Aliment Pharmacol Ther. 2015 Mar 1.
Randomised clinical trial: deep remission in biologic and immunomodulator naïve patients with Crohn's disease - a SONIC post hoc analysis.
Colombel JF, Reinisch W, Mantzaris GJ, et al.

BACKGROUND: As treatment goals in Crohn's disease (CD) evolve, targets now include clinical remission (CR), mucosal healing (MH) and biological remission [C-reactive protein normalisation (CRPnorm )]. AIMS: To evaluate the association of baseline factors and treatment with the achievement of different composite remission parameters at week 26.

METHODS: This post hoc analysis of the SONIC trial evaluated different composite remission measures at week 26 in a subgroup of patients with Crohn's disease activity index (CDAI) scores, CRP, and endoscopic data available at baseline and week 26 (N = 188). Assessed composite remission measures were: CR (CDAI < 150) and MH (absence of any mucosal ulcerations), previously referred to as 'deep remission;' and alternative composite endpoints: CR + CRPnorm (CRP < 0.8 mg/dL); CRPnorm + MH; and CR + CRPnorm + MH.

RESULTS: Among analysed patients, 136/188 (72.3%) achieved CR and 90/188 (47.9%) achieved MH at week 26. All composite outcomes were significantly greater (Bonferroni significance level, P ≤ 0.016) with combination therapy (i.e. infliximab and azathioprine; 52.3-63.6%) vs. azathioprine monotherapy (12.9-29.0%; p ≤ 0.005 for all comparisons). Composite remission rates including MH were significantly greater with combination therapy (52.3-56.9%) vs. infliximab (25.6-32.3%; P ≤ 0.015 for all comparisons except CRPnorm + MH, P = 0.017) and vs. azathioprine monotherapy (12.9-20.4%; P ≤ 0.002 for all comparisons). Median serum trough infliximab concentrations among patients who achieved MH or CR + MH were greater when compared with those among patients who did not achieve MH (P = 0.018) or CR + MH (P = 0.053). Among the subgroup of patients with early Crohn's disease, MH alone or in combination with composite remission criteria significantly improved clinical outcomes of patients who received combination therapy.

CONCLUSIONS: Combination therapy was more effective in achieving various composite remission measures vs. azathioprine or infliximab monotherapy. These data illustrate that 'deep remission' is achievable with combination therapy in a high percentage of patients with early Crohn's disease.

Gastroenterology. 2015 Feb 24. pii: S0016-5085(15)00253-X.
Trough Concentrations of Infliximab Guide Dosing for Patients with Inflammatory Bowel Disease.
Vande Casteele N, Ferrante M, Van Assche G, et al.

BACKGROUND & AIMS: Infliximab, a tumor necrosis factor antagonist, is effective for treating patients with Crohn's disease (CD) and ulcerative colitis (UC). We aimed to determine whether dosing based on therapeutic drug monitoring increases rate of remission and whether continued concentration-based dosing is superior to clinically based dosing of infliximab for maintaining remission in patients with CD and UC.

METHODS: We performed a 1 y, randomized, controlled trial at a tertiary referral center, including 263 adults (178 with CD and 85 with UC) with stable responses to maintenance infliximab therapy. Doses were escalated or reduced using an algorithm to reach a target trough concentration (TC) of 3-7 μg/mL in all patients (optimization phase). Patients were randomly assigned (1:1) to groups that received infliximab dosing based on their clinical features (n=123) or continued dosing based on TCs (n=128) (maintenance phase). The primary endpoint was clinical and biochemical remission at 1 y after the optimization phase. RESULTS: At screening, 115/263 patients had a TC of infliximab of 3-7 μg/mL (43.7%). Of 76 patients with TCs <3 g="" ml="" 69="" patients="" 91="" achieved="" tcs="" of="" 3-7="" after="" dose="" escalation="" this="" resulted="" in="" a="" higher="" proportion="" cd="" remission="" than="" before="" 88="" vs="" 65="" p="" and="" decrease="" the="" median="" concentration="" c-reactive="" protein="" compared="" to="" increase="" 3="" 2="" 4="" mg="" l="" 001="" these="" changes="" were="" not="" observed="" with="" uc="" 72="">7 μg/mL, 67 patients (93%) achieved TCs of 3-7 μg/mL after dose reduction. This resulted in a 28% reduction in drug cost than before dose reduction (P<.001). Sixty-six percent of patients whose dosing was based on clinical features and 69% whose dosing was based on TC achieved remission, the primary endpoint (P=.686). Disease relapsed in 21 patients who received clinically based dosing (17%) and 9 patients who received concentration-based dosing (7%) (P=.018).

