David Laharie

Maintenance of remission among patients with Crohn's disease on antimetabolite therapy after infliximab therapy is stopped.

BACKGROUND & AIMS It is important to determine whether infliximab therapy can be safely interrupted in patients with Crohns disease who have undergone a period of prolonged remission. We assessed the risk of relapse after infliximab therapy was discontinued in patients on combined maintenance therapy with antimetabolites and identified factors associated with relapse. METHODS We performed a prospective study of 115 patients with Crohns disease who were treated for at least 1 year with scheduled infliximab and an antimetabolite and had been in corticosteroid-free remission for at least 6 months. Infliximab was stopped, and patients were followed up for at least 1 year. We associated demographic, clinical, and biologic factors with time to relapse using a Cox model. RESULTS After a median follow-up period of 28 months, 52 of the 115 patients experienced a relapse; the 1-year relapse rate was 43.9% ± 5.0%. Based on multivariable analysis, risk factors for relapse included male sex, the absence of surgical resection, leukocyte counts >6.0 × 10(9)/L, and levels of hemoglobin ≤145 g/L, C-reactive protein ≥5.0 mg/L, and fecal calprotectin ≥300 μg/g. Patients with no more than 2 of these risk factors (approximately 29% of the study population) had a 15% risk of relapse within 1 year. Re-treatment with infliximab was effective and well tolerated in 88% of patients who experienced a relapse. CONCLUSIONS Approximately 50% of patients with Crohns disease who were treated for at least 1 year with infliximab and an antimetabolite agent experienced a relapse within 1 year after discontinuation of infliximab. However, patients with a low risk of relapse can be identified using a combination of clinical and biologic markers.

Ineffectiveness of Lactobacillus johnsonii LA1 for prophylaxis of postoperative recurrence in Crohn's disease: a randomised, double blind, placebo controlled GETAID trial.

Background and aims: Early endoscopic recurrence is frequent after intestinal resection for Crohn’s disease. Bacteria are involved, and probiotics may modulate immune responses to the intestinal flora. Here we tested the probiotic strain Lactobacillus johnsonii LA1 in this setting. Patients and methods: This was a randomised, double blind, placebo controlled study. Patients were eligible if they had undergone surgical resection of <1 m, removing all macroscopic lesions within the past 21 days. Patients were randomised to receive two packets per day of lyophilised LA1 (2×109 cfu) or placebo for six months; no other treatment was allowed. The primary endpoint was endoscopic recurrence at six months, with grade >1 in Rutgeerts’ classification or an adapted classification for colonic lesions. Endoscopic score was the maximal grade of ileal and colonic lesions. Analyses were performed primarily on an intent to treat basis. Results: Ninety eight patients were enrolled (48 in the LA1 group). At six months, endoscopic recurrence was observed in 30/47 patients (64%) in the placebo group and in 21/43 (49%) in the LA1 group (p = 0.15). Per protocol analysis confirmed this result. Endoscopic score distribution did not differ significantly between the LA1 and placebo groups. There were four clinical recurrences in the LA1 group and three in the placebo group. Conclusion:L johnsonii LA1 (4×109 cfu/day) did not have a sufficient effect, if any, to prevent endoscopic recurrence of Crohn’s disease.

Ciclosporin versus infliximab in patients with severe ulcerative colitis refractory to intravenous steroids: a parallel, open-label randomised controlled trial

BACKGROUND Ciclosporin and infliximab are potential rescue treatments to avoid colectomy in patients with acute severe ulcerative colitis refractory to intravenous corticosteroids. We compared the efficacy and safety of these drugs for this indication. METHODS In this parallel, open-label, randomised controlled trial, patients were aged at least 18 years, had an acute severe flare of ulcerative colitis defined by a Lichtiger score greater than 10 points, and had been given an unsuccessful course of high-dose intravenous steroids. None of the patients had previously received ciclosporin or infliximab. Between June 1, 2007, and Aug 31, 2010, patients at 27 European centres were randomly assigned (via computer-derived permutation tables; 1:1) to receive either intravenous ciclosporin (2 mg/kg per day for 1 week, followed by oral drug until day 98) or infliximab (5 mg/kg on days 0, 14, and 42). In both groups, azathioprine was started at day 7 in patients with a clinical response. Neither patients nor investigators were masked to study treatment. The primary efficacy outcome was treatment failure defined by absence of a clinical response at day 7, a relapse between day 7 and day 98, absence of steroid-free remission at day 98, a severe adverse event leading to treatment interruption, colectomy, or death. Analysis was by intention to treat. This trial is registered with EudraCT (2006-005299-42) and ClinicalTrials.gov (NCT00542152). FINDINGS 115 patients were randomly assigned; 58 patients were allocated to receive ciclosporin and 57 to receive infliximab. Treatment failure occurred in 35 (60%) patients given ciclosporin and 31 (54%) given infliximab (absolute risk difference 6%; 95% CI -7 to 19; p=0·52). Nine (16%) patients in the ciclosporin group and 14 (25%) in the infliximab group had severe adverse events. INTERPRETATION Ciclosporin was not more effective than infliximab in patients with acute severe ulcerative colitis refractory to intravenous steroids. In clinical practice, treatment choice should be guided by physician and centre experience. FUNDING Association François Aupetit, Société Nationale Française de Gastroentérologie, and the International Organization for the study of Inflammatory Bowel Disease.

