Crohn's disease

SummaryCrohn's disease is a relapsing systemic inflammatory disease, mainly affecting the gastrointestinal tract with extraintestinal manifestations and associated immune disorders. Genome wide association studies identified susceptibility loci that—triggered by environmental factors—result in a disturbed innate (ie, disturbed intestinal barrier, Paneth cell dysfunction, endoplasmic reticulum stress, defective unfolded protein response and autophagy, impaired recognition of microbes by pattern recognition receptors, such as nucleotide binding domain and Toll like receptors on dendritic cells and macrophages) and adaptive (ie, imbalance of effector and regulatory T cells and cytokines, migration and retention of leukocytes) immune response towards a diminished diversity of commensal microbiota. We discuss the epidemiology, immunobiology, amd natural history of Crohn's disease; describe new treatment goals and risk stratification of patients; and provide an evidence based rational approach to diagnosis (ie, work-up algorithm, new imaging methods [ie, enhanced endoscopy, ultrasound, MRI and CT] and biomarkers), management, evolving therapeutic targets (ie, integrins, chemokine receptors, cell-based and stem-cell-based therapies), prevention, and surveillance

Market Access Analysis of Biologics and Small-Molecule Inhibitors for Inflammatory Bowel Disease Among US Health Insurance Policies.

BACKGROUND AND AIMS:Treatment pathways for ulcerative colitis (UC) and Crohn's disease (CD) are shifting to a more individualized, risk-stratified approach. The perception is that insurance policies may not have implemented this paradigm shift, particularly regarding access to newer agents. We evaluated patient access to advanced therapies by analyzing policy information from the Managed Markets Insight and Technology database. METHODS:Coverage status as of December 2018 for all US lives was queried for adalimumab, infliximab, infliximab-dyyb, tofacitinib, ustekinumab, and vedolizumab by indication (UC and/or CD) and medical or pharmacy coverage benefit. Coverage status was classified by the number of biologic steps before access to specified drug as "No Biologic," "1 Prior Biologic," "2+ Prior Biologics," "Not Covered." Unknown lives were excluded from the analyses. RESULTS:Coverage analysis was available for approximately 302 million lives under each medical and pharmacy benefit. Our analysis indicates that approximately half of covered lives had access to all agents (except tofacitinib) as first-line therapy; two-thirds had access after one biologic exposure. Among newer agents, vedolizumab had the widest coverage. For indications of UC and CD, 81% of known lives had access to vedolizumab with no prior biologic exposure required ("No Biologic"), 95% after "No Biologic" + "1 prior Biologic." Geographic variations were identified for coverage patterns. CONCLUSIONS:This US-based healthcare policy analysis points to an increased access to advanced therapies for UC and CD. An individualized, risk-stratified treatment approach integrating advanced therapies, including those recently approved, into treatment pathways for UC and CD is feasible

Budesonide Foam Has a Favorable Safety Profile for Inducing Remission in Mild-to-Moderate Ulcerative Proctitis or Proctosigmoiditis.

BackgroundBudesonide foam, a rectally administered, second-generation corticosteroid with extensive hepatic first-pass metabolism, is efficacious for the treatment of mild-to-moderate ulcerative proctitis and ulcerative proctosigmoiditis.AimThe aim of this study was to comprehensively assess the safety and pharmacokinetic profile of budesonide foam.MethodsData from five phase III studies were pooled to further evaluate safety, including an open-label study (once-daily treatment for 8 weeks), an active-comparator study (once-daily treatment for 4 weeks), and two placebo-controlled studies and an open-label extension study (twice-daily treatment for 2 weeks, then once daily for 4 weeks). Data from the placebo-controlled studies and two phase I studies (i.e., patients with mild-to-moderate ulcerative colitis and healthy volunteers) were pooled to evaluate the pharmacokinetics of budesonide foam.ResultsA similar percentage of patients reported adverse events in the budesonide foam and placebo groups, with the majority of adverse events being mild or moderate in intensity (93.3 vs 96.0%, respectively). Adverse events occurred in 41.4 and 36.3% of patients receiving budesonide foam and placebo, respectively. Mean morning cortisol concentrations remained within the normal range for up to 8 weeks of treatment; there were no clinically relevant effects of budesonide foam on the hypothalamic-pituitary-adrenal axis. Population pharmacokinetic analysis demonstrated low systemic exposure after budesonide foam administration.ConclusionsThis integrated analysis demonstrated that budesonide foam for the induction of remission of distal ulcerative colitis is safe overall, with no clinically relevant effects on the hypothalamic-pituitary-adrenal axis

