Dig Dis Sci. 2015 Dec 15.
Pharmacokinetics of infliximab and reduction of treatment for inflammatory bowel diseases.
Williet N, Paul S, Peyrin-Biroulet L, et al.

Local or national policy, patients' preferences, safety and/or economic concerns, or reimbursement issues may dictate stopping drug in inflammatory bowel diseases (IBD) patients. Sustained deep remission is an important predictor of a better outcome after anti-tumor necrosis (TNF) factor therapy discontinuation, including infliximab (IFX) in IBD patients, but this is not sufficient to prevent future relapse in these patients. In IBD patients under combotherapy, trough level of infliximab (TRI) could be helpful to choose stopping one of the two drugs. In patients on IFX monotherapy, TRI could help to decide reduction of drug dosing, particularly in IBD patients with supratherapeutic trough levels. Incidental findings of undetectable TRI in patients with deep remission may identify a subset of patients who may be considered for IFX cessation. Controlled trials further assessing this issue are eagerly awaited. Pending these trials, clear international recommendations for discontinuing anti-TNF therapy are needed.

J Crohns Colitis. 2016 Jan 6.
Non-adherence to anti-TNF therapy is associated with illness perceptions and clinical outcomes in outpatients with inflammatory bowel disease: results from a prospective multicentre study.
Have MV, Oldenburg B, Kaptein AA, et al.

BACKGROUND AND AIMS: Non-adherence to anti-tumor necrosis factor (TNF) agents in patients with inflammatory bowel disease (IBD) is a serious problem. In this study, we assessed risk factors for non-adherence and examined the association between adherence to anti-TNF agents and loss of response (LOR).
METHODS: In this multicentre, 12-month observational study, outpatients with IBD were included. Demographic and clinical characteristics were recorded. Adherence was measured with the Modified Morisky Adherence Scale-8 (MMAS-8) and 12-month pharmacy refills (medication possession ratio, MPR). Risk factors included demographic and clinical characteristics, medication beliefs and illness perceptions. Cox regression analysis was performed to determine the association between MPR and LOR to anti-TNF, IBD-related surgery or hospitalization, dose intensification or discontinuation of anti-TNF.
RESULTS: In total, 128 patients were included (67 infliximab, 61 adalimumab), mean age 37 (±SD 14) years, 71 (56%) females. Median disease duration was 8 (IQR 4-14) years. Clinical disease activity was present in 41/128 (32%) patients, 36/127 (28%) patients had a MMAS-8 < 6 ("low adherence") and 25/99 (25%) patients had a MPR<80% (non-adherence). Risk factors for non-adherence included adalimumab use (OR 10.1, 95%CI 2.62-40.00), stronger emotional response (OR 1.16, 95%CI 1.02-1.31) and shorter timeline perception, i.e. short perceived illness duration (OR 0.60, 95%CI 0.38-0.96). Adherence is linearly and negatively (OR 0.14, 95%CI 0.03-0.63) associated with LOR.
CONCLUSION: Non-adherence to anti-TNF agents is strongly associated with LOR to anti-TNF agents, adalimumab use and illness perceptions. The latter may provide an important target for interventions aimed at improving adherence and health outcomes.

World J Gastroenterol. 2015 Dec 28;21(48):13566-73.
Fecal calprotectin correlated with endoscopic remission for Asian inflammatory bowel disease patients.
Lin WC, Wong JM, Tung CC, et al.

AIM: To evaluate the correlation between fecal calprotectin (fC), C-reactive protein (CRP), and endoscopic disease score in Asian inflammatory bowel disease (IBD) patients.
METHODS: Stool samples were collected and assessed for calprotectin levels by Quantum Blue Calprotectin High Range Rapid test. Crohn's disease endoscopic index of severity (CDEIS) and ulcerative colitis endoscopic index of severity (UCEIS) were used for endoscopic lesion scoring.
RESULTS: A total of 88 IBD patients [36 patients with Crohn's disease (CD) and 52 with ulcerative colitis (UC)] were enrolled. For CD patients, fC correlated with CDEIS (r = 0.465, P = 0.005) and CRP (r = 0.528, P = 0.001). fC levels in UC patients correlated with UCEIS (r = 0.696, P < 0.0001) and CRP (r = 0.529, P = 0.0005). Calprotectin could predict endoscopic remission (CDEIS < 6) with 50% sensitivity and 100% specificity (AUC: 0.74) in CD patients when using 918 μg/g as the cut-off. When using 191 μg/g as the cut-off in UC patients, calprotectin could be used for predicting endoscopic remission (UCEIS < 3) with 88% sensitivity and 75% specificity (AUC: 0.87).
CONCLUSION: fC correlated with both CDEIS and UCEIS. fC could be used as a predictor of endoscopic remission for Asian IBD patients.

