Efficacy of methotrexate treatment in patients with probable rheumatoid arthritis: A double‐blind,randomized, placebo‐controlled trial

Objective

To determine whether patients with undifferentiated arthritis (UA; inflammatory, nontraumatic arthritis that cannot be diagnosed using current classification criteria) benefit from treatment with methotrexate (MTX).

Methods

The PRObable rheumatoid arthritis: Methotrexate versus Placebo Treatment (PROMPT) study was a double‐blind, placebo‐controlled, randomized, multicenter trial involving 110 patients with UA who fulfilled the American College of Rheumatology (ACR) 1958 criteria for probable RA. Treatment started with MTX (15 mg/week) or placebo tablets, and every 3 months the dosage was increased if the Disease Activity Score was >2.4. After 12 months, the study medication was tapered and discontinued. Patients were followed up for 30 months. When a patient fulfilled the ACR criteria for RA (primary end point), the study medication was changed to MTX. Joint damage was scored on radiographs of the hands and feet.

Results

In 22 of the 55 patients (40%) in the MTX group, UA progressed to RA compared with 29 of 55 patients (53%) in the placebo group. However, in the MTX group, patients fulfilled the ACR criteria for RA at a later time point than in the placebo group (P = 0.04), and fewer patients showed radiographic progression over 18 months (P = 0.046).

Conclusion

This study provides evidence for the efficacy of MTX treatment in postponing the diagnosis of RA, as defined by the ACR 1987 criteria, and retarding radiographic joint damage in UA patients.

     

Fcγ receptor type IIIA genotype and response to tumor necrosis factor α–blocking agents in patients with rheumatoid arthritis

Objective

To determine whether a functional single‐nucleotide polymorphism in the gene encoding Fcγ receptor type IIIA (FcγRIIIA) correlates with the response to treatment with tumor necrosis factor α inhibitors in rheumatoid arthritis (RA).

Methods

The study population comprised 282 Swedish patients with RA in whom the therapeutic efficacy of conventional disease‐modifying antirheumatic drugs had been insufficient. Infliximab or etanercept treatment was initiated, and patients were evaluated after 3 months, using the American College of Rheumatology 20% improvement criteria (ACR20), the ACR50, and the ACR70 or the European League Against Rheumatism (EULAR) criteria. The chi‐square test was used to compare response rates across FcγRIIIA genotypes.

Results

No differences in genotype distribution were observed among nonresponders compared with ACR20 responders (P = 0.80), ACR50 responders (P = 0.56), or ACR70 responders (P = 0.91). Similar results were observed when analyzing infliximab and etanercept separately or when using the EULAR response criteria.

Conclusion

Unlike the findings of a previous study, the results of the current study suggest that the 158V/F polymorphism of FcγRIIIA is very unlikely to influence the clinical efficacy of infliximab or etanercept in patients with RA.

     

Evaluation of the efficacy and safety of pamapimod,a p38 MAP kinase inhibitor,in a double‐blind,methotrexate‐controlled study of patients with active rheumatoid arthritis

Objective

To determine the efficacy and safety of pamapimod (a selective inhibitor of the α‐isoform of p38 MAP kinase) as monotherapy in comparison with methotrexate (MTX) treatment in adult patients with active rheumatoid arthritis (RA).

Methods

Patients were randomly assigned to 1 of 4 treatment groups and received 12 weeks of double‐blind treatment. One group received MTX (7.5 mg/week with planned escalation to 20 mg/week), and 3 groups received pamapimod (50, 150, or 300 mg) once daily. The primary efficacy end point was the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at 12 weeks. Secondary end points included ACR50 and ACR70 responses, change from baseline in the Disease Activity Score in 28 joints (DAS28), categorical analyses of DAS28/European League Against Rheumatism response, and change from baseline in each parameter of the ACR core set of measures. Safety monitoring included recording of adverse events (AEs), laboratory testing, immunology assessments, administration of electrocardiograms, and assessment of vital signs.

Results

Patients assigned to receive MTX and pamapimod had similar demographics and baseline characteristics. At week 12, fewer patients taking pamapimod had an ACR20 response (23%, 18%, and 31% in the 50‐, 150‐, and 300‐mg groups, respectively) compared with patients taking MTX (45%). Secondary efficacy end points showed a similar pattern. AEs were typically characterized as mild and included infections, skin disorders, and dizziness. Pamapimod was generally well tolerated, but the 300‐mg dose appeared to be more toxic than either the 2 lower doses or MTX.

Conclusion

The present results showed that pamapimod was not as effective as MTX in the treatment of active RA.

     

Treatment of rheumatoid arthritis with anakinra,a recombinant human interleukin‐1 receptor antagonist,in combination with methotrexate: Results of a twenty‐four–week,multicenter, randomized,double‐blind,placebo‐controlled trial

Objective

To evaluate the efficacy and safety of anakinra in combination with methotrexate (MTX) in patients with active rheumatoid arthritis (RA).

