Combining infliximab with methotrexate for the induction and maintenance of remission in refractory Crohn's disease: a controlled pilot study. Methotrexate in chronic active Crohn's disease: a double-blind, randomized, Israeli multicenter trial. Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Methotrexate in Crohn's disease: results of a randomized, double-blind, placebo-controlled trial. A comparison of methotrexate with placebo for the maintenance of remission in Crohn's disease. North American Crohn's Study Group Investigators. Methotrexate for the treatment of Crohn's disease. The North American Crohn's Study Group Investigators.
Immunosuppression of chronic active Crohn's disease resistant or intolerant to purine antimetabolites still remains a clinical challenge. To obtain long-lasting effects with the anti-TNF-alpha antibody infliximab repeated infusions are often required. Methotrexate has been shown to be a moderately effective drug in maintaining remission in Crohn's disease. The aim of the present pilot study was to evaluate the combination of infliximab and methotrexate as therapy for refractory Crohn's disease.
                Nineteen patients with chronic active Crohn's disease resistant or intolerant to azathioprine were enrolled. Patients received either two infusions of infliximab (5 mg/kg) alone (n=8) or in combination with long-term methotrexate at a dosage of 20 mg/week (n=11) over 48 weeks.
                Two out of eight patients receiving infliximab monotherapy and four out of 11 patients treated with infliximab and concomitant methotrexate had discontinued study treatment by week 48, solely because of lack of efficacy. Clinical remission at week 48 was observed in five out of seven patients treated with infliximab and methotrexate, but only in two out of six patients receiving infliximab monotherapy. In addition, patients treated with concomitant methotrexate achieved remission earlier (median time 2 versus 18 weeks) and needed fewer steroids (median prednisolone dose 0 versus 11.8 mg). Despite an increased mean number of adverse events per patient in the methotrexate group, the proportions of patients experiencing any adverse events and serious adverse events were similar across treatment groups.
                The combination of infliximab with long-term methotrexate may be a promising concept in refractory Crohn's disease. Our data prompt larger trials. At present only one large controlled study has indicated that parenteral methotrexate may be effective in chronic active Crohn's disease (CD).
                To evaluate the effectiveness of oral methotrexate in chronic steroid-dependent CD.
                Patients with active CD, who have received steroids and/or immunosuppressives for at least 4 months during the preceding 12 months and with a current Harvey-Bradshaw index of > or = 7 were studied.
                Methotrexate (12.5 mg weekly) or 6-mercaptopurine (50 mg daily), or placebo were given during the 9 months of the trial in addition to steroids and 5-aminosalicylic acid as clinically indicated.
                Eighty-four patients were included (methotrexate, 26 patients; 6-mercaptopurine, 32 patients; placebo, 26 patients). The proportion of patients entering first remission as well as the proportions of patients relapsing after first remission were not significantly different between the groups. The mean Harvey-Bradshaw index and the mean monthly steroid dose were also similar. However, when each patient was evaluated as his or her own control, the reduction in steroid dose, the general well being, and the reduction in abdominal pain were significantly better in the methotrexate treated patients.
                Methotrexate at a weekly oral dose of 12.5 mg was found to be moderately better than 6-mercaptopurine and placebo in patients with chronic active CD. Not all patients with rheumatoid arthritis can tolerate or respond to methotrexate, a standard treatment for this disease. There is evidence that antitumour necrosis factor alpha (TNFalpha) is efficacious in relief of signs and symptoms. We therefore investigated whether infliximab, a chimeric human-mouse anti-TNFalpha monoclonal antibody would provide additional clinical benefit to patients who had active rheumatoid arthritis despite receiving methotrexate.
                In an international double-blind placebo-controlled phase III clinical trial, 428 patients who had active rheumatoid arthritis, who had received continuous methotrexate for at least 3 months and at a stable dose for at least 4 weeks, were randomised to placebo (n=88) or one of four regimens of infliximab at weeks 0, 2, and 6. Additional infusions of the same dose were given every 4 or 8 weeks thereafter on a background of a stable dose of methotrexate (median 15 mg/week for > or =6 months, range 10-35 mg/wk). Patients were assessed every 4 weeks for 30 weeks.
                At 30 weeks, the American College of Rheumatology (20) response criteria, representing a 20% improvement from baseline, were achieved in 53, 50, 58, and 52% of patients receiving 3 mg/kg every 4 or 8 weeks or 10 mg/kg every 4 or 8 weeks, respectively, compared with 20% of patients receiving placebo plus methotrexate (p<0.001 for each of the four infliximab regimens vs placebo). A 50% improvement was achieved in 29, 27, 26, and 31% of infliximab plus methotrexate in the same treatment groups, compared with 5% of patients on placebo plus methotrexate (p<0.001). Infliximab was well-tolerated; withdrawals for adverse events as well as the occurrence of serious adverse events or serious infections did not exceed those in the placebo group.
                During 30 weeks, treatment with infliximab plus methotrexate was more efficacious than methotrexate alone in patients with active rheumatoid arthritis not previously responding to methotrexate. Immunosuppression with methotrexate may be useful in the treatment of Crohn's disease. We tested the efficacy of methotrexate in refractory Crohn's disease in a randomized, controlled trial.
