Parambir S. Dulai

Association of Pharmacological Treatments for Obesity With Weight Loss and Adverse Events: A Systematic Review and Meta-analysis

IMPORTANCE Five medications have been approved for the management of obesity, but data on comparative effectiveness are limited. OBJECTIVE To compare weight loss and adverse events among drug treatments for obesity using a systematic review and network meta-analysis. DATA SOURCES MEDLINE, EMBASE, Web of Science, Scopus, and Cochrane Central from inception to March 23, 2016; clinical trial registries. STUDY SELECTION Randomized clinical trials conducted among overweight and obese adults treated with US Food and Drug Administration-approved long-term weight loss agents (orlistat, lorcaserin, naltrexone-bupropion, phentermine-topiramate, or liraglutide) for at least 1 year compared with another active agent or placebo. DATA EXTRACTION AND SYNTHESIS Two investigators identified studies and independently abstracted data using a predefined protocol. A Bayesian network meta-analysis was performed and relative ranking of agents was assessed using surface under the cumulative ranking (SUCRA) probabilities. Quality of evidence was assessed using GRADE criteria. MAIN OUTCOMES AND MEASURES Proportions of patients with at least 5% weight loss and at least 10% weight loss, magnitude of decrease in weight, and discontinuation of therapy because of adverse events at 1 year. RESULTS Twenty-eight randomized clinical trials with 29 018 patients (median age, 46 years; 74% women; median baseline body weight, 100.5 kg; median baseline body mass index, 36.1) were included. A median 23% of placebo participants had at least 5% weight loss vs 75% of participants taking phentermine-topiramate (odds ratio [OR], 9.22; 95% credible interval [CrI], 6.63-12.85; SUCRA, 0.95), 63% of participants taking liraglutide (OR, 5.54; 95% CrI, 4.16-7.78; SUCRA, 0.83), 55% taking naltrexone-bupropion (OR, 3.96; 95% CrI, 3.03-5.11; SUCRA, 0.60), 49% taking lorcaserin (OR, 3.10; 95% CrI, 2.38-4.05; SUCRA, 0.39), and 44% taking orlistat (OR, 2.70; 95% CrI, 2.34-3.09; SUCRA, 0.22). All active agents were associated with significant excess weight loss compared with placebo at 1 year-phentermine-topiramate, 8.8 kg (95% CrI, -10.20 to -7.42 kg); liraglutide, 5.3 kg (95% CrI, -6.06 to -4.52 kg); naltrexone-bupropion, 5.0 kg (95% CrI, -5.94 to -3.96 kg); lorcaserin, 3.2 kg (95% CrI, -3.97 to -2.46 kg); and orlistat, 2.6 kg (95% CrI, -3.04 to -2.16 kg). Compared with placebo, liraglutide (OR, 2.95; 95% CrI, 2.11-4.23) and naltrexone-bupropion (OR, 2.64; 95% CrI, 2.10-3.35) were associated with the highest odds of adverse event-related treatment discontinuation. High attrition rates (30%-45% in all trials) were associated with lower confidence in estimates. CONCLUSIONS AND RELEVANCE Among overweight or obese adults, orlistat, lorcaserin, naltrexone-bupropion, phentermine-topiramate, and liraglutide, compared with placebo, were each associated with achieving at least 5% weight loss at 52 weeks. Phentermine-topiramate and liraglutide were associated with the highest odds of achieving at least 5% weight loss.

Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: Systematic review and meta‐analysis

Liver fibrosis is the most important predictor of mortality in nonalcoholic fatty liver disease (NAFLD). Quantitative risk of mortality by fibrosis stage has not been systematically evaluated. We aimed to quantify the fibrosis stage–specific risk of all‐cause and liver‐related mortality in NAFLD. Through a systematic review and meta‐analysis, we identified five adult NAFLD cohort studies reporting fibrosis stage–specific mortality (0‐4). Using fibrosis stage 0 as a reference population, fibrosis stage–specific mortality rate ratios (MRRs) with 95% confidence intervals (CIs) for all‐cause and liver‐related mortality were estimated. The study is reported according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses statement. Included were 1,495 NAFLD patients with 17,452 patient years of follow‐up. Compared to NAFLD patients with no fibrosis (stage 0), NAFLD patients with fibrosis were at an increased risk for all‐cause mortality, and this risk increased with increases in the stage of fibrosis: stage 1, MRR = 1.58 (95% CI 1.19‐2.11); stage 2, MRR = 2.52 (95% CI 1.85‐3.42); stage 3, MRR = 3.48 (95% CI 2.51‐4.83); and stage 4, MRR = 6.40 (95% CI 4.11‐9.95). The results were more pronounced as the risk of liver‐related mortality increased exponentially with each increase in the stage of fibrosis: stage 1, MRR = 1.41 (95% CI 0.17‐11.95); stage 2, MRR = 9.57 (95% CI 1.67‐54.93); stage 3, MRR = 16.69 (95% CI 2.92‐95.36); and stage 4, MRR = 42.30 (95% CI 3.51‐510.34). Limitations of the study include an inability to adjust for comorbid conditions or demographics known to impact fibrosis progression in NAFLD and the inclusion of patients with simple steatosis and nonalcoholic steatohepatitis without fibrosis in the reference comparison group. Conclusion: The risk of liver‐related mortality increases exponentially with increase in fibrosis stage; these data have important implications in assessing the utility of each stage and benefits of regression of fibrosis from one stage to another. (Hepatology 2017;65:1557‐1565).

The Real-World Effectiveness and Safety of Vedolizumab for Moderate-Severe Crohn's Disease: Results From the US VICTORY Consortium.

Objectives:We assessed the real-world effectiveness and safety of vedolizumab (VDZ) in moderate–severe Crohn’s disease (CD).Methods:Retrospective cohort study of seven medical centers, from May 2014 to December 2015. Adults with moderate-severe CD treated with VDZ, with follow-up after initiation of therapy, were included. Using the multivariable Cox proportional hazard analyses, we identified independent predictors of clinical remission or mucosal healing with VDZ. Rates of serious infection (requiring antibiotics, resulting in discontinuation of VDZ, hospitalization or death) and serious adverse events (discontinuation of VDZ, hospitalization or death) were described quantitatively.Results:We included 212 patients with moderate–severe CD (median age 34 years; 40% male; 90% tumor necrosis factor (TNF)-antagonist exposed) with a median follow-up (IQR) of 39 weeks (25–53). Twelve-month cumulative rates of clinical remission, mucosal healing, and deep remission (clinical remission+mucosal healing) were 35%, 63%, and 26%, respectively. Individuals with prior TNF-antagonist exposure (hazard ratio (HR) 0.40; 95% confidence interval (CI): 0.20–0.81), smoking history (HR 0.47; 95% CI: 0.25–0.89), active perianal disease (HR 0.49; 95% CI: 0.27–0.88), and severe disease activity (HR 0.54; 95% CI: 0.31–0.95) were less likely to achieve clinical remission. Those with prior TNF-antagonist exposure (HR 0.29; 95% CI: 0.12–0.73), and severe disease activity (HR 0.54; 95% CI: 0.31–0.95) were less likely to achieve mucosal healing. During 160 patient years of follow-up (PYF) and 1,433 VDZ infusions, 5 patients developed infusion reactions (3.5 per 1,000 infusions), 21 developed serious infections (13 per 100 PYF), and 17 developed serious adverse events (10 per 100 PYF). A minority of adverse events required discontinuation of therapy (6 per 100 PYF).Conclusions:VDZ is a safe and effective treatment option for moderate–severe CD in routine practice. Clinical remission and deep remission (clinical remission and mucosal healing) can be achieved in 1/3 of individuals, and a minority of individuals require discontinuation of therapy due to adverse events.

