Adalimumab for long‐term treatment of psoriatic arthritis: Forty‐eight week data from the adalimumab effectiveness in psoriatic arthritis trial

Objective

To evaluate the efficacy and safety of treatment with adalimumab, a fully human anti–tumor necrosis factor (anti‐TNF) monoclonal antibody, over 48 weeks in patients with moderate to severe psoriatic arthritis (PsA).

Methods

Patients who completed the Adalimumab Effectiveness in Psoriatic Arthritis Trial (ADEPT), a 24‐week, double‐blind study of adalimumab versus placebo in PsA, could elect to receive open‐label adalimumab, 40 mg subcutaneously every other week after week 24. Radiographs were obtained at week 48 and were read with radiographs obtained previously. Clinical and radiographic efficacy data were analyzed overall and in patient subsets. Safety data were collected over 48 weeks.

Results

At week 48, patients from the adalimumab arm of ADEPT (n = 151) had achieved American College of Rheumatology 20% improvement (ACR20), ACR50, and ACR70 response rates of 56%, 44%, and 30%, respectively. Among those evaluated with the Psoriasis Area and Severity Index (PASI) (n = 69), PASI50, PASI75, PASI90, and PASI100 response rates (≥50%, ≥75%, ≥90%, and 100% reduction in PASI scores, respectively) were 67%, 58%, 46%, and 33%, respectively (ACR and PASI response rates were analyzed using nonresponder imputation). Improvements in disability, as measured by the Disability Index of the Health Assessment Questionnaire (mean change in score –0.4) were sustained from week 24 to week 48. At week 24 and week 48, the mean changes from baseline in the modified total Sharp score were –0.1 and 0.1, respectively, for patients who received adalimumab for 48 weeks (n = 133), and 0.9 and 1.0, respectively, for patients who received placebo for 24 weeks followed by adalimumab for 24 weeks (n = 141). Adalimumab demonstrated clinical and radiographic efficacy regardless of whether patients were receiving methotrexate (MTX) at baseline. Adalimumab was generally safe and well tolerated through week 48.

Conclusion

Adalimumab improved joint and skin manifestations, reduced disability, and inhibited radiographic progression over 48 weeks in patients with PsA who were participants in ADEPT. MTX use at baseline was not required for clinical or radiographic efficacy. Adalimumab had a good safety profile through week 48.

     

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.

     

Adalimumab significantly reduces both spinal and sacroiliac joint inflammation in patients with ankylosing spondylitis: A multicenter,randomized, double‐blind,placebo‐controlled study

Objective

To compare the efficacy of adalimumab versus placebo in reducing spinal and sacroiliac (SI) joint inflammation, by magnetic resonance imaging (MRI) in patients with active ankylosing spondylitis (AS).

Methods

This was a randomized, multicenter, double‐blind, placebo‐controlled study. Patients (n = 82) received 40 mg adalimumab or placebo every other week during an initial 24‐week double‐blind period. MRIs of both the spine and SI joints were obtained at baseline, week 12, and week 52. Spinal and SI joint inflammation were measured using the Spondyloarthritis Research Consortium of Canada (SPARCC) MRI index.

Results

The spine SPARCC score in placebo‐treated patients increased by a mean of 9.4% from baseline, compared with a mean decrease of 53.6% in adalimumab‐treated patients (P < 0.001); the SI joint SPARCC score decreased by a mean of 12.7% from baseline in placebo‐treated patients and by 52.9% in adalimumab‐treated patients (P = 0.017). The response in adalimumab‐treated patients was maintained at week 52. Placebo‐treated patients were switched to open‐label adalimumab treatment at week 24 and experienced similar reductions in spinal and SI joint inflammation by week 52. Similar large reductions in the spine and SI joint SPARCC scores were noted, even in patients who failed to meet the ASsessment in Ankylosing Spondylitis (International Working Group) criteria (nonresponders) at 12 weeks. In adalimumab‐treated patients, a reduced C‐reactive protein concentration at week 12 was significantly associated with improvement in the spine SPARCC score (P = 0.018).

