Efficacy of certolizumab pegol with and without concomitant use of disease-modifying anti-rheumatic drugs over 4 years in psoriatic arthritis patients: results from the RAPID-PsA randomized controlled trial

To report long-term efficacy of certolizumab pegol (CZP) treatment with and without concomitant DMARDs in patients with psoriatic arthritis (PsA). RAPID-PsA (NCT01087788) was double-blind and placebo-controlled to week 24, dose-blind to week 48, and open-label to week 216. Patients had active PsA with ≥?1 failed DMARD. At baseline, patients were randomized 1:1:1 to CZP 200 mg every 2 weeks: CZP 400 mg every 4 weeks: placebo. CZP-randomized patients continued their dose into open-label. Observed case efficacy data are reported to week 216 for week 0 CZP-randomized patients (dose combined) with and without baseline DMARD use (DMARD+/DMARD?). Dactylitis (tenderness and ≥?10% difference in swelling between affected and opposite digits) and enthesitis were measured using Leeds Dactylitis Index (LDI) and Leeds Enthesitis Index (LEI). 273/409 randomized patients received CZP from baseline: 199/273 (72.9%) DMARD+ and 74/273 (27.1%) DMARD? patients. 141/199 (70.9%) DMARD+ and 42/74 (56.8%) DMARD? patients completed Week 216. DMARD+ (79.7%) and 83.3% of DMARD? patients achieved ACR20 response at week 216; 79.2 and 78.1% achieved 75% improvement from baseline in Psoriasis Area and Severity Index (PASI75). High proportions of DMARD+/DMARD? patients with extra-articular manifestations at baseline reported total resolution at week 216; dactylitis 91.4% of DMARD+ and 93.3% of DMARD? patients, enthesitis 74.4% of DMARD+ and 87.5% of DMARD? patients. Long-term improvements in PsA symptoms were observed with CZP monotherapy or concomitant DMARDs, across important psoriatic disease domains, including joint disease, psoriasis, nail disease, dactylitis, and enthesitis.Trial registration: NCT01087788     

Adalimumab for the treatment of patients with moderately to severely active psoriatic arthritis: results of a double-blind, randomized, placebo-controlled trial

OBJECTIVE: Adalimumab, a fully human, anti-tumor necrosis factor monoclonal antibody, was evaluated for its safety and efficacy compared with placebo in the treatment of active psoriatic arthritis (PsA). METHODS: Patients with moderately to severely active PsA and a history of inadequate response to nonsteroidal antiinflammatory drugs were randomized to receive 40 mg adalimumab or placebo subcutaneously every other week for 24 weeks. Study visits were at baseline, weeks 2 and 4, and every 4 weeks thereafter. The primary efficacy end points were the American College of Rheumatology 20% improvement (ACR20) response at week 12 and the change in the modified total Sharp score of structural damage at week 24. Secondary end points were measures of joint disease, disability, and quality of life in all patients, as well as the severity of skin disease in those patients with psoriasis involving at least 3% of body surface area. RESULTS: At week 12, 58% of the adalimumab-treated patients (87 of 151) achieved an ACR20 response, compared with 14% of the placebo-treated patients (23 of 162) (P < 0.001). At week 24, similar ACR20 response rates were maintained and the mean change in the modified total Sharp score was -0.2 in patients receiving adalimumab and 1.0 in those receiving placebo (P < 0.001). Among the 69 adalimumab-treated patients evaluated with the Psoriasis Area and Severity Index (PASI), 59% achieved a 75% PASI improvement response at 24 weeks, compared with 1% of the 69 placebo-treated patients evaluated (P < 0.001). Disability and quality of life measures were also significantly improved with adalimumab treatment compared with placebo. Adalimumab was generally safe and well-tolerated. CONCLUSION: Adalimumab significantly improved joint and skin manifestations, inhibited structural changes on radiographs, lessened disability due to joint damage, and improved quality of life in patients with moderately to severely active PsA.     

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 (> or =50%, > or =75%, > or =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.     