MRI and MRE for non-invasive quantitative assessment of hepatic steatosis and fibrosis in NAFLD and NASH: Clinical trials to clinical practice.

Non-alcoholic fatty liver disease (NAFLD) represents one of the most common causes of chronic liver disease, and its prevalence is rising worldwide. The occurrence of non-alcoholic steatohepatitis (NASH) is associated with a substantial increase in disease related morbidity and mortality. Accordingly, there has been a surge of innovation surrounding drug development in an effort to off-set the natural progression and long-term risks of this disease. Disease assessment within clinical trials and clinical practice for NAFLD is currently done with liver biopsies. Liver biopsy-based assessments, however, remain imprecise and are not without cost or risk. This carries significant implications for the feasibility and costs of bringing therapeutic interventions to market. A need therefore arises for reliable and highly accurate surrogate end-points that can be used in phase 2 and 3 clinical trials to reduce trial size requirements and costs, while improving feasibility and ease of implementation in clinical practice. Significant advances have now been made in magnetic resonance technology, and magnetic resonance imaging (MRI) and elastrography (MRE) have been demonstrated to be highly accurate diagnostic tools for the detection of hepatic steatosis and fibrosis. In this review article, we will summarize the currently available evidence regarding the use of MRI and MRE among NAFLD patients, and the evolving role these surrogate biomarkers will play in the rapidly advancing arena of clinical trials in NASH and hepatic fibrosis. Furthermore, we will highlight how these tools can be readily applied to routine clinical practice, where the growing burden of NAFLD will need to be met with enhanced monitoring algorithms.

Risks of Serious Infection or Lymphoma With Anti–Tumor Necrosis Factor Therapy for Pediatric Inflammatory Bowel Disease: A Systematic Review

BACKGROUND & AIMS Many physicians hesitate to recommend anti-tumor necrosis factor (TNF) therapy for pediatric patients with inflammatory bowel disease (IBD) because of concerns about risk of infection and cancer. We performed a systematic review to quantify the incidence of serious infection, lymphoma, and death among pediatric patients with IBD who received anti-TNF therapy. These values were compared with those expected from other treatments, from adults with IBD, and from the general pediatric population. METHODS We searched MEDLINE, EMBASE, the Cochrane Collaboration, and Web of Knowledge for studies of infliximab therapy for children with ulcerative colitis or Crohns disease, or adalimumab therapy for children with Crohns disease. Standardized incidence ratios (SIRs) were calculated, comparing rates of infection and cancer among pediatric patients exposed to anti-TNF agents vs expected rates from pediatric patients not exposed to anti-TNF therapies or adult patients exposed to anti-TNF agents. Our analysis included 5528 patients with 9516 patient-years of follow-up evaluation (PYF). RESULTS The rate of serious infections among pediatric patients treated with anti-TNF agents (352/10,000 PYF) was similar to that of pediatric patients who received immunomodulator monotherapy (333/10,000 PYF; SIR, 1.06; 95% confidence interval [CI], 0.83-1.36), but significantly lower than the expected rate for pediatric patients treated with steroids (730/10,000 PYF; SIR, 0.48; 95% CI, 0.40-0.58) or adults treated with anti-TNF agents (654/10,000 PYF; SIR, 0.54; 95% CI, 0.43-0.67). Five treatment-related deaths occurred (4 from sepsis and 1 from arrhythmia). Two patients developed lymphoma (2.1/10,000 PYF). This value was similar to the expected rate of lymphoid neoplasia in the entire pediatric population (5.8/100,000 PYF; SIR, 3.5; 95% CI, 0.35-19.6), and lower than the population of pediatric patients receiving thiopurine monotherapy (4.5/10,000 PYF; SIR, 0.47; 95% CI, 0.03-6.44), and among adults treated with anti-TNF agents (6.1/10,000 PYF; SIR, 0.34; 95% CI, 0.04-1.51). CONCLUSIONS Based on a systematic review, the risk of lymphoma was no greater among children with IBD who received anti-TNF therapy than those treated with other IBD therapies or adults treated with anti-TNF agents. The rate of serious infection was significantly lower among pediatric patients with IBD treated with anti-TNF agents than those treated with steroids, or adults with IBD who received anti-TNF therapy.