Methods

Patients with moderate‐to‐severe active RA who were receiving MTX for 6 consecutive months, with stable doses for ≥3 months (those with disease duration of >6 months but <12 years) were randomized into 6 groups: placebo or 0.04, 0.1, 0.4, 1.0, or 2.0 mg/kg of anakinra administered in a single, daily, subcutaneous injection. The primary efficacy end point was the proportion of subjects who met the American College of Rheumatology 20% improvement criteria (attained an ACR20 response) at week 12.

Results

A total of 419 patients were randomized in the study. Patient demographics and disease status were similar in the 6 treatment groups. The ACR20 responses at week 12 in the 5 active treatment plus MTX groups demonstrated a statistically significant (P = 0.001) dose‐response relationship compared with the ACR20 response in the placebo plus MTX group. The ACR20 response rate in the anakinra 1.0‐mg/kg (46%; P = 0.001) and 2.0‐mg/kg (38%; P = 0.007) dose groups was significantly greater than that in the placebo group (19%). The ACR20 responses at 24 weeks were consistent with those at 12 weeks. Similar improvements in anakinra‐treated subjects were noted in individual ACR components, erythrocyte sedimentation rate, onset of ACR20 response, sustainability of ACR20 response, and magnitude of ACR response. Anakinra was safe and well tolerated. Injection site reaction was the most frequently noted adverse event, and this led to premature study withdrawal in 7% (1.0‐mg/kg group) to 10% (2.0‐mg/kg group) of patients receiving higher doses.

Conclusion

In patients with persistently active RA, the combination of anakinra and MTX was safe and well tolerated and provided significantly greater clinical benefit than MTX alone.

     

Golimumab,a new human anti–tumor necrosis factor α antibody,administered intravenously in patients with active rheumatoid arthritis: Forty‐eight–week efficacy and safety results of a phase III randomized,double‐blind,placebo‐controlled study

Objective

To assess the efficacy and safety of intravenous administration of golimumab in patients with rheumatoid arthritis (RA).

Methods

Adult patients with RA in whom disease activity was persistent despite treatment with methotrexate (MTX) at a dosage of 15–25 mg/week for ≥4 weeks were randomized to receive intravenous infusions of placebo plus MTX or intravenous infusions of golimumab at a dose of 2 mg/kg or 4 mg/kg, with or without MTX, every 12 weeks through week 48. Patients with <20% improvement in the swollen and tender joint counts could enter early escape and receive additional active treatment (week 16) or could have their dose regimen adjusted (week 24). The primary end point was the proportion of patients achieving a 50% response according to the American College of Rheumatology improvement criteria (ACR50) at week 14.

Results

The primary study end point was not met (at week 14, an ACR50 response was observed in 21% of the patients treated with golimumab plus MTX compared with 13% of the patients treated with placebo plus MTX [P = 0.051]). By week 24, significantly more patients treated with golimumab plus MTX had achieved an ACR50 response. Differences in the proportion of patients achieving an ACR50 response between the group receiving golimumab monotherapy and the group receiving placebo plus MTX were not significant at either week 14 (16% versus 13%) or week 24 (10% versus 9%). At week 48, the proportions of patients achieving ACR20 and ACR50 responses were highest among those who had received golimumab 4 mg/kg plus MTX (70% and 48%, respectively). Concomitant treatment with MTX was associated with a lower incidence of antibodies to golimumab. The most commonly reported adverse events through week 48 were infections (48% of patients treated with golimumab with or without MTX and 41% of patients receiving placebo plus MTX).

Conclusion

The primary end point was not met. However, intravenously administered golimumab plus MTX appears to have benefit in the longer‐term reduction of RA signs/symptoms in MTX‐resistant patients, with no unexpected safety concerns.

     

Comparison of the clinical efficacy and safety of subcutaneous versus oral administration of methotrexate in patients with active rheumatoid arthritis: Results of a six‐month,multicenter, randomized,double‐blind,controlled, phase IV trial

Objective

To compare the efficacy and safety of subcutaneous (SC) versus oral administration of methotrexate (MTX) in patients with active rheumatoid arthritis (RA).

Methods

MTX‐naive patients with active RA (Disease Activity Score in 28 joints ≥4) were eligible for the study if they had not previously taken biologic agents and had not taken disease‐modifying antirheumatic drugs for 2 weeks prior to randomization. Patients were randomly assigned to receive 15 mg/week of MTX either orally (2 7.5‐mg tablets plus a dummy prefilled syringe; n = 187 patients) or SC (prefilled syringe containing 10 mg/ml plus 2 dummy tablets; n = 188 patients) for 24 weeks. At week 16, patients who did not meet the American College of Rheumatology criteria for 20% improvement (ACR20) were switched from 15 mg of oral MTX to 15 mg of SC MTX and from 15 mg of SC MTX to 20 mg of SC MTX for the remaining 8 weeks, still in a blinded manner. The primary outcome was an ACR20 response at 24 weeks.

