Persistent disease activity is associated with a poor prognosis in inflammatory bowel disease (IBD). Therefore, monitoring of patients with intent to suppress subclinical inflammation has emerged as ...a treatment concept. As endoscopic monitoring is invasive and resource intensive, identification of valid markers of disease activity is a priority. The objective was to evaluate the diagnostic accuracy of C-reactive protein (CRP), fecal calprotectin (FC), and stool lactoferrin (SL) for assessment of endoscopically defined disease activity in IBD.
Databases were searched from inception to November 6, 2014 for relevant cohort and case-control studies that evaluated the diagnostic accuracy of CRP, FC, or SL and used endoscopy as a gold standard in patients with symptoms consistent with active IBD. Sensitivities and specificities were pooled to generate operating property estimates for each test using a bivariate diagnostic meta-analysis.
Nineteen studies (n=2499 patients) were eligible. The pooled sensitivity and specificity estimates for CRP, FC, and SL were 0.49 (95% confidence interval (CI) 0.34-0.64) and 0.92 (95% CI 0.72-0.96), 0.88 (95% CI 0.84-0.90) and 0.73 (95% CI 0.66-0.79), and 0.82 (95% CI 0.73-0.88) and 0.79 (95% CI 0.62-0.89), respectively. FC was more sensitive than CRP in both diseases and was more sensitive in ulcerative colitis than Crohn's disease.
Although CRP, FC, and SL are useful biomarkers, their value in managing individual patients must be considered in specific clinical contexts.
Ozanimod, a selective sphingosine-1-phosphate receptor modulator, is under investigation for the treatment of inflammatory bowel disease.
We conducted a phase 3, multicenter, randomized, ...double-blind, placebo-controlled trial of ozanimod as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. In the 10-week induction period, patients in cohort 1 were assigned to receive oral ozanimod hydrochloride at a dose of 1 mg (equivalent to 0.92 mg of ozanimod) or placebo once daily in a double-blind manner, and patients in cohort 2 received open-label ozanimod at the same daily dose. At 10 weeks, patients with a clinical response to ozanimod in either cohort underwent randomization again to receive double-blind ozanimod or placebo for the maintenance period (through week 52). The primary end point for both periods was the percentage of patients with clinical remission, as assessed with the three-component Mayo score. Key secondary clinical, endoscopic, and histologic end points were evaluated with the use of ranked, hierarchical testing. Safety was also assessed.
In the induction period, 645 patients were included in cohort 1 and 367 in cohort 2; a total of 457 patients were included in the maintenance period. The incidence of clinical remission was significantly higher among patients who received ozanimod than among those who received placebo during both induction (18.4% vs. 6.0%, P<0.001) and maintenance (37.0% vs. 18.5% among patients with a response at week 10, P<0.001). The incidence of clinical response was also significantly higher with ozanimod than with placebo during induction (47.8% vs. 25.9%, P<0.001) and maintenance (60.0% vs. 41.0%, P<0.001). All other key secondary end points were significantly improved with ozanimod as compared with placebo in both periods. The incidence of infection (of any severity) with ozanimod was similar to that with placebo during induction and higher than that with placebo during maintenance. Serious infection occurred in less than 2% of the patients in each group during the 52-week trial. Elevated liver aminotransferase levels were more common with ozanimod.
Ozanimod was more effective than placebo as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. (Funded by Bristol Myers Squibb; True North ClinicalTrials.gov number, NCT02435992.).
Summary
Background
Biosimilar versions of widely prescribed drugs, including the tumour‐necrosis factor antagonist infliximab, are becoming increasingly available. As biosimilars are not identical ...copies of reference products, evidence may be required to demonstrate that switching between a reference biologic and biosimilars is safe and efficacious. To establish interchangeability, US Food and Drug Administration guidance states that studies must demonstrate that biosimilars remain equivalent or non‐inferior to a reference product after multiple switches between products.
Aims
To investigate the evidence evaluating the safety and efficacy of switching between reference and biosimilar infliximab in patients with inflammatory disorders, including Crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis.
Methods
Published studies presenting data on switching between reference and biosimilar infliximab were identified by searching the MEDLINE database. Congress s were identified by searching the EMBASE database and manually searching s from relevant congresses.