2015 Dec 15;314(23):2524-34.
Autologous hematopoetic stem cell transplantation for refractory Crohn disease: a randomized clinical trial.
Hawkey CJ, Allez M, Clark MM, et al.

IMPORTANCE: Case reports and series suggest hematopoietic stem cell transplantation (HSCT) may benefit some patients with Crohn disease.
OBJECTIVE: To evaluate the effect of autologous HSCT on refractory Crohn disease.
DESIGN, SETTING, AND PARTICIPANTS: Parallel-group randomized clinical trial conducted in 11 European transplant units from July 2007 to September 2011, with follow-up through March 2013. Patients were aged 18 to 50 years with impaired quality of life from refractory Crohn disease not amenable to surgery despite treatment with 3 or more immunosuppressive or biologic agents and corticosteroids.
INTERVENTIONS: All patients underwent stem cell mobilization before 1:1 randomization to immunoablation and HSCT (n = 23) or control treatment (HSCT deferred for 1 year [n = 22]). All were given standard Crohn disease treatment as needed.
MAIN OUTCOMES AND MEASURES: Sustained disease remission at 1 year, a composite primary end point comprising clinical remission (Crohn Disease Activity Index (CDAI) < 150 [range, 0-600]), no use of corticosteroids or immunosuppressive or biologic drugs for at least the last 3 months, and no endoscopic or radiological evidence of active (erosive) disease anywhere in the gastrointestinal (GI) tract. Secondary outcomes were individual components of the primary composite outcome and other measures of disease activity, laboratory results, quality of life and functional status, and GI tract imaging.
RESULTS: Twenty-three patients underwent HSCT and 22 received standard Crohn disease treatment (controls). Sustained disease remission was achieved in 2 patients undergoing HSCT (8.7%) vs 1 control patient (4.5%) (absolute difference, 4.2% [95% CI, -14.2% to 22.6%]; P = .60). Fourteen patients undergoing HSCT (61%) vs 5 control patients (23%) had discontinued immunosuppressive or biologic agents or corticosteroids for at least 3 months (difference, 38.1% [95% CI, 9.3% to 59.3%]; P = .01). Ten vs 2 patients had a CDAI less than 150 (remission) at the final evaluation, 8 (34.8%) vs 2 (9.1%) for 3 or more months (difference, 25.7% [95% CI, 1.1% to 47.1%]; P = .052). Eight (34.8%) vs 2 (9.1%) patients were adjudicated free of active disease on endoscopy and radiology at final assessment (difference, 25.7% [95% CI, 1.1% to 47.1%]; P = .054). There were 76 serious adverse events in patients undergoing HSCT vs 38 in controls. One patient undergoing HSCT died.
CONCLUSIONS AND RELEVANCE: Among adult patients with refractory Crohn disease not amenable to surgery who had impaired quality of life, HSCT, compared with conventional therapy, did not result in a statistically significant improvement in sustained disease remission at 1 year and was associated with significant toxicity. These findings do not support the widespread use of HSCT for patients with refractory Crohn disease.

Clin Gastroenterol Hepatol. 2015 Dec 8.
Infliximab concentration thresholds during induction therapy are associated with short-term mucosal healing in patients with ulcerative colitis.
Papamichael K, Van Stappen T, Casteele NV, et al.

