Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. Rapid alleviation of signs and symptoms of rheumatoid arthritis with intravenous or subcutaneous administration of adalimumab in combination with methotrexate. Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis (COMET): a randomised, double-blind, parallel treatment trial. Therapeutic effects of the combination of methotrexate and bucillamine in early rheumatoid arthritis: a multicenter, double-blind, randomized controlled study.
Tumor necrosis factor (TNF) is an important proinflammatory cytokine that mediates inflammatory synovitis and articular matrix degradation in rheumatoid arthritis (RA). We investigated the ability of adalimumab, a human anti-TNF monoclonal antibody, to inhibit the progression of structural joint damage, reduce the signs and symptoms, and improve physical function in patients with active RA receiving concomitant treatment with methotrexate (MTX).
                In this multicenter, 52-week, double-blind, placebo-controlled study, 619 patients with active RA who had an inadequate response to MTX were randomized to receive adalimumab 40 mg subcutaneously every other week (n = 207), adalimumab 20 mg subcutaneously every week (n = 212), or placebo (n = 200) plus concomitant MTX. The primary efficacy end points were radiographic progression at week 52 (total Sharp score by a modified method [TSS]), clinical response at week 24 (improvements of at least 20% in the American College of Rheumatology core criteria [ACR20]), and physical function at week 52 (disability index of the Health Assessment Questionnaire [HAQ]).
                At week 52, there was statistically significantly less radiographic progression, as measured by the change in TSS, in the patients receiving adalimumab either 40 mg every other week (mean +/- SD change 0.1 +/- 4.8) or 20 mg weekly (0.8 +/- 4.9) as compared with that in the placebo group (2.7 +/- 6.8) (P < or = 0.001 for each comparison). In addition, there were statistically significant changes in the components of the TSS. At week 24, ACR20 responses were achieved by 63% and 61% of patients in the adalimumab 40 mg every other week and 20 mg weekly groups, respectively, versus 30% of patients in the placebo group (P < or = 0.001 for each comparison). At week 52, ACR20 responses were achieved by 59% and 55% of patients taking adalimumab 40 mg every other week and 20 mg weekly, respectively, versus 24% of patients taking placebo (P < or = 0.001 for each comparison). At week 52, physical function as measured by the HAQ demonstrated statistically significant improvement with adalimumab 40 mg every other week and 20 mg weekly compared with placebo (mean change in HAQ score -0.59 and -0.61, respectively, versus -0.25; P < or = 0.001 for each comparison). A total of 467 patients (75.4%) completed 52 weeks of treatment. Adalimumab was generally well tolerated. Discontinuations occurred in 22.0% of adalimumab-treated patients and in 30.0% of placebo-treated patients. The rate of adverse events (both serious and nonserious) was comparable in the adalimumab and placebo groups, although the proportion of patients reporting serious infections was higher in patients receiving adalimumab (3.8%) than in those receiving placebo (0.5%) (P < or = 0.02), and was highest in the patients receiving 40 mg every other week.
                In this 52-week trial, adalimumab was more effective than placebo at inhibiting the progression of structural joint damage, reducing the signs and symptoms, and improving physical function in patients with active RA who had demonstrated an incomplete response to MTX. This randomized, placebo-controlled, double-blind, Phase 1 study assessed the magnitude, onset, and duration of response with intravenous (i.v.) and subcutaneous (s.c.) adalimumab (Humira, Abbott Laboratories) combined with methotrexate (MTX) in patients with active rheumatoid arthritis (RA) despite previous MTX therapy.
                Fifty-four patients were randomized to two injections of i.v. or s.c. adalimumab (1 mg/kg) or placebo while continuing on MTX (mean dose, 15.7 mg/week). Dosing intervals were determined by the European League Against Rheumatism (EULAR) response criteria, and were allowed to range from 1 to 3 months. Efficacy was mainly assessed using the EULAR response criteria and the American College of Rheumatology (ACR) response criteria.
                Moderate EULAR response was achieved at least once within 29 days after the first injection in 83% and 61% of patients receiving i.v. and s.c. adalimumab respectively, compared with 44% for placebo [probability (p) < or = 0.05 for i.v. adalimumab versus placebo]. A 20% improvement in disease activity according to the ACR criteria (ACR20 response) was achieved by 72% and 67% of patients receiving i.v. and s.c. adalimumab respectively, compared with 28% for placebo (p < or = 0.01 and p < or = 0.05, respectively, versus placebo). By Day 15 after the first and second injections, statistically significant moderate EULAR and ACR20 response rates were achieved with either i.v. or s.c. adalimumab compared with placebo (p < or = 0.05). The mean times to second injection for i.v. adalimumab, s.c. adalimumab, and placebo were 42.2 days (range: 27-84 days), 38.3 days (range: 26-85 days), and 28.4 days (range: 26-32 days), respectively (minimum time allowed by the protocol between the first and second injections was 4 weeks). Adalimumab in combination with MTX was well tolerated, with no patients being withdrawn because of adverse events.