Continued inhibition of radiographic progression in patients with psoriatic arthritis following 2 years of treatment with etanercept

OBJECTIVE: Clinical and radiographic responses were evaluated in patients with psoriatic arthritis (PsA) treated for up to 2 years with etanercept. METHODS: Patients were previously randomized to receive placebo or etanercept in a double-blind study and chose to participate in the current open-label extension phase. All patients received etanercept 25 mg twice weekly. Radiographic progression was determined at baseline, 1 year, and 2 years using the Sharp method modified to include joints frequently affected in PsA. Arthritis and psoriasis responses were determined using American College of Rheumatology 20% (ACR20) improvement criteria, PsA response criteria (PsARC), and the psoriasis area severity index (PASI). RESULTS: Of 205 patients randomized, 169 entered open-label, and 141 [71 randomized to receive placebo (placebo/etanercept) and 70 randomized to receive etanercept (etanercept/etanercept)] had radiographic data available for analysis at 2 years. ACR20 criteria, PsARC, and PASI 50 criteria were met by 64%, 84%, and 62%, respectively, of etanercept/etanercept patients at the end of the 48-week open-label period. Placebo/etanercept patients achieved comparable results within 12 weeks that were sustained at 48 weeks (63%, 80%, and 73%). Radiographic progression was inhibited in the etanercept/ etanercept patients (mean adjusted change in total Sharp score of -0.38 from baseline to 2 yrs). In placebo/etanercept patients, disease progression was inhibited once patients began receiving etanercept (mean adjusted change of -0.22 from 1 year to 2 years). Adverse event rates were similar to those observed during randomized phase, with only one serious adverse event deemed possibly related to etanercept. CONCLUSION: These data demonstrate a sustained benefit of etanercept treatment, including inhibition of radiographic progression, in patients with PsA.     

Performance of response criteria for assessing peripheral arthritis in patients with psoriatic arthritis: analysis of data from randomised controlled trials of two tumour necrosis factor inhibitors

BACKGROUND: In recent clinical trials in patients with psoriatic arthritis (PsA), the response criteria and disease activity measures that have been used were those developed for rheumatoid arthritis. However, these have not yet been validated in PsA. OBJECTIVE: To compare the responsiveness and discriminative capacity of the psoriatic arthritis response criteria (PsARC), American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) response criteria and the Disease Activity Score (DAS) and core-set measures in patients with PsA and peripheral arthritis, using the data from two randomised placebo-controlled trials of tumour necrosis factor inhibitors. METHODS: In an infliximab trial, 104 patients with active PsA were randomised to receive placebo or infliximab for 16 weeks. In an etanercept trial, 60 patients with active PsA were randomised to receive placebo or etanercept for 12 weeks. Data from baseline and the end of the intervention phase were used from each study. Responsiveness was assessed using the standardised response mean and effect size. Capacity to discriminate between the active drug and placebo was assessed using t values or a chi2 test. Measures were ranked in order of their t value or chi2 value. RESULTS: The EULAR criteria performed better in discriminating the active drug from placebo than the ACR20 improvement criteria, which in turn performed better than the PsARC. It was also found that the pooled indices (DAS and DAS28) were generally more responsive, and performed better in discriminating active drug from placebo, than the single core-set measures. CONCLUSION: Response criteria and pooled indices developed for rheumatoid arthritis are useful for the assessment of arthritis in PsA clinical trials.     

Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial

BACKGROUND & AIMS: This study evaluated the efficacy and safety of adalimumab, a fully human, anti-tumor necrosis factor monoclonal antibody administered subcutaneously, in the maintenance of response and remission in patients with moderate to severe Crohn's disease (CD). METHODS: Patients received open-label induction therapy with adalimumab 80 mg (week 0) followed by 40 mg (week 2). At week 4, patients were stratified by response (decrease in Crohn's Disease Activity Index > or =70 points from baseline) and randomized to double-blind treatment with placebo, adalimumab 40 mg every other week (eow), or adalimumab 40 mg weekly through week 56. Co-primary end points were the percentages of randomized responders who achieved clinical remission (Crohn's Disease Activity Index score <150) at weeks 26 and 56. RESULTS: The percentage of randomized responders in remission was significantly greater in the adalimumab 40-mg eow and 40-mg weekly groups versus placebo at week 26 (40%, 47%, and 17%, respectively; P < .001) and week 56 (36%, 41%, and 12%, respectively; P < .001). No significant differences in efficacy between adalimumab eow and weekly were observed. More patients receiving placebo discontinued treatment because of an adverse event (13.4%) than those receiving adalimumab (6.9% and 4.7% in the 40-mg eow and 40-mg weekly groups, respectively). CONCLUSIONS: Among patients who responded to adalimumab, both adalimumab eow and weekly were significantly more effective than placebo in maintaining remission in moderate to severe CD through 56 weeks. Adalimumab was well-tolerated, with a safety profile consistent with previous experience with the drug.     