Conclusion

Adalimumab significantly reduced both spinal and SI joint inflammation in patients with active AS after 12 weeks of treatment, and these improvements were maintained for up to 52 weeks.

     

Efficacy and safety of adalimumab in patients with ankylosing spondylitis: Results of a multicenter,randomized, double‐blind,placebo‐controlled trial

Objective

To evaluate the safety and efficacy of adalimumab, a fully human recombinant IgG1 monoclonal antibody that specifically targets human tumor necrosis factor, in patients with active ankylosing spondylitis (AS).

Methods

This was a multicenter, randomized (2:1 ratio), double‐blind, placebo‐controlled study to evaluate a subcutaneous injection of adalimumab, 40 mg every other week, compared with placebo for 24 weeks. The primary efficacy end point was the percentage of patients with a 20% response according to the ASsessment in Ankylosing Spondylitis International Working Group criteria for improvement (ASAS20) at week 12. Secondary outcome measures included the ASAS20 at week 24 and multiple measures of disease activity, spinal mobility, and function, as well as ASAS partial remission.

Results

At week 12, 58.2% of adalimumab‐treated patients (121 of 208) achieved an ASAS20 response, compared with 20.6% of placebo‐treated patients (22 of 107) (P < 0.001). More patients in the adalimumab group (45.2% [94 of 208]) than in the placebo group (15.9% [17 of 107]) had at least a 50% improvement in the Bath Ankylosing Spondylitis Disease Activity Index at week 12 (P < 0.001). Significant improvements in the ASAS40 response and the response according to the ASAS5/6 criteria at weeks 12 and 24 were also demonstrated (P < 0.001). Partial remission was achieved by more adalimumab‐treated patients than placebo‐treated patients (22.1% versus 5.6%; P < 0.001). Adalimumab‐treated patients reported more adverse events (75.0% versus 59.8% of placebo‐treated patients; P < 0.05), but there was no statistically significant difference in the incidence of infections. Most adverse events were mild or moderate in severity.

Conclusion

Adalimumab was well‐tolerated during the 24‐week study period and was associated with a significant and sustained reduction in the signs and symptoms of active AS.

     

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

Objective

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).

Methods

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]).

Results

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 ≤ 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 ≤ 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 ≤ 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 ≤ 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 ≤ 0.02), and was highest in the patients receiving 40 mg every other week.

Conclusion

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.

     

Oral apremilast in the treatment of active psoriatic arthritis: Results of a multicenter,randomized, double‐blind,placebo‐controlled study

Objective

To evaluate the efficacy and safety of apremilast, a novel, orally available small molecule that specifically targets phosphodiesterase 4, in the treatment of active psoriatic arthritis (PsA).

Methods

This phase II, multicenter, randomized, double‐blind, placebo‐controlled study included the following: a 12‐week treatment phase, with patients receiving placebo, apremilast 20 mg twice per day, or apremilast 40 mg once per day; a 12‐week treatment‐extension phase, with patients in the placebo group re‐randomized to receive apremilast; and a 4‐week observational phase after treatment cessation. The primary end point was the proportion of patients achieving the American College of Rheumatology criteria for 20% improvement (ACR20) at week 12. Safety assessments included adverse events (AEs), physical examinations, vital signs, laboratory parameters, and electrocardiograms.

Results

Of the 204 patients with PsA who were randomized to a treatment group, 165 completed the treatment phase. At the end of the treatment phase (week 12), 43.5% of patients receiving apremilast 20 mg twice per day (P < 0.001) and 35.8% of those receiving 40 mg once per day (P = 0.002) achieved an ACR20 response, compared with 11.8% of those receiving placebo. At the end of the treatment‐extension phase (week 24), >40% of patients in each group (patients receiving apremilast 20 mg twice per day, patients receiving apremilast 40 mg once per day, and patients in the placebo group re‐randomized to receive apremilast) achieved the ACR20 level of improvement. Most patients in the treatment phase (84.3%) and treatment‐extension phase (68.3%) reported ≥1 AE. Diarrhea, headache, nausea, fatigue, and nasopharyngitis were reported most frequently; most events were mild or moderate. No clinically relevant laboratory or electrocardiographic abnormalities were reported.

