Sandborn, William J.

SummaryBackgroundThere are limited data to inform positioning of agents for treating moderate‐severe ulcerative colitis (UC).AimTo assess comparative efficacy and safety of different therapies as first‐line (biologic‐naïve) and second‐line (prior exposure to anti‐tumour necrosis factor(TNF)‐α) agents for moderate‐severe UC, through a systematic review and network meta‐analysis, and appraise quality of evidence (QoE) using grading of recommendations, assessment, development and evaluation (GRADE) approach.MethodsWe identified randomised controlled trials (RCTs) in adults with moderate‐severe UC treated with anti‐TNF agents, anti‐integrin agents and janus kinase (JAK) inhibitors, as first‐line or second‐line agents, and compared with placebo or another active agent. Efficacy outcomes were induction/maintenance of remission and mucosal healing; and safety outcomes were serious adverse events and infections. Network meta‐analyses were performed, and ranking was assessed using surface under the cumulative ranking (SUCRA) probabilities.ResultsIn biologic‐naïve patients (12 trials, no head‐to‐head comparisons), infliximab and vedolizumab were ranked highest for induction of clinical remission (infliximab: odds ratio [OR], 4.10 [95% confidence intervals [CI], 2.58‐6.52]; SUCRA,0.85; vedolizumab:SUCRA,0.82) and mucosal healing (infliximab:SUCRA,0.91; vedolizumab:SUCRA,0.81) (moderate QoE). In patients with prior anti‐TNF exposure (4 trials, no head‐to‐head comparisons), tofacitinib was ranked highest for induction of clinical remission (OR, 11.88 [2.32‐60.89]; SUCRA, 0.96) and mucosal healing (moderate QoE). Differences in trial design limited comparability of trials of maintenance therapy for efficacy. Vedolizumab was ranked safest in terms of serious adverse events (SUCRA, 0.91), and infection (SUCRA, 0.75) in maintenance trials.ConclusionsInfliximab and vedolizumab are ranked highest as first‐line agents, and tofacitinib is ranked highest as second‐line agent, for induction of remission and mucosal healing in patients with moderate‐severe UC, based on indirect comparisons. Head‐to‐head trials are warranted to inform clinical decision‐making with greater confidence.

Objective Microscopic colitis (MC) is a common cause of chronic diarrhoea, often with additional symptoms. No validated instruments exist to assess disease activity in MC, making it difficult to compare efficacy of treatments between clinical trials. We aimed to identify clinical features that independently predicted disease severity and create a Microscopic Colitis Disease Activity Index (MCDAI). Design Patients with MC were prospectively administered a survey assessing their GI symptoms and the IBD Questionnaire (IBDQ). A single investigator also scored a physician global assessment (PGA) of disease severity on a 10-point scale. Multiple linear regression identified which symptoms best predicted the PGA. These symptoms were then combined in a weighted formula to create the MCDAI. The relationship between MCDAI and the IBDQ was investigated. Results Of the 175 patients enrolled, 13 (7.4%) did not complete the survey. The remaining 162 had a median age of 66 years (range, 57–73) and 74% were female. Several clinical features were independently associated with PGA (number of unformed stools daily, presence of nocturnal stools, abdominal pain, weight loss, faecal urgency and faecal incontinence). These parameters were combined to create the MCDAI, which strongly predicted the PGA (R 2 =0.80). A 1-unit decrease in disease activity (ΔMCDAI) was associated with a 9-unit increase in quality of life (ΔIBDQ). Conclusions The MCDAI strongly predicted the PGA and correlated with a validated measure of quality of life. Several symptoms in addition to diarrhoea are associated with disease severity in MC.

SummaryBackgroundSubtotal or total colectomy or proctocolectomy with permanent ileostomy (TC‐PI) may be a treatment option for medically refractory colonic Crohn's disease (CD).AimTo perform a systematic review and meta‐analysis to evaluate the rate, risk factors and outcomes of CD recurrence after TC‐PI.MethodsIn a systematic review ending 31 March 2016, we identified 18 cohort studies (1438 adults) who underwent TC‐PI for colonic CD (median follow‐up, 7.4 years; interquartile range, 5.3–9.0). We estimated pooled rates [with 95% confidence interval (CI)] of clinical and surgical recurrence, and risk factors for disease recurrence.ResultsOn meta‐analysis, the risk of clinical recurrence after TC‐PI was 28.0% (95% CI, 21.7–35.3; 14 studies, 260/1004 patients), with a 5 and 10‐year median cumulative rate of 23.5% (range, 7–35) and 40% (range, 11–60) respectively. The risk of surgical recurrence was 16.0% (95% CI, 11.1–22.7; 10 studies; 183/1092 patients), with a 5 and 10‐year median cumulative rate of 10% (range, 3–29) and 18.5% (range, 14–34) respectively. The risk of clinical and surgical recurrence in patients without ileal disease at baseline was 11.5% (95% CI, 7.7–16.8) and 10.4% (95% CI, 4.5–22.5) respectively. History of ileal disease was associated with 3.2 times higher risk of disease recurrence (RR, 3.2; 95% CI, 1.8–5.6). Other inconsistent risk factors for disease recurrence were penetrating disease and young age at disease onset.ConclusionsSmall bowel clinical recurrence occurs in about 28% of patients after total colectomy with permanent ileostomy for colonic Crohn's disease. Disease recurrence risk is 3.2 times higher in patients with history of ileal disease, and continued medical therapy may be advisable in this population. In patients without ileal inflammation at surgery, continued endoscopic surveillance may identify asymptomatic disease recurrence to guide therapy.

