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.

     

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.

     

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.

     

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.

     

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.

     

Alefacept in combination with methotrexate for the treatment of psoriatic arthritis: Results of a randomized,double‐blind,placebo‐controlled study

Objective

To evaluate the efficacy and safety of alefacept in combination with methotrexate (MTX) for the treatment of psoriatic arthritis (PsA).

Methods

Patients were eligible for this randomized, double‐blind, placebo‐controlled trial if they were ages 18–70 years and had active PsA (≥3 swollen joints and ≥3 tender joints) despite treatment with MTX for ≥3 months (a stable dosage for ≥4 weeks prior to enrollment). Patients were stratified according to psoriasis body surface area (BSA) involvement (≥3% or <3%). Alefacept (15 mg) or placebo was administered intramuscularly once weekly for 12 weeks in combination with MTX, followed by 12 weeks of observation during which only MTX treatment was continued. The primary efficacy end point was the proportion of patients achieving a 20% improvement in disease activity according to the American College of Rheumatology criteria (an ACR20 response) at week 24.

Results

One hundred eighty‐five patients were randomly assigned to receive alefacept plus MTX (n = 123) or placebo plus MTX (n = 62). At week 24, 54% of patients in the alefacept plus MTX group achieved an ACR20 response, compared with 23% of patients in the placebo plus MTX group (P < 0.001). Mean reductions in tender and swollen joint counts in patients receiving alefacept plus MTX were –8.0 and –6.3, respectively. In patients with psoriasis involving ≥3% BSA (n = 87), a 50% reduction from the baseline Psoriasis Area Severity Index at week 14 was achieved by 53% of patients receiving alefacept plus MTX compared with 17% of those receiving placebo plus MTX (P < 0.001). Most adverse events were mild to moderate in severity. In the alefacept plus MTX group, the incidence of serious adverse events was low (1.6%), and no opportunistic infections or malignancies were reported.

Conclusion

Alefacept in combination with MTX may be an effective and safe treatment for PsA.

     

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.

     

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 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.

     

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 at least one tumor necrosis factor inhibitor: Results of a forty‐eight–week randomized,double‐blind,placebo‐controlled,parallel‐group phase III trial

Objective

To evaluate the safety and efficacy of ocrelizumab plus methotrexate (MTX) or leflunomide (LEF) in patients with active rheumatoid arthritis (RA) and an inadequate response to tumor necrosis factor α inhibitors.

Methods

This was a multicenter randomized, double‐blind, placebo‐controlled, parallel‐group study that continued over 48 weeks. Patients receiving stable doses of MTX or LEF were randomized to receive 2 infusions of placebo (n = 277), ocrelizumab 200 mg (n = 278), or ocrelizumab 500 mg (n = 285) on days 1 and 15 as well as at weeks 24 and 26. Coprimary end points were the proportion of patients with response according to the American College of Rheumatology 20% improvement criteria (ACR20) 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

ACR20 responses were 22.0% in the placebo group, 42.2% in the ocrelizumab 200 mg group, and 47.9% in the ocrelizumab 500 mg group at 24 weeks and 19.5%, 48.7%, and 50.7%, respectively, at 48 weeks (P < 0.0001 versus placebo for each comparison at each time point). At 48 weeks, patients receiving both doses of ocrelizumab showed significantly improved ACR50 and ACR70 responses of ∼3‐fold versus placebo. Only those in the ocrelizumab 500 mg group showed statistically significant (P = 0.0017) inhibition of joint damage progression (mean change in the SHS) relative to placebo (61% inhibition) at 48 weeks. Overall adverse events and infections during the 48 weeks of study were comparable in all treatment groups. Serious infections were observed more frequently in patients taking ocrelizumab (5.1% and 4.3%) than in those taking placebo (2.5%).

Conclusion

Patients in both of the ocrelizumab groups met the clinical primary efficacy end points. Inhibition of change in the SHS was statistically significant at 48 weeks for those in the ocrelizumab 500 mg group. The rate of serious infections in this trial was higher for both ocrelizumab doses as compared with placebo.

     

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.

     

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.

     

Rituximab for rheumatoid arthritis refractory to anti–tumor necrosis factor therapy: Results of a multicenter,randomized, double‐blind,placebo‐controlled,phase III trial evaluating primary efficacy and safety at twenty‐four weeks

Objective

To determine the efficacy and safety of treatment with rituximab plus methotrexate (MTX) in patients with active rheumatoid arthritis (RA) who had an inadequate response to anti–tumor necrosis factor (anti‐TNF) therapies and to explore the pharmacokinetics and pharmacodynamics of rituximab in this population.

Methods

We evaluated primary efficacy and safety at 24 weeks in patients enrolled in the Randomized Evaluation of Long‐Term Efficacy of Rituximab in RA (REFLEX) Trial, a 2‐year, multicenter, randomized, double‐blind, placebo‐controlled, phase III study of rituximab therapy. Patients with active RA and an inadequate response to 1 or more anti‐TNF agents were randomized to receive intravenous rituximab (1 course, consisting of 2 infusions of 1,000 mg each) or placebo, both with background MTX. The primary efficacy end point was a response on the American College of Rheumatology 20% improvement criteria (ACR20) at 24 weeks. Secondary end points were responses on the ACR50 and ACR70 improvement criteria, the Disease Activity Score in 28 joints, and the European League against Rheumatism (EULAR) response criteria at 24 weeks. Additional end points included scores on the Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT‐F), Health Assessment Questionnaire (HAQ) Disability Index (DI), and Short Form 36 (SF‐36) instruments, as well as Genant‐modified Sharp radiographic scores at 24 weeks.