Results

At week 24, significantly more patients treated with SC MTX than with oral MTX showed ACR20 (78% versus 70%) and ACR70 (41% versus 33%) responses. Patients with a disease duration ≥12 months had even higher ACR20 response rates (89% for SC administration and 63% for oral). In 52 of the ACR20 nonresponders (14%), treatment was switched at week 16. Changing from oral to SC MTX and from 15 mg to 20 mg of SC MTX resulted in 30% and 23% ACR20 response rates, respectively, in these patients. MTX was well tolerated. The rate of adverse events was similar in all groups.

Conclusion

This 6‐month prospective, randomized, controlled trial is the first to examine oral versus SC administration of MTX. We found that SC administration was significantly more effective than oral administration of the same MTX dosage. There was no difference in tolerability.

     

The PREMIER study: A multicenter,randomized, double‐blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early,aggressive rheumatoid arthritis who had not had previous methotrexate treatment

Objective

To compare the efficacy and safety of adalimumab plus methotrexate (MTX) versus MTX monotherapy or adalimumab monotherapy in patients with early, aggressive rheumatoid arthritis (RA) who had not previously received MTX treatment.

Methods

This was a 2‐year, multicenter, double‐blind, active comparator–controlled study of 799 RA patients with active disease of <3 years' duration who had never been treated with MTX. Treatments included adalimumab 40 mg subcutaneously every other week plus oral MTX, adalimumab 40 mg subcutaneously every other week, or weekly oral MTX. Co‐primary end points at year 1 were American College of Rheumatology 50% improvement (ACR50) and mean change from baseline in the modified total Sharp score.

Results

Combination therapy was superior to both MTX and adalimumab monotherapy in all outcomes measured. At year 1, more patients receiving combination therapy exhibited an ACR50 response (62%) than did patients who received MTX or adalimumab monotherapy (46% and 41%, respectively; both P < 0.001). Similar superiority of combination therapy was seen in ACR20, ACR70, and ACR90 response rates at 1 and 2 years. There was significantly less radiographic progression (P ≤ 0.002) among patients in the combination treatment arm at both year 1 and year 2 (1.3 and 1.9 Sharp units, respectively) than in patients in the MTX arm (5.7 and 10.4 Sharp units) or the adalimumab arm (3.0 and 5.5 Sharp units). After 2 years of treatment, 49% of patients receiving combination therapy exhibited disease remission (28‐joint Disease Activity Score <2.6), and 49% exhibited a major clinical response (ACR70 response for at least 6 continuous months), rates approximately twice those found among patients receiving either monotherapy. The adverse event profiles were comparable in all 3 groups.

Conclusion

In this population of patients with early, aggressive RA, combination therapy with adalimumab plus MTX was significantly superior to either MTX alone or adalimumab alone in improving signs and symptoms of disease, inhibiting radiographic progression, and effecting clinical remission.

     

The effectiveness and toxicity of cyclosporin A in rheumatoid arthritis: longitudinal analysis of a population‐based registry

Objective

To determine factors associated with response or toxicity to cyclosporin A (CSA) in a population‐based inception cohort with rheumatoid arthritis (RA).

Methods

Prospectively collected longitudinal measures including tender joint count (JC), duration of morning stiffness (MS), systolic and diastolic blood pressure (SBP, DBP), and serum creatinine (SCr) were modeled using generalized estimating equations. Survival methods were used to estimate CSA continuation time and its determinants.

Results

Of 133 patients (75% female, median RA duration 13 years), 37 discontinued CSA because of ineffectiveness( 19 ) or because of toxicity( 18 ) including increased SCr in 10, hypertension in 4, infections in 3, and gingival hyperplasia in 1. Patients remained on CSA a median of 75 months (95% confidence interval [CI] 38–112). Those receiving concomitant methotrexate (MTX) were more than 4 times as likely to continue on CSA therapy (hazard ratio 0.22, 95% CI 0.10–0.94). A lower final JC was predicted by a longer CSA treatment duration (relative risk [RR] 0.99 per month, 95% CI 0.98–0.99) and concomitant MTX therapy (RR 0.79, 95% CI 0.63–0.99); decreased MS was predicted only by longer CSA treatment duration (reduction of 2.0 minutes per month, 95% CI 1.1–3.0). Each previous disease‐modifying antirheumatic drug (DMARD) exposure predicted a rise in SCr (35 μmole/liter, 95% CI 22–48), SBP (7.2 mm Hg, 95% CI 2.7–11.7), and DBP (3.8 mm Hg, 95% CI 3.0–6.4).