CONCLUSIONS: Targeting patients' infliximab TCs to 3-7 μg/mL results in a more efficient use of the drug. After dose optimization, continued concentration-based dosing was not superior to clinically based dosing for achieving remission after 1 y, but was associated with fewer flares during the course of treatment. Dig Liver Dis. 2015 Feb 4. pii: S1590-8658(15)00179-6.

Dig Liver Dis. 2015 Feb 4. pii: S1590-8658(15)00179-6.
Managing pediatric acute severe ulcerative colitis according to the 2011 ECCO-ESPGHAN guidelines: Efficacy of infliximab as a rescue therapy.
Aloi M, D'Arcangelo G, Capponi M, et al.

BACKGROUND: The effectiveness of medical therapy in paediatric acute severe colitis is scarcely described. We aimed to assess the efficacy of infliximab in children prospectively enrolled at Sapienza University of Rome between May 2010 and 2012.

METHODS: Clinical assessment and laboratory data were recorded at admission and at day 3 and 5. All patients received corticosteroids; infliximab was administered in refractory patients. Colectomy rate was assessed at 2-year follow-up.

RESULTS: Thirty-one patients (mean age 10.6±4.9 years, 52% females) were included: 21 responded to corticosteroids (68%), 10 were refractory and received infliximab (32%). Among the latter, 2 required urgent colectomy (20%); 80% responded, however 50% of these required elective colectomy during follow-up. Patients refractory to corticosteroids showed a significantly shorter interval from ulcerative colitis diagnosis to acute severe colitis compared to responders (7.4±9.6 vs. 23.1±21.6 months, respectively; p=0.01), and a higher rate of colectomy at follow-up (50% vs. 14%, respectively; p=0.007). More than 2 courses of corticosteroids before acute severe colitis were predictive of surgical need (OR 4.4).

CONCLUSION: Despite its short-term efficacy, infliximab did not modify the long-term surgical rate of paediatric acute severe colitis in our cohort. Children with an early severe colitis commonly need a second-line therapy, whilst frequent courses of corticosteroids are predictive of a poor outcome. Inflamm Bowel Dis. 2015 Feb 26. [Epub ahead of print]

Inflamm Bowel Dis. 2015 Feb 26.
Benefits and risks of combining anti-tumor necrosis factor with immunomodulator therapy in pediatric inflammatory bowel disease.
Cozijnsen MA, Escher JC, Griffiths A, et al.

Since the introduction of anti-tumor necrosis factor (TNF) therapy as treatment of inflammatory bowel disease (IBD), care of pediatric and adult patients with IBD has significantly improved. To further improve treatment efficacy and durability, multiple trials have compared the efficacy of combination therapy, using anti-TNF therapy combined with an immunomodulator (a thiopurine or methotrexate), with that of anti-TNF monotherapy with contradicting results. The safety of combined therapy has been questioned after several reported cases of hepatosplenic T-cell lymphoma in young patients with IBD so treated. Physicians prescribing anti-TNF therapy to patients with IBD are required to weigh the benefits of combined therapy with its risks. To inform physicians treating children with IBD of these benefits and risks, we reviewed studies in pediatric and adult patients with IBD comparing efficacy, durability, and/or safety of combined therapy with anti-TNF monotherapy.