Conclusion

Treatment with apremilast at a dosage of 20 mg twice per day or 40 mg once per day demonstrated efficacy in comparison with placebo and was generally well tolerated in patients with active PsA. The balance of efficacy, tolerability, and safety supports further study of apremilast in PsA.

     

Atacicept in patients with rheumatoid arthritis and an inadequate response to methotrexate: Results of a phase II,randomized, placebo‐controlled trial

Objective

To assess the efficacy, safety, and biologic activity of atacicept in tumor necrosis factor antagonist–naive patients with rheumatoid arthritis (RA) in whom the response to methotrexate treatment was inadequate.

Methods

In this phase II study, patients with active RA (n = 311) were randomized 1:1:1:1 to receive placebo, atacicept 150 mg weekly with or without a 4‐week loading period (twice‐weekly dosing), or open‐label adalimumab 40 mg every other week, for 25 weeks. The primary end point was 20% improvement in disease severity according to the American College of Rheumatology criteria, assessed using the C‐reactive protein level (ACR20‐CRP), at week 26. Secondary end points included additional assessments of efficacy, biologic activity, and safety.

Results

The proportion of patients meeting the primary end point (ACR20‐CRP response) did not differ significantly in the atacicept groups and the placebo group (46% in the placebo group, 45% in the atacicept loading group, and 58% in the atacicept nonloading group). In contrast, an ACR20‐CRP response was observed in 71% of patients in the adalimumab group (P < 0.001 versus placebo). ACR50‐CRP response rates were significantly higher in all active‐treatment groups compared with placebo, but ACR70‐CRP response rates were superior only in the adalimumab group. Atacicept treatment reduced the levels of serum IgG, IgA, and IgM rheumatoid factor and the levels of circulating mature B cells and plasma cells. The effects of treatment were similar with and without loading. Immunoglobulin levels returned toward baseline values during the treatment‐free followup period (week 38). The most frequent adverse events associated with atacicept represented common illnesses. No serious infections occurred among patients treated with atacicept.

Conclusion

The primary end point (ACR20‐CRP response) was not met despite significant biologic effects of atacicept that were consistent with its proposed mechanism of action. Modest effects of atacicept were seen for some secondary efficacy end points. Treatment with atacicept raised no new safety concerns.

     

Golimumab,a new human tumor necrosis factor α antibody,administered every four weeks as a subcutaneous injection in psoriatic arthritis: Twenty‐four–week efficacy and safety results of a randomized,placebo‐controlled study

Objective

To assess the efficacy and safety of golimumab in patients with active psoriatic arthritis (PsA).

Methods

Adult patients with PsA who had at least 3 swollen and 3 tender joints and active psoriasis were randomly assigned to receive subcutaneous injections of placebo (n = 113), golimumab 50 mg (n = 146), or golimumab 100 mg (n = 146) every 4 weeks through week 20. Efficacy assessments through week 24 included the American College of Rheumatology 20% improvement criteria (ACR20), the Psoriasis Area and Severity Index (PASI) in patients in whom at least 3% of the body surface area was affected by psoriasis at baseline, the Short Form 36 Health Survey (SF‐36), the disability index of the Health Assessment Questionnaire (HAQ), the Nail Psoriasis Severity Index (NAPSI), the physician's global assessment of psoriatic nail disease, and enthesitis (using the PsA‐modified Maastricht Ankylosing Spondylitis Enthesitis Score [MASES] index).

Results

At week 14, 48% of all patients receiving golimumab, 51% of patients receiving golimumab 50 mg, and 45% of patients receiving golimumab 100 mg achieved an ACR20 response (the primary end point), compared with 9% of patients receiving placebo (P < 0.001 for all comparisons). Among the 74% of patients in whom at least 3% of the body surface area was affected by psoriasis at baseline, 40% of those in the golimumab 50 mg group and 58% of those in the golimumab 100 mg group had at least 75% improvement in the PASI at week 14 (major secondary end point), compared with 3% of placebo‐treated patients (P < 0.001 for both doses). Significant improvement was observed for other major secondary end points (the HAQ and the SF‐36), the NAPSI, the physician's global assessment of psoriatric nail disease, and the PsA‐modified MASES index in each golimumab group compared with placebo. This efficacy was maintained through week 24. Golimumab was generally well tolerated.