BACKGROUND & AIMS: Mucosal healing is an independent predictor of sustained clinical remission in patients with ulcerative colitis (UC) treated with infliximab. We investigated whether infliximab concentrations during induction therapy are associated with short-term mucosal healing (STMH) in patients with UC.
METHODS: We performed a retrospective, single-center analysis of data collected from a tertiary referral center, from 101 patients with UC who received scheduled induction therapy with infliximab at weeks 0, 2, and 6 and had an endoscopic evaluation at baseline and after induction therapy. STMH was defined as Mayo endoscopic sub-score ≤1, assessed at weeks 10-14, with baseline sub-score ≥2. In a prospective study, infliximab concentrations were evaluated in serum samples collected at weeks 0, 2, 6, and 14 of infliximab therapy, using an ELISA we developed.
RESULTS: Fifty-four patients (53.4%) achieved STMH. Patients with STMH had a higher median infliximab concentration at weeks 2, 6, and 14 than patients without STMH. A receiver operating characteristic (ROC) analysis identified infliximab concentration thresholds of 28.3 (area under the ROC curve [AUROC], 0.638), 15 (AUROC, 0.688), and 2.1 μg/ml (AUROC, 0.781) that associated with STMH at weeks 2, 6 and 14, respectively. Multiple logistic regression analysis identified infliximab concentration ≥15 at week 6 (P=.025; odds ratio, 4.6; 95% confidence interval, 1.2-17.1) and ≥2.1 μg/ml at week 14 (P=.004; odds ratio, 5.6; 95% confidence interval, 1.7-18) as independent factors associated with STMH.
CONCLUSIONS: In an analysis of data from real-life clinical practice, we associated infliximab concentrations during the induction therapy with STMH in patients with UC.

Aliment Pharmacol Ther. 2016 Feb;43(4):482-513.
Review article: the practical management of acute severe ulcerative colitis.
Seah D, De Cruz P.

BACKGROUND: Acute severe ulcerative colitis (ASUC) is a life-threatening condition for which optimal management strategies remain ill-defined. AIM: To review the evidence regarding the natural history, diagnosis, monitoring and treatment of ASUC to inform an evidence-based approach to management.
METHODS: Relevant articles addressing the management of ASUC were identified from a search of MEDLINE, the Cochrane Library and conference proceedings.
RESULTS: Of ASUC, 31-35% is steroid-refractory. Infliximab and ciclosporin salvage therapies have improved patient outcomes in randomised controlled trials. Short-term response rates (within 3 months) have ranged from 40% - 54% for ciclosporin and 46-83% for infliximab. Long-term clinical response rates (≥1 year) have ranged from 42%-50% for ciclosporin and 50-65% for infliximab. Short-term and long-term colectomy rates have been respectively: 26-47% and 36-58% for ciclosporin, and 0-50% and 35-50% for infliximab. Mortality rates for ciclosporin and infliximab-treated patients have been: 0-5% and 0-2%, respectively. At present, management challenges include the selection, timing and assessment of response to salvage therapy, utilisation of therapeutic drug monitoring and long-term maintenance of remission.
CONCLUSIONS: Optimal management of acute severe ulcerative colitis should be guided by risk stratification using predictive indices of corticosteroid response. Timely commencement and assessment of response to salvage therapy is critical to reducing morbidity and mortality. Emerging pharmacokinetic models and therapeutic drug monitoring may assist clinical decision-making and facilitate a shift towards individualised acute severe ulcerative colitis therapies.

J Crohns Colitis. 2016 Jan 7.
Systematic review and meta-analysis: placebo rates in induction and maintenance trials of ulcerative colitis.
Jairath V, Zou G, Parker CE, et al.