Conclusions

Combination CSA/MTX prolongs therapy and reduces JC. Long‐term CSA treatment was fairly well tolerated. Previous DMARD use appears to be a determinant for the development of toxicity.

     

Adalimumab,a fully human anti–tumor necrosis factor α monoclonal antibody,for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: The ARMADA trial

Objective

To evaluate the efficacy and safety of adalimumab (D2E7), a fully human monoclonal tumor necrosis factor α antibody, in combination with methotrexate (MTX) in patients with active rheumatoid arthritis (RA) despite treatment with MTX.

Methods

In a 24‐week, randomized, double‐blind, placebo‐controlled study, 271 patients with active RA were randomly assigned to receive injections of adalimumab (20 mg, 40 mg, or 80 mg subcutaneously) or placebo every other week while continuing to take their long‐term stable dosage of MTX. The primary efficacy end point was the American College of Rheumatology criteria for 20% improvement (ACR20) at 24 weeks.

Results

An ACR20 response at week 24 was achieved by a significantly greater proportion of patients in the 20‐mg, 40‐mg, and 80‐mg adalimumab plus MTX groups (47.8%, 67.2%, and 65.8%, respectively) than in the placebo plus MTX group (14.5%) (P < 0.001). ACR50 response rates with the 20‐mg, 40‐mg, and 80‐mg adalimumab dosages (31.9%, 55.2%, and 42.5%, respectively) were significantly greater than that with placebo (8.1%) (P = 0.003, P < 0.001, and P < 0.001, respectively). The 40‐mg and 80‐mg doses of adalimumab were associated with an ACR70 response (26.9% and 19.2%, respectively) that was statistically significantly greater than that with placebo (4.8%) (P < 0.001 and P = 0.020). Responses were rapid, with the greatest proportion of adalimumab‐treated patients achieving an ACR20 response at the first scheduled visit (week 1). Adalimumab was safe and well tolerated; comparable numbers of adalimumab‐treated patients and placebo‐treated patients reported adverse events.

Conclusion

The addition of adalimumab at a dosage of 20 mg, 40 mg, or 80 mg administered subcutaneously every other week to long‐term MTX therapy in patients with active RA provided significant, rapid, and sustained improvement in disease activity over 24 weeks compared with MTX plus placebo.

     

Treatment of rheumatoid arthritis with methotrexate and hydroxychloroquine,methotrexate and sulfasalazine,or a combination of the three medications: Results of a two‐year,randomized, double‐blind,placebo‐controlled trial

Objective

To compare the efficacy of combination therapy with methotrexate (MTX) and hydroxychloroquine (HCQ), MTX and sulfasalazine (SSZ), and MTX, HCQ, and SSZ in patients with rheumatoid arthritis (RA).

Methods

RA patients (n = 171) who had not previously been treated with combinations of the study medications were randomized to receive 1 of the 3 treatment combinations in this 2‐year, double‐blind, placebo‐controlled protocol. HCQ was given at a dosage of 200 mg twice a day. The dosage of MTX was accelerated from 7.5 mg/week to 17.5 mg/week in all patients who were not in remission. Similarly, the dosage of SSZ was escalated from 500 mg twice a day to 1 gm twice a day in patients who were not in remission. The primary end point of the study was the percentage of patients who had a 20% response to therapy according to the American College of Rheumatology (ACR) criteria at 2 years.

Results

Intent‐to‐treat analysis revealed that patients receiving the triple combination responded best, with 78% achieving an ACR 20% response at 2 years, compared with 60% of those treated with MTX and HCQ (P = 0.05) and 49% of those treated with MTX and SSZ (P = 0.002). Similar trends were seen for the ACR 50% response, with 55%, 40%, and 29% of patients in the 3 treatment groups, respectively, achieving these results at 2 years (P = 0.005 for the triple combination group versus the MTX and SSZ group). All combination treatments were well‐tolerated. Fourteen patients (evenly distributed among the 3 groups) withdrew from the protocol because of symptoms that were potentially related to the study medication.

Conclusion

The triple combination of MTX, SSZ, and HCQ is well‐tolerated, and its efficacy is superior to that of the double combination of MTX and SSZ and is marginally superior to that of the double combination of MTX and HCQ.

     

Comparison of etanercept and methotrexate,alone and combined,in the treatment of rheumatoid arthritis: Two‐year clinical and radiographic results from the TEMPO study,a double‐blind,randomized trial

Objective

To evaluate the efficacy, including radiographic changes, and safety of etanercept and methotrexate (MTX), used in combination and alone, in patients with rheumatoid arthritis (RA) in whom previous treatment with a disease‐modifying antirheumatic drug other than MTX had failed.