Conclusion

Treatment with golimumab at doses of 50 mg and 100 mg significantly improved active PsA and associated skin and nail psoriasis through week 24.

     

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.

     

Open‐label study of infliximab treatment for psoriatic arthritis: Clinical and magnetic resonance imaging measurements of reduction of inflammation

Objective

To evaluate infliximab efficacy and safety in disease‐modifying antirheumatic drug–unresponsive psoriatic arthritis (PsA).

Methods

In a 54‐week, open‐label, compassionate‐use study, 10 patients received intravenous infliximab (5 mg/kg; weeks 0, 2, 6; individualized dosing after week 10). Patients continued their current therapy (stable dose) until week 10. Assessments were performed at weeks 2, 6, 10, and 54. Magnetic resonance imaging (MRI) objectively measured joint inflammation at weeks 0 and 10.

Results

Patients achieved a 20% improvement according to the American College of Rheumatology (ACR) criteria (ACR20) in all patients by week 2; 8 patients improved 70% (ACR70) at week 10; 6 patients maintained ACR70 after week 54. Week 10 MRI revealed an 82.5% mean reduction in inflammation from baseline, and psoriasis area and severity index scores were reduced by 71.3% ± 16.7%. There were no significant adverse events, severe infections, or infusion reactions.

Conclusion

Infliximab was effective, safe, and well tolerated in PsA. Arthritis and psoriasis improved in all patients during the 54‐week evaluation. Further investigation of the use of infliximab for PsA and psoriasis is warranted.

     

The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: Results of a double‐blind,placebo‐controlled phase IIa trial of three dosage levels of CP‐690,550 versus placebo

Objective

To determine the efficacy, safety, and tolerability of 3 different dosages of CP‐690,550, a potent, orally active JAK inhibitor, in patients with active rheumatoid arthritis (RA) in whom methotrexate, etanercept, infliximab, or adalimumab caused an inadequate or toxic response.

Methods

Patients (n = 264) were randomized equally to receive placebo, 5 mg of CP‐690,550, 15 mg of CP‐690,550, or 30 mg of CP‐690,550 twice daily for 6 weeks, and were followed up for an additional 6 weeks after treatment. The primary efficacy end point was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at 6 weeks.

Results

By week 6, the ACR20 response rates were 70.5%, 81.2%, and 76.8% in the 5 mg, 15 mg, and 30 mg twice daily groups, respectively, compared with 29.2% in the placebo group (P < 0.001). Improvements in disease activity in CP‐690,550–treated patients compared with placebo were seen in all treatment groups as early as week 1. ACR50 and ACR70 response rates significantly improved in all treatment groups by week 4. The most common adverse events reported were headache and nausea. The infection rate in both the 15 mg twice daily group and the 30 mg twice daily group was 30.4% (versus 26.2% in the placebo group). No opportunistic infections or deaths occurred. Increases in mean low‐density lipoprotein cholesterol and high‐density lipoprotein cholesterol levels, and increases in mean serum creatinine level (0.04–0.06 mg/dl) were seen in all CP‐690,550 treatment arms.

Conclusion

Our findings indicate that CP‐690,550 is efficacious in the treatment of RA, resulting in rapid, statistically significant, and clinically meaningful reductions in the signs and symptoms of RA. Further studies of CP‐690,550 in RA are warranted.

     

Comparison of long‐term clinical outcome with etanercept treatment and adalimumab treatment of rheumatoid arthritis with respect to immunogenicity

Objective

To compare rates of sustained low and minimal disease activity and remission according to the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria during 3‐year followup in rheumatoid arthritis (RA) patients treated with etanercept and adalimumab in routine care.