Risks and benefits of tumor necrosis factor-alpha inhibitors in the management of psoriatic arthritis: systematic review and metaanalysis of randomized controlled trials

OBJECTIVE: To evaluate the efficacy and safety of tumor necrosis factor-alpha (TNF-alpha) inhibitors in the management of psoriatic arthritis (PsA). METHODS: We searched electronic databases to identify randomized controlled trials (RCT) of adalimumab, etanercept, and infliximab used in patients with PsA. Random effects metaanalysis was undertaken to produce pooled estimates of the relative risk, risk difference, or the weighted mean difference for efficacy and safety outcomes using Stata version 9.0. RESULTS: Six RCT met the inclusion criteria, including 982 patients. All 3 TNF-alpha inhibitors were significantly more effective than placebo on the basis of Psoriatic Arthritis Response Criteria (PsARC) and American College of Rheumatology response criteria ACR20, ACR50, and ACR70 ratings. There were no significant differences between TNF-alpha inhibitors and placebo in the proportions of patients experiencing withdrawal for any reason (RR 0.48, 95% CI 0.20-1.18), or withdrawal due to adverse events (RR 2.14, 95% CI 0.73-6.27), serious adverse events (RR 0.98, 95% CI 0.55-1.77), or upper respiratory tract infections (RR 0.91, 95% CI 0.65-1.28). Pooled rates for injection site reactions were significantly higher for adalimumab and etanercept than for placebo (RR 2.48, 95% CI 1.16-5.29), but there was no significant difference in the proportion of patients experiencing infusion reactions with infliximab (RR 1.03, 95% CI 0.48-2.20) compared against placebo. Indirect analysis did not demonstrate any significant differences between the TNF-alpha inhibitors. CONCLUSION: TNF-alpha inhibitors are effective treatments for PsA with no important added risks associated with their short-term use. There is still a need for longterm risk-benefit assessment of using these drugs for the management of PsA.     

Adalimumab for the treatment of patients with moderately to severely active psoriatic arthritis: Results of a double‐blind,randomized, placebo‐controlled trial

Objective

Adalimumab, a fully human, anti–tumor necrosis factor monoclonal antibody, was evaluated for its safety and efficacy compared with placebo in the treatment of active psoriatic arthritis (PsA).

Methods

Patients with moderately to severely active PsA and a history of inadequate response to nonsteroidal antiinflammatory drugs were randomized to receive 40 mg adalimumab or placebo subcutaneously every other week for 24 weeks. Study visits were at baseline, weeks 2 and 4, and every 4 weeks thereafter. The primary efficacy end points were the American College of Rheumatology 20% improvement (ACR20) response at week 12 and the change in the modified total Sharp score of structural damage at week 24. Secondary end points were measures of joint disease, disability, and quality of life in all patients, as well as the severity of skin disease in those patients with psoriasis involving at least 3% of body surface area.

Results

At week 12, 58% of the adalimumab‐treated patients (87 of 151) achieved an ACR20 response, compared with 14% of the placebo‐treated patients (23 of 162) (P < 0.001). At week 24, similar ACR20 response rates were maintained and the mean change in the modified total Sharp score was −0.2 in patients receiving adalimumab and 1.0 in those receiving placebo (P < 0.001). Among the 69 adalimumab‐treated patients evaluated with the Psoriasis Area and Severity Index (PASI), 59% achieved a 75% PASI improvement response at 24 weeks, compared with 1% of the 69 placebo‐treated patients evaluated (P < 0.001). Disability and quality of life measures were also significantly improved with adalimumab treatment compared with placebo. Adalimumab was generally safe and well‐tolerated.

Conclusion

Adalimumab significantly improved joint and skin manifestations, inhibited structural changes on radiographs, lessened disability due to joint damage, and improved quality of life in patients with moderately to severely active PsA.