BACKGROUND AN AIM: Minimization of the placebo responses in randomized controlled trials (RCTs) is essential for efficient evaluation of new interventions. Placebo rates have been high in ulcerative colitis (UC) clinical trials and factors influencing this are poorly understood. We quantify placebo response and remission rates in UC RCTs and identify trial design factors influencing them.
METHODS: MEDLINE, EMBASE and the Cochrane Library were searched from inception through April 2014 for placebo controlled trials in adult patients with UC of a biological agent, corticosteroid, immunosuppressant or aminosalicylate. Data were independently doubly extracted. Quality was assessed using the Cochrane risk of bias tool.
RESULTS: Fifty-one trials (48 induction and 10 maintenance phases) were identified. Placebo response and remission rates were pooled according to random-effects models and mixed effects meta-regression models used to evaluate effects of study-level characteristics on these rates. Pooled estimates of placebo remission and response rates for induction trials were 10% (95% confidence interval [CI] 7%-13%) and 33% (95% CI 29%-37%) respectively. Corresponding values for maintenance trials were 19% (95% CI 11%-30%) and 22% (95% CI 17%-28%). Trials enrolling patients with more active disease confirmed by endoscopy (endoscopy subscore ≥2) were associated with lower placebo rates. Conversely, placebo rates increased with increasing trial duration and number of study visits.
CONCLUSIONS: Objective assessment of greater disease activity at trial entry by endoscopy lowered placebo rates, whereas increasing trial duration and more interactions with healthcare providers increased placebo rates. These findings have important implications for design and conduct of clinical trials.

J Crohns Colitis. 2016 Jan 13.
Systematic review and meta-analysis: serum infliximab levels during maintenance therapy and outcomes in inflammatory bowel disease.
Moore C, Corbett G, Moss AC.

BACKGROUND & AIMS: A number of observational studies have reported an association between serum levels of infliximab at various thresholds, and clinical outcomes in IBD. This association has not previously been systematically analyzed.
METHODS: Systematic review of studies that reported serum infliximab levels according to outcomes in IBD. Primary outcome was clinical remission, and secondary outcomes included endoscopic remission, CRP levels and colectomy. Meta-analysis of raw data was performed where appropriate. A quality assessment was also undertaken.
RESULTS: Twenty two studies met the inclusion criteria, including 3483 patients. Twelve studies reported IFX levels in a manner suitable for determining effect estimates. During maintenance therapy, patients in clinical remission had significantly higher mean trough IFX levels than patients not in remission; 3.1 μg/ml versus 0.9 μg/ml. The standardized mean difference in serum IFX levels between groups was 0.6 μg/ml (95% CI 0.4-0.9, p=0.0002). Patients with an IFX level > 2 μg/ml were more likely to be in clinical remission (RR 2.9, 95% CI 1.8-4.7, p<0.001), or achieve endoscopic remission (RR 3, 95% CI 1.4 -6.5, p=0.004) than patients with levels < 2 μg/ml.
CONCLUSIONS: There is a significant difference between serum infliximab levels in patients with IBD in remission, compared to those who relapse. A trough threshold during maintenance >2 μg/ml is associated with a greater probability of clinical remission and mucosal healing.

Curr Gastroenterol Rep. 2016 Jan;18(1):5.
Understanding endoscopic disease activity in IBD: how to incorporate it into practice.
Christensen B, Rubin DT.

Endoscopic assessment of disease activity is an essential part of clinical practice in inflammatory bowel disease (IBD) and is used for diagnosis, prognosis, monitoring for dysplasia and increasingly for the evaluation of mucosal or endoscopic response to therapy. Recently, mucosal or endoscopic healing has emerged as a key goal of therapy as it has been found that patients who achieve endoscopic remission have improved outcomes compared to those who do not, and this may be independent of their clinical disease activity. However, there is currently no validated definition of mucosal healing and there are numerous endoscopic scoring systems proposed to define endoscopic activity and response to therapy in both ulcerative colitis and Crohn's disease. This article will discuss the most common endoscopic scores used to measure endoscopic disease activity in IBD, the pros and cons of each of these scoring systems and proposed definitions for endoscopic response or remission that exist for each. In addition, the role of endoscopy in prognosticating the disease course is discussed and how endoscopy can be utilized as part of a "treat-to-target" treatment strategy where endoscopy results direct decisions regarding medical strategies in clinical practice is highlighted.

Expert Rev Gastroenterol Hepatol. 2016 Jan 14.
Emerging therapeutic targets and strategies in Crohn's disease.
Furfaro F, Fiorino G, Allocca M, et al.