Methods

Four hundred seven RA patients previously unexposed to tumor necrosis factor antagonists were treated with etanercept (n = 203) or adalimumab (n = 204) and assessed at 3‐ and later 6‐month intervals. Treatment allocation was at the discretion of the treating rheumatologist. Clinical parameters were measured at each time point, as were anti‐adalimumab antibodies in adalimumab‐treated patients. Achievement of clinical outcome was defined as the occurrence of sustained (at least 12 consecutive months) low disease activity (28‐joint Disease Activity Score [DAS28] <3.2), minimal disease activity (DAS28 <2.6), or ACR/EULAR remission based on the Simplified Disease Activity Index (SDAI). Non‐overlapping response rates were calculated.

Results

Among the adalimumab group, 13% reached sustained low disease activity but not sustained minimal disease activity, 15% reached sustained minimal disease activity but not sustained remission according to the SDAI, and 16% reached sustained ACR/EULAR remission. In the etanercept group the corresponding rates were 16%, 11%, and 12%, respectively (P = 0.42, overall test for linear trend). Adalimumab‐treated patients without anti‐adalimumab antibodies (n = 150 [74%]) had the best outcomes, and adalimumab‐treated patients with anti‐adalimumab antibodies the worst, with outcomes in etanercept‐treated patients in between (P < 0.0001). Differences were most apparent in the sustained SDAI remission and sustained minimal disease activity categories. For example, 40% of anti‐adalimumab antibody–negative patients, 23% of etanercept‐treated patients, and 4% of anti‐adalimumab antibody–positive patients achieved at least sustained minimal disease activity.

Conclusion

Overall, etanercept and adalimumab treatment appear similar in inducing a good long‐term clinical outcome. However, in the case of adalimumab this is strongly dependent on the presence or absence of anti‐adalimumab antibodies.

     

Golimumab in psoriatic arthritis: One‐year clinical efficacy,radiographic, and safety results from a phase III,randomized, placebo‐controlled trial

Objective

Golimumab, administered subcutaneously every 4 weeks, has been shown to be effective in reducing the signs and symptoms of active psoriatic arthritis (PsA) through week 24 of the GO‐REVEAL study. Herein we report 1‐year clinical, radiographic, and safety findings.

Methods

Adult patients with active PsA (≥3 swollen and ≥3 tender joints) were randomly assigned to receive subcutaneous placebo, golimumab 50 mg, or golimumab 100 mg every 4 weeks through week 20. At week 16, patients with <10% improvement from baseline in swollen and tender joint counts entered a blinded early escape phase, with placebo crossover to golimumab 50 mg, golimumab 50 mg increased to 100 mg, and golimumab 100 mg continued at 100 mg. Patients receiving placebo who did not enter the early escape phase crossed over to golimumab 50 mg at week 24. Findings through 1 year are reported, including the second of 2 coprimary end points (i.e., change from baseline to week 24 in PsA‐modified Sharp/van der Heijde score [SHS]).

Results

A total of 405 patients were randomized: 113 to placebo and 146 each to the golimumab 50 mg and 100 mg groups. Mean changes in PsA‐modified SHS from baseline to week 24 for the combined golimumab 50 mg and 100 mg group (−0.09) and the golimumab 50 mg group (−0.16) were significantly different versus placebo (0.27) (P = 0.015 and P = 0.011, respectively). Radiographic benefit was maintained through week 52 with golimumab. Clinical efficacy, including improvement in joint and skin responses and physical function, was maintained through 1 year. The frequency/types of adverse events were similar to those reported through week 24.

Conclusion

Treatment of PsA with golimumab inhibited structural damage progression and demonstrated continued clinical efficacy and safety through 1 year.

     

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.

     

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.

     

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.

     

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.

     

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.

     

Efficacy,pharmacodynamics, and safety of VX‐702, a novel p38 MAPK inhibitor,in rheumatoid arthritis: Results of two randomized,double‐blind,placebo‐controlled clinical studies

Objective

To assess the efficacy and safety of VX‐702, a p38 MAPK inhibitor, in patients with active, moderate‐to‐severe rheumatoid arthritis (RA).

Methods

Two 12‐week, double‐blind, placebo‐controlled studies of VX‐702 were conducted in patients with active, moderate‐to‐severe RA. In the VeRA study, 313 patients received placebo or 2 daily doses of VX‐702. In Study 304, 117 patients received placebo, daily VX‐702, or twice weekly VX‐702 in addition to concomitant methotrexate (MTX). Study end points included the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (an ACR20 response), ACR50 and ACR70 responses, changes in the serum levels of biomarkers of inflammation, and safety assessments.