     

Indirect comparison of etanercept, infliximab, and adalimumab for psoriatic arthritis: mixed treatment comparison using placebo as common comparator

Psoriatic arthritis (PsA) is a chronic inflammatory joint disorder that is commonly associated with skin psoriatic lesions and can lead to severe disability. Current pharmacologic therapy for PsA includes TNFα-blocking agents for patients who are intolerant of or have an inadequate response to conventional disease-modifying antirheumatic drugs. Currently, there are no published randomized controlled trials providing a head-to-head comparison of the effectiveness of the three TNFα-blocking agents used most often to treat patients with PsA (adalimumab, etanercept, and infliximab). In this study, we have performed the first indirect comparison among these biologic agents, in this setting, using a mixed treatment comparison analysis of the data from pivotal trials regarding efficacy profiles of adalimumab, etanercept, and infliximab evaluated as American College of Rheumatology (ACR) 20 response. Our results suggest that etanercept is expected to provide the greatest ACR20 response among the anti-TNFα agents compared with placebo in the treatment of patients with PsA unresponsive to conventional treatments. This analysis may be relevant for clinical decision-making, hence improving the management of PsA patients.     

Sustained benefits of infliximab therapy for dermatologic and articular manifestations of psoriatic arthritis: results from the infliximab multinational psoriatic arthritis controlled trial (IMPACT)

OBJECTIVE: To investigate the efficacy and tolerability of infliximab therapy for the articular and dermatologic manifestations of active psoriatic arthritis (PsA). METHODS: One hundred four patients with PsA in whom prior therapy with at least 1 disease-modifying antirheumatic drug (DMARD) had failed were recruited into this investigator-initiated, multicenter, randomized, double-blind, placebo-controlled clinical trial. During the initial blinded portion of the study, patients received infusions of infliximab (5 mg/kg) or placebo at weeks 0, 2, 6, and 14. After week 16, patients initially assigned to receive placebo crossed over to receive infliximab 5 mg/kg every 8 weeks through week 50, while patients initially randomized to infliximab continued to receive active treatment at the same dose through week 50. The primary efficacy outcome was achievement of the American College of Rheumatology 20% criteria for improvement in rheumatoid arthritis (ACR20) at week 16. Additional predefined clinical efficacy assessments included the Psoriasis Area and Severity Index (PASI) score, the ACR50 and ACR70 criteria, the Disease Activity Score in 28 joints, the Health Assessment Questionnaire, ratings of enthesitis and dactylitis, and the Psoriatic Arthritis Response Criteria score. RESULTS: The proportion of infliximab-treated patients who achieved an ACR20 response at week 16 (65%) was significantly higher than the proportion of placebo-treated patients who achieved this response (10%). In addition, 46% of infliximab-treated patients achieved an ACR50 response, and 29% achieved an ACR70 response; no placebo-treated patient achieved these end points. Among patients who had PASI scores of >/=2.5 at baseline, 68% of infliximab-treated patients achieved improvement of >/=75% in the PASI score at week 16 compared with none of the placebo-treated patients. Continued therapy with infliximab resulted in sustained improvement in articular and dermatologic manifestations of PsA through week 50. The incidence of adverse events was similar between the treatment groups. CONCLUSION: Therapy with infliximab at a dose of 5 mg/kg significantly improved the signs and symptoms of arthritis, psoriasis, dactylitis, and enthesitis in patients with active PsA that had been resistant to DMARD therapy. With continued infliximab treatment, benefits were sustained through 50 weeks. The benefit-to-risk ratio appeared favorable in this study population.     

Lymphocyte depletion with fludarabine in patients with psoriatic arthritis: clinical and immunological effects

