Brian W. Behm

Tumor necrosis factor‐alpha antibody for maintenance of remission in Crohn's disease

BACKGROUNDnCrohns disease may be refractory to conventional treatments including corticosteroids and immunosuppressives. Recent studies suggest TNF-alpha blocking agents may be effective in maintaining remission in Crohns disease.nnnOBJECTIVESnTo conduct a systematic review of the evidence for the effectiveness of TNF-alpha blocking agents in the maintenance of remission in patients with Crohns disease.nnnSEARCH STRATEGYnMEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials and the IBD/FBD Review Group Specialized Trials Register were searched for relevant studies published between 1966-2007. Manual searches of references from potentially relevant papers were performed to identify additional studies. Experts in the field and study authors were contacted to identify unpublished data.nnnSELECTION CRITERIAnRandomized controlled trials involving patients > 18 years with Crohns disease who had a clinical response or clinical remission with a TNF-alpha blocking agent, or patients with Crohns disease in remission but unable to wean corticosteroids, who were then randomized to maintenance of remission with a TNF-alpha blocking agent or placebonnnDATA COLLECTION AND ANALYSISnTwo independent authors performed data extraction and assessment of the methodological quality of each trial. Outcome measures reported in the primary studies included clinical remission, clinical response, and steroid-sparing effects.nnnMAIN RESULTSnNine studies met all inclusion criteria. Four different anti-TNF-alpha agents were evaluated (infliximab in 3 studies, CDP571 in 3 studies, adalimumab in 2 studies, and certolizumab in 1 study). There is evidence from three randomized controlled trials that infliximab maintains clinical remission (RR 2.50; 95% CI 1.64 to 3.80), maintains clinical response (RR 1.66; 95% CI 1.00 to 2.76), has corticosteroid-sparing effects (RR 3.13; 95% CI 1.25 to 7.81), and maintains fistula healing (RR 1.87; 95% CI 1.15 to 3.04) in patients with Crohns disease with a response to infliximab induction therapy. There were no significant differences in remission rates between infliximab doses of 5 mg/kg or 10 mg/kg. There is evidence from two randomized controlled trials that adalimumab maintains clinical remission (RR 2.86; 95% CI 2.01 to 4.02), maintains clinical response (RR 2.69; 95% CI 1.88 to 3.86), and has corticosteroid-sparing effects (RR 2.81, 95% CI 1.46 to 5.43) in patients with Crohns disease who have responded or entered remission with adalimumab induction therapy. There were no significant differences in remission rates between adalimumab 40 mg weekly or every other week. There is evidence from one randomized controlled trial that certolizumab pegol maintains clinical remission (RR 1.68; 95% CI 1.30 to 2.16) and maintains clinical response (RR 1.74; 95% CI 1.41 to 2.13) in patients who have responded to certolizumab induction therapy. There is no evidence to support the use of CDP571 for the maintenance of remission in Crohns disease.nnnAUTHORS CONCLUSIONSnInfliximab 5 mg/kg or 10 mg/kg, given every 8 weeks, is effective for the maintenance of remission and maintenance of fistula healing in patients who have responded to infliximab induction therapy. Adalimumab 40 mg weekly or every other week is effective for the maintenance of remission in patients who have responded to adalimumab induction therapy. Certolizumab pegol 400 mg every 4 weeks is effective for the maintenance of remission in patients who have responded to certolizumab induction therapy. No comparative trials have evaluated the relative efficacy of these agents. Adverse events are similar in the infliximab, adalimumab, and certolizumab groups compared with placebo, but study size and duration generally are insufficient to allow an adequate assessment of serious adverse events associated with long-term use.

