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Effect of Methotrexate Plus Adalimumab on the Achievement of Rheumatoid Arthritis Therapeutic Goals: Post Hoc Analysis of Japanese Patients (MELODY Study).

ABSTRACT: INTRODUCTION:There is insufficient evidence regarding the appropriate dose of methotrexate (MTX) required to achieve specific treatment goals in patients with rheumatoid arthritis (RA) receiving biologic drugs in Japan. The present study aimed to assess the dose-response effect of MTX in combination with adalimumab (ADA) to achieve low disease activity (LDA) and/or remission at 24 weeks in RA patients. METHODS:This analysis used data of the ADA all-case survey in Japan (n = 7740), and 5494 patients who received ADA and MTX were classified into five groups by weighted average MTX dose (>0-<4, 4-<6, 6-<8, 8-< 10, and ?10 mg/week). Of the 5494 patients, 3097 with baseline 28-joint disease activity score based on erythrocyte sedimentation rate >3.2 were analyzed for effectiveness by MTX dose. RESULTS:In biologic-naïve patients (n = 1996/3097), LDA/remission rates increased with MTX up to 6-<8 mg/week and then plateaued at higher doses (LDA, p = 0.0440; remission, p = 0.0422). In biologic-exposed patients (n = 1101/3097), LDA/remission rates increased with MTX dose (LDA, p = 0.0009; remission p = 0.0143). The incidences of serious adverse drug reactions (ADRs) and serious infections did not differ by MTX dose, but total ADRs and infections were significantly higher (p < 0.05) with increased MTX doses. CONCLUSION:The appropriate MTX doses in combination with ADA to achieve LDA and/or remission at week 24 were different between biologic-naïve and biologic-exposed patients with RA, suggesting that 8 mg/week of MTX would be enough for biologic-naïve patients. TRIAL REGISTRATION:ClinicalTrials.gov identifier, NCT01076959. FUNDING:AbbVie and Eisai Co., Ltd.

SUBMITTER: Koike T

PROVIDER: S-EPMC4999573 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Effect of Methotrexate Plus Adalimumab on the Achievement of Rheumatoid Arthritis Therapeutic Goals: Post Hoc Analysis of Japanese Patients (MELODY Study).

Koike Takao T Harigai Masayoshi M Ishiguro Naoki N Inokuma Shigeko S Takei Syuji S Takeuchi Tsutomu T Yamanaka Hisashi H Takasaki Yoshinari Y Mimori Tsuneyo T Hiramatsu Katsutoshi K Komatsu Shuichi S Tanaka Yoshiya Y

Rheumatology and therapy 20151222 1

<h4>Introduction</h4>There is insufficient evidence regarding the appropriate dose of methotrexate (MTX) required to achieve specific treatment goals in patients with rheumatoid arthritis (RA) receiving biologic drugs in Japan. The present study aimed to assess the dose-response effect of MTX in combination with adalimumab (ADA) to achieve low disease activity (LDA) and/or remission at 24 weeks in RA patients.<h4>Methods</h4>This analysis used data of the ADA all-case survey in Japan (n = 7740), ...[more]

PMID: 27747511

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Project description:ObjectiveTo evaluate long-term clinical, functional and radiographic outcomes in an open-label extension (OLE) study in patients with rheumatoid arthritis (RA) receiving adalimumab monotherapy or adalimumab+methotrexate following attainment of low disease activity (LDA) with adalimumab+methotrexate.MethodsMethotrexate-naive patients with early RA were randomised to adalimumab, methotrexate or adalimumab +methotrexate in a double-blind, 2-year study. Patients who completed the study and achieved LDA (28-joint Disease Activity Score using C reactive protein (DAS28(CRP)<3.2) could receive adalimumab monotherapy for up to 8 additional years in the OLE; open-label methotrexate could be added per investigator's discretion. This post hoc analysis included data up to OLE year 3 (study year 5) from patients receiving adalimumab+methotrexate who achieved LDA at year 2 followed by adalimumab monotherapy or methotrexate reinitiation. Normal physical function was defined as Disability Index of the Health Assessment Questionnaire <0.5 and radiographic non-progression as change in modified total Sharp score ≤0.5.ResultsOf 140 patients initiating adalimumab monotherapy, 84 (60%) received adalimumab only (methotrexate non-use) and 56 (40%) reinitiated methotrexate (methotrexate use) during OLE treatment. Median (IQR) time to first methotrexate use was 5.1 (0.1-31.4) weeks. Among methotrexate users, 61% retained LDA, 48% achieved DAS28(CRP) <2.6, 45% had normal physical function and 46% had no radiographic progression at year 5; for non-users, 63%, 50%, 58% and 50%, respectively, achieved these milestones. Adverse event rates were similar between methotrexate non-use and use patients.ConclusionsAdalimumab monotherapy effectively maintained good clinical, functional and radiographic outcomes for up to 3 additional years in ≥50% of patients who attained LDA after 2 years of adalimumab+methotrexate therapy.Trial registration numberNCT00195663; Post-results.

