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Preliminary study for predicting better methotrexate efficacy in Japanese patients with rheumatoid arthritis.

ABSTRACT: BACKGROUND:Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by systemic inflammatory status, joint destruction, disability, and pain. Methotrexate (MTX) has been confirmed to reduce disease activity and delay or stabilize the development of bone erosions. However, major drawbacks are that patients show great interindividual variability in response to MTX and the unpredictable occurrence of side effects. A strategy for personalized MTX treatment to predict its efficacy and toxicity has not yet been determined. To establish personalized MTX therapy in Japanese patients with rheumatoid arthritis, we performed a preliminary study for predicting better methotrexate efficacy including single-nucleotide polymorphisms (SNPs) for MTX-related transporters/enzymes. METHODS:Disease control status (good or poor) was judged by the number of Disease Activity Scores (DAS28) of <2 for 6-12 months. The response index R was calculated by the improved area under the curve (AUC) of the DAS28 score for 0-3 or 0-6 months by dividing the cumulative dose of MTX during 0-3 or 0-6 months, respectively. Genotyping of alleles of RFC1 80G?>?A, RFC1 -43 T?>?C, FPGS 1994G?>?A, GGH 401C?>?T, MTHFR 1298A?>?C, and TYMS 3'-UTR (-6/+6) was performed using the real-time PCR system. RESULTS:Seven of 21 patients were judged as good responders in terms of disease control, and the remainder as poor responders. For 0-3 months after starting MTX administration, the median cumulative dose and improved DAS28 AUC in the good and poor response groups were 96.0 mg and 25.4 and 118.0 mg and 23.4, respectively. For 0-6 months, the median cumulative dose and improved DAS28 AUC in the good and poor response groups were 192.0 mg and 51.0 and 214.0 mg and 47.6, respectively. Statistically significant differences between the 2 groups in the 0-6-month period were observed in DAS28 AUC improvement and index R. A slight tendency for a correlation between G/G genotypes and A allele genotypes in RFC1 80 genotypes was observed, although it did not reach statistical significance. CONCLUSION:This study suggested that aggressive RA treatment with MTX from the early period of administration is necessary to obtain a good response after 6 months, although no SNPs predicting a better treatment response to MTX were identified.

SUBMITTER: Hashiguchi M

PROVIDER: S-EPMC4895805 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Preliminary study for predicting better methotrexate efficacy in Japanese patients with rheumatoid arthritis.

Hashiguchi Masayuki M Tsuru Tomomi T Miyawaki Kumika K Suzaki Midori M Hakamata Jun J Shimizu Mikiko M Irie Shin S Mochizuki Mayumi M

Journal of pharmaceutical health care and sciences 20160607

<h4>Background</h4>Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by systemic inflammatory status, joint destruction, disability, and pain. Methotrexate (MTX) has been confirmed to reduce disease activity and delay or stabilize the development of bone erosions. However, major drawbacks are that patients show great interindividual variability in response to MTX and the unpredictable occurrence of side effects. A strategy for personalized MTX treatment to predict its effic ...[more]

PMID: 27274398

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Project description:BACKGROUND:Sirukumab, a high-affinity human monoclonal antibody that selectively binds to interleukin-6, has demonstrated efficacy in the treatment of rheumatoid arthritis (RA) in global phase 1 and phase 2 studies. The present study evaluated the safety and efficacy of sirukumab, as monotherapy in Japanese patients with RA refractory to methotrexate or sulfasalazine. METHODS:In this phase 3, double-blind study, 122 patients (age ? 20 years) were randomized (1:1, 61 patients in each arm) to sirukumab administered subcutaneously: 50 mg once every 4 weeks (q4w) or 100 mg once every 2 weeks (q2w) through 52 weeks. Disease-modifying anti-rheumatic drugs were allowed after 24 weeks. Safety was assessed and efficacy was evaluated using American College of Rheumatology (ACR) responses, Disease Activity Score C-reactive protein (DAS28-CRP) and Health Assessment Questionnaire-Disability Index (HAQ-DI). RESULTS:Amongst the 122 randomized patients, 99 (81.1%) patients completed the study. Adverse events (AEs) were reported in 114/122 (93.4%) patients and serious AEs were reported in 9/122 (7.4%) patients. No deaths, major cardiovascular AEs, serious gastrointestinal perforations or tuberculosis cases were reported during this study period. Grade 3 hematologic abnormalities (neutropenia and leukopenia) were reported in seven patients and no grade 4 abnormalities were observed. ACR20 responses were observed within 2 weeks, achieved in 47/61 (77.0%, 50 mg q4w) patients and 44/61 (72.1%, 100 mg q2w) patients at week 16 and maintained through week 52. ACR50/70, DAS28-CRP and HAQ-DI responses were also maintained through week 52 in both groups. CONCLUSIONS:Safety findings were comparable between the two treatment groups. The 52-week administration of sirukumab at 50 mg q4w and 100 mg q2w was generally tolerable and with measurable efficacy in Japanese patients with RA refractory to methotrexate and sulfasalazine. TRIAL REGISTRATION:NCT01689532 . Registered 18 September 2012.

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.

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Preliminary study for predicting better methotrexate efficacy in Japanese patients with rheumatoid arthritis.

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Preliminary study for predicting better methotrexate efficacy in Japanese patients with rheumatoid arthritis.

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