Vedolizumab for induction and maintenance of remission in ulcerative colitis

BACKGROUNDnCellular adhesion molecules play an important role in the pathogenesis of ulcerative colitis, making selective blockade of these molecules a promising therapeutic strategy. Vedolizumab, a recombinant humanized IgG1 monoclonal antibody, inhibits adhesion and migration of leukocytes into the gastrointestinal tract by binding the alpha4beta7 integrin. Animal studies have suggested that vedolizumab may be a useful therapy for ulcerative colitis. This updated systematic review summarizes the current evidence on the use of vedolizumab for induction and maintenance of remission in ulcerative colitis.nnnOBJECTIVESnThe primary objectives were to determine the efficacy and safety of vedolizumab used for induction and maintenance of remission in ulcerative colitis.nnnSEARCH METHODSnA computer-assisted search for relevant studies (inception to 15 June 2014) was performed using PubMed, MEDLINE, EMBASE and CENTRAL. References from published articles and conference proceedings were searched to identify additional citations.nnnSELECTION CRITERIAnRandomized controlled trials comparing vedolizumab to placebo or a control therapy for induction or maintenance of remission in ulcerative colitis were included.nnnDATA COLLECTION AND ANALYSISnTwo authors independently extracted data and assessed the risk of bias for each trial. The primary outcomes were failure to induce clinical remission and relapse. Secondary outcomes included failure to induce a clinical response, failure to induce endoscopic remission, failure to induce an endoscopic response, quality of life, adverse events, serious adverse events and withdrawal due to adverse events. We calculated the relative risk (RR) and 95% confidence intervals (CI) for each outcome. Data were analyzed on an intention-to-treat basis. The overall quality of the evidence supporting the outcomes was evaluated using the GRADE criteria.nnnMAIN RESULTSnFour studies (606 patients) were included. All of the studies were rated as having a low risk of bias. Pooled analyses revealed that vedolizumab was significantly superior to placebo for induction of remission, clinical response, and endoscopic remission and prevention of relapse. After 4 to 6 weeks of therapy 77% (293/382) of vedolizumab patients failed to enter clinical remission compared to 92% (205/224) of placebo patients (RR 0.86, 95% CI 0.80 to 0.91; 4 studies 606 patients). After 6 weeks of therapy 48% of vedolizumab patients failed to have a clinical response compared to 72% of placebo patients (RR 0.68, 95% CI 0.59 to 0.78; 3 studies 601 patients). After 4 to 6 weeks of therapy 68% of vedolizumab patients failed to enter endoscopic remission compared to 81% of placebo patients (RR 0.82, 95% CI 0.75 to 0.91; 3 studies, b583 patients). After 52 weeks of therapy, 54% of vedolizumab patients had a clinical relapse compared to 84% of placebo patients (RR 0.67, 95% CI 0.59 to 0.77; 1 study, 373 patients). One small study (28 patients) found no statistically significant difference in endoscopic response (RR 1.00, 95% CI 0.62 to 1.61). GRADE analyses indicated that the overall quality of the evidence for the primary outcomes was high for induction of remission and moderate for relapse (due to sparse data 246 events). There was no statistically significant difference between vedolizumab and placebo in terms of the risk of any adverse event (RR 0.99, 95% CI 0.93 to 1.07), or serious adverse events (RR 1.01, 95% CI 0.72 to 1.42). There was a statistically significant difference in withdrawals due to adverse events. Six per cent of vedolizumab patients withdrew due to an adverse event compared to 11% of placebo patients (RR 0.55, 95% CI 0.35 to 0.87; 2 studies, 941 patients). Adverse events commonly reported across the studies included: worsening ulcerative colitis, headache, nasopharyngitis, upper respiratory tract infection, nausea, and abdominal pain.nnnAUTHORS CONCLUSIONSnModerate to high quality data from four studies shows that vedolizumab is superior to placebo for induction of clinical remission and response and endoscopic remission in patients with moderate to severely active ulcerative colitis and prevention of relapse in patients with quiescent ulcerative colitis. Moderate quality data from one study suggests that vedolizumab is superior to placebo for prevention of relapse in patients with quiescent ulcerative colitis. Adverse events appear to be similar to placebo. Future trials are needed to define the optimal dose, frequency of administration and long-term efficacy and safety of vedolizumab used for induction and maintenance therapy of ulcerative colitis. Vedolizumab should be compared to other currently approved therapies for ulcerative colitis in these trials.

Vedolizumab for induction and maintenance of remission in ulcerative colitis: a Cochrane systematic review and meta-analysis.