OBJECTIVE: To obtain preliminary information on the safety and efficacy of fludarabine in PsA and analyse its immunomodulatory effects in peripheral blood and synovial tissue. METHODS: 15 patients with active PsA who did not respond to DMARDs were randomly allocated to receive fludarabine every four weeks or placebo. Primary outcomes were the proportion of patients who met the ACR20 and the psoriatic arthritis response criteria (PsARC) at 16 weeks. Secondary outcomes were changes in tender or swollen joint counts and scores of the psoriasis area and severity index (PASI). Phenotypic analysis of peripheral blood mononuclear cells (PBMC), synovial immunohistochemistry, and functional analysis of PBMC were used to determine the immunomodulatory effects of fludarabine. RESULTS: At 16 weeks the ACR20 criteria were met by 3/7 (43%) fludarabine treated v 0/8 placebo treated patients (p=0.08); the PsARC was achieved by 4/7 (57%) fludarabine treated v 2/8 (25%) placebo treated patients; and 3/7 (43%) fludarabine treated v 0/7 placebo treated patients had > or =20% improvement in the PASI. Marked peripheral lymphopenia involving naive (CD4(+) CD45RA(+)) and memory (CD4(+) CD45RO(+)) T cells, CD8(+) T cells, and B cells was seen in fludarabine treated patients. CONCLUSIONS: In PsA fludarabine induces significant peripheral, but modest, synovial lymphopenia, and a trend towards improved clinical response.     

Infliximab improves signs and symptoms of psoriatic arthritis: results of the IMPACT 2 trial

OBJECTIVES: To evaluate further in a phase III, double blind trial the efficacy of infliximab in patients with active psoriatic arthritis (PsA), as observed in the smaller IMPACT trial. METHODS: 200 patients with active PsA unresponsive to previous treatment were randomised to infusions of infliximab 5 mg/kg or placebo at weeks 0, 2, 6, 14, and 22. Patients with inadequate response entered early escape at week 16. The primary measure of clinical response was ACR20. Other measures included Psoriatic Arthritis Response Criteria (PsARC), Psoriasis Area and Severity Index (PASI), and dactylitis and enthesopathy assessments. RESULTS: At week 14, 58% of patients receiving infliximab and 11% of those receiving placebo achieved an ACR20 response and 77% of infliximab patients and 27% of placebo patients achieved PsARC (both p<0.001). Among the 85% of patients with at least 3% body surface area psoriasis involvement at baseline, 53/83 (64%) patients receiving infliximab had at least 75% improvement in PASI compared with 2/87 (2%) patients receiving placebo at week 14 (p<0.001). These therapeutic effects were maintained through the last evaluation (week 24). Fewer infliximab patients than placebo patients had dactylitis at week 14 (18% v 30%; p = 0.025) and week 24 (12% v 34%; p<0.001). Fewer infliximab patients (22%) than placebo patients (34%) had active enthesopathy at week 14 (p = 0.016); corresponding figures at week 24 were 20% and 37% (p = 0.002). Infliximab was generally well tolerated, with a similar incidence of adverse events in each group. CONCLUSIONS: Infliximab 5 mg/kg through 24 weeks significantly improved active PsA, including dactylitis and enthesopathy, and associated psoriasis.     

A randomized,double‐blind,placebo‐controlled,phase III study of the human anti‐tumor necrosis factor antibody adalimumab administered as subcutaneous injections in Korean rheumatoid arthritis patients treated with methotrexate

Objective: Adalimumab is a fully human, monoclonal, antitumour necrosis factor antibody approved for the treatment of rheumatoid arthritis (RA) in more than 60 countries. We investigated the efficacy and safety of 40 mg every‐other‐week (eow) subcutaneous injections of adalimumab with methotrexate (MTX) versus placebo with MTX in Korean patients with RA with insufficient responses to MTX. Methods: This was a 24‐week, randomized, double‐blind, placebo‐controlled, phase III study conducted at six sites in Korea. The primary efficacy endpoint was a 20% improvement in the American College of Rheumatology response criteria (ACR20) at week 24. Secondary endpoints included ACR50, ACR70, and individual ACR components. Beginning at week 18, non‐responders (< 20% reduction in swollen and tender joint counts) could switch to rescue therapy with open‐label adalimumab 40 mg eow. Results: Of the 128 patients enrolled, 65 received adalimumab and 63 received placebo. An ACR20 response at week 24 was achieved by 61.5% of patients receiving adalimumab versus 36.5% receiving placebo (P < 0.01). ACR50 and ACR70 responses were achieved by 43.1% and 21.5% of adalimumab patients versus 14.3% and 7.9% of placebo patients (P < 0.001 and P < 0.05, respectively). Adalimumab significantly improved all seven ACR core components. Statistically significant improvements in ACR20 were observed with adalimumab as early as week 2. Adalimumab was generally well tolerated; there were no significant differences in incidences of adverse events between groups. Conclusions: In Korean patients with RA with insufficient responses to MTX, combination therapy with adalimumab and MTX was more efficacious than placebo and MTX in reducing RA signs and symptoms.     