Background and aim Disease activity for Crohn's disease (CD) and UC is typically defined based on symptoms at a moment in time, and ignores the long-term burden of disease. The aims of this study were to select the attributes determining overall disease severity, to rank the importance of and to score these individual attributes for both CD and UC. Methods Using a modified Delphi panel, 14 members of the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) selected the most important attributes related to IBD. Eighteen IOIBD members then completed a statistical exercise (conjoint analysis) to create a relative ranking of these attributes. Adjusted utilities were developed by creating proportions for each level within an attribute. Results For CD, 15.8% of overall disease severity was attributed to the presence of mucosal lesions, 10.9% to history of a fistula, 9.7% to history of abscess and 7.4% to history of intestinal resection. For UC, 18.1% of overall disease severity was attributed to mucosal lesions, followed by 14.0% for impact on daily activities, 11.2% C reactive protein and 10.1% for prior experience with biologics. Overall disease severity indices were created on a 100-point scale by applying each attribute's average importance to the adjusted utilities. Conclusions Based on specialist opinion, overall CD severity was associated more with intestinal damage, in contrast to overall UC disease severity, which was more dependent on symptoms and impact on daily life. Once validated, disease severity indices may provide a useful tool for consistent assessment of overall disease severity in patients with IBD.

SummaryBackgroundMatrix metalloproteinase‐9 is a proteolytic enzyme whose expression is increased in ulcerative colitis.AimTo evaluate the safety and efficacy of GS‐5745, a fully humanised anti‐matrix metalloproteinase‐9 monoclonal antibody, in moderately‐to‐severely active ulcerative colitis.MethodsWe randomised 74 patients with ulcerative colitis to treatment with single or multiple ascending intravenous or subcutaneous doses of GS‐5745 or placebo. Multiple‐dose cohorts received either IV infusions (0.3, 1.0, 2.5 or 5.0 mg/kg GS‐5745 or placebo) every 2 weeks (three total IV infusions) or five weekly SC injections (150 mg GS‐5745 or placebo). The primary outcomes were the safety, tolerability and pharmacokinetics of escalating single and multiple doses of GS‐5745. Exploratory analyses in the multiple‐dose cohorts included clinical response (≥3 points or 30% decrease from baseline in Mayo Clinic score and ≥1 point decrease in the rectal bleeding subscore or a rectal bleeding subscore ≤1) and clinical remission (a complete Mayo Clinic score ≤2 with no subscore >1) at Day 36. Biological effects associated with a clinical response to GS‐5745 were explored using histological and molecular approaches.ResultsTwenty‐three of the 42 patients (55%) receiving multiple doses of GS‐5745 had adverse events, compared with 5/8 patients (63%) receiving placebo. GS‐5745 showed target‐mediated drug disposition, approximately dose‐proportional increases in maximum plasma concentration and more than dose‐proportional increases in the area under the plasma drug concentration‐time curve. Clinical response occurred in 18/42 patients (43%) receiving GS‐5745 compared with 1/8 patients (13%) receiving placebo. Clinical remission occurred in 6/42 patients (14%) receiving GS‐5745 and 0/8 (0%) receiving placebo. Patients with a clinical response to GS‐5745 had reductions in matrix metalloproteinase‐9 tissue levels (mean 48.9% decrease from baseline compared with a mean 18.5% increase in nonresponders, P = 0.008) significant improvements in histopathology scores (confirmed with three separate histological disease activity indices), as well as changes in colonic gene expression that were consistent with reduced inflammation.ConclusionThis phase 1 trial provides preliminary evidence for the safety and therapeutic potential of GS‐5745 in the treatment of ulcerative colitis.