Systematic review: monotherapy with antitumour necrosis factor α agents versus combination therapy with an immunosuppressive for IBD

The treatment of IBD has evolved significantly over the past 15 years. Historically, steroids and immunosuppressive drugs, such as methotrexate (MTX), azathioprine (AZA) and 6-mercaptopurine (6-MP) had been the mainstay of therapy. When infliximab (IFX) was approved for the treatment of Crohns disease, it began the era of trying to understand how best to optimise our available treatment options. Initially, antitumour necrosis factor (anti-TNF) agents were used after immunosuppressives failed. Then, evidence showed that using AZA together with IFX early in the disease course was more effective than the typical sequential treatment algorithm.1 With the addition of newer anti-TNF drugs and development of different treatment regimens,2–5 there are still significant questions related to the most effective therapeutic strategy. Perhaps the most controversial of these questions is when to use anti-TNF monotherapy versus combination therapy with 6-MP, AZA or MTX. When considering patients with rheumatoid arthritis, where anti-TNF therapy also has a demonstrated efficacy, it is clear from randomised controlled trials (RCT) that the use of combination therapy improves clinical outcomes.6 Although it is logical that a similar benefit should exist in IBD, the evidence base upon which to make decisions is less robust, leading to patient and provider concerns regarding the balance between efficacy and toxicity. Providers have two sources of data to rely upon when addressing this concern with IBD patients, RCTs and observational data. RCTs are more rigorous, generally have better patient follow-up, and more often include prospective measurement of study end-points using well-accepted and often validated outcome measures. For this reason, RCTs result in a relatively robust assessment of key outcome measures such as clinical response, remission and mucosal healing. Although the data from RCTs may not directly translate to the ‘real world’,7 whatever generalisability is lost due to the application of strict inclusion …

Radiofrequency ablation for long- and ultralong-segment Barrett's esophagus: a comparative long-term follow-up study

BACKGROUND The safety, efficacy, and durability of radiofrequency ablation (RFA), with or without EMR, have been established for long-segment Barretts esophagus (LSBE). Ablating ultralong-segment Barretts esophagus (ULSBE) may be associated with increased stricture formation, eradication failure, and treatment session requirements. OBJECTIVES Our primary objective was to compare eradication and stricture rates between LSBE (≥3 to <8 cm) and ULSBE (≥8 cm). Our secondary objective was to evaluate treatment durability and session requirements. DESIGN Retrospective review of prospectively collected data. SETTING Tertiary care facility. PATIENTS A total of 72 patients (34 ULSBE, 38 LSBE; mean Barretts segment length of 10.8 and 4.7 cm) underwent RFA between August 2005 and September 2010. Mean follow-up was 45 and 34 months, respectively. MAIN OUTCOME MEASUREMENTS Eradication and complication rates for ULSBE and LSBE. RESULTS Eradication rates for dysplasia (90% vs 88%, P = 1.0) and intestinal metaplasia (IM) (77% vs 82%, P = .77) were similar. ULSBE patients required more overall (P < .01) and circumferential (P < .01) RFA; however, stricture rates were identical (14%). There was no dysplasia recurrence, and IM recurrence was similar (ULSBE, 23%; LSBE, 16%; P = .52). At 3 years, IM remained eradicated in 65% of ULSBE and 82% of LSBE, without maintenance RFA. On multivariate regression analysis, increasing Barretts length was associated with a reduced likelihood for eradicating IM (odds ratio 0.87; 95% CI, 0.75-1.00), but not dysplasia (odds ratio 1.13; 95% CI, 0.95-1.35). LIMITATIONS Single center. CONCLUSION ULSBE can be treated in its entirety at each session with efficacy and safety comparable to LSBE. ULSBE requires more effort to achieve IM eradication, and RFA is less durable in maintaining this eradication at 3-year follow-up.