Project description:ObjectivesMethotrexate is considered to be first-line therapy for rheumatoid arthritis (RA). However, a substantial proportion of treated patients do not achieve the desired goals of therapy. This analysis aimed to identify predictors of insufficient response to methotrexate in patients with early RA.MethodsThe Optimal Protocol for Treatment Initiation with Methotrexate and Adalimumab (OPTIMA) and PREMIER studies in patients with RA for <1 and <3 years, respectively, examined the efficacy of methotrexate and adalimumab in methotrexate-naive patients. This post hoc analysis included patients for whom initial methotrexate monotherapy was not successful after 6 months. Candidate predictors of insufficient response and clinically relevant radiographic progression (CRRP) included demographics, baseline disease characteristics and time-averaged disease variables over a 12-week interval. In OPTIMA, adalimumab was added to therapy after insufficient treatment response; in PREMIER, initial methotrexate therapy was continued; clinical, functional and radiologic outcomes were assessed after 1 year.ResultsBaseline 28-joint Disease Activity Score based on C-reactive protein (DAS28(CRP)) and time-averaged DAS28(CRP) over 4, 8 and 12 weeks were the strongest predictors of insufficient response to methotrexate and CRRP. Addition of adalimumab to methotrexate therapy was associated with better clinical, functional and radiographic outcomes after 1 year compared with continuing on methotrexate monotherapy.ConclusionsIn patients with early RA, baseline disease characteristics and early disease activity can predict response to methotrexate treatment and radiographic progression at 6 months. The addition of adalimumab at 6 months after methotrexate failure is associated with improved outcomes. These results support treatment-to-target strategies and timely adaptation of therapy in patients with early RA.Trial registration numberNCT00420927, NCT00195663; Post-results.

Project description:IntroductionThe objective of this study was to evaluate the real-world safety and effectiveness of adalimumab with methotrexate (MTX) in disease-modifying antirheumatic drug (DMARD)- and biologic-naïve Japanese patients with rheumatoid arthritis (RA) at risk of progressive structural joint damage.MethodsThis multicenter, prospective, observational, postmarketing surveillance study was conducted between February 2013 and April 2015 at 84 centers in Japan. Patients with RA at risk of progressive structural joint damage were enrolled and initiated treatment with adalimumab and MTX. Adverse events were recorded up to week 28. Effectiveness/disease activity was assessed using the Disease Activity Score based on a 28-joint count with erythrocyte sedimentation rate and C-reactive protein (DAS28-4ESR and DAS28-4CRP), Clinical Disease Activity Index, and Simplified Disease Activity Index at 0, 4, 12, and 24 weeks. DAS28-4CRP response was evaluated in the low-dose (<8 mg/week) and high-dose (≥8 mg to ≤16 mg/week) MTX groups at week 24.ResultsOne hundred fifty-seven of 163 patients comprised the safety cohort: mean (SD) age, 56.5 (13.9) years; females, 65.6%; rheumatoid factor positive, 73.2%; anti-cyclic citrullinated peptide antibody positive, 66.9%; bone erosions, 51.6%; mean disease duration, 9.5 months. The majority of patients (≥80%) had moderate or high disease activity at baseline, and ≥50% with available data achieved remission or low disease activity at week 24 (DAS28-4CRP <3.2). Five serious adverse drug reactions occurred in four patients, including pyelonephritis, Pneumocystis jiroveci pneumonia, interstitial lung disease, pleurisy, and pericarditis; the outcomes were either recovered or recovering. Significant improvements/reductions in disease activity over 24 weeks were noted in all effectiveness measures (P < 0.0001). Most of the population achieved DAS28-4CRP remission (<2.6) at week 24 regardless of the MTX dose.ConclusionAdalimumab in combination with MTX could be a beneficial treatment option for DMARD- and biologic-naïve Japanese patients with RA at risk of progressive structural joint damage.FundingAbbVie GK and Eisai.Trial registrationClinicalTrials.gov identifier, NCT01783730.