Results

Patients assigned to placebo (n = 209) and rituximab (n = 311) had active, longstanding RA. At week 24, significantly more (P < 0.0001) rituximab‐treated patients than placebo‐treated patients demonstrated ACR20 (51% versus 18%), ACR50 (27% versus 5%), and ACR70 (12% versus 1%) responses and moderate‐to‐good EULAR responses (65% versus 22%). All ACR response parameters were significantly improved in rituximab‐treated patients, who also had clinically meaningful improvements in fatigue, disability, and health‐related quality of life (demonstrated by FACIT‐F, HAQ DI, and SF‐36 scores, respectively) and showed a trend toward less progression in radiographic end points. Rituximab depleted peripheral CD20+ B cells, but the mean immunoglobulin levels (IgG, IgM, and IgA) remained within normal ranges. Most adverse events occurred with the first rituximab infusion and were of mild‐to‐moderate severity. The rate of serious infections was 5.2 per 100 patient‐years in the rituximab group and 3.7 per 100 patient‐years in the placebo group.

Conclusion

At 24 weeks, a single course of rituximab with concomitant MTX therapy provided significant and clinically meaningful improvements in disease activity in patients with active, longstanding RA who had an inadequate response to 1 or more anti‐TNF therapies.

     

Very early treatment with infliximab in addition to methotrexate in early,poor‐prognosis rheumatoid arthritis reduces magnetic resonance imaging evidence of synovitis and damage,with sustained benefit after infliximab withdrawal: Results from a twelve‐month randomized,double‐blind,placebo‐controlled trial

Objective

Anti–tumor necrosis factor α agents are among the most effective therapies for rheumatoid arthritis (RA). However, their optimal use is yet to be determined. This 12‐month double‐blind study attempted remission induction using standard therapy with or without infliximab in patients with early, poor‐prognosis RA. The primary end point was synovitis (measured by magnetic resonance imaging [MRI]). Clinical observations continued to 24 months.

Methods

All patients had fewer than 12 months of symptoms. Assessments included full metrologic evaluation, laboratory tests, radiographs, functional evaluation using the Health Assessment Questionnaire (HAQ), and quality of life measurement using the RA Quality of Life (RAQoL) questionnaire. MRI was performed at 0, 4, 14, and 54 weeks; MR images were scored blindly. Patients received methotrexate (MTX) and were randomized to receive either infliximab or placebo for 12 months.

Results

Twenty patients were recruited (mean age 52 years, mean symptom duration 6 months, mean C‐reactive protein level 42 mg/liter, and 65% rheumatoid factor positive). At 1 year, all MRI scores were significantly better, with no new erosions in the infliximab plus MTX group; a greater percentage of infliximab plus MTX–treated patients fulfilled the American College of Rheumatology (ACR) 50% and 70% improvement criteria (78% versus 40% in the placebo plus MTX group and 67% versus 30%, respectively) and had a greater functional benefit (P < 0.05 for all comparisons). Importantly, at 1 year after stopping induction therapy, response was sustained in 70% of the patients in the infliximab plus MTX group, with a median Disease Activity Score in 28 joints (DAS28) of 2.05 (remission range). At 2 years, there were no significant between‐group differences in the DAS28, ACR response, or radiographic scores, but differences in the HAQ and RAQoL scores were maintained (P < 0.05).

Conclusion

Remission induction with infliximab plus MTX provided a significant reduction in MRI evidence of synovitis and erosions at 1 year. At 2 years, functional and quality of life benefits were sustained, despite withdrawal of infliximab therapy. These data may have significant implications for the optimal use of expensive biologic therapies.

     

Methotrexate treatment in juvenile localized scleroderma: A randomized,double‐blind,placebo‐controlled trial

Objective

Juvenile localized scleroderma is a chronic progressive fibrotic disorder of the skin that causes permanent disability and aesthetic damage. This study was undertaken to assess the safety and efficacy of methotrexate (MTX) in the treatment of juvenile localized scleroderma.

Methods

In this double‐blind study, patients with active juvenile localized scleroderma were randomized (2:1) to receive oral MTX (15 mg/m², maximum 20 mg) or placebo once weekly, for 12 months or until treatment failure. Both groups received oral prednisone (1 mg/kg/day, maximum 50 mg) for the first 3 months. A target lesion was evaluated clinically, with infrared thermography and using a computerized scoring system with skin score rate (SSR) evaluation. Response to treatment was defined as the absence of new lesions, SSR ≤1, and a decrease in lesion temperature of at least 10% compared to baseline. Treatment failure was defined as the occurrence of new lesions, SSR >1, or increased lesion temperature. All analyses were done on the intent‐to‐treat population.