Methods

Patients with RA were treated with etanercept (25 mg subcutaneously twice weekly), oral MTX (up to 20 mg weekly), or combination therapy with etanercept plus MTX through a second year, in a double‐blinded manner. Clinical response was assessed using American College of Rheumatology (ACR) criteria and the Disease Activity Score (DAS), in a modified intent‐to‐treat analysis with the last observation carried forward (LOCF) and in a population of completers. Radiographs of the hands, wrists, and forefeet were scored for erosions and joint space narrowing at annual intervals.

Results

A total of 503 of 686 patients continued into year 2 of the study. During the 2 years, significantly fewer patients receiving combination therapy withdrew from the study (29% of the combination therapy group, 39% of the etanercept group, and 48% of the MTX group). Both the LOCF and the completer analyses yielded similar results. The ACR 20% improvement (ACR20), ACR50, and ACR70 responses and the remission rates (based on a DAS of <1.6) were significantly higher with combination therapy than with either monotherapy (P < 0.01). Similarly, improvement in disability (based on the Health Assessment Questionnaire) was greater with combination therapy (P < 0.01). The combination therapy group showed significantly less radiographic progression than did either group receiving monotherapy (P < 0.05); moreover, radiographic progression was significantly lower in the etanercept group compared with the MTX group (P < 0.05). For the second consecutive year, overall disease progression in the combination therapy group was negative, with the 95% confidence interval less than zero. Adverse events were similar in the 3 treatment groups.

Conclusion

Etanercept in combination with MTX reduced disease activity, slowed radiographic progression, and improved function more effectively than did either monotherapy over a 2‐year period. No increase in toxicity was associated with combination treatment with etanercept plus MTX.

     

A 48‐week,randomized, double‐blind,double‐observer,placebo‐controlled multicenter trial of combination methotrexate and intramuscular gold therapy in rheumatoid arthritis: Results of the METGO study

Objective

To evaluate the efficacy and safety of adding intramuscular (IM) gold to the treatment regimen of patients with rheumatoid arthritis (RA) who have a suboptimal response to methotrexate (MTX).

Methods

A randomized, double‐blind, double‐observer, placebo‐controlled multicenter trial of 48 weeks was conducted. Sixty‐five RA patients who had a suboptimal response to ≥12 weeks of MTX therapy were randomly assigned to receive weekly IM gold or placebo in addition to MTX. Gold was administered according to a standard protocol developed for the study. The primary outcome measure was the percentage of patients who met the American College of Rheumatology (ACR) 20% improvement criteria (achieved an ACR20 response) at week 48. Secondary outcomes included the percentages of patients achieving ACR50 and ACR70 responses, the individual criteria that make up the primary outcome, quality of life, direct and indirect health care costs, intraarticular steroid use, and adverse events, among other measures. Statistical analyses were based on an intent‐to‐treat strategy.

Results

Sixty‐one percent of patients receiving gold achieved an ACR20 response compared with 30% of patients receiving placebo (χ² = 6.04, P = 0.014; logistic regression odds ratio 3.64 [95% confidence interval 1.3, 10.4], P = 0.016). Twenty‐six percent of patients receiving gold achieved an ACR50 response compared with 4% of patients receiving placebo (P = 0.017), and 21% of patients receiving gold achieved an ACR70 response compared with 0% of patients receiving placebo (P = 0.011). From both clinical and cost‐effectiveness perspectives, gold was the preferred and dominant strategy. Study treatment was discontinued in 23 patients (14 in the placebo group compared with 9 in the gold group; P = 0.022) due to loss to followup, adverse events, or lack of efficacy.

Conclusion

In RA patients with a suboptimal response to MTX, adding weekly IM gold causes significant clinical improvement. Adverse events were minor, and IM gold–related adverse events led to discontinuation in only 11% of the gold group over 48 weeks.

     

Ultrasound Can Improve the Accuracy of the 2010 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Rheumatoid Arthritis to Predict the Requirement for Methotrexate Treatment

Objective

The 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for rheumatoid arthritis (RA) refer to a possible use of ultrasound “for confirmation of the clinical findings.” We undertook this study to determine the optimized definition of ultrasound‐detected synovitis for the 2010 ACR/EULAR criteria and to assess the impact of its use on the accuracy of RA classification.

Methods

One hundred nine patients with musculoskeletal symptoms for ≤3 years were enrolled in the study. Patients underwent clinical, laboratory, radiographic, and comprehensive ultrasonographic assessments at baseline and received routine management from expert rheumatologists who were blinded to the ultrasound findings.