Project description:IntroductionThe treatment of rheumatoid arthritis (RA) patients with anti-tumor necrosis factor alpha (TNF?) biological drugs has dramatically improved the prognosis of these patients. However, a third of the treated patients do not respond to this therapy. Thus, the search for biomarkers of clinical response to these agents is currently highly active. Our aim is to analyze the number and distribution of circulating monocytes, and of their CD14?highCD16?, CD14?highCD16? and CD14?lowCD16+ subsets in methotrexate (MTX) non-responder patients with RA, and to determine their value in predicting the clinical response to adalimumab plus MTX treatment.MethodsThis prospective work investigated the number of circulating monocytes, and of their CD14?highCD16?, CD14?highCD16? and CD14?lowCD16? subsets, in 35 MTX non-responder patients with RA before and after three and six months of anti-TNF? treatment using multiparametric flow cytometry. The number of circulating monocytes in an age- and sex-matched healthy population was monitored as a control.ResultsNon-responder patients with RA show an increased number of monocytes and of their CD14?highCD16?, CD14?highCD16? and CD14?lowCD16? subsets after three months of adalimumab plus MTX treatment that remained significantly increased at six months. In contrast, significant normalization of the numbers of circulating monocytes was found in responders at three months of adalimumab plus MTX treatment that lasts up to six months. CX3CR1 expression is increased in monocytes in non-responders. At three months of anti-TNF? treatment the number of circulating monocytes and their subsets was associated with at least 80% sensitivity, 84% specificity and an 86% positive predictive value (PPV) in terms of discriminating between eventual early responders and non-responders.ConclusionsThe absolute number of circulating monocytes and of their CD14?highCD16?, CD14?highCD16? and CD14?lowCD16? subsets at three months of adalimumab plus MTX treatment, have a predictive value (with high specificity and sensitivity) in terms of the clinical response after six months of anti-TNF? treatment in patients with RA.

Project description:BackgroundThis post hoc analysis assessed clinical and functional responses to tofacitinib monotherapy, tofacitinib + methotrexate (MTX), and adalimumab + MTX, in patients with rheumatoid arthritis enrolled in the ORAL Strategy study, including evaluation of patient-level data using cumulative probability plots.MethodsIn the 12-month, phase IIIb/IV ORAL Strategy study, patients with rheumatoid arthritis and an inadequate response to MTX were randomized to receive tofacitinib 5 mg twice daily (BID), tofacitinib 5 mg BID + MTX, or adalimumab 40 mg every other week + MTX. In this post hoc analysis, cumulative probability plots were generated for mean percent change from baseline (%∆) in the Clinical Disease Activity Index (CDAI; clinical response) and mean change from baseline (∆) in the Health Assessment Questionnaire-Disability Index (HAQ-DI; functional response) at month 12. Median C-reactive protein (CRP) levels by time period were summarized by CDAI remission (≤ 2.8) status at months 6 and 12.ResultsData for 1146 patients were analyzed. At month 12, cumulative probability plots for %∆CDAI and ∆HAQ-DI were similar across treatments in patients with greater response. At lower levels of response, patients receiving tofacitinib monotherapy did not respond as well as those receiving combination therapies. With tofacitinib + MTX, numerically higher baseline CRP levels and numerically larger post-baseline CRP reductions were seen in patients achieving CDAI remission at months 6 and 12 vs those who did not.ConclusionsThese results suggest that patients with a greater response did well, irrespective of which therapy they received. Patients with lesser response had better outcomes with combination therapies vs tofacitinib monotherapy, suggesting they benefitted from MTX. High pre-treatment CRP levels may be associated with better response to tofacitinib + MTX.Trial registrationClinicalTrials.gov, NCT02187055. Registered on 08 July 2014.

Dataset Information

Effect of Methotrexate Plus Adalimumab on the Achievement of Rheumatoid Arthritis Therapeutic Goals: Post Hoc Analysis of Japanese Patients (MELODY Study).

Publications

Effect of Methotrexate Plus Adalimumab on the Achievement of Rheumatoid Arthritis Therapeutic Goals: Post Hoc Analysis of Japanese Patients (MELODY Study).

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