Tofacitinib, an oral janus kinase inhibitor, in active ulcerative colitis

Background: ulcerative colitis is a chronic inflammatory disease of the colon for which current treatments are not universally effective. One additional treatment may be tofacitinib (CP-690,550), an oral inhibitor of Janus kinases 1, 2, and 3 with in vitro functional specificity for kinases 1 and 3 over kinase 2, which is expected to block signaling involving gamma chain-containing cytokines including interleukins 2, 4, 7, 9, 15, and 21. These cytokines are integral to lymphocyte activation, function, and proliferation. Methods: in a double-blind, placebo-controlled, phase 2 trial, we evaluated the efficacy of tofacitinib in 194 adults with moderately to severely active ulcerative colitis. Patients were randomly assigned to receive tofacitinib at a dose of 0.5 mg, 3 mg, 10 mg, or 15 mg or placebo twice daily for 8 weeks. The primary outcome was a clinical response at 8 weeks, defined as an absolute decrease from baseline in the score on the Mayo scoring system for assessment of ulcerative colitis activity (possible score, 0 to 12, with higher scores indicating more severe disease) of 3 or more and a relative decrease from baseline of 30% or more with an accompanying decrease in the rectal bleeding subscore of 1 point or more or an absolute rectal bleeding subscore of 0 or 1. Results: the primary outcome, clinical response at 8 weeks, occurred in 32%, 48%, 61%, and 78% of patients receiving tofacitinib at a dose of 0.5 mg (P=0.39), 3 mg (P=0.55), 10 mg (P=0.10), and 15 mg (P1) at 8 weeks occurred in 13%, 33%, 48%, and 41% of patients receiving tofacitinib at a dose of 0.5 mg (P=0.76), 3 mg (P=0.01), 10 mg (P<0.001), and 15 mg (P<0.001), respectively, as compared with 10% of patients receiving placebo. There was a dose-dependent increase in both low-density and high-density lipoprotein cholesterol. Three patients treated with tofacitinib had an absolute neutrophil count of less than 1500. Conclusions: patients with moderately to severely active ulcerative colitis treated with tofacitinib were more likely to have clinical response and remission than those receiving placebo. (Funded by Pfizer; ClinicalTrials.gov number, NCT00787202)

Treat to Target: A Proposed New Paradigm for the Management of Crohn's Disease.

International audience: The traditional management of CD, based on progressive, step-wise treatment intensification with re-evaluation of response according to symptoms, does not improve long-term outcomes of CD and places patients at risk for bowel damage. The introduction of novel therapies and the development of new approaches to treatment in rheumatoid arthritis led to better outcomes for patients. Prominent among these is a "treat to target" strategy that is based on regular assessment of disease activity using objective clinical and biological outcome measures and the subsequent adjustment of treatments. This approach is complementary to the concept of early intervention in high risk patients. This review evaluates current literature on this topic and proposes a definition for the concept treating to targets for Crohn's disease

Agreement of site and central readings of ileocolonoscopic scores in Crohn's disease: comparison using data from the EXTEND trial

Background and AimsCentralized endoscopic scoring may reduce variability, but evidence is lacking in patients with Crohn’s disease. We assessed the agreement of endoscopic scorings between site endoscopists and one central reader by using data from the adalimumab Crohn’s disease clinical trial EXTEND.MethodsAgreement between readers for Crohn’s Disease Endoscopic Index of Severity (CDEIS)–scored endoscopies from 6 sites and Simple Endoscopic Score for Crohn’s Disease (SES-CD)–scored endoscopies from 19 sites in EXTEND was evaluated at baseline and weeks 12 and 52. Agreement on total scores was calculated by using intraclass correlation coefficient (ICC). Kappa statistic or Spearman correlation coefficient measured the agreement between readers for each ileocolonic segment on CDEIS variables including deep ulceration, surface involved, and ulcerated surface and SES-CD variables including ulcerated surface, size of ulcers, and affected surface.ResultsICCs on mean scores at baseline and weeks 12 and 52 were 0.78, 0.92, and 0.86 (CDEIS), and 0.77, 0.86, and 0.82 (SES-CD), respectively. Site endoscopists consistently reported higher scores. High agreement was observed for most segments and all time points for CDEIS variables and SES-CD large ulcers. Weak agreement occurred for the right side of the colon at all time points for CDEIS deep ulceration and SES-CD large ulcers and at baseline and week 12 for CDEIS ulcerated surface. Fair/moderate agreement occurred for SES-CD ulcerated surface and moderate/high agreement for affected surface for all segments and time points.ConclusionsSite and central readers showed high agreement on total CDEIS and SES-CD scores overall, whereas variability for individual segments was observed. Weakest agreement occurred at baseline, with a greater difference for SES-CD than for CDEIS score. (Clinical trial registration number: NCT00348283.