Results

Sensitivity and specificity of the 2010 ACR/EULAR criteria using different definitions of synovitis to identify patients who developed a disease requiring methotrexate (MTX) treatment within 1 year were 58.5% and 79.4%, respectively, for clinical synovitis (tenderness or swelling), 78.0% and 79.4%, respectively, for ultrasound‐detected synovitis with a gray‐scale (GS) imaging score ≥1 (GS ≥1 ultrasound synovitis), and 56.1% and 93.7%, respectively, for GS ≥2 ultrasound synovitis or a synovial power Doppler (PD) signal score ≥1 (GS ≥2/PD ≥1 ultrasound synovitis). Receiver operating characteristic curve analysis for the criteria scores revealed the largest area under the curve with GS ≥2/PD ≥1 ultrasound synovitis.

Conclusion

Ultrasound assessment improves the accuracy of the 2010 ACR/EULAR criteria for identifying patients with a disease requiring MTX treatment. Our data provide preliminary but vital information for the methodology to confirm the presence of synovitis using ultrasound in the 2010 ACR/EULAR criteria.

     

Double‐blind randomized controlled clinical trial of the interleukin‐6 receptor antagonist,tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate

Objective

To establish the safety and efficacy of repeat infusions of tocilizumab (previously known as MRA), a humanized anti–interleukin‐6 (IL‐6) receptor antibody, alone and in combination with methotrexate (MTX), for the treatment of rheumatoid arthritis (RA).

Methods

The study group comprised 359 patients with active RA in whom the response to MTX was inadequate. During a stabilization period, these patients received their current dose of MTX for at least 4 weeks. Following stabilization, they were randomized to 1 of 7 treatment arms, as follows: tocilizumab at doses of 2 mg/kg, 4 mg/kg, or 8 mg/kg either as monotherapy or in combination with MTX, or MTX plus placebo.

Results

A 20% response (improvement) according to the American College of Rheumatology criteria (ACR20 response) was achieved by 61% and 63% of patients receiving 4 mg/kg and 8 mg/kg of tocilizumab as monotherapy, respectively, and by 63% and 74% of patients receiving those doses of tocilizumab plus MTX, respectively, compared with 41% of patients receiving placebo plus MTX. Statistically significant ACR50 and ACR70 responses were observed in patients receiving combination therapy with either 4 mg/kg or 8 mg/kg of tocilizumab plus MTX (P < 0.05). A dose‐related reduction in the Disease Activity Score in 28 joints was observed from week 4 onward, in all patients except those receiving monotherapy with 2 mg/kg of tocilizumab. In the majority of patients who received 8 mg/kg of tocilizumab, the C‐reactive protein level/erythrocyte sedimentation rate normalized, while placebo plus MTX had little effect on these laboratory parameters. Tocilizumab was mostly well tolerated, with a safety profile similar to that of other biologic and immunosuppressive therapies. Alanine transaminase and aspartate transaminase levels followed a sawtooth pattern (rising and falling between infusions). There were moderate but reversible increases in the nonfasting total cholesterol and triglyceride levels and reversible reductions in the high‐density lipoprotein cholesterol and neutrophil levels. There were 2 cases of sepsis, both of which occurred in patients who were receiving combination therapy with 8 mg/kg of tocilizumab plus MTX.

Conclusion

These results indicate that targeted blockade of IL‐6 signaling is a highly efficacious and promising means of decreasing disease activity in RA.

     

Safety and efficacy of ocrelizumab in patients with rheumatoid arthritis and an inadequate response to methotrexate: Results of a forty‐eight–week randomized,double‐blind,placebo‐controlled,parallel‐group phase III trial

Objective

To evaluate the efficacy and safety of treatment with ocrelizumab plus methotrexate (MTX) in patients with active rheumatoid arthritis (RA) and an inadequate response to MTX.

Methods

STAGE was a phase III randomized, double‐blind, parallel‐group international study to evaluate the safety and efficacy of ocrelizumab compared with placebo in patients with active RA continuing MTX treatment. Patients receiving stable doses of MTX were randomized to receive 2 infusions of placebo (n = 320), ocrelizumab 200 mg (n = 343), or ocrelizumab 500 mg (n = 343) on days 1 and 15 as well as weeks 24 and 26. Coprimary end points were the proportion of patients with an American College of Rheumatology 20% improvement criteria (ACR20) response at weeks 24 and 48. Secondary end points included the change from baseline in the modified Sharp/van der Heijde score (SHS) and the ACR50/70 responses.

Results

The ACR20 response rates were 35.7% in the placebo group, 56.9% in the ocrelizumab 200 mg group, and 54.5% in the ocrelizumab 500 mg group at 24 weeks, and 27.6%, 58.3%, and 62.1%, respectively, at 48 weeks (P < 0.0001 versus placebo for each dose at both time points). At week 48, both of the ocrelizumab doses improved the ACR50 and ACR70 response rates 3‐fold as compared with placebo and showed a statistically significant (P < 0.0001) reduction in joint damage progression relative to placebo (mean change in SHS reduced by 85% and 100% for the 200‐mg and 500‐mg doses, respectively). Rates of serious infection were comparable in the placebo (3.48 per 100 patient‐years) and ocrelizumab 200 mg (3.54 per 100 patient‐years) groups but were elevated in the ocrelizumab 500 mg group (8.66 per 100 patient‐years).