Crohn's disease (CD) is an immune-mediated inflammatory bowel disease, in which inflammation is driven by a complex interaction between the microbiota, immune cells, genes and mediators. New mechanisms of action and several cytokines have been identified as factors involved in the inflammatory process in CD, and many new molecules have been developed to treat this complex disease. New agents have been developed that target leukocyte trafficking, block or adhesion molecules for example, as well as the development of antibodies against classic inflammatory cytokines or therapies directed against IL-12/23 and Janus kinases. The development of selective mechanisms of action and targeting of different cytokines or inflammatory mediators for each patient presents the biggest challenge for the future in CD therapy. Such agents are currently at different phases of development. We aim to review the current literature data on a targeted approach in CD, which could be promising alternative approach for CD patients in the near future.

Aliment Pharmacol Ther. 2016 Jan 13.
Tacrolimus vs. anti-tumour necrosis factor agents for moderately to severely active ulcerative colitis: a retrospective observational study.
Yamamoto T, Shimoyama T, Umegae S, et al.

BACKGROUND: There have been no comparative studies of tacrolimus vs. anti-tumour necrosis factor (anti-TNF) agents to determine which treatment is safer or more effective in refractory ulcerative colitis (UC). AIM: To compare short-term safety and efficacy of tacrolimus vs. anti-TNF agents for active UC. METHODS: One hundred patients with moderate-to-severe active UC were studied. Fifty patients were treated with oral tacrolimus (TAC group). The other 50 patients were treated with anti-TNF agents (anti-TNF group): 40 with infliximab and 10 with adalimumab. Primary endpoints were clinical response and remission rates, colectomy rate, and the incidence of adverse events during 12 weeks. RESULTS: The incidence of adverse events was 12% in the TAC vs. 18% in the anti-TNF groups (P = 0.58). At week 12, clinical remission rate was 40% in the TAC vs. 28% in the anti-TNF groups (P = 0.29). Clinical response (including remission) rate was 62% in the TAC vs. 64% in the anti-TNF groups (P > 0.99). Five patients (10%) in the TAC and 8 (16%) in the anti-TNF groups required colectomy (P = 0.55). In a subgroup analysis restricted to severely active UC, the response rate was 50% in the TAC vs. 25% in the anti-TNF groups (P = 0.24). In severely active UC, the response rate tended to be higher in patients treated with tacrolimus, albeit not statistically significant. CONCLUSIONS: Both tacrolimus and anti-TNF agents appeared to be safe and effective in the management of moderate-to-severe active UC. However, randomised controlled trials are warranted to confirm the results obtained in this study.

J Crohns Colitis. 2016 Jan 11.
Anti-tumour necrosis factor α therapies and inflammatory bowel disease pregnancy outcomes: a meta-analysis.
Shihab Z, Yeomans ND, De Cruz P.

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) commonly affects women during their reproductive years, leading to concerns regarding pregnancy outcomes and therapeutic safety. The aim of this study was to assess the risks associated with anti-tumour necrosis factor α (anti-TNFα) therapy for pregnancy outcomes, including rates of congenital abnormality, based on published studies.
METHODS: Published studies were screened from on-line databases and international meeting abstracts. A meta-analysis was performed for adverse pregnancy outcomes (APOs), congenital abnormalities (CAs), preterm birth (PTB) and low birth weight (LBW). The prevalence of CAs was compared with whole-population pooled registry data.
RESULTS: In women exposed to anti-TNFα the pooled odds ratio for APOs was 1.14 (95% confidence interval [CI] 0.73-1.78; p = 0.55) compared with disease-matched controls. The pooled odds ratios for CAs, PTB and LBW were 0.89 (0.37-2.13; p = 0.79), 1.21 (0.74-2.00; p = 0.45) and 1.36 (0.77-2.38; p = 0.29) respectively. The rate of CAs in TNFα-exposed women was not statistically different from that in population-wide registries (difference 0.4%, 95% CI -2.0 to +2.7).
CONCLUSIONS: Anti-TNFα therapy does not increase the risk of APOs, CAs, PTB or LBW compared with disease-matched controls. Furthermore, the risk of CAs is not increased when published prevalence data are compared with data for the general population. These findings may offer some reassurance for women and physicians regarding the safety profile of anti-TNFα during pregnancy in IBD.