Factors Associated With Short- and Long-Term Outcomes of Therapy for Crohn’s Disease

Background & AimsOur post hoc analysis assessed the association of early (at weeks 26–30) clinical, endoscopic, biologic, and pharmacokinetic outcomes with corticosteroid-free remission at week 50 (CSFR50); CSFR50 was observed in 55.2% and 65.4% of patients treated with infliximab, alone or in combination with azathioprine, respectively.MethodsWe analyzed data from 203 patients: 96 received infliximab monotherapy and 107 received combination therapy. Receiver operating characteristic analysis was used to set cut-off points for the week 30 trough serum infliximab concentration (SIC30) and percentage change, from baseline, in the C-reactive protein (CRP) level at week 26, to predict CSFR50. Univariate and multivariate procedures analyzed predictive parameters of CSFR50 (odds ratio [OR] and 95% confidence interval [CI]). Mucosal healing (MH, zero ulcers) and CRP normalization (<8.0 mg/L) also were assessed.ResultsTrough SIC30 was higher in patients with than without CSFR50. Patients given combination therapy had higher trough SIC30s than those given monotherapy. Median trough SIC30 was significantly higher in patients with than without CSFR50 among those on infliximab monotherapy (2.14 vs 0.80 μg/mL; P = .006), but not for those on combination therapy (3.56 vs 3.54 μg/mL; P=.31). In patients with increased baseline levels of CRP (n = 120), corticosteroid-free remission at week 26 (CSFR26) (OR, 4.09; 95% CI, 1.65–10.11), and trough SIC30s of 3.0 μg/mL or greater (OR, 3.20; 95% CI, 1.38–7.42) were associated significantly with CSFR50. In patients evaluable for MH (n = 123), trough SIC30s of 3.0 μg/mL or greater (OR, 3.34; 95% CI, 1.53–7.28) and CRP normalization (OR, 2.69; 95% CI, 1.10–6.54) were associated significantly with MH at week 26 (MH26). Furthermore, CSFR26 (OR, 4.43; 95% CI, 1.81–10.82) and MH26 (OR, 3.01; 95% CI, 1.33–6.81) were associated significantly with CSFR50.ConclusionsTrough SIC30 is associated positively with MH26; CSFR26 and MH26 are independent predictors of CSFR50. Trough SIC30 of 3.0 μg/mL or greater early during maintenance treatment is an important determinant of clinical and endoscopic Crohn’s disease outcomes. ClinicalTrials.gov number, NCT00094458

Endoscopic, radiologic, and histologic healing with vedolizumab in patients with active Crohn's disease