Adalimumab for treating rheumatoid arthritis

OBJECTIVE: To assess the efficacy and safety of adalimumab in the treatment of rheumatoid arthritis (RA). METHODS: A Cochrane systematic review was performed. The literature search, selection and assessment of the methodological quality of the studies, and the data extraction were performed according to the standard methodology of the Cochrane reviews. Outcome measures included American College of Rheumatology (ACR) and European League Against Rheumatism responses, Disease Activity Score 28 and components of the ACR response, and radiographic and safety data. Weighted mean difference and relative risk were used for reporting continuous and dichotomous data, respectively. Number needed to treat (NNT) or to harm (NNH) were estimated when appropriate. When significant heterogeneity was not found, data were pooled. RESULTS: Six studies with 2,390 patients were included in this review. With adalimumab 40 mg every other week (eow) + methotrexate versus placebo + methotrexate, the absolute risk differences to achieve an ACR20, ACR50, and ACR70 response at 52 weeks were 35%, 32%, and 19% with NNT of 2.9, 3.1, and 5.3, respectively. At 52 weeks, adalimumab 40 mg eow and 20 mg every week (ew) significantly slowed the radiological progression. With adalimumab 40 mg eow versus placebo, the absolute risk differences to achieve an ACR20, ACR50, and ACR70 response at 24/26 weeks were 23.64%, 15.31%, and 12.22% with NNT of 5.0, 7.0, and 9.0, respectively. In most of the analyzed studies and comparisons, there were no significant differences in safety outcomes between adalimumab and control groups. CONCLUSION: On the basis of studies reviewed here, adalimumab is efficacious in the treatment of RA. No serious adverse effects occurred.     

Adalimumab, a fully human anti tumor necrosis factor-alpha monoclonal antibody, and concomitant standard antirheumatic therapy for the treatment of rheumatoid arthritis: results of STAR (Safety Trial of Adalimumab in Rheumatoid Arthritis)

OBJECTIVE: This study, known as STAR (Safety Trial of Adalimumab in Rheumatoid Arthritis), evaluated the safety and efficacy of adalimumab (Humira), a fully human monoclonal tumor necrosis factor-alpha (TNF-a) antibody, when given with standard antirheumatic therapy in patients with active rheumatoid arthritis (RA) not adequately responding to such therapies. Standard antirheumatic therapy included traditional disease modifying antirheumatic drugs (DMARD), low dose corticosteroids, nonsteroidal antiinflammatory drugs (NSAID), and/or analgesics. METHODS: In this 24-week, double-blind, placebo-controlled study, 636 patients with RA were randomly assigned to receive adalimumab 40 mg subcutaneously (sc) every other week (n = 318) or placebo (n = 318) while continuing standard antirheumatic therapy. The frequencies of adverse events, serious adverse events, severe or life-threatening adverse events, adverse events leading to withdrawal, infection, or serious infection were the primary endpoints. Secondary endpoints were determined by American College of Rheumatology (ACR) response criteria. RESULTS: During the study, the majority of patients received concomitant traditional DMARD (83.5%) and/or corticosteroids, NSAID, and/or analgesics (97.3%). Overall, 56.0% of patients continued treatment with one, 23.6% with 2, and 3.9% with > or = 3 traditional DMARD. At 24 weeks, there were no statistically significant differences between the adalimumab and placebo groups in their respective rates of adverse events (86.5% vs 82.7%), serious adverse events (5.3% vs 6.9%), severe or life-threatening adverse events (11.9% vs 15.4%), or those leading to withdrawal (2.8% vs 2.2%). There were also no statistically significant differences in the rates of infections (52.2% vs 49.4%) or serious infections (1.3% vs 1.9%) between the groups. The incidence and types of adverse events did not vary between adalimumab- and placebo-treated patients by the number of concomitant traditional DMARD (0, 1, or 2). Adalimumab-treated patients compared with placebo-treated patients achieved statistically superior ACR20 (52.8% vs 34.9%), ACR50 (28.9% vs 11.3%), and ACR70 (14.8% vs 3.5%) response rates at Week 24 (p < or = 0.001). CONCLUSION: This study demonstrated that addition of adalimumab 40 mg given sc every other week to concomitant standard antirheumatic therapy is well tolerated and provides significant improvements in signs and symptoms of RA. The data indicate that adalimumab is a safe and effective therapeutic option in patients with active RA who have an inadequate response to standard antirheumatic therapy, including one or more traditional DMARD, corticosteroids, NSAID, and analgesics.     

