Basiliximab does not increase efficacy of corticosteroids in patients with steroid-refractory ulcerative colitis.

BACKGROUND & AIMS: Basiliximab is a chimeric monoclonal antibody that binds CD25 and thereby inhibits interleukin (IL)-2-mediated proliferation of lymphocytes. IL-2 might contribute to the resistance of T cells to corticosteroids. We investigated the efficacy and safety of basiliximab as a corticosteroid-sensitizing agent in patients with corticosteroid-refractory ulcerative colitis (UC). METHODS: We studied 149 patients with moderate to severe UC (Mayo score ≥6 and endoscopic subscore ≥2) despite treatment for at least 14 days with oral prednisone (40-50 mg/day). Subjects were randomly assigned to groups that were given 20 mg (n = 46) or 40 mg (n = 52) basiliximab or placebo (n = 51) at weeks 0, 2, and 4. All subjects received 30 mg/day prednisone through week 2; the dose was reduced by 5 mg each week to 20 mg/day, which was maintained until week 8. At week 8, we compared the rates of clinical remission (Mayo score ≤2, no subscore >1) for patients given basiliximab with the rate for patients given placebo. RESULTS: Twenty-eight percent of patients given placebo, 29% of those given the 40-mg dose of basiliximab, and 26% of those given the 20-mg dose of basiliximab achieved clinical remission (P = 1.00 vs placebo for each dose). Basiliximab was generally well tolerated. Six subjects who received basiliximab had serious adverse events (6.1%) compared with 2 who received placebo (3.9%; P = .72). In subjects given basiliximab, incomplete saturation of CD25 (<50%) on peripheral T cells was associated with the presence of anti-basiliximab antibodies (odds ratio, 21; 95% confidence interval, 2.4-184). CONCLUSIONS: Basiliximab does not increase the effect of corticosteroids in the induction of remission in outpatients with corticosteroid-resistant moderate to severe UC.

Can endoscopy be avoided in the assessment of ulcerative colitis in clinical trials?

BACKGROUND: There is no gold standard index in the measurement of ulcerative colitis (UC) disease activity in clinical trials. Mucosal healing has been described as an important clinical endpoint requiring endoscopic assessment, which is unpleasant for the patient and may hamper recruitment to trials. The aim of this study was to determine whether endoscopy is necessary in the assessment of UC disease activity and whether a noninvasive disease activity index (partial Mayo score) could be used to predict the Mayo score. METHODS: In all, 149 subjects with moderate to severe UC enrolled in a clinical trial were assessed using total and partial Mayo scores. Histologic assessment of biopsies was performed. A regression model was constructed to predict total Mayo score from the partial Mayo score and histology score from the Mayo score. A Bland-Altman test of agreement was performed. RESULTS: The partial Mayo score correlated closely with the total Mayo score at week 4 (rho = 0.97) and week 8 (rho = 0.98). The model to predict total from partial Mayo score showed excellent correlation (rho = 0.97) and good agreement with the total Mayo score at week 4 and the week 8 validation set (rho = 0.97) and accurately classified disease severity (kappa = 0.82). The model to predict histology score from the Mayo score correlated only moderately with the actual histology score at week 4 (rho = 0.59) and week 8 (rho = 0.36). CONCLUSIONS: The Mayo score can be accurately predicted from the partial Mayo score. A noninvasive index can replace the Mayo score in future clinical trials.

Clinical experience of methotrexate in Crohn's disease: response, safety and monitoring of treatment.

BACKGROUND: Methotrexate is an immunosuppressant used in the treatment of patients with Crohn's disease who are intolerant or refractory to azathioprine. AIM: To present clinical experience in terms of response, side effects and reason for cessation of methotrexate treatment as well as adherence to monitoring regimens. DESIGN: Retrospective review of case records of 37 patients taking methotrexate for Crohn's disease at the Bristol Royal Infirmary, a large UK teaching hospital. Thirty-five patients used oral methotrexate. RESULTS: Response rate to methotrexate was 78% at 3 months. Adverse events were uncommon and rarely dangerous. Monitoring of treatment did not adhere to British Society of Gastroenterology guidelines. CONCLUSION: Oral methotrexate is effective and safe in the treatment of Crohn's disease. This is in contrast to findings of previous series, which have mainly reported on intramuscular methotrexate use. Monitoring of treatment is currently inadequate and consensus should be sought for a pragmatic monitoring schedule to resolve this important governance issue.

The effects of cytokines on suppression of lymphocyte proliferation by dexamethasone.

Treatment failure occurs in up to 30% of patients treated with steroids for inflammatory diseases. The aim of this study was to explore the potential role of 21 cytokines in steroid-resistant inflammatory disease and to develop methods to restore steroid sensitivity through cytokine manipulation. The dexamethasone inhibition of lymphocyte proliferation assay correlates with the outcome of steroid therapy in ulcerative colitis (UC) and other inflammatory diseases. Using this assay, PBMC production of 21 cytokines, assayed by cytokine bead array, was correlated with percentage of suppression of proliferation by 10(-6) M dexamethasone (Imax) in 26 healthy volunteers. Effects of the addition of exogenous cytokines to induce steroid resistance in PBMCs from healthy volunteers and cytokine blockade to improve steroid sensitivity in PBMCs from patients with steroid-resistant UC were then explored. Production of IL-1alpha, IL-10, IL-17, IFN-gamma, G-CSF, GM-CSF, TNF-alpha, and IFN-inducible protein 10 (IP-10) correlated significantly with in vitro steroid sensitivity; however, only IL-2 and TNF-alpha reduced steroid sensitivity when added exogenously. Addition of IL-10 enhanced steroid suppression. Immunoneutralization or receptor blockade of IL-2, but not TNF-alpha, IFN-gamma, IL-4, IL-17, or IP-10 increased steroid sensitivity in cells from steroid-resistant UC patients. Neutralization of IL-10 reduced steroid sensitivity. Of the large panel of cytokines studied, IL-2 appears to have the greatest antagonistic effect on the antiproliferative effect of steroids. These data suggest that IL-2 inhibition in vivo may improve the response to steroids in steroid-resistant individuals.