Systematic review with meta-analysis: faecal diversion for management of perianal Crohn's disease

Temporary faecal diversion is sometimes used for management of refractory perianal Crohns disease (CD) with variable success.

Incidence, Risk Factors, and Outcomes of Colorectal Cancer in Patients With Ulcerative Colitis With Low-Grade Dysplasia: A Systematic Review and Meta-analysis

Background & Aims Little is known about outcomes of patients with ulcerative colitis with low‐grade dysplasia (UC‐LGD). We estimated the incidence of and risk factors for progression to colorectal cancer (CRC) in cohorts of patients with UC‐LGD who underwent surveillance (surveillance cohort), and the prevalence of dysplasia‐related findings among patients who underwent colectomy for UC‐LGD (surgical cohort). Methods We performed a systematic literature review through June 1, 2016, to identify cohort studies of adults with UC‐LGD. We estimated pooled incidence rates of CRC and risk factors associated with dysplasia progression in surveillance cohorts, and prevalence of synchronous advanced neoplasia (CRC and/or high‐grade dysplasia) in surgical cohorts. Results In 14 surveillance cohort studies of 671 patients with UC‐LGD (52 developed CRC), the pooled annual incidence of CRC was 0.8% (95% confidence interval [CI], 0.4–1.3); the pooled annual incidence of advanced neoplasia was 1.8% (95% CI, 0.9–2.7). Risk of CRC was higher when LGD was diagnosed by expert gastrointestinal pathologist (1.5%) than by community pathologists (0.2%). Factors significantly associated with dysplasia progression were concomitant primary sclerosing cholangitis (odds ratio [OR], 3.4; 95% CI, 1.5–7.8), invisible dysplasia (vs visible dysplasia; OR, 1.9; 95% CI, 1.0–3.4), distal location (vs proximal location; OR, 2.0; 95% CI, 1.1–3.7), and multifocal dysplasia (vs unifocal dysplasia; OR, 3.5; 95% CI, 1.5–8.5). In 12 surgical cohort studies of 450 patients who underwent colectomy for UC‐LGD, 34 patients had synchronous CRC (pooled prevalence, 17%; 95% CI, 8–33). Conclusion In a systematic review of the literature, we found that among patients with UC‐LGD under surveillance, the annual incidence of progression to CRC was 0.8%; differences in rates of LGD diagnosis varied with pathologists’ level of expertise. Concomitant primary sclerosing cholangitis, invisible dysplasia, distal location, and multifocal LGD are high‐risk features associated with dysplasia progression.

Obesity in IBD: epidemiology, pathogenesis, disease course and treatment outcomes

Incidence of IBD is rising in parallel with overweight and obesity. Contrary to conventional belief, about 15–40% of patients with IBD are obese, which might contribute to the development of IBD. Findings from cross-sectional and retrospective cohort studies are conflicting on the effect of obesity on natural history and course of IBD. Most studies are limited by small sample size, low event rates, non-validated assessment of disease activity and lack robust longitudinal follow-up and have incomplete adjustment for confounding factors. The effect of obesity on the efficacy of IBD-related therapy remains to be studied, though data from other autoimmune diseases suggests that obesity results in suboptimal response to therapy, potentially by promoting rapid clearance of biologic agents leading to low trough concentrations. These data provide a rationale for using weight loss interventions as adjunctive therapy in patients with IBD who are obese. Obesity also makes colorectal surgery technically challenging and might increase the risk of perioperative complications. In this Review, we highlight the existing literature on the epidemiology of obesity in IBD, discuss its plausible role in disease pathogenesis and effect on disease course and treatment response, and identify high-priority areas of future research.