Clin Gastroenterology Hepatol. 2015 Feb 24.
Effectiveness and safety of immunomodulators with anti-TNF therapy in Crohn's disease.
Osterman MT, Haynes K, Delzell E, et al.

BACKGROUND & AIMS: The benefit of continuing immunomodulators when "stepping up" to anti-tumor necrosis factor (anti-TNF) therapy for Crohn's disease (CD) is uncertain. This study assessed the effectiveness and safety of immunomodulators with anti-TNF therapy in CD.

METHODS: We conducted a retrospective cohort study of new users of anti-TNF therapy for CD in Medicare. Users of anti-TNF combination therapy with immunomodulators were matched to up to 3 users of anti-TNF monotherapy via propensity score and compared using 3 metrics of effectiveness - surgery, hospitalization, and discontinuation of anti-TNF therapy or surgery - and 2 metrics of safety - serious infection and non-Candida opportunistic infection. Cox regression was used for all analyses.

RESULTS: Among new users of infliximab, we matched 381 users of combination therapy to 912 users of monotherapy; among new users of adalimumab, we matched 196 users of combination therapy to 505 users of monotherapy. Combination therapy occurred predominantly as "step up" after thiopurine therapy. The rates of surgery (hazard ratio [HR] 1.20, 95% CI 0.73-1.96), hospitalization (HR 0.82 [0.57-1.19]), discontinuation of anti-TNF therapy or surgery (HR 1.09, [0.88-1.34]), and serious infection (HR 0.93 [0.88-1.34]) did not differ between users of anti-TNF combination therapy and monotherapy. However, the risk of opportunistic infection (HR 2.64 [1.21-5.73]) and herpes zoster (HR 3.16 [1.25-7.97]) were increased with combination therapy.

CONCLUSIONS: We found that continuation of immunomodulators after "stepping up" to anti-TNF therapy did not improve outcomes but was associated with an increased risk of opportunistic infection.

J Gastroenterol Hepatol. 2015 Mar 25.
The Asia Pacific consensus statements on Crohn's disease part 1: definition, diagnosis and epidemiology.
Ooi CJ, Hilmi I, Makharia GK, et al.

Inflammatory bowel disease (IBD) was previously thought to be rare in Asia, but emerging data indicate rising incidence and prevalence of IBD in the region. The Asia Pacific Working Group on Inflammatory Bowel Disease was established in Cebu, Philippines, at the Asia Pacific Digestive Week conference in 2006 under the auspices of the Asian Pacific Association of Gastroenterology (APAGE) with the goal of developing best management practices, coordinating research and raising awareness of IBD in the region. The consensus group previously published recommendations for the diagnosis and management of ulcerative colitis (UC) with specific relevance to the Asia-Pacific region.1 The present consensus statements were developed following a similar process to address the epidemiology, diagnosis and management of Crohn's disease (CD). The goals of these statements are to pool the pertinent literature specifically highlighting relevant data and conditions in the Asia-Pacific region relating to the economy, health systems, background infectious diseases, differential diagnoses and treatment availability. It does not intend to be all-comprehensive and future revisions are likely to be required in this ever-changing field.
J Gastroenterol Hepatol. 2015 Mar 25.

Clin Gastroenterol Hepatol. 2015 Mar 9. pii: S1542-3565(15)00246-3.
Changes in the Lemann index values during the first years of Crohn's disease.
Gilletta C, Lewin M, Bourrier A, et al.

BACKGROUND & AIMS: Stricturing or penetrating lesions develop over time in most patients with Crohn's disease. The Lémann Index indicates the degree of digestive damage at a given time in 1 individual. We tracked changes in Lémann Index scores in an inception cohort of patients and looked for factors associated with digestive damage. METHODS: We studied 221 patients diagnosed with Crohn's disease from 2004 through 2011 who received 2 or 3 serial morphological evaluations over a period of 2-10 y. We collected cross-sectional images and had them reviewed by a gastroenterologist and a radiologist; Lémann index scores were calculated. A value of 2 was chosen as the cut-off for substantial transparietal damage. Factors associated with score >2 at last evaluation and progression of index scores were identified using univariate analysis and logistic regression analyses.