Background:We performed a systematic review to evaluate the efficacy and safety of vedolizumab for induction and maintenance of remission in ulcerative colitis. Methods:A literature search to June 2014 identified all applicable randomized trials. Outcome measures were clinical and endoscopic remission, clinical and endoscopic response, quality of life, and adverse events. The risk ratio (RR) and 95% confidence intervals (CI) were estimated for each outcome. Study quality was evaluated using the Cochrane risk of bias tool. The GRADE criteria were used to assess the quality of the evidence. Main Results:Four studies (606 patients) were included. The risk of bias was low. Pooled analyses indicated that vedolizumab was significantly superior to placebo for induction of remission (RR = 0.86, 95% CI, 0.80–0.91), clinical response (RR = 0.82, 95% CI, 0.75–0.91), endoscopic remission (RR = 0.82, 95% CI, 0.75–0.91), and for achieving remission at 52 weeks in week 6 responders (RR = 2.73, 95% CI, 1.78–4.18). GRADE analyses suggested that the overall quality of the evidence was high for induction of remission and moderate for maintenance therapy (due to sparse data consisting of 246 events). No statistically significant difference was observed in the incidence of adverse events between vedolizumab and placebo. Conclusions:Vedolizumab is superior to placebo as induction and maintenance therapy for ulcerative colitis. Future studies are needed to define long-term efficacy and safety of this agent.

Humanized antibody to the alpha4beta7 integrin for induction of remission in ulcerative colitis.

BACKGROUNDnCellular adhesion molecules play an important role in the pathogenesis of ulcerative colitis, making selective blockade of these molecules a promising therapeutic strategy. MLN-02, a recombinant humanized IgG1 monoclonal antibody, inhibits adhesion and migration of leukocytes into the gastrointestinal tract by binding the alpha4beta7 integrin. Animal studies have suggested that MLN-02 may be a useful therapy for ulcerative colitis. This systematic review summarizes the current evidence on the use of MLN-02 for induction of remission in ulcerative colitis.nnnOBJECTIVESnTo determine the efficacy and safety of MLN-02 for induction of remission in ulcerative colitis.nnnSEARCH STRATEGYnA computer-assisted search of MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and the Cochrane Inflammatory Bowel Disease Specialized Trial Register was performed to identify relevant publications. References from recent reviews and published articles were searched to identify additional citations. Manual searches to identify key conference abstracts were performed. Unpublished data from on-going trials were identified by correspondence with authors and experts in the field and from the manufacturer of MLN-02.nnnSELECTION CRITERIAnRandomized controlled trials comparing MLN-02 to placebo or a control therapy for the induction of remission in ulcerative colitis were included.nnnDATA COLLECTION AND ANALYSISnTwo independent reviewers performed data extraction and assessment of the methodological quality of each trial. Data were analyzed using Review Manager (RevMan 4.2).nnnMAIN RESULTSnOne study satisfied the inclusion criteria for this review. In this study, MLN-02 was found to be effective for induction of clinical response (RR = 1.78, 95% CI 1.22 to 2.60) and remission (RR = 2.25, 95% CI 1.17 to 4.36) in patients with moderately severe ulcerative colitis. Patients receiving MLN-02 had higher IBDQ scores than patients receiving placebo. There was a trend toward increased endoscopic remission with MLN-02 relative to placebo, although this difference was not statistically significant (total MLN-02 20% versus placebo 8%; P = 0.05; RR = 2.46, 95% CI 0.98 to 6.15). Adverse events occurred in a similar proportion of patients treated with MLN-02 compared to placebo (RR = 1.60, 95% CI 0.67 to 3.83). Neutralizing antibodies were found in a significant proportion of patients receiving MLN-02, and in the group of patients with high antibody titers clinical remission rates were no different than placebo. No opportunistic infections were reported.nnnAUTHORS CONCLUSIONSnData from one trial suggests that MLN-02 may be effective for induction of clinical response and remission in patients with moderately severe ulcerative colitis. Adverse events appear to be similar to placebo, although immunogenicity may be an issue. Further trials are needed to confirm the results of this study and to define the optimal dose and frequency of administration of MLN-02.

Dexlansoprazole MR for the management of gastroesophageal reflux disease

Dexlansoprazole modified release (MR; Dexilant™), the R-enantiomer of lansoprazole, was approved in the USA in 2009 for the management of erosive esophagitis and nonerosive reflux disease. Dexlansoprazole MR has a unique dual delayed-release delivery system that was designed to address unmet needs that may accompany the use of single-release proton pump inhibitors (PPIs), specifically, their short plasma half-life and requirement for meal-associated dosing. The delivery technology of dexlansoprazole MR is designed to release the drug in two separate pH-dependent phases, the first in the proximal duodenum and the second in the more distal small intestine. This extends plasma concentration and pharmacodynamic effects of dexlansoprazole MR beyond those of single-release PPIs and allows for dosing at any time of the day without regard to meals. This added convenience, along with excellent healing of esophagitis and symptom relief, substantiate its use in patients with gastroesophageal reflux disease requiring PPI treatment.