                Randomized, double-blind placebo-controlled trial of methotrexate in 33 patients with steroid-dependent Crohn's disease, 33% of whom had previously failed therapy with 6-mercaptopurine. Patients were given placebo or oral methotrexate 15 mg/week, or adjusted up to 22.5 mg/week, for up to 1 year or until treatment failure. Outcome was assessed by reduction in prednisone dosage, Crohn's Disease Activity Index, hospital admission, and laboratory parameters.
                Four patients were dropped from the study for non-compliance and one because of intercurrent illness, and 28 patients could be evaluated. Fewer methotrexate-treated patients (6/13 or 46%) had flares of Crohn's disease as compared to placebo-treated patients (12/15 or 80%), but this did not achieve statistical significance (p<0.1). There was a non-significant trend toward an increased number of significant side effects in the methotrexate-treated patients (3/13 or 23%) as compared to the placebo-treated patients (0/15 or 0%) (p<0.2). Laboratory indices of inflammation did not differ between the two groups.
                The methotrexate-treated group showed a trend toward fewer Crohn's disease flares, balanced by an increased number of significant side effects. Patients with Crohn's disease often have relapses. Better treatments are needed for the maintenance of remission. Although methotrexate is an effective short-term treatment for Crohn's disease, its role in maintaining remissions is not known.
                We conducted a double-blind, placebo-controlled, multicenter study of patients with chronically active Crohn's disease who had entered remission after 16 to 24 weeks of treatment with 25 mg of methotrexate given intramuscularly once weekly. Patients were randomly assigned to receive either methotrexate at a dose of 15 mg intramuscularly once weekly or placebo for 40 weeks. No other treatments for Crohn's disease were permitted. We compared the efficacy of treatment by analyzing the proportion of patients who remained in remission at week 40. Remission was defined as a score of 150 or less on the Crohn's Disease Activity Index.
                Forty patients received methotrexate, and 36 received placebo. At week 40, 26 patients (65 percent) were in remission in the methotrexate group, as compared with 14 (39 percent) in the placebo group (P=0.04; absolute reduction in the risk of relapse, 26.1 percent; 95 percent confidence interval, 4.4 percent to 47.8 percent). Fewer patients in the methotrexate group than in the placebo group required prednisone for relapse (11 of 40 [28 percent] vs. 21 of 36 [58 percent], P=0.01). None of the patients who received methotrexate had a severe adverse event; one patient in this group withdrew because of nausea.
                In patients with Crohn's disease who enter remission after treatment with methotrexate, a low dose of methotrexate maintains remission. Although corticosteroids are highly effective in improving symptoms of Crohn's disease, they may have substantial toxicity. In some patients, attempts to discontinue corticosteroids are unsuccessful.
                We conducted a double-blind, placebo-controlled multicenter study of weekly injections of methotrexate in patients who had chronically active Crohn's disease despite a minimum of three months of prednisone therapy. Patients were randomly assigned to treatment with intramuscular methotrexate (25 mg once weekly) or placebo for 16 weeks. The patients also received prednisone (20 mg once a day), which was tapered over 10 weeks unless their condition worsened. The primary outcome measure was clinical remission at the end of the 16-week trial. Remission was defined by the discontinuation of prednisone and a score of < or = 150 points on the Crohn's Disease Activity Index.
                A total of 141 patients were randomly assigned in a 2:1 ratio to methotrexate (94 patients) or placebo (47 patients). After 16 weeks, 37 patients (39.4 percent) were in clinical remission in the methotrexate group, as compared with 9 patients (19.1 percent) in the placebo group (P = 0.025; relative risk, 1.95; 95 percent confidence interval, 1.09 to 3.48). The patients in the methotrexate group received less prednisone overall than those in the placebo group (P = 0.026). The mean (+/- SE) score on the Crohn's Disease Activity Index after 16 weeks of treatment was significantly lower in the methotrexate group (162 +/- 12) than in the placebo group (204 +/- 17, P = 0.002). The changes in quality-of-life scores and serum orosomucoid concentrations were similar. In the methotrexate group, 16 patients (17 percent) withdrew from treatment because of adverse events (including asymptomatic elevation of serum aminotransferase in 7 and nausea in 6), as compared with 1 patient (2 percent) in the placebo group.
                In a group of patients with chronically active Crohn's disease, methotrexate was more effective than placebo in improving symptoms and reducing requirements for prednisone.
There is evidence from a single large randomized trial which suggests that intramuscular methotrexate (25 mg/week) provides a benefit for induction of remission and complete withdrawal from steroids in patients with refractory Crohn's disease. Lower dose oral methotrexate does not appear to provide any significant benefit relative to placebo or active comparator. However, these trials were small and further studies of oral methotrexate may be justified. Comparative studies of methotrexate to drugs such as azathioprine or 6-mercaptopurine would require the randomization of large numbers of patients. The addition of methotrexate to infliximab therapy does not appear to provide any additional benefit over infiximab monotherapy. However these studies were relatively small and further research is needed to determine the role of methotrexate when used in conjunction with infliximab or other biological therapies.