Results

The numerically superior ACR20 response rates among patients receiving VX‐702 compared with those receiving placebo in both studies did not reach pairwise statistical significance at the highest doses in either study. At week 12 in the VeRA study, ACR20 response rates were 40%, 36%, and 28% among patients receiving 10 mg of VX‐702, 5 mg of VX‐702, and placebo, respectively. In Study 304, the response rates were 40%, 44%, and 22% for patients receiving 10 mg VX‐702 daily plus MTX, 10 mg VX‐702 twice weekly plus MTX, and placebo, respectively. Reductions in the levels of C‐reactive protein, soluble tumor necrosis factor receptor p55, and serum amyloid A were observed as early as week 1 in both studies, but these levels rapidly returned to baseline values by week 4. The overall frequency of adverse events was similar between the VX‐702 and placebo groups. In the VeRA study, serious infections were more frequent in the VX‐702 groups compared with the placebo group (2.4% versus 0%) but not in Study 304 (2.6% versus 4.9%).

Conclusion

The modest clinical efficacy plus the transient suppression of biomarkers of inflammation observed in this study suggest that p38 MAPK inhibition may not provide meaningful, sustained suppression of the chronic inflammation seen in RA.

     

Therapeutic benefit of blocking interleukin‐6 activity with an anti–interleukin‐6 receptor monoclonal antibody in rheumatoid arthritis: A randomized,double‐blind,placebo‐controlled,dose‐escalation trial

Objective

To investigate the safety and efficacy of MRA, a recombinant human anti–interleukin‐6 (anti–IL‐6) receptor monoclonal antibody of the IgG1 subclass that inhibits the function of IL‐6, in patients with established rheumatoid arthritis (RA).

Methods

A randomized, double‐blind, placebo‐controlled, dose‐escalation trial was conducted in 45 patients with active RA, as defined by the American College of Rheumatology (ACR) revised criteria. Patients were sequentially allocated to receive a single intravenous dose of either 0.1, 1, 5, or 10 mg/kg of MRA or placebo. The primary efficacy end point was meeting the ACR 20% response criteria at week 2 after treatment.

Results

Demographic features were similar between treatment groups. At week 2, a significant treatment difference was observed between the 5 mg/kg of MRA and placebo, with 5 patients (55.6%) in the MRA cohort and none in the placebo cohort achieving ACR 20% improvement. There was no statistically significant difference in the ACR 20% response between the other 3 MRA cohorts and placebo at week 2. The mean disease activity score at week 2 in those who received 5 mg/kg and 10 mg/kg of MRA was 4.8 and 4.7 (P < 0.001 and P < 0.001 by analysis of variance), respectively. These mean scores were statistically significantly lower than those in the 0.1‐ and 1‐mg/kg MRA and the placebo cohorts (6.4, 6.2, and 7.0, respectively). The erythrocyte sedimentation rate and C‐reactive protein values fell significantly in the 5‐ and 10‐mg/kg MRA cohorts and normalized 2 weeks after treatment. Seventeen patients (5, 4, 6, 2, and 0 patients in the placebo, 0.1‐, 1‐, 5‐, and 10‐mg/kg MRA cohorts, respectively) required corticosteroid or disease‐modifying antirheumatic drug treatment because of active disease before study end. They were regarded as nonresponders from the time they received these treatments. Diarrhea was the most common adverse event, occurring in 8% of patients. Seven patients (15.6%) reported a severe adverse event (3, 1, 2, and 2 patients in the placebo, 0.1‐, 1‐, and 10‐mg/kg MRA cohorts). There were no serious adverse events that were thought to be related to the study drug.

Conclusion

This is the first randomized controlled trial showing that inhibition of IL‐6 significantly improved the signs and symptoms of RA and normalized the acute‐phase reactants. Further research with multiple dosing is necessary to define the most appropriate therapeutic regimen of MRA in RA.