BACKGROUND & AIMS: Vedolizumab is a gut-selective monoclonal antibody for the treatment of moderately to severely active Crohn's disease (CD). We performed a prospective study of endoscopic, radiologic, and histologic healing in patients with CD who received vedolizumab therapy. METHODS: We performed a phase 3b, open-label, single-group study of 101 patients with at least 3 months of active CD (a CD Activity Index [CDAI] score of 220-450, a simple endoscopic score for CD [SES-CD] of 7 or more, 1 or more mucosal ulcerations [identified by endoscopy], and failure of conventional therapy) from March 2015 through December 2017. Among the patients enrolled, 54.5% had previous failure of 1 or more tumor necrosis factor (TNF) antagonists and 44.6% had severe endoscopic disease activity (SES-CD scores above 15) at baseline. Participants received vedolizumab (300 mg intravenously) at weeks 0, 2, and 6, and then every 8 weeks thereafter, for 26 weeks (primary study) or 52 weeks (substudy, 56 patients). The primary endpoint at week 26 was endoscopic remission (SES-CD score of 4 or less); other endpoints included endoscopic response (50% reduction in SES-CD), radiologic remission (magnetic resonance index of activity score below 7), and histologic response (modified global histologic disease activity score of 4 or less). RESULTS: At week 26, 11.9% of patients were in endoscopic remission (95% confidence interval [CI] 6.3-9.8); at week 52, 17.9% of the patients were in endoscopic remission (95% CI 8.9-30.4). Higher proportions of patients naïve to TNF antagonists achieved endoscopic remission than patients with TNF-antagonist-failure at weeks 26 and 52. Higher proportion of patients with moderate CD (SES-CD scores, 7-15) achieved endoscopic remission at weeks 26 and 52 than patients with severe CD (SES-CD scores above 15). The proportion of patients with complete mucosal healing increased over time, with greater rates of healing in the colon than in the ileum. Remission was detected by magnetic resonance enterography in 21.9% of patients at week 26 (95% CI 9.3-40.0) and in 38.1% at week 52 (95% CI 18.1-61.6). At week 26, 24.4% of patients had a histologic response in the colon (95% CI 15.3-35.4) and 28.3% of patients had a histologic response in the ileum (95% CI 17.5-41.4). At week 52, 20.5% of patients had a histologic response in the colon (95% CI 9.8-35.3) and 34.3% of patients had a histologic response in the ileum (95% CI 19.1-52.2). There were no notable safety issues, including worsening of extraintestinal manifestations. CONCLUSIONS: In a phase 3b trial, we found that 26 and 52 weeks of treatment with vedolizumab (300 mg, at weeks 0, 2, and 6, and then every 8 weeks thereafter) induces endoscopic, radiologic, and histologic healing in patients with moderately to severely active CD. ClinicalTrials.gov no: NCT02425111. ispartof: GASTROENTEROLOGY vol:157 issue:4 pages:1007-+ ispartof: location:United States status: publishe

Efficacy and Safety of Vedolizumab Subcutaneous Formulation in a Randomized Trial of Patients With Ulcerative Colitis

BACKGROUND & AIMS: Maintenance treatment with vedolizumab, a monoclonal antibody that inhibits the gut-selective α4β7 integrin, is administered intravenously. Some patients might prefer a subcutaneous formulation of vedolizumab for maintenance treatment. Subcutaneous vedolizumab was investigated as maintenance treatment in patients with moderately to severely active ulcerative colitis. METHODS: We performed a phase 3, double-blind, double-dummy trial at 141 sites in 29 countries from December 18, 2015 through August 21, 2018. Patients with moderately to severely active ulcerative colitis received open-label treatment with intravenous vedolizumab 300 mg at weeks 0 and 2. At week 6, patients with clinical response were randomly assigned maintenance treatment with subcutaneous vedolizumab 108 mg every 2 weeks, intravenous vedolizumab 300 mg every 8 weeks, or placebo. The primary end point was clinical remission at week 52, which was defined as a total Mayo score of ≤2 and no subscore >1. RESULTS: Among the randomized 216 patients, clinical remission at week 52 was achieved by 46.2%, 42.6%, and 14.3% of patients in the subcutaneous vedolizumab, intravenous vedolizumab, and placebo groups, respectively (subcutaneous vedolizumab vs placebo: Δ32.3%; 95% confidence interval, 19.7%-45.0%; P < .001). The subcutaneous vedolizumab group also had greater endoscopic improvement and durable clinical response at week 52 compared with placebo (both P < .001). The incidence of injection-site reactions was more frequent in patients given subcutaneous vedolizumab (10.4%) than intravenous vedolizumab (1.9%) or placebo (0%); these were not treatment limiting, most were mild, and none resulted in discontinuation. Subcutaneous and intravenous vedolizumab safety profiles were otherwise similar. CONCLUSIONS: Subcutaneous vedolizumab is effective as maintenance therapy in patients with moderately to severely active ulcerative colitis who had a clinical response to intravenous vedolizumab induction therapy. It has a favorable safety and tolerability profile. ClinicalTrials.gov ID: NCT02611830; EudraCT 2015-000480-14. ispartof: GASTROENTEROLOGY vol:158 issue:3 pages:562-+ ispartof: location:United States status: publishe