Results
A total of 113 journal articles and 149 s were found. Of these, 70 were considered relevant and included in this analysis. Most of the publications were uncontrolled, observational studies. Data from six randomised, controlled trials were identified. In general, the evidence revealed no clinically important efficacy or safety signals associated with switching.
Conclusions
While available data have not identified significant risks associated with a single switch between reference and biosimilar infliximab, the studies available currently report on only single switches and were mostly observational studies lacking control arms. Additional data are needed to explore potential switching risks in various populations and scenarios.
The efficacy of vedolizumab, an α4β7 integrin antibody, in Crohn's disease is unknown.
In an integrated study with separate induction and maintenance trials, we assessed intravenous vedolizumab ...therapy (300 mg) in adults with active Crohn's disease. In the induction trial, 368 patients were randomly assigned to receive vedolizumab or placebo at weeks 0 and 2 (cohort 1), and 747 patients received open-label vedolizumab at weeks 0 and 2 (cohort 2); disease status was assessed at week 6. In the maintenance trial, 461 patients who had had a response to vedolizumab were randomly assigned to receive placebo or vedolizumab every 8 or 4 weeks until week 52.
At week 6, a total of 14.5% of the patients in cohort 1 who received vedolizumab and 6.8% who received placebo were in clinical remission (i.e., had a score on the Crohn's Disease Activity Index CDAI of ≤150, with scores ranging from 0 to approximately 600 and higher scores indicating greater disease activity) (P=0.02); a total of 31.4% and 25.7% of the patients, respectively, had a CDAI-100 response (≥100-point decrease in the CDAI score) (P=0.23). Among patients in cohorts 1 and 2 who had a response to induction therapy, 39.0% and 36.4% of those assigned to vedolizumab every 8 weeks and every 4 weeks, respectively, were in clinical remission at week 52, as compared with 21.6% assigned to placebo (P<0.001 and P=0.004 for the two vedolizumab groups, respectively, vs. placebo). Antibodies against vedolizumab developed in 4.0% of the patients. Nasopharyngitis occurred more frequently, and headache and abdominal pain less frequently, in patients receiving vedolizumab than in patients receiving placebo. Vedolizumab, as compared with placebo, was associated with a higher rate of serious adverse events (24.4% vs. 15.3%), infections (44.1% vs. 40.2%), and serious infections (5.5% vs. 3.0%).
Vedolizumab-treated patients with active Crohn's disease were more likely than patients receiving placebo to have a remission, but not a CDAI-100 response, at week 6; patients with a response to induction therapy who continued to receive vedolizumab (rather than switching to placebo) were more likely to be in remission at week 52. Adverse events were more common with vedolizumab. (Funded by Millennium Pharmaceuticals; GEMINI 2 ClinicalTrials.gov number, NCT00783692.).
Tofacitinib, an oral, small-molecule Janus kinase inhibitor, was shown to have potential efficacy as induction therapy for ulcerative colitis in a phase 2 trial. We further evaluated the efficacy of ...tofacitinib as induction and maintenance therapy.
We conducted three phase 3, randomized, double-blind, placebo-controlled trials of tofacitinib therapy in adults with ulcerative colitis. In the OCTAVE Induction 1 and 2 trials, 598 and 541 patients, respectively, who had moderately to severely active ulcerative colitis despite previous conventional therapy or therapy with a tumor necrosis factor antagonist were randomly assigned to receive induction therapy with tofacitinib (10 mg twice daily) or placebo for 8 weeks. The primary end point was remission at 8 weeks. In the OCTAVE Sustain trial, 593 patients who had a clinical response to induction therapy were randomly assigned to receive maintenance therapy with tofacitinib (either 5 mg or 10 mg twice daily) or placebo for 52 weeks. The primary end point was remission at 52 weeks.
In the OCTAVE Induction 1 trial, remission at 8 weeks occurred in 18.5% of the patients in the tofacitinib group versus 8.2% in the placebo group (P=0.007); in the OCTAVE Induction 2 trial, remission occurred in 16.6% versus 3.6% (P<0.001). In the OCTAVE Sustain trial, remission at 52 weeks occurred in 34.3% of the patients in the 5-mg tofacitinib group and 40.6% in the 10-mg tofacitinib group versus 11.1% in the placebo group (P<0.001 for both comparisons with placebo). In the OCTAVE Induction 1 and 2 trials, the rates of overall infection and serious infection were higher with tofacitinib than with placebo. In the OCTAVE Sustain trial, the rate of serious infection was similar across the three treatment groups, and the rates of overall infection and herpes zoster infection were higher with tofacitinib than with placebo. Across all three trials, adjudicated nonmelanoma skin cancer occurred in five patients who received tofacitinib and in one who received placebo, and adjudicated cardiovascular events occurred in five who received tofacitinib and in none who received placebo; as compared with placebo, tofacitinib was associated with increased lipid levels.