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.

     

阿达木单抗联合甲氨蝶呤治疗类风湿关节炎的多中心、随机、双盲、安慰剂对照临床研究

目的 评价阿达木单抗联合甲氨蝶呤(MTX)治疗类风湿关节炎(RA)的疗效与安全性.方法 随机、双盲、平行、安慰剂对照的多中心临床试验.302例入组前已经至少接受MTX 3个月治疗且剂量稳定≥28 d的活动性RA患者,随机分为40 mg阿达木单抗+MTX组(A组,121例)、80 mg阿达木单抗+MTX组(B组,121例)、安慰剂+MTX组(C组,60例).患者隔周皮下注射阿达木单抗或安慰剂,双盲治疗期为12周.完成双盲期的患者进入后12周开放期,3组患者均予隔周皮下注射40 mg阿达木单抗.在双盲期和开放期的患者同时继续接受研究前稳定剂量的MTX.观察主要疗效指标[双盲期治疗第12周修改的美国风湿病学会疗效标准提高20%(ACR20)有效率]、次要疗效指标[第24周ACR20有效率;第12周、第24周修改的美国风湿病学会疗效标准提高50%(ACR50)、修改的美国风湿病学会疗效标准提高70%(ACR70)有效率]、压痛关节数、肿胀关节数、疼痛视觉模拟评分,医生对疾病活动性整体评价、患者对疾病活动性整体评价、健康评价问卷(HAQ)评分、评估健康相关生活质量简表36(SF-36)评分及不良事件.结果 (1)双盲期,ACR20有效率C组为35.0%,A组为57.0%,B组为51.2%,A组、B组与C组比较,P<0.05;A组ACR50、ACR70有效率分别为32.2%、15.7%,与C组比较,P<0.05;A组压痛关节数、肿胀关节数、C反应蛋白水平的改善优于C组(P<0.05);B组肿胀关节数、C反应蛋白水平的改善优于C组(P<0.05).(2)开放期,A组、B组ACR20、ACR50、ACR70有效率仍维持或有所提高,而C组的ACR20、ACR50、ACR70有效率则升高至与A组、B组类似的水平.在压痛关节数、肿胀关节数、疼痛视觉模拟评分、HAQ、SF-36方面,3组均比基线、第12周时有更明显的好转.(3)双盲期与开放期中超过5%的患者有不良事件(上呼吸道感染、鼻咽炎和注射部位瘙痒),多数为轻～中度.有3例患者在研究期间出现结核病.在双盲期,有3例(1.2%)受试者出现了严重不良事件,但研究者判定与药物无关或可能无关.在开放期,有8例(2.7%)受试者出现了严重不良事件,其中3例判定与药物无关或可能无关.结论 阿达木单抗联合MTX治疗RA的疗效优于单用MTX,可显著提高治疗有效率并持续改善症状、体征、实验室炎性活动指标,减少功能障碍并提高整体生活质量,同时具有良好的安全性与耐受性.     

Etanercept and infliximab for the treatment of psoriatic arthritis: a systematic review

OBJECTIVE: To review the evidence on the clinical effectiveness of etanercept and infliximab for the treatment of active and progressive psoriatic arthritis (PsA) in patients with an inadequate response to standard treatment (including DMARD therapy). METHODS: A systematic review was conducted. The literature search covered a range of 13 medical databases and submissions were provided by the manufacturers of etanercept and infliximab. Randomised controlled trials (RCTs) of etanercept or infliximab that reported outcomes of disease activity in PsA were reviewed. RESULTS: There were two good quality double-blind, placebo-controlled RCTs each for etanercept and infliximab. The results demonstrated that after initial treatment (12 weeks for etanercept and 14 or 16 weeks for infliximab) both drugs had statistically significant beneficial effects compared with placebo on ACR 20, 50 and 70, PsARC and HAQ scores. Efficacy was not dependent upon concomitant methotrexate. Results at 24 weeks indicated that the response to treatment is maintained. Effects on psoriasis were beneficial, particularly with infliximab. Uncontrolled radiographic assessment data at one year indicated a beneficial effect of both etanercept and infliximab on the progression of joint disease. CONCLUSION: Our review indicates that both etanercept and infliximab are efficacious in the treatment of PsA with beneficial effects on both joint and psoriasis symptoms and on functional status. There are limited data indicating that etanercept and infliximab can delay joint disease progression. Further long-term data are required to confirm and consolidate the evidence base for both drugs.     

Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic drug treatment has failed

OBJECTIVE: To evaluate the efficacy and safety of monotherapy with adalimumab in patients with RA for whom previous DMARD treatment has failed. METHODS: In a 26 week, double blind, placebo controlled, phase III trial, 544 patients with RA were randomised to monotherapy with adalimumab 20 mg every other week, 20 mg weekly, 40 mg every other week, 40 mg weekly, or placebo. The primary efficacy end point was > or =20% improvement in the ACR core criteria (ACR20 response). Secondary efficacy end points included ACR50, ACR70, EULAR responses, and the Disability Index of the Health Assessment Questionnaire (HAQ DI). RESULTS: After 26 weeks, patients treated with adalimumab 20 mg every other week, 20 mg weekly, 40 mg every other week, and 40 mg weekly had significantly better response rates than those treated with placebo: ACR20 (35.8%, 39.3%, 46.0%, 53.4%, respectively v 19.1%; p< or =0.01); ACR50 (18.9%, 20.5%, 22.1%, 35.0% v 8.2%; p< or =0.05); ACR70 (8.5%, 9.8%, 12.4%, 18.4% v 1.8%; p< or =0.05). Moderate EULAR response rates were significantly greater with adalimumab than with placebo (41.5%, 48.2%, 55.8%, 63.1% v 26.4%; p< or =0.05). Patients treated with adalimumab achieved better improvements in mean HAQ DI than those receiving placebo (-0.29, -0.39, -0.38, -0.49 v -0.07; p< or =0.01). No significant differences were found between adalimumab and placebo treated patients for serious adverse events, serious infections, or malignancies. Injection site reaction occurred in 10.6% and 0.9% of adalimumab and placebo treated patients, respectively (p< or =0.05). CONCLUSION: Among patients with RA for whom previous DMARD treatment had failed, adalimumab monotherapy achieved significant, rapid, and sustained improvements in disease activity and improved physical function and was safe and well tolerated.     

Efficacy, pharmacokinetics, and safety of adalimumab in pediatric patients with juvenile idiopathic arthritis in Japan

The objective of this study was to evaluate the efficacy, pharmacokinetics, and safety of adalimumab in patients with polyarticular juvenile idiopathic arthritis (JIA) in Japan. Patients aged 4 to 17?years were enrolled in a single-arm, open-label, multicentre study of adalimumab. Patients weighing <30?kg received 20?mg every other week (eow), and those ??30?kg received 40?mg eow. Concomitant methotrexate (MTX) was allowed (??10?mg/m² per week). The primary efficacy outcome was the percent of patients with American College of Rheumatology Pediatric 30 response (ACR Pedi 30) at week?16. JIA core variables, serum adalimumab concentrations, and anti-adalimumab antibodies (AAAs) were analysed. Patients were monitored for adverse events (AEs). Twenty-five patients (20 with concomitant MTX at baseline and 5 without) were enrolled: 24 patients completed 16?weeks of therapy and 22 patients completed 60?weeks. At week?16, 90?% of patients with MTX and 100?% without MTX achieved ACR Pedi 30; response rates were maintained through week?60 in 94 and 80?% of patients, respectively. Each JIA core variable improved over time. Six patients became AAA positive (two each at weeks?8, 16, and 60), some of which were transient. All six AAA-positive patients achieved ACR Pedi 30 at week?16, and four maintained that response at week?60. Six patients (all with MTX) experienced nine serious AEs (JIA, pyrexia, arthralgia, pneumonia, hepatitis B infection, pharyngitis, dehydration, pharyngeal pain, and pneumonia). In pediatric patients with polyarticular JIA in Japan, adalimumab was safe and effective for reducing disease activity for up to 60?weeks.