Achieving synergy: Linking an internet-based inflammatory bowel disease cohort to a community-based inception cohort and multicentered cohort in inflammatory bowel disease

Background: Traditional cohort studies are important contributors to our understanding of inflammatory bowel diseases, but they are labor intensive and often do not focus on patient-reported outcomes. Internet-based studies provide new opportunities to study patient-reported outcomes and can be efficiently implemented and scaled. If a traditional cohort study was linked to an Internet-based study, both studies could benefit from added synergy. Existing cohort studies provide an opportunity to develop and test processes for cohort linkage. The Crohn's and Colitis Foundation of America's (CCFA) Partners study is an Internet-based cohort of more than 14,000 participants. The Ocean State Crohn's and Colitis Area Registry (OSCCAR) is an inception cohort. The Sinai-Helmsley Alliance for Research Excellence (SHARE) is a multicentered cohort of inflammatory bowel disease patients. Both the later cohorts include medical record abstraction, patient surveys, and biospecimen collection. Objective: Given the complementary nature of these existing cohorts, we sought to corecruit and link data. Methods: Eligible OSCCAR and SHARE participants were invited to join the CCFA Partners study and provide consent for data sharing between the 2 cohorts. After informed consent, participants were directed to the CCFA Partners website to complete enrollment and a baseline Web-based survey. Participants were linked across the 2 cohorts by the matching of an email address. We compared demographic and clinical characteristics between OSCCAR and SHARE participants who did and did not enroll in CCFA Partners and the data linkage. Results: Of 408 participants in the OSCCAR cohort, 320 were eligible for participation in the CCFA Partners cohort. Of these participants, 243 consented to participation; however, only 44 enrolled in CCFA Partners and completed the linkage. OSCCAR participants who enrolled in CCFA Partners were better educated (17% with doctoral degrees) than those who did not (3% with doctoral degrees, P=.01). In the SHARE cohort, 436 participants enrolled and linked to the Partners cohort. More women (60% vs 50%) linked and those who linked were predominantly white (96%; P<.01). Crohn's disease patients who linked had lower mean scores on the Harvey-Bradshaw Index (3.6 vs 4.4, P<.01). Ulcerative colitis patients who linked had less extensive disease than those who did not link (45% vs 60%, P<.01). Conclusions: Linkage of CCFA Partners with cohorts such as OSCCAR and SHARE may be a cost-effective way to expand the infrastructure for clinical outcomes and translational research. Although linkage is feasible from a technical, legal, and regulatory perspective, participant willingness appears to be a limiting factor. Overcoming this barrier will be needed to generate meaningful sample sizes to conduct studies of biomarkers, natural history, and clinical effectiveness using linked data

Methotrexate Is Not Superior to Placebo in Maintaining Steroid-Free Response or Remission in Ulcerative Colitis

Background & Aims: Parenteral methotrexate induces clinical remission but not endoscopic improvement of mucosal inflammation in patients with ulcerative colitis (UC). We performed a randomized, placebo-controlled trial to assess the efficacy of parenteral methotrexate in maintaining steroid-free response or remission in patients with UC after induction therapy with methotrexate and steroids. Methods: We performed a 48-week trial, from February 2012 through May 2016, of 179 patients with active UC (Mayo score of 6–12 with endoscopy subscore ≥ 2) despite previous conventional or biological therapy. The study comprised a 16-week open label methotrexate induction period followed by a 32-week double-blind, placebo-controlled maintenance period. Patients were given subcutaneous methotrexate (25 mg/wk) and a 12-week steroid taper. At week 16, steroid-free responders were randomly assigned to groups that either continued methotrexate (25 mg/wk, n = 44) or were given placebo (n = 40) until week 48. We compared the efficacy of treatment by analyzing the proportion of patients who remained relapse free and were in remission at week 48 without use of steroids or other medications to control disease activity. Results: Ninety-one patients (51%) achieved response at week 16, and 84 patients were included in the maintenance period study. During this period, 60% of patients in the placebo group (24/40) and 66% in the methotrexate group (29/44) had a relapse of UC (P =.75). At week 48, 30% of patients in the placebo group (12/40) and 27% of patients in the methotrexate group (12/44) were in steroid-free clinical remission without need for additional therapies (P =.86). No new safety signals for methotrexate were detected. Conclusions: Parenteral methotrexate (25 mg/wk) was not superior to placebo in preventing relapses of UC in patients who achieved steroid-free response during induction therapy. ClinicalTrials.gov, Number: NCT01393405

Developing a Standard Set of Patient-Centred Outcomes for inflammatory Bowel Disease-an international, cross-disciplinary consensus

