[The liver and methotrexate]. / Foie et méthotrexate.

Methotrexate is proposed for the treatment of inflammatory disorders such as rheumatoid arthritis, psoriasis and Crohn's disease. The liver toxicity of methotrexate has been investigated and prolonged treatment can induce liver fibrosis. Moreover, alcohol consumption, diabetes and obesity are associated with liver fibrosis in patients treated with this drug. Therefore, liver fibrosis associated with methotrexate could be due to associated factors instead of methotrexate itself. Recommendations to monitor and diagnose methotrexate induced liver damage vary depending on the disease. Frequent evaluation of liver fibrosis with liver biopsy is recommended during therapy, especially in patients treated for psoriasis. Noninvasive methods, such as the FibroScan, could be useful for the assessment of liver fibrosis associated with methotrexate and hence, need further evaluation.

Association Between Infliximab Trough Levels and the Occurrence of Paradoxical Manifestations in Patients with Inflammatory Bowel Disease: a Case-Control Study.

BACKGROUND AND AIM: Anti-tumour necrosis factor [TNF] agents have dramatically improved the prognosis of inflammatory bowel disease [IBD]. However, despite their good safety profile, use of these agents may lead to paradoxical manifestations involving skin or joints. Pathogenesis of such side effects is poorly understood and may involve anti-TNF pharmacokinetics. The aim of the present study was to look for an association between infliximab trough levels [ITL] and cutaneous [CPM] or rheumatological [RPM] paradoxical manifestations. METHODS: IBD patients receiving infliximab as maintenance therapy were included in a cross-sectional prospective monocentre study. At inclusion, patients had an ITL measurement [LISA-TRACKER®, Biomedical Diagnostics BMD] and were assessed for paradoxical manifestations: a CPM was defined by new onset or exacerbation of pre-existing psoriasis lesions during IFX therapy, and an RPM by new onset of severe poly-arthralgia during IFX therapy. RESULTS: Among the 121 patients included [69 female; median age: 38.9 years; 92 with Crohn's disease], 7% had CPM and 8% RPM. Median ITL values were 5.87 [range: 0.52-19.53] µg/ml in patients with CPM and 1.90 [0.00-13.5] µg/ml in those with RPM, as compared respectively with 5.12 [0.00-49.12] µg/ml in patients without CPM [p = 0.56] and 5.57 [0.00-49.12] µg/ml in those without RPM [p = 0.058]. No prognostic factor was associated with CPM. The single factor associated with RPM was elevated antinuclear antibodies. CONCLUSION: ITL were not elevated in IBD patients developing cutaneous or rheumatological paradoxical manifestations when receiving IFX as maintenance therapy. As suggested by the high level of antinuclear antibodies, RPM could be related to an induced autoimmune disorder.

Mucosal healing with methotrexate in Crohn's disease: a prospective comparative study with azathioprine and infliximab.

BACKGROUND: Mucosal healing has become a new therapeutic goal in Crohn's disease and can be achieved with azathioprine (AZA) or biologics. Methotrexate (MTX) is an effective drug for both the induction and maintenance of remission in Crohn's disease. However, mucosal healing with MTX has been poorly investigated. AIM: To assess the mucosal healing rate in patients with Crohn's disease with clinical response to MTX as compared with AZA or infliximab (IFX). METHODS: From October 2007 to May 2009, consecutive patients with Crohn's disease were prospectively enrolled into a single-centre study when they met the following criteria: previous identification of mucosal ulcerations with ileo-colonoscopy, clinical remission within at least 3 months with MTX, AZA or IFX monotherapy, usual indication for colonoscopy in Crohn's disease (dysplasia/cancer screening, suspected stenosis) excluding assessment for mucosal healing. Mucosal healing was defined as absence of mucosal ulceration in all segments. RESULTS: Fifty-one patients with Crohn's disease (38 female; median age: 42 years) were included: 18 receiving MTX, 18 AZA and 15 IFX. Mucosal healing was achieved in 2/18 (11%) with MTX, in 9/18 (50%) with AZA (P =0.011 vs. MTX) and in 9/15 (60%) with IFX (P=0.008 vs. MTX). CONCLUSION: In patients with Crohn's disease in sustained clinical remission, mucosal healing is less frequently achieved with MTX as compared with AZA or IFX.

Prediction of Crohn's disease relapse with faecal calprotectin in infliximab responders: a prospective study.

BACKGROUND: Faecal calprotectin is a reliable tool for predicting Crohn's disease (CD) relapse in patients with sustained remission. Prediction of relapse with faecal calprotectin has been less studied in patients with severe CD treated with anti-TNF. AIM: To identify an association between faecal calprotectin concentration and CD clinical relapse in patients achieving remission with infliximab (IFX). METHODS: From February 2007 to October 2008, consecutive patients with refractory luminal CD were prospectively included when they received three IFX infusions (5mg/kg at weeks 0, 2 and 6) followed by maintenance with an immunomodulator alone. Faecal calprotectin and C-reactive protein (CRP) were measured at entry and at week 14 (w14). RESULTS: Sixty-five patients (43W; median age: 30.4years) were included, and 50 (77%) were in clinical remission off steroids at w14; twenty-three of fifty (46%) experienced CD clinical relapse during the first year of follow-up. Median faecal calprotectin level at w14 was similar in patients with and without CD clinical relapse (200 and 150µg/g respectively). When considering two suggested faecal calprotectin cut-offs to predict CD relapse, sensitivities and specificities were 61% and 48% for 130µg/g, respectively, and 43% and 57% for 250µg/g. Neither faecal calprotectin nor CRP at baseline and at w14 could predict relapse even when CD location subgroup analysis was considered. CONCLUSION: In patients responding to an infliximab induction regimen, faecal calprotectin measurement at w14 cannot predict Crohn's disease clinical relapse at 1year.

The tolerance and efficacy of a postponed retreatment with infliximab in Crohn's disease primary responders.

BACKGROUND: In Crohn's disease (CD) patients naïve to immunomodulators primary responding to infliximab (IFX) induction, maintenance with scheduled IFX or with immunomodulators is possible. The benefit of additional IFX infusions after failure of maintenance with immunomodulators is not known. AIM: To assess the efficacy and factors associated with efficacy of postponed IFX retreatment. METHODS: All CD primary responders to an IFX induction regimen in maintenance with immunomodulators were retrospectively included when they received at least one additional IFX infusion after week 14. Efficacy was defined as clinical response at week 4 and absence of intolerance leading to discontinuation. RESULTS: Sixty-one patients were retreated with IFX with a 38-week median time from induction. Efficacy was achieved in 80% patients. Twelve patients had no clinical benefit: seven acute hypersensitivity reactions and five loss of response. By multivariate analysis, the only factor associated with no efficacy was a median time >50 weeks from induction to retreatment (odds ratio = 7.38; 95%CI: 1.38-39.59; P = 0.02). CONCLUSION: Postponed retreatment with IFX in CD primary responders should be administered within 50 weeks after induction, for better efficacy and tolerance.