Early administration of azathioprine vs conventional management of Crohn's Disease: a randomized controlled trial.

BACKGROUND & AIMS Immunomodulator therapy is effective for patients with Crohns disease (CD) but has not been shown to affect disease progression, presumably because it is given too late after diagnosis. We compared the efficacy of early treatment (within 6 months after diagnosis) with azathioprine versus conventional management of patients at high risk for disabling disease. METHODS We performed an open-label trial of adults with a diagnosis of CD for less than 6 months who were at risk for disabling disease. From July 2005 to November 2010, patients at 24 French centers were randomly assigned to treatment with azathioprine (2.5 mg ∙ kg(-1) ∙ day(-1), n = 65) or conventional management (azathioprine only in cases of corticosteroid dependency, chronic active disease with frequent flares, poor response to corticosteroids, or development of severe perianal disease) (n = 67). The primary end point was the proportion of trimesters spent in corticosteroid-free and anti-tumor necrosis factor (TNF)-free remission during the first 3 years after inclusion. RESULTS During the 3-year follow-up period, 16 patients in the azathioprine group were switched to mercaptopurine or methotrexate therapy because of intolerance or poor efficacy. Forty-one patients in the conventional management group required immunosuppressant therapy (61%; median time to first prescription, 11 months). In the azathioprine group, a median 67% of trimesters were spent in remission (interquartile range, 11%-85%) compared with 56% in the conventional management group (interquartile range, 29%-73%) (P = .69). Among secondary outcomes, a higher cumulative proportion of patients in the azathioprine group were free of perianal surgery than in the conventional management group (96% ± 3% and 82% ± 6% at month 36, respectively; P = .036). The cumulative proportion of patients free of intestinal surgery and anti-TNF therapy did not differ between groups. CONCLUSIONS Based on results from a clinical trial, administration of azathioprine within 6 months of diagnosis of CD was no more effective than conventional management in increasing time of clinical remission. Clinicaltrials.gov, Number NCT00546546.

A multicenter experience with infliximab for ulcerative colitis: outcomes and predictors of response, optimization, colectomy, and hospitalization.

OBJECTIVES:The objective of this study was to evaluate short- and long-term outcomes of infliximab in ulcerative colitis (UC), including infliximab optimization, colectomy, and hospitalization.METHODS:This was a retrospective multicenter study. All adult patients who received at least one infliximab infusion for UC were included. Cumulative probabilities of event-free survival were estimated by the Kaplan–Meier method. Independent predictors were identified using binary logistic regression or Cox proportional-hazards regression, and results were expressed as odds ratios or hazard ratios (HRs), respectively.RESULTS:Between January 2000 and August 2009, 191 UC patients received infliximab therapy. Median follow-up per patient was 18 months (interquartile range=25–75th, 8–32 months). Primary non-response was noted in 42 patients (22.0%). “Hemoglobin at infliximab initiation ≤9.4 g/dl” (odds ratio=4.35; 95% confidence interval (CI)=1.81–10.42) was a positive predictor of non-response to infliximab. Infliximab optimization was required in 36 (45.0%) of 80 patients on scheduled infliximab therapy. The only predictor of infliximab optimization was “infliximab indication for acute severe colitis” (HR=2.75; 95% CI=1.23–6.12). Thirty-six patients (18.8%) underwent colectomy. Predictors of colectomy were: “no clinical response after infliximab induction” (HR=7.06; 95% CI=3.36–14.83), “C-reactive protein at infliximab initiation >10 mg/l” (HR=5.11; 95% CI=1.77–14.76), “infliximab indication for acute severe colitis” (HR=3.40; 95% CI=1.48–7.81), and “previous treatment with cyclosporine” (HR=2.53; 95% CI=1.22–5.28). Sixty-nine patients (36.1%) were hospitalized at least one time and UC-related hospitalizations rate was 29 per 100 patient-years (95% CI=24–35 per 100 patient-years). Predictors of first hospitalization were: “no clinical response after infliximab induction” (HR=3.87; 95% CI=2.29–6.53), “infliximab indication for acute severe colitis” (HR=3.13, 95% CI=1.65–5.94), “disease duration at infliximab initiation ≤50 months” (HR=2.14, 95% CI=1.25–3.66), “hemoglobin at infliximab initiation ≤11.8 g/dl” (HR=1.77; 95% CI=1.03–3.04), and “previous treatment with methotrexate” (HR=0.30; 95% CI=0.09–0.97).CONCLUSIONS:Primary non-response to infliximab was noted in one fifth of patients and increased by seven and four the risks of colectomy and hospitalization, respectively. Infliximab optimization, colectomy, and hospitalization were required in half, one fifth, and one third of patients, respectively. Infliximab indication for acute severe colitis increased by three the risks of infliximab optimization, colectomy, and UC-related hospitalization.