RESULTS: Median index Lémann Index scores were 2.3 (intra-quartile range [IQR], 1.2-3.9) at first evaluation, 3.5 (IQR, 1.2-8.6) 2-5 y after diagnosis, and 8.3 (IQR, 1.2-12.1) 5-10 y after diagnosis. Index scores increased significantly at each stage compared with initial or previous values (P<.0001). After 73 months (IQR, 51-96) of follow up, 138 patients had a Lémann Index score >2.0. The only early factor that predicted later damage was first index value. Intestinal resection, time, and percentage of time elapsed with a clinically active disease were associated with progressing damage.

CONCLUSIONS: Based on an analysis of patients with Crohn's disease using the Lémann Index, nearly two thirds have substantial mucosal damage 2-10 y after diagnosis. High Lémann index scores at first evaluation, time, persistent clinical activity, and intestinal resection are associated with damage.

Digestion. 2015 Mar 24;91(3):233-238.
Combination therapy with infliximab and thiopurine compared to infliximab monotherapy in maintaining remission of postoperative Crohn's disease.
Sakuraba A, Okamoto S, Matsuoka K, et al.

BACKGROUND AND AIMS: Infliximab is an efficacious agent used for the induction and maintenance of remission in Crohn's disease (CD), and recent studies suggested that it may also prevent the recurrence of this disease after surgery. The present study was performed to assess the efficacy and safety of infliximab in the postoperative setting, and to identify whether combination treatment with thiopurines had any additional beneficial effect as compared to mono-therapy.

METHODS: We performed a retrospective cohort study to compare the efficacy of infliximab mono-therapy and combination treatment with a thiopurine in preventing recurrence after surgery.

RESULTS: Forty-one patients who received infliximab as maintenance treatment following surgery from May 2002 to April 2010 were identified. Twenty-four were naive to infliximab, and 17 who underwent surgery during infliximab treatment were continued on it following surgery. The median follow-up period was 27 months (range 12-66 months). All patients continued infliximab as maintenance treatment, but 10 required dose intensification due to clinical recurrence. Kaplan-Meier analysis demonstrated that the use of concomitant thiopurine was correlated with the continuation of infliximab treatment at an 8-week interval (log-rank test p = 0.018). The rate of adverse event was 9.8% with no patient experiencing severe adverse reactions.

CONCLUSION: Infliximab appears to be safe and it prevented clinical recurrence after surgery. Concomitant thiopurine use predicted response toward continuation of therapy at an 8-week interval. Prospective controlled studies to assess the efficacy of combination treatment in the postoperative setting are warranted.

Gastroenterology. 2015 Feb;148(2):344-54.e5; quiz e14-5.
Comparative effectiveness of immunosuppressants and biologics for inducing and maintaining remission in Crohn's disease: a network meta-analysis.
Hazlewood GS, Rezaie A, Borman M, et al.

BACKGROUND & AIMS: There is controversy regarding the best treatment for patients with Crohn's disease because of the lack of direct comparative trials. We compared therapies for induction and maintenance of remission in patients with Crohn's disease, based on direct and indirect evidence.

METHODS: We performed systematic reviews of MEDLINE, EMBASE, and Cochrane Central databases, through June 2014. We identified randomized controlled trials (N = 39) comparing methotrexate, azathioprine/6-mercaptopurine, infliximab, adalimumab, certolizumab, vedolizumab, or combined therapies with placebo or an active agent for induction and maintenance of remission in adult patients with Crohn's disease. Pairwise treatment effects were estimated through a Bayesian random-effects network meta-analysis and reported as odds ratios (OR) with a 95% credible interval (CrI).