Placebo controlled trials have demonstrated that a tapering course of corticosteroids is an effective therapy for active Crohn’s disease. A populationbased study of 109 patients with Crohn’s disease undergoing their first course of corticosteroids showed that, at the end of one year, 44% of patients were steroid responsive, 36% were steroid dependent and 20% were steroid refractory. Side effects occur frequently during a four-month tapering course of corticosteroids, including moon face, acne, infection, ecchymoses, hypertension, hirsutism, petechial bleeding and striae. More serious side effects occur with long term use, including hypertension, diabetes, infection, osteonecrosis, osteoporosis, myopathy, cataracts, glaucoma and psychosis. Low dose corticosteroids, alternate-day corticosteroids and mesalamine (5-aminosalicylate) are not effective steroid-sparing agents in patients with Crohn’s disease. Controlled ileal release budesonide, 6 mg/day, is an effective steroid-sparing agent, but it does result in some decrease in adrenal function. Azathioprine, 6-mercaptopurine and methotrexate are all effective steroidsparing agents, as is the humanized, anti-tumour necrosis factor monoclonal antibody, CDP571. A preliminary, uncontrolled study has suggested that the mouse/human chimeric monoclonal antibody infliximab may also be steroid sparing. Surgical resection is an effective strategy to reduce steroid use in the short to intermediate term, but postoperative reoccurrence of Crohn’s disease occurs frequently. Given the morbidity associated with prolonged corticosteroid use, medical and surgical treatment strategies to reduce steroid use should be employed routinely.

Objective Vedolizumab is a gut-selective antibody to α 4 β 7 integrin for the treatment of ulcerative colitis (UC) and Crohn's disease (CD). We report an integrated summary of the safety of vedolizumab. Design Safety data (May 2009–June 2013) from six trials of vedolizumab were integrated. Adverse events were evaluated in patients who received ≥1 dose of vedolizumab or placebo and were reported as exposure-adjusted incidence rates as the number of patients experiencing the event per 100 person-years (PYs) of exposure. Predictors of serious infection were assessed using a Cox proportional hazards model. Results In total, 2830 patients had 4811 PYs of vedolizumab exposure (median exposure range, 1–1977 days). No increased risk of any infection or serious infection was associated with vedolizumab exposure. Serious clostridial infections, sepsis and tuberculosis were reported infrequently (≤0.6% of patients). No cases of progressive multifocal leucoencephalopathy were observed. Independent risk factors for serious infection in UC were prior failure of a tumour necrosis factor α antagonist (HR, 1.99; 95% CIs 1.16 to 3.42; p=0.0122) and narcotic analgesic use (HR, 2.68; 95% CI 1.57 to 4.58; p=0.0003), and in CD were younger age (HR, 0.97; 95% CI 0.95 to 0.98; p<0.0001), corticosteroid (HR, 1.88; 95% CI 1.35 to 2.63; p=0.0002) or narcotic analgesic use (HR, 2.72; 95% CI 1.90 to 3.89; p<0.0001). Investigator-defined infusion-related reactions were reported for ≤5% of patients in each study. Eighteen vedolizumab-exposed patients (<1%) were diagnosed with a malignancy. Conclusions Vedolizumab has a favourable safety profile with low incidence rates of serious infections, infusion-related reactions and malignancies over an extended treatment period. Trial registration number NCT01177228, NCT00619489 , NCT00783718 , NCT00783692 , NCT01224171 , NCT00790933 .

BACKGROUND: Delayed-release oral mesalamine 2.4 g/day to 4.8 g/day has been shown to be effective in treating mildly to moderately active ulcerative colitis (UC), but it is unknown whether an initial dose of 4.8 g/day is more effective than 2.4 g/day in patients with mildly to moderately active UC and in the subgroup with moderate disease.PATIENTS AND METHODS: A six-week, multicentre, randomized, double-blind, controlled trial assessing the safety and clinical efficacy of a new dose (ASCEND I) of medication randomly assigned 301 adults with mildly to moderately active UC to delayed-release oral mesalamine 2.4 g/day (400 mg tablet [n=154]) or 4.8 g/day (800 mg tablet [n=147]). The primary efficacy end point was overall improvement (ie, treatment success), defined as complete remission or response to therapy from baseline to week 6. Primary safety end points were adverse events and laboratory evaluations. Data were also analyzed separately for the prespecified subgroup of patients with moderate UC at baseline.RESULTS: Treatment success was not statistically different between the treatment groups at week 6; 51% of the group (77 of 150) who received delayed-release oral mesalamine 2.4 g/day and 56% of the group (76 of 136) who received 4.8 g/day reached the efficacy end point (P=0.441). Among the moderate disease subgroup, however, the higher initial dose was more effective; 57% of patients (53 of 93) given delayed-release oral mesalamine 2.4 g/day and 72% of patients (55 of 76) given 4.8 g/day achieved treatment success (P=0.0384). Both regimens were well tolerated.CONCLUSIONS: Delayed-release oral mesalamine is an effective and well-tolerated initial therapy in patients with mildly to moderately active UC, and a 4.8 g/day dose may enhance treatment success rates in patients with moderate disease compared with mesalamine 2.4 g/day.