflammation levels by reversing inflammation-induced cholesterol metabolism changes. We reviewed data on lipid levels and cardiovascular events, alongside recommendations for managing lipid levels during tofacitinib treatment in patients with UC, based on up-to-date expert guidelines. Methods Data were identified from a phase 3/open-label, long-term extension (OLE) tofacitinib UC clinical program (cutoff May 27, 2019). Literature was identified from PubMed (search terms “lipid,” “cholesterol,” “lipoprotein,” “cardiovascular,” “inflammation,” “atherosclerosis,” “tofacitinib,” “rheumatoid arthritis,” “psoriasis,” “inflammatory bowel disease,” “ulcerative colitis,” “hyperlipidemia,” and “guidelines”) and author knowledge. Data were available from 4 phase 3 clinical trials of 1124 patients with moderately to severely active UC who received ≥1 dose of tofacitinib 5 or 10 mg twice daily in induction (two identical trials), maintenance, and OLE studies (treatment duration ≤6.8 years; 2576.4 patient-years of drug exposure). Results In the OLE study, tofacitinib treatment was not associated with major changes from baseline in total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, total cholesterol/high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol/high-density lipoprotein cholesterol, with lipid levels and ratios generally remaining stable over time. The major adverse cardiovascular events incidence rate was 0.26/100 patient-years (95% confidence interval, 0.11-0.54). Conclusions Lipid levels and ratios remained generally unchanged from baseline in the OLE study after tofacitinib treatment, and major adverse cardiovascular events were infrequent. Long-term studies are ongoing. ClinicalTrials.gov identifiers NCT01465763, NCT01458951, NCT01458574, NCT01470612