Results

Of the 85 patients screened, 70 (ages 6–17 years) were randomized (46 to the MTX group, 24 to the placebo group). The mean disease duration was 2.3 years. After an initial response in all patients, disease relapsed in 15 MTX‐treated patients (32.6%) and 17 placebo‐treated patients (70.8%) (P < 0.005). New lesions appeared in 3 MTX‐treated patients (6.5%) versus 4 placebo‐treated patients (16.7%). The mean SSR decreased from 1 to 0.79 in the MTX group and increased from 1 to 1.1 in the placebo group, and the mean target lesion temperature decreased by 44.4% in the MTX group versus 12.1% in the placebo group. Twenty‐six patients in the MTX group (56.5%) and 11 patients in the placebo group (45.8%) developed mild side effects related to treatment. None of the side effects were severe enough to necessitate treatment discontinuation.

Conclusion

Our findings indicate that MTX is efficacious in the treatment of juvenile localized scleroderma and is well tolerated.

     

Treatment of rheumatoid arthritis with humanized anti–interleukin‐6 receptor antibody: A multicenter,double‐blind,placebo‐controlled trial

Objective

Interleukin‐6 (IL‐6) is a pleiotropic cytokine that regulates the immune response, inflammation, and hematopoiesis. Overproduction of IL‐6 plays pathologic roles in rheumatoid arthritis (RA), and the blockade of IL‐6 may be therapeutically effective for the disease. This study was undertaken to evaluate the safety and efficacy of a humanized anti–IL‐6 receptor antibody, MRA, in patients with RA.

Methods

In a multicenter, double‐blind, placebo‐controlled trial, 164 patients with refractory RA were randomized to receive either MRA (4 mg/kg body weight or 8 mg/kg body weight) or placebo. MRA was administered intravenously every 4 weeks for a total of 3 months. The clinical responses were measured using the American College of Rheumatology (ACR) criteria.

Results

Treatment with MRA reduced disease activity in a dose‐dependent manner. At 3 months, 78% of patients in the 8‐mg group, 57% in the 4‐mg group, and 11% in the placebo group achieved at least a 20% improvement in disease activity according to the ACR criteria (an ACR20 response) (P < 0.001 for 8‐mg group versus placebo). Forty percent of patients in the 8‐mg group and 1.9% in the placebo group achieved an ACR50 response (P < 0.001). The overall incidences of adverse events were 56%, 59%, and 51% in the placebo, 4‐mg, and 8‐mg groups, respectively, and the adverse events were not dose dependent. A blood cholesterol increase was observed in 44.0% of the patients. Liver function disorders and decreases in white blood cell counts were also observed, but these were mild and transient. There was no increase in antinuclear antibodies or anti‐DNA antibodies. Anti‐MRA antibodies were detected in 2 patients.

Conclusion

Treatment with MRA was generally well tolerated and significantly reduced the disease activity of RA.

     

LY2439821, a humanized anti–interleukin‐17 monoclonal antibody,in the treatment of patients with rheumatoid arthritis: A phase I randomized,double‐blind,placebo‐controlled,proof‐of‐concept study

Objective

We undertook this study to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of LY2439821, a humanized anti–interleukin‐17 (anti–IL‐17) monoclonal antibody, in a first in‐human trial in rheumatoid arthritis (RA) patients taking oral disease‐modifying antirheumatic drugs (DMARDs).

Methods

This randomized, double‐blind, placebo‐controlled study consisted of 2 parts. In part A, 20 patients received 1 intravenous (IV) dose of LY2439821 (0.06, 0.2, 0.6, or 2.0 mg/kg, escalating) or placebo followed by 8 weeks of evaluation. End points included safety, tolerability, and pharmacokinetics. In part B, 77 patients received 1 IV dose of LY2439821 (0.2, 0.6, or 2.0 mg/kg) or placebo every 2 weeks for a total of 5 doses, with a total evaluation period of 16 weeks. End points included safety, tolerability, pharmacokinetics/pharmacodynamics, and efficacy (Disease Activity Score in 28 joints [DAS28] and percentages of patients meeting American College of Rheumatology 20%, 50%, or 70% improvement criteria [achieving an ACR20, ACR50, or ACR70 response]). The primary efficacy end point was the DAS28 at week 10.

Results

Baseline characteristics were similar across all groups. Changes in the DAS28 were significantly greater in the 0.2 mg/kg, 2.0 mg/kg, and all‐LY2439821–combined groups (−2.3, −2.4, and −2.3, respectively) than in the placebo group (−1.7) at week 10 (P ≤ 0.05), and these differences were significant as early as week 1. Percentages of ACR20, ACR50, and ACR70 responses as well as improvements in the ACR core set of measures were greater in LY2439821‐treated patients than in placebo‐treated patients at multiple time points. There was no apparent dose‐response relationship in treatment‐emergent adverse events.

Conclusion

LY2439821 added to oral DMARDs improved signs and symptoms of RA, with no strong adverse safety signal noted. This first evaluation of LY2439821 supports neutralization of IL‐17 as a potential novel goal for the treatment of RA.

     

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.