                Either i.v. or s.c. adalimumab added to MTX significantly improved the signs and symptoms of RA compared with MTX alone. Subcutaneously administered adalimumab appeared to provide a response that was as great, as rapid, and as enduring as that with i.v. adalimumab. Remission and radiographic non-progression are goals in the treatment of early rheumatoid arthritis. The aim of the combination of methotrexate and etanercept in active early rheumatoid arthritis (COMET) trial is to compare remission and radiographic non-progression in patients treated with methotrexate monotherapy or with methotrexate plus etanercept.
                542 outpatients who were methotrexate-naive and had had early moderate-to-severe rheumatoid arthritis for 3-24 months were randomly assigned to receive either methotrexate alone titrated up from 7.5 mg a week to a maximum of 20 mg a week by week 8 or methotrexate (same titration) plus etanercept 50 mg a week. Coprimary endpoints at 52 weeks were remission measured with the disease activity score in 28 joints (DAS28) and radiographic non-progression measured with modified total Sharp score. Treatment was allocated with a computerised randomisation and enrolment system, which masked both participants and carers. Analysis was done by modified intention to treat with last observation carried forward for missing data. This study is registered with ClinicalTrials.gov, number NCT00195494).
                274 participants were randomly assigned to receive combined treatment and 268 methotrexate alone. 132 of 265 (50%, 95% CI 44-56%) patients who took combined treatment and were available for assessment achieved clinical remission compared with 73 of 263 (28%, 23-33%) taking methotrexate alone (effect difference 22.05%, 95%CI 13.96-30.15%, p<0.0001). 487 evaluable patients had severe disease (DAS28>5.1). 196 of 246 (80%, 75-85%) and 135 of 230 (59%, 53-65%), respectively, achieved radiographic non-progression (20.98%, 12.97-29.09%, p<0.0001). Serious adverse events were similar between groups.
                Both clinical remission and radiographic non-progression are achievable goals in patients with early severe rheumatoid arthritis within 1 year of combined treatment with etanercept plus methotrexate.
                Wyeth Research. Disease-modifying antirheumatic drug (DMARD) combination therapies are used widely, but there have been few reports clearly demonstrating that combination therapy is more effective than DMARD monotherapy. We conducted a multicenter, double-blind controlled trial in order to clarify that the combination of methotrexate and bucillamine is more effective than either alone. The subjects of this study were 71 patients with active rheumatoid arthritis within 2 years of onset. Dosages were 8 mg methotrexate with 5 mg folic acid per week (MTX group), 200 mg bucillamine per day (BUC group), or both MTX and BUC (combination group). Clinical effects and adverse reactions were observed for 96 weeks. The ACR 20 response rate was 79.2% in the combination group, significantly higher than the rates of 43.5% for the MTX group (P = 0.008) and 45.8% for the BUC group (P = 0.0178). The cumulative survival curve of maintaining the ACR 20 response was significantly higher in the combination group than in the MTX and BUC groups (P = 0.0123 and P = 0.0088, respectively). The mean increase in the total Sharp score over 96 weeks was 12.6 +/- 9.0 in the combination group, significantly lower (P = 0.0468) than the value of 28.0 +/- 28.3 for the single DMARD (combined MTX and BUC) group. The incidence of adverse reactions did not differ significantly between the three groups. It was concluded that the combination therapy with MTX and BUC showed significantly higher clinical efficacy than either of the single DMARD therapies.
On the basis of the studies reviewed here, adalimumab in combination with methotrexate is efficacious and safe in the treatment of the rheumatoid arthritis. Adalimumab 40 mg sc e.o.w. and 20 mg e.w. slows the radiographic progression at 52 weeks. Adalimumab in combination with DMARDs other than methotrexate is also efficacious and safe, even though data from one only study are available and the number of patients in each group is low. Adalimumab in monotherapy is efficacious and safe in the treatment of the rheumatoid arthritis but the effect size is lower than with combined therapy.