Conclusion

With both ocrelizumab doses, the primary end point was met, and the signs and symptoms of RA were significantly improved at weeks 24 and 48. Ocrelizumab also significantly inhibited the progression of joint damage. A higher rate of serious infections was observed with 500 mg of ocrelizumab as compared with ocrelizumab 200 mg or placebo.

     

Propensity‐adjusted association of methotrexate with overall survival in rheumatoid arthritis

Objective

While medications used to treat rheumatoid arthritis (RA) may affect survival in RA, few studies take into account the propensity for medication use, which may reflect selection bias in treatment allocation in survival models. We undertook this study to examine the relationship between methotrexate (MTX) use and mortality in RA, after controlling for individual propensity scores for MTX use.

Methods

We studied 5,626 RA patients prospectively for 25 years to determine the risk of death associated with MTX use, modeled in time‐varying Cox regression models. We used the random forest method to generate individual propensity scores for MTX use at study entry and during followup in a time‐varying manner; these scores were included in the multivariate model. We also investigated whether selective discontinuation of MTX immediately prior to death altered the risk of mortality, and we examined the association of duration of MTX use with survival.

Results

During followup, 666 patients (12%) died. MTX use was associated with reduced risk of death (adjusted hazard ratio 0.30 [95% confidence interval 0.09–1.03]). Selective MTX cessation immediately before death did not account for the protective association of MTX use with mortality. Only MTX use for >1 year was associated with lower risks of mortality, but associations were not stronger with longer durations of use.

Conclusion

MTX use was associated with a 70% reduction in mortality in RA.

     

A clinical pharmacogenetic model to predict the efficacy of methotrexate monotherapy in recent‐onset rheumatoid arthritis

Objective

To develop a clinical pharmacogenetic model to predict the efficacy of methotrexate (MTX) in rheumatoid arthritis (RA).

Methods

Two hundred five patients with newly diagnosed RA and active disease were treated with MTX (initiated at a dosage of 7.5 mg/week and increased to 15 mg/week after 4 weeks) and folic acid (1 mg/day). If the Disease Activity Score (DAS) was >2.4 at 3 months, the dosage of MTX was increased up to 25 mg/week. Twenty‐four baseline variables possibly influencing disease state and drug response were selected. In addition, 17 polymorphisms in 13 genes related to the MTX mechanism of action, purine and pyrimidine synthesis, were determined. Factors were compared between responders (defined as patients with a DAS ≤2.4 at 6 months) and nonresponders. In case of differences, a stepwise selection procedure identified the predictors for response. A clinical score was designed by simplifying regression coefficients of the independent variables. Cutoff levels were chosen based on the clinical score, and positive and negative response rates were calculated. An evaluation of the model was performed in a second group of patients.

Results

The model for MTX efficacy consisted of sex, rheumatoid factor and smoking status, the DAS, and 4 polymorphisms in the AMPD1, ATIC, ITPA, and MTHFD1 genes. This prediction model was transformed into a scoring system ranging from 0 to 11.5. Scores of ≤3.5 had a true positive response rate of 95%. Scores of ≥6 had a true negative response rate of 86%. Sixty percent of the patients were categorized as either responders or nonresponders, whereas 32% of the patients were categorized using a nongenetic model. Evaluation of the model in 38 additional patients with RA supported the results.

Conclusion

This study established a model for predicting the efficacy of MTX in patients with RA. This pharmacogenetic model may lead to better‐tailored initial treatment decisions in patients with RA.

     

Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: Twelve‐month results of a phase iib,double‐blind,randomized, placebo‐controlled trial

Objective

To determine the clinical efficacy, safety, and immunogenicity of abatacept (CTLA‐4Ig), a selective costimulation modulator, in patients with rheumatoid arthritis (RA) that has remained active despite methotrexate (MTX) therapy.

Methods

This was a 12‐month, multicenter, randomized, double‐blind, placebo‐controlled study. A total of 339 patients with active RA despite MTX therapy were randomly assigned to receive 10 mg/kg abatacept (n = 115), 2 mg/kg abatacept (n = 105), or placebo (n = 119). This report focuses on the results observed at month 12 of a phase IIb trial.