Background and Aims: Success in delivering value-based healthcare involves measuring outcomes that matter most to patients. Our aim was to develop a minimum Standard Set of patient-centred outcome measures for inflammatory bowel disease [IBD], for use in different healthcare settings. Methods: An international working group [n = 25] representing patients, patient associations, gastroenterologists, surgeons, specialist nurses, IBD registries and patient-reported outcome measure [PROM] methodologists participated in a series of teleconferences incorporating a modified Delphi process. Systematic review of existing literature, registry data, patient focus groups and open review periods were used to reach consensus on a minimum set of standard outcome measures and risk adjustment variables. Similar methodology has been used in 21 other disease areas [www.ichom.org]. Results: A minimum Standard Set of outcomes was developed for patients [aged =16] with IBD. Outcome domains included survival and disease control [survival, disease activity/remission, colorectal cancer, anaem

Multiethnic Meta-Analysis Identifies RAI1 as a Possible Obstructive Sleep Apnea-related Quantitative Trait Locus in Men.

Obstructive sleep apnea (OSA) is a common heritable disorder displaying marked sexual dimorphism in disease prevalence and progression. Previous genetic association studies have identified a few genetic loci associated with OSA and related quantitative traits, but they have only focused on single ethnic groups, and a large proportion of the heritability remains unexplained. The apnea-hypopnea index (AHI) is a commonly used quantitative measure characterizing OSA severity. Because OSA differs by sex, and the pathophysiology of obstructive events differ in rapid eye movement (REM) and non-REM (NREM) sleep, we hypothesized that additional genetic association signals would be identified by analyzing the NREM/REM-specific AHI and by conducting sex-specific analyses in multiethnic samples. We performed genome-wide association tests for up to 19,733 participants of African, Asian, European, and Hispanic/Latino American ancestry in 7 studies. We identified rs12936587 on chromosome 17 as a possible quantitative trait locus for NREM AHI in men (N = 6,737; P = 1.7 × 10 &lt;sup&gt;-8&lt;/sup&gt; ) but not in women (P = 0.77). The association with NREM AHI was replicated in a physiological research study (N = 67; P = 0.047). This locus overlapping the RAI1 gene and encompassing genes PEMT1, SREBF1, and RASD1 was previously reported to be associated with coronary artery disease, lipid metabolism, and implicated in Potocki-Lupski syndrome and Smith-Magenis syndrome, which are characterized by abnormal sleep phenotypes. We also identified gene-by-sex interactions in suggestive association regions, suggesting that genetic variants for AHI appear to vary by sex, consistent with the clinical observations of strong sexual dimorphism

Review of the safety and efficacy of ustekinumab

Ustekinumab is a subcutaneously and intravenously administered fully human monoclonal immunoglobulin (IgG1) antibody targeting the interleukin (IL)-12/23 shared P40 subunit. The pivotal role of IL-12/23 inflammatory-mediated pathways is increasingly recognized in a plethora of immune-mediated inflammatory disorders including Crohn’s disease, psoriasis, and multiple sclerosis. In a randomized controlled trial of ustekinumab in moderate-to-severe Crohn’s disease, clinical response was achieved most notably in infliximab-experienced primary and secondary nonresponders and suboptimal responders

Infliximab for the treatment of fistulas in patients with Crohn's disease

Enterocutaneous fistulas are a serious complication of Crohn's disease and are difficult to treat. Infliximab, a chimeric monoclonal antibody to tumor necrosis factor alpha, has recently been developed as a treatment for Crohn's disease. We conducted a randomized, multicenter, double-blind, placebo-controlled trial of infliximab for the treatment of fistulas in patients with Crohn's disease. The study included 94 adult patients who had draining abdominal or perianal fistulas of at least three months' duration as a complication of Crohn's disease. Patients were randomly assigned to receive one of three treatments: placebo (31 patients), 5 mg of infliximab per kilogram of body weight (31 patients), or 10 mg of infliximab per kilogram (32 patients); all three were to be administered intravenously at weeks 0, 2, and 6. The primary end point was a reduction of 50 percent or more from base line in the number of draining fistulas observed at two or more consecutive study visits. A secondary end point was the closure of all fistulas. Sixty-eight percent of the patients who received 5 mg of infliximab per kilogram and 56 percent of those who received 10 mg per kilogram achieved the primary end point, as compared with 26 percent of the patients in the placebo group (P=0.002 and P=0.02, respectively). In addition, 55 percent of the patients assigned to receive 5 mg of infliximab per kilogram and 38 percent of those assigned to 10 mg per kilogram had closure of all fistulas, as compared with 13 percent of the patients assigned to placebo (P=0.001 and P=0.04, respectively). The median length of time during which the fistulas remained closed was three months. More than 60 percent of patients in all the groups had adverse events. For patients treated with infliximab, the most common were headache, abscess, upper respiratory tract infection, and fatigue. Infliximab is an efficacious treatment for fistulas in patients with Crohn's diseas