Severe Skin Lesions Cause Patients with Inflammatory Bowel Disease to Discontinue Anti-Tumor Necrosis Factor Therapy.

BACKGROUND & AIMS Psoriasiform and eczematiform lesions are associated with anti-tumor necrosis factor (TNF)-α therapies. We assessed clinical characteristics, risk factors, and outcomes of skin disease in patients with inflammatory bowel diseases that presented with psoriasiform and eczematiform lesions induced by anti-TNF-α agents. METHODS We studied 85 patients (69 with Crohns disease, 15 with ulcerative colitis, and 1 with indeterminate colitis; 62 women) with inflammatory skin lesions (62 psoriasiform and 23 eczematiform lesions). RESULTS Twenty-four patients had a history of inflammatory skin lesions and 15 had a familial history of inflammatory skin disease. Locations of eczematiform lesions varied whereas scalp and flexural varieties were mostly psoriasiform. Skin lesions emerged but inflammatory bowel disease was quiescent in 69 patients following treatment with any type of anti-TNF-α agent (60 with infliximab, 20 with adalimumab, and 5 with certolizumab). Topical therapy resulted in partial or total remission in 41 patients. Patients with psoriasiform lesions that were resistant to topical therapy and that changed anti-TNF-α therapies once or twice developed recurring lesions. Overall, uncontrolled skin lesions caused 29 patients to stop taking TNF-α inhibitors. CONCLUSIONS Inflammatory skin lesions following therapy with TNF-α inhibitors occurred most frequently among women and patients with a personal or familial history of inflammatory skin disease; lesions did not correlate with intestinal disease activity. Recurring and intense skin lesions caused 34% of patients in this study to discontinue use of anti-TNF-α agents.

The efficacy and safety of a third anti-TNF monoclonal antibody in Crohn’s disease after failure of two other anti-TNF antibodies

Background  Adalimumab (ADA) and certolizumab pegol (CZP) have demonstrated efficacy in Crohn’s disease (CD) patients previously treated with infliximab (IFX).

Impact of mucosal healing on long‐term outcomes in ulcerative colitis treated with infliximab: a multicenter experience

Mucosal healing can be achieved with infliximab (IFX).

Saccharomyces boulardii does not prevent relapse of Crohn's disease.

BACKGROUND & AIMS Saccharomyces boulardii is a probiotic yeast that has been shown to have beneficial effects on the intestinal epithelial barrier and digestive immune system. There is preliminary evidence that S boulardii could be used to treat patients with Crohns disease (CD). We performed a randomized, placebo-controlled trial to evaluate the effects of S boulardii in patients with CD who underwent remission during therapy with steroids or aminosalicylates. METHODS We performed a prospective study of 165 patients who achieved remission after treatment with steroids or salicylates; they were randomly assigned to groups given S boulardii (1 g/day) or placebo for 52 weeks. The primary end point was the percentage of patients in remission at week 52. Time to relapse, Crohns disease activity index scores, and changes in parameters of inflammation were secondary end points. RESULTS CD relapsed in 80 patients, 38 in the S boulardii group (47.5%) and 42 in the placebo group (53.2%, a nonsignificant difference). The median time to relapse did not differ significantly between patients given S boulardii (40.7 weeks) vs placebo (39.0 weeks). There were no significant differences between groups in mean Crohns disease activity index scores or erythrocyte sedimentation rates or in median levels of C-reactive protein. In a post hoc analysis, nonsmokers given S boulardii were less likely to experience a relapse of CD than nonsmokers given placebo, but this finding requires confirmation. CONCLUSIONS Although the probiotic yeast S boulardii is safe and well tolerated, it does not appear to have any beneficial effects for patients with CD in remission after steroid or salicylate therapies.

Risk of new or recurrent cancer under immunosuppressive therapy in patients with IBD and previous cancer

Objective To explore the risk of new or recurrent cancer among patients with IBD and previous cancer, exposed or not to immunosuppressants. Design Among the 17 047 patients of the CESAME prospective observational cohort who were enrolled from May 2004 to June 2005, and followed-up until December 2007, we identified 405 patients with cancer diagnosed previous to study entry. We calculated the rates of incident cancer in patients with or without previous cancer, and we assessed by survival analysis and nested case-control study the impact of immunosuppressants on the risk of incident new or recurrent cancer in patients with previous cancer. Results The rate of incident cancer was 21.1/1000 patient-years (PY) and 6.1/1000 PY in patients with and without previous cancer, respectively. The multivariate-adjusted HR of incident cancer between patients with and without previous cancer was 1.9 (95% CI 1.2 to 3.0, p=0.003). Among patients with previous cancer, the rates of new and recurrent cancers were, respectively, 13.2/1000 PY and 6.0/1000 PY in the 312 patients who were not taking immunosuppressant at the time of study entry, and 23.1/1000 PY and 3.9/1000 PY in the 93 patients treated with immunosuppressants at study entry. There was no significant association between the exposure to immunosuppressants and the risk of new or recurrent cancer. Conclusions Patients with IBD with a history of cancer are at increased risk of developing any (new or recurrent) cancer, with a predominant incidence of new cancers. Treatment with immunosuppressants has no overall major impact per se on this risk.