RESULTS: Infliximab, the combination of infliximab and azathioprine (infliximab + azathioprine), adalimumab, and vedolizumab were superior to placebo for induction of remission. In pair-wise comparisons of anti-tumor necrosis factor agents, infliximab + azathioprine (OR, 3.1; 95% CrI, 1.4-7.7) and adalimumab (OR, 2.1; 95% CrI, 1.0-4.6) were superior to certolizumab for induction of remission. All treatments were superior to placebo for maintaining remission, except for the combination of infliximab and methotrexate. Adalimumab, infliximab, and infliximab + azathioprine were superior to azathioprine/6-mercaptopurine: adalimumab (OR, 2.9; 95% CrI, 1.6-5.1), infliximab (OR, 1.6; 95% CrI, 1.0-2.5), infliximab + azathioprine (OR, 3.0; 95% CrI, 1.7-5.5) for maintenance of remission. Adalimumab and infliximab + azathioprine were superior to certolizumab: adalimumab (OR, 2.5; 95% CrI, 1.4-4.6) and infliximab + azathioprine (OR, 2.6; 95% CrI, 1.3-6.0). Adalimumab was superior to vedolizumab (OR, 2.4; 95% CrI, 1.2-4.6).

CONCLUSIONS: Based on a network meta-analysis, adalimumab and infliximab + azathioprine are the most effective therapies for induction and maintenance of remission of Crohn's disease

Gastroenterology. 2015 Mar 21. pii: S0016-5085(15)00381-9.
The Toronto consensus guidelines for nonhospitalized ulcerative colitis: a welcome update but not the end of the story.
Ananthakrishnan AN, Kane SV.
No abstract available.

Gastroenterology. 2015 Mar 4. pii: S0016-5085(15)00303-0.
Clinical practice guidelines for the medical management of nonhospitalized ulcerative colitis: the Toronto consensus.
Bressler B, Marshall JK, Bernstein CN, et al.

Dig Dis Sci. 2015 Mar 22. [Epub ahead of print]
Effect of immunosuppressive therapies for the treatment of inflammatory bowel disease on response to routine vaccinations: a meta-analysis.
Nguyen DL, Nguyen ET, Bechtold ML.

BACKGROUND: Several studies have evaluated the effect of immunosuppressive therapy for the treatment of inflammatory bowel disease (IBD) on response to routine vaccinations. The overall effect of specific classes of medications (i.e., immunomodulator vs. biologics) on vaccine response remains undefined. The aim of this study was to determine the effect of each class of immunosuppressive therapy in IBD patients on response to routine vaccinations.

METHODS: A comprehensive search of PubMed/MEDLINE, Scopus, CINAHL, and Cochrane databases was performed (December 2014). All studies on adults comparing vaccine response among IBD patients on immunosuppression with non-immunosuppressed patients were included. Meta-analysis was performed using the Mantel-Haenszel (fixed effects) model with odds ratio (OR) to assess for adequate vaccine response.

RESULTS: In the pooled analysis of nine studies (N = 1474), we found that there was nearly a 60 % lower chance of achieving adequate seroprotection in the group that received immunosuppressive therapy compared to the group that was not on any immunosuppressive therapies (OR 0.41 95 % CI 0.30, 0.55, p < 0.001). Specifically, we also demonstrated that patients on immunomodulator monotherapy had a twofold higher probability of achieving adequate immune response to vaccination, compared to patients on anti-tumor necrosis factor (anti-TNF) monotherapy (OR 1.92 95 % CI 1.30, 2.84).

CONCLUSION: In conclusion, IBD patients on immunosuppressive therapy have a significantly lower response to routine vaccinations. The greatest effect is seen among patients on anti-TNF and combination immunosuppressive therapy. Routine monitoring of vaccine titers post-vaccination is important to ensure that adequate immunologic response has been achieved among IBD patients.


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