Results

A significantly greater percentage of patients treated with 10 mg/kg abatacept met the American College of Rheumatology 20% improvement criteria (achieved an ACR20 response) at 1 year compared with patients who received placebo (62.6% versus 36.1%; P < 0.001). Greater percentages of patients treated with 10 mg/kg abatacept also achieved ACR50 responses (41.7% versus 20.2%; P < 0.001) and ACR70 responses (20.9% versus 7.6%; P = 0.003) compared with patients who received placebo. For patients treated with 10 mg/kg abatacept, there were also statistically significant and clinically important improvements in modified Health Assessment Questionnaire scores compared with patients who received placebo (49.6% versus 27.7%; P < 0.001). Abatacept at a dosage of 10 mg/kg elicited an increase in rates of remission (Disease Activity Score in 28 joints of <2.6) compared with placebo at 1 year (34.8% versus 10.1%; P < 0.001). The incidence of adverse events was comparable between the groups, and no significant formation of neutralizing antibodies was noted.

Conclusion

Abatacept was associated with significant reductions in disease activity and improvements in physical function that were maintained over the course of 12 months in patients with RA that had remained active despite MTX treatment. Abatacept was found to be well tolerated and safe over the course of 1 year. Abatacept in combination with MTX has the potential to play an important role in future RA therapy.

     

The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: Results of a phase IIB randomized,double‐blind,placebo‐controlled,dose‐ranging trial

Objective

To examine the efficacy and safety of different rituximab doses plus methotrexate (MTX), with or without glucocorticoids, in patients with active rheumatoid arthritis (RA) resistant to disease‐modifying antirheumatic drugs (DMARDs), including biologic agents.

Methods

A total of 465 patients were randomized into 9 treatment groups: 3 rituximab groups (placebo [n = 149], 500 mg [n = 124], or 1,000 mg [n = 192] on days 1 and 15) each also taking either placebo glucocorticoids, intravenous methylprednisolone premedication, or intravenous methylprednisolone premedication plus oral prednisone for 2 weeks. All patients received MTX (10–25 mg/week); no other DMARDs were permitted.

Results

Significantly more patients who received 2 500‐mg or 2 1,000‐mg infusions of rituximab met the American College of Rheumatology 20% improvement criteria (achieved an ACR20 response) at week 24 (55% and 54%, respectively) compared with placebo (28%; P < 0.0001). ACR50 responses were achieved by 33%, 34%, and 13% of patients, respectively (P < 0.001), and ACR70 responses were achieved by 13%, 20%, and 5% of patients (P < 0.05). Changes in the Disease Activity Score in 28 joints (−1.79, −2.05, −0.67; P < 0.0001) and moderate to good responses on the European League Against Rheumatism criteria (P < 0.0001) reflected the ACR criteria responses. Glucocorticoids did not contribute significantly to the primary efficacy end point, ACR20 response at 24 weeks. Intravenous glucocorticoid premedication reduced the frequency and intensity of first infusion–associated events; oral glucocorticoids conferred no additional safety benefit. Rituximab was well tolerated; the type and severity of infections was similar to those for placebo.

Conclusion

Both rituximab doses were effective and well tolerated when added to MTX therapy in patients with active RA. The primary end point (ACR20 response) was independent of glucocorticoids, although intravenous glucocorticoid premedication improved tolerability during the first rituximab infusion.

     

The clinical picture of rheumatoid arthritis according to the 2010 American College of Rheumatology/European League Against Rheumatism criteria: Is this still the same disease?

Objective

To examine the implications of using the new classification criteria for rheumatoid arthritis (RA) in clinical practice in a cohort of patients with very early arthritis.

Methods

The study group comprised 301 disease‐modifying antirheumatic drug–naive patients with early arthritis. The baseline diagnosis was assessed by applying the 1987 American College of Rheumatology (ACR) and 2010 ACR/European League Against Rheumatism (EULAR) criteria for RA as well as established diagnostic criteria for other rheumatic diseases. Diagnostic and prognostic data were collected after 2 years of followup. Fulfillment of the 2010 ACR/EULAR criteria was evaluated in the subset of patients in whom undifferentiated arthritis (UA) was diagnosed when the 1987 ACR criteria were applied, and fulfillment of RA criteria over time was tested by applying the 2 different criteria sets.

Results

The median arthritis duration at baseline was 4 months (range 0–12 months). At baseline, 28% of the patients fulfilled the 1987 ACR criteria, and 45% fulfilled the 2010 ACR/EULAR criteria for RA. Among the patients classified as having UA at baseline according to the 1987 ACR criteria, 36% had fulfilled the 2010 ACR/EULAR criteria already at baseline. Among the patients classified as having UA at baseline but who fulfilled the 1987 ACR criteria after 2 years of followup, 85% had fulfilled the 2010 ACR/EULAR criteria at baseline. Patients with early disease who fulfilled the 2010 ACR/EULAR criteria were less likely to be autoantibody positive and more likely to have monarthritis at presentation than those fulfilling the 1987 ACR criteria.

Conclusion

Use of the 2010 ACR/EULAR criteria clearly allows earlier diagnosis of RA, although the clinical picture is slightly different on the group level, and RA may be falsely diagnosed in some patients with self‐limiting disease.