Narcotic Use and Misuse in Crohn's Disease

Background:The rate of narcotic misuse in the inflammatory bowel disease population is not well studied. The primary aim of this study was to determine in Crohns disease (CD) whether a concurrent functional gastrointestinal disorder (FGID) was associated with increased rates of chronic narcotic use. Second, we aimed to identify potential risk factors for narcotic misuse. Methods:A retrospective chart review of patients with CD followed at the University of Virginias Gastroenterology Clinic from 2006 to 2011 was performed. The prescription monitoring program was accessed to confirm narcotic prescription filling histories. Narcotic misuse was defined as narcotic prescriptions filled from 4 or more prescribers and at 4 or more different pharmacies. Results:Nine hundred thirty-one patients with CD were included in the study cohort. Eighty-seven (9.3%) patients were identified as having a concurrent FGID, and 192 (20%) were taking chronic narcotics. Patients with FGID were more likely to be taking chronic narcotics (44% versus 18%, P < 0.001). Thirty-seven percent (32/87) of patients with an FGID were misusing narcotics, compared with 9.6% (81/844) (P < 0.0001). Multivariate logistic regression demonstrated a significant association of misuse in patients with a concurrent FGID (odds ratio = 3.33, 95% confidence interval, 1.87–5.93). Conclusions:Twenty percent of patients with CD were using chronic narcotics with higher rates in those with FGID. Using the prescription monitoring program, a significant proportion of patients with CD with an FGID were misusing narcotics. We would recommend screening for narcotic misuse in patients with CD with a concomitant FGID and consider using prescription monitoring programs to identify others at risk for misuse.

Nonadherence to Biologic Therapies in Inflammatory Bowel Disease

BackgroundnNonadherence to medications is common with patients with inflammatory bowel disease (IBD). The aim of this study was to assess adherence to biologic medications prescribed for IBD and to identify risk factors for biologic nonadherence.nnnMethodsnThis was a single center retrospective cohort study investigating IBD patient adherence to biologic therapies over a 2-year period from September 2014 to September 2016. Specialty pharmacy and infusion center records were obtained and a modified medication possession ratio was calculated. Patient characteristics associated with nonadherence in a univariate model were placed into a multivariate logistic regression to assess independent predictors of nonadherence.nnnResultsnThree hundred sixty-five patients met inclusion criteria; 63 patients were on vedolizumab. Three hundred and one patients (82%) had Crohns disease. The pooled 24-month adherence rate was 66%; adherence to individual biologic therapy included vedolizumab 83%, infliximab 70%, adalimumab 57%, and certolizumab pegol 50%. Facility-administered biologics were independently associated with higher adherence than self-administered biologics (OR 2.39, 95% CI 1.50 - 3.80). Additional risk factors for nonadherence included younger age (OR 1.22, 95% CI 1.01-1.47) and noncommercial insurance (OR 1.78, 95% CI 1.01 - 3.13).nnnConclusionsnThis is the first study to assess adherence to vedolizumab in IBD patients, which was higher than 3 other commonly prescribed biologic medications. Self-administered injections were strongly associated with biologic nonadherence. Younger age and noncommercial insurance also were associated with biologic nonadherence. Modality of administration should be taken into account when selecting a biologic agent for treatment of IBD.

Medical management of Crohn's disease: current therapy and recent advances

Crohns disease is a chronic inflammatory disease involving the gastrointestinal tract and affects millions of people worldwide. Despite significant advances in the medical management of Crohns disease over the past decade, there is no consensus on what constitutes optimal medical treatment. For many years, corticosteroids and sulfasalazine were the mainstay of therapy. More recently, immunomodulators such as azathioprine and methotrexate have been used in both the induction and maintenance of remission. The 1998 introduction of infliximab, a biologic agent active against tumor necrosis factor-α, has also led to considerable advances in the management of Crohns disease. In addition, data from randomized controlled trials involving the immunomodulators azathioprine, 6-mercaptopurine and methotrexate have been accumulated, advancing our knowledge on how to best to use these agents for the induction and maintenance of remission in patients with Crohns disease. This advancement of knowledge has allowed clinicians to use a more rational, evidence-based approach to the management of Crohns disease.

