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. Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic drug treatment has failed. Combination treatment with methotrexate, cyclosporine, and intraarticular betamethasone compared with methotrexate and intraarticular betamethasone in early active rheumatoid arthritis: an investigator-initiated, multicenter, randomized, double-blind, parallel-group, placebo-controlled study. Golimumab, a human anti-tumor necrosis factor alpha monoclonal antibody, injected subcutaneously every four weeks in methotrexate-naive patients with active rheumatoid arthritis: twenty-four-week results of a phase III, multicenter, randomized, double-blind, placebo-controlled study of golimumab before methotrexate as first-line therapy for early-onset rheumatoid arthritis. Combination therapy with sulfasalazine and methotrexate is more effective than either drug alone in patients with rheumatoid arthritis with a suboptimal response to sulfasalazine: results from the double-blind placebo-controlled MASCOT study. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial.
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. To evaluate the efficacy and safety of monotherapy with adalimumab in patients with RA for whom previous DMARD treatment has failed.
                In a 26 week, double blind, placebo controlled, phase III trial, 544 patients with RA were randomised to monotherapy with adalimumab 20 mg every other week, 20 mg weekly, 40 mg every other week, 40 mg weekly, or placebo. The primary efficacy end point was > or =20% improvement in the ACR core criteria (ACR20 response). Secondary efficacy end points included ACR50, ACR70, EULAR responses, and the Disability Index of the Health Assessment Questionnaire (HAQ DI).
                After 26 weeks, patients treated with adalimumab 20 mg every other week, 20 mg weekly, 40 mg every other week, and 40 mg weekly had significantly better response rates than those treated with placebo: ACR20 (35.8%, 39.3%, 46.0%, 53.4%, respectively v 19.1%; p< or =0.01); ACR50 (18.9%, 20.5%, 22.1%, 35.0% v 8.2%; p< or =0.05); ACR70 (8.5%, 9.8%, 12.4%, 18.4% v 1.8%; p< or =0.05). Moderate EULAR response rates were significantly greater with adalimumab than with placebo (41.5%, 48.2%, 55.8%, 63.1% v 26.4%; p< or =0.05). Patients treated with adalimumab achieved better improvements in mean HAQ DI than those receiving placebo (-0.29, -0.39, -0.38, -0.49 v -0.07; p< or =0.01). No significant differences were found between adalimumab and placebo treated patients for serious adverse events, serious infections, or malignancies. Injection site reaction occurred in 10.6% and 0.9% of adalimumab and placebo treated patients, respectively (p< or =0.05).
                Among patients with RA for whom previous DMARD treatment had failed, adalimumab monotherapy achieved significant, rapid, and sustained improvements in disease activity and improved physical function and was safe and well tolerated. To investigate whether disease control can be achieved in early active rheumatoid arthritis (RA) by treatment with methotrexate and intraarticular betamethasone, and whether the addition of cyclosporine to the regimen has any additional effect.
                Patients (n = 160) were randomized to receive methotrexate 7.5 mg/week plus cyclosporine 2.5 mg/kg of body weight/day (combination therapy) or methotrexate plus placebo-cyclosporine (monotherapy). At weeks 0, 2, 4, 6, and 8 and every 4 weeks thereafter, betamethasone was injected into swollen joints (maximum 4 joints or 4 ml per visit). Beginning at week 8, if synovitis was present, the methotrexate dosage was increased stepwise up to 20 mg/week, with a subsequent stepwise increase in the cyclosporine or placebo-cyclosporine dosage up to 4 mg/kg.
                At 52 weeks, 20% improvement according to the American College of Rheumatology criteria (ACR20) was achieved in 85% of the combination therapy group versus 68% of the monotherapy group (P = 0.02). The median individual overall ACR response (ACR-N) in the 2 groups was 80.0% (interquartile range 40.1-91.8%) and 54.5% (interquartile range 2.4-87.8%), respectively (P = 0.025). At 48 and 52 weeks, ACR remission criteria were met in 35% of the combination therapy group and 28% of the monotherapy group. Progression in the Larsen score at 52 weeks was -0.2 +/- 6.5 and 0.4 +/- 6.9 (mean +/- SD) in the combination therapy and monotherapy groups, respectively. Serum creatinine levels increased by 7%, and hypertrichosis was more prevalent, in the combination therapy group.
                Combined treatment with methotrexate and intraarticular glucocorticoid showed excellent disease control and stopped the progression of erosions in patients with early active RA, who had a poor prognosis. Addition of cyclosporine improved the ACR20 and ACR-N responses, whereas the ACR50 and ACR70 responses, remission rates, and radiographic changes did not differ between the 2 study groups. To assess the safety and efficacy of golimumab in methotrexate (MTX)-naive patients with active rheumatoid arthritis (RA).
                MTX-naive patients with RA (n = 637) were randomized to receive placebo plus MTX (group 1), golimumab 100 mg plus placebo (group 2), golimumab 50 mg plus MTX (group 3), or golimumab 100 mg plus MTX (group 4). Subcutaneous injections of golimumab or placebo were administered every 4 weeks. The dosage of MTX/placebo capsules started at 10 mg/week and escalated to 20 mg/week. The primary end point, the proportion of patients meeting the American College of Rheumatology 50% improvement criteria (achieving an ACR50 response) at week 24, required significant differences between groups 3 and 4 combined (combined group) versus group 1 and significant differences in a pairwise comparison (group 3 or group 4 versus group 1).