In patients with moderately to severely active ulcerative colitis, tofacitinib was more effective as induction and maintenance therapy than placebo. (Funded by Pfizer; OCTAVE Induction 1, OCTAVE Induction 2, and OCTAVE Sustain ClinicalTrials.gov numbers, NCT01465763 , NCT01458951 , and NCT01458574 , respectively.).
Although tumor necrosis factor (TNF) antagonists have shown clear benefits over conventional treatments for inducing and maintaining clinical remission in both Crohn's disease and ulcerative colitis, ...a high proportion of patients lose response over time. Given the scarce alternative of treatments when treatment failure occurs, it is highly desirable to optimize both initial response and long-term continuation of TNF antagonists. One of the most well-characterized factors associated with loss of response to these agents is the development of immunogenicity, whereby the production of neutralizing antidrug antibodies accelerates drug clearance, leading to subtherapeutic drug concentrations and, ultimately, to treatment failure. However, other patient-related factors, such as sex and/or body size, and disease severity, including TNF burden and serum albumin concentration among others, also may influence the pharmacokinetics of these agents. Nevertheless, the evidence generated to date about these complex interactions is scarce, and further prospective studies evaluating their influence on the pharmacokinetics of TNF antagonists are needed. Drug adjustment empirically based on clinical symptoms often is inaccurate and may lead to suboptimal outcomes. Recent evidence shows that maintenance of an optimal therapeutic drug concentration is associated with improved clinical outcomes. Therefore, incorporation of therapeutic drug monitoring into clinical practice may allow clinicians to optimize treatment by maintaining effective drug concentrations over time.
The traditional management of Crohn's disease, which is based on progressive, step-wise treatment intensification with re-evaluation of response according to symptoms, does not improve long-term ...outcomes of Crohn's disease 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 by 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 of treating to targets for Crohn's disease.
Gut-selective blockade of lymphocyte trafficking by vedolizumab may constitute effective treatment for ulcerative colitis.
We conducted two integrated randomized, double-blind, placebo-controlled ...trials of vedolizumab in patients with active disease. In the trial of induction therapy, 374 patients (cohort 1) received vedolizumab (at a dose of 300 mg) or placebo intravenously at weeks 0 and 2, and 521 patients (cohort 2) received open-label vedolizumab at weeks 0 and 2, with disease evaluation at week 6. In the trial of maintenance therapy, patients in either cohort who had a response to vedolizumab at week 6 were randomly assigned to continue receiving vedolizumab every 8 or 4 weeks or to switch to placebo for up to 52 weeks. A response was defined as a reduction in the Mayo Clinic score (range, 0 to 12, with higher scores indicating more active disease) of at least 3 points and a decrease of at least 30% from baseline, with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1.
Response rates at week 6 were 47.1% and 25.5% among patients in the vedolizumab group and placebo group, respectively (difference with adjustment for stratification factors, 21.7 percentage points; 95% confidence interval CI, 11.6 to 31.7; P<0.001). At week 52, 41.8% of patients who continued to receive vedolizumab every 8 weeks and 44.8% of patients who continued to receive vedolizumab every 4 weeks were in clinical remission (Mayo Clinic score ≤2 and no subscore >1), as compared with 15.9% of patients who switched to placebo (adjusted difference, 26.1 percentage points for vedolizumab every 8 weeks vs. placebo 95% CI, 14.9 to 37.2; P<0.001 and 29.1 percentage points for vedolizumab every 4 weeks vs. placebo 95% CI, 17.9 to 40.4; P<0.001). The frequency of adverse events was similar in the vedolizumab and placebo groups.
Vedolizumab was more effective than placebo as induction and maintenance therapy for ulcerative colitis. (Funded by Millennium Pharmaceuticals; GEMINI 1 ClinicalTrials.gov number, NCT00783718.).
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