Treatment of type-1 hepatorenal syndrome with pentoxifylline: A randomized placebo controlled clinical trial

INTRODUCTIONnType-1 hepatorenal syndrome (HRS-1) portends a poor prognosis in patients with cirrhosis. Currently available medical therapies are largely ineffective, save for liver transplantation. We aimed to determine if pentoxifylline (PTX) therapy in addition to the standard of care of volume expansion with albumin and vasoconstriction with midodrine and octreotide (AMO) is safe and efficacious compared to AMO in HRS-1 treatment.nnnMATERIAL AND METHODSnHospitalized subjects with decompensated cirrhosis and HRS-1 were enrolled. PTX or placebo was administered with AMO therapy for up to 14 days. The primary endpoint was HRS-1 resolution (serum creatinine ≤ 1.5 g/dL for > 24 h). Secondary endpoints were change in creatinine and MELD score, partial treatment response, 30-and 180-day overall and transplant free survival.nnnRESULTSnTwelve subjects with mean age 58.9 ± 6.2 years were enrolled and randomized. Mean MELD score was 26.5 ± 7.4 and 58.3% were male. Overall cohort 30- and 180-day survival was 58.3% and 33.3% respectively. Two subjects underwent liver transplantation. HRS-1 resolution (16.7% vs. 16.7%, p = 1.000), partial treatment response (33.3% vs. 16.7%, p = 0.505), change in creatinine (+0.48 g/dL, 95% CI -0.49-1.46 vs. +0.03 g/dL, 95% CI -0.64- 0.70, p = 0.427), 30-day survival (66.6% vs. 50.0%, p = 0.558) and 180-day survival (50.0% vs. 16.7%, p = 0.221) were similar between the two groups. Serious adverse events necessitating treatment discontinuation were rare (n = 1, PTX).nnnDISCUSSIONnThe addition of PTX to AMO in the treatment of HRS-1 is safe when compared to the current standard of care. Future large-scale prospective study to validate the efficacy of this treatment seems warranted.INTRODUCTIONnAdiponectin and resistin levels are increased in patients with cirrhosis, but it prognostic significance is unknown. We sought to investigate the factors associated with adiponectin and resistin levels and its clinical significance in patients with cirrhosis.nnnMATERIALS AND METHODSnThis was a prospective cohort study that included 122 subjects with cirrhosis who attended an outpatient clinic and were initially evaluated in 2012. Serum adiponectin and resistin levels were measured in samples collected in 2012 (adiponectin and resistin) and 2014 (adiponectin). Thirty healthy subjects served as a control group.nnnRESULTSnHigher adiponectin (21.59 μg/mL vs. 12.52 μg/mL, P < 0.001) and resistin levels (3.83 ng/mL vs. 2.66 ng/mL, P < 0.001) were observed among patients with cirrhosis compared to controls. Patients classified as Child-Pugh B/C had higher adiponectin levels in relation to ChildPugh A patients. At second measurement, adiponectin levels increased significantly in non-transplant patients and decreased in liver transplant recipients. Univariate Cox analysis showed that among patients with alcoholic liver disease, adiponectin levels were associated with lower transplant-free survival (HR = 1.034, 95% CI 1.006 - 1.062, P = 0.016). The transplant-free survival was significantly lower among patients with alcoholic liver disease and adiponectin ≥ 17 μg/mL (26.55 months, 95% CI 21.40-31.70) as compared to those with levels < 17 μg/mL (33.76 months, 95% CI 30.70-36.82) (P = 0.045). No relationship was found between the levels of resistin and survival.nnnCONCLUSIONnAdiponectin but not resistin levels were associated with intensity of liver dysfunction and worse prognosis in patients with alcoholic liver disease, suggesting a potential as a prognostic biomarker.

Chronic Cholestatic Liver Injury Attributable to Vedolizumab

Abstract Drug-induced liver injury is a rare but clinically important diagnosis. Vedolizumab is an α4β7 integrin inhibitor recently approved for use in patients with moderate-to-severe inflammatory bowel disease. Cases of hepatoxicity due to vedolizumab in the pre-marketing stage were rare, and all cases resolved upon drug withdrawal. We present here the first reported case of hepatotoxicity attributable to vedolizumab, which despite drug cessation persisted with chronic cholestatic liver injury.