                An intent-to-treat (ITT) analysis of the ACR50 response at week 24 did not show a significant difference between the combined group and group 1 (38.4% and 29.4%, respectively; P=0.053), while a post hoc modified ITT analysis (excluding 3 untreated patients) of the ACR50 response showed statistically significant differences between the combined group and group 1 (38.5% versus 29.4%; P=0.049) and between group 3 (40.5%; P=0.038) but not group 4 (36.5%; P=0.177) and group 1. Group 2 was noninferior to group 1 for the ACR50 response at week 24 (33.1%; 95% confidence interval lower bound -5.2%; predefined delta value for noninferiority -10%). The combination of golimumab plus MTX demonstrated a significantly better response compared with placebo plus MTX in most other efficacy parameters, including response/remission according to the Disease Activity Score in 28 joints. Serious adverse events occurred in 7%, 3%, 6%, and 6% of patients in groups 1, 2, 3, and 4, respectively.
                Although the primary end point was not met, the modified ITT analysis of the primary end point and other prespecified efficacy measures demonstrated that the efficacy of golimumab plus MTX is better than, and the efficacy of golimumab alone is similar to, the efficacy of MTX alone in reducing RA signs and symptoms in MTX-naive patients, with no unexpected safety concerns. Optimal use of disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis is vital if progression of disease is to be reduced. Methotrexate (MTX) and sulfasalazine (SASP) are widely used inexpensive DMARDs, recently often combined despite no firm evidence of benefit from previous studies. Aim: To establish whether a combination of SASP and MTX is superior to either drug alone in patients with rheumatoid arthritis with a suboptimal response to 6 months of SASP.
                A randomised controlled study of step-up DMARD treatment in early rheumatoid arthritis. In phase I, 687 patients received SASP for 6 months. Those with a disease activity score (DAS) > or =2.4 were offered additional treatment in phase II (SASP alone, MTX alone or a combination of the two). The primary outcome measure was change in DAS.
                At 6 months, 191 (28%) patients had a DAS <2.4, 123 (18%) were eligible but did not wish to enter phase II, 130 (19%) stopped SASP because of reversible adverse events and 165 (24%) entered phase II. DAS at 18 months was significantly lower in those who received combination treatment compared with those who received either SASP or MTX: monotherapy arms did not differ. Improvement in European League Against Rheumatism and American College of Rheumatology 20, 50 and 70 scores favoured combination therapy.
                In this "true-to-life" study, an inexpensive combination of DMARDs proved more effective than monotherapy in patients with rheumatoid arthritis with a suboptimal response to SASP. There was no increase in toxicity. These results provide an evidence base for the use of this combination as a component of tight control strategies. Etanercept and methotrexate are effective in the treatment of rheumatoid arthritis but no data exist on concurrent initiation or use of the combination compared with either drug alone. We aimed to assess combination treatment with etanercept and methotrexate versus the monotherapies in patients with rheumatoid arthritis.
                In a double-blind, randomised, clinical efficacy, safety, and radiographic study, 686 patients with active rheumatoid arthritis were randomly allocated to treatment with etanercept 25 mg (subcutaneously twice a week), oral methotrexate (up to 20 mg every week), or the combination. Clinical response was assessed by criteria of the American College of Rheumatology (ACR). The primary efficacy endpoint was the numeric index of the ACR response (ACR-N) area under the curve (AUC) over the first 24 weeks. The primary radiographic endpoint was change from baseline to week 52 in total joint damage and was assessed with the modified Sharp score. Analysis was by intention to treat.
                Four patients did not receive any drug; thus 682 were studied. ACR-N AUC at 24 weeks was greater for the combination group compared with etanercept alone and methotrexate alone (18.3%-years [95% CI 17.1-19.6] vs 14.7%-years [13.5-16.0], p<0.0001, and 12.2%-years [11.0-13.4], p<0.0001; respectively). The mean difference in ACR-N AUC between combination and methotrexate alone was 6.1 (95% CI 4.5-7.8, p<0.0001) and between etanercept and methotrexate was 2.5 (0.8-4.2, p=0.0034). The combination was more efficacious than methotrexate or etanercept alone in retardation of joint damage (mean total Sharp score -0.54 [95% CI -1.00 to -0.07] vs 2.80 [1.08 to 4.51], p<0.0001, and 0.52 [-0.10 to 1.15], p=0.0006; respectively). The mean difference in total Sharp score between combination and methotrexate alone was -3.34 (95% CI -4.86 to -1.81, p<0.0001) and between etanercept and methotrexate was -27 (-3.81 to -0.74, p=0.0469). The number of patients reporting infections or adverse events was similar in all groups.
                The combination of etanercept and methotrexate was significantly better in reduction of disease activity, improvement of functional disability, and retardation of radiographic progression compared with methotrexate or etanercept alone. These findings bring us closer to achievement of remission and repair of structural damage in rheumatoid arthritis.
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.