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Baricitinib, Methotrexate, or Combination in Patients With Rheumatoid Arthritis and No or Limited Prior Disease-Modifying Antirheumatic Drug Treatment.

ABSTRACT: We undertook this phase III study to evaluate baricitinib, an orally administered JAK-1/JAK-2 inhibitor, as monotherapy or combined with methotrexate (MTX) compared to MTX monotherapy in patients with active rheumatoid arthritis (RA) who had received no or minimal conventional synthetic disease-modifying antirheumatic drugs (DMARDs) and who were naive to biologic DMARDs.A total of 588 patients were randomized 4:3:4 to receive MTX monotherapy (once weekly), baricitinib monotherapy (4 mg once daily), or the combination of baricitinib and MTX for 52 weeks. The primary end point assessment was a noninferiority comparison of baricitinib monotherapy to MTX monotherapy based on the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 24.The study met its primary objective. Moreover, baricitinib monotherapy was found to be superior to MTX monotherapy at week 24, with a higher ACR20 response rate (77% versus 62%; P???0.01). Similar results were observed for combination therapy. Compared to MTX monotherapy, significant improvements in disease activity and physical function were observed for both baricitinib groups as early as week 1. Radiographic progression was reduced in both baricitinib groups compared to MTX monotherapy; the difference was statistically significant for baricitinib plus MTX. The rates of serious adverse events (AEs) were similar across treatment groups, while rates of some treatment-emergent AEs, including infections, were increased with baricitinib plus MTX. Three deaths were reported, all occurring in the MTX monotherapy group. Malignancies, including nonmelanoma skin cancer, were reported in 1 patient receiving MTX monotherapy, 1 receiving baricitinib monotherapy, and 4 receiving baricitinib plus MTX.Baricitinib alone or in combination with MTX demonstrated superior efficacy with acceptable safety compared to MTX monotherapy as initial therapy for patients with active RA.

SUBMITTER: Fleischmann R

PROVIDER: S-EPMC5347954 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Baricitinib, Methotrexate, or Combination in Patients With Rheumatoid Arthritis and No or Limited Prior Disease-Modifying Antirheumatic Drug Treatment.

Fleischmann Roy R Schiff Michael M van der Heijde Désirée D Ramos-Remus Cesar C Spindler Alberto A Stanislav Marina M Zerbini Cristiano A F CA Gurbuz Sirel S Dickson Christina C de Bono Stephanie S Schlichting Douglas D Beattie Scott S Kuo Wen-Ling WL Rooney Terence T Macias William W Takeuchi Tsutomu T

Arthritis & rheumatology (Hoboken, N.J.) 20170301 3

<h4>Objective</h4>We undertook this phase III study to evaluate baricitinib, an orally administered JAK-1/JAK-2 inhibitor, as monotherapy or combined with methotrexate (MTX) compared to MTX monotherapy in patients with active rheumatoid arthritis (RA) who had received no or minimal conventional synthetic disease-modifying antirheumatic drugs (DMARDs) and who were naive to biologic DMARDs.<h4>Methods</h4>A total of 588 patients were randomized 4:3:4 to receive MTX monotherapy (once weekly), baric ...[more]

PMID: 27723271

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Project description:BackgroundThis study evaluates patient-reported outcomes (PROs) in a double-blind, phase III study of baricitinib as monotherapy or combined with methotrexate (MTX) in patients with active rheumatoid arthritis (RA) with no or minimal prior conventional synthetic disease-modifying antirheumatic drugs (DMARDs) and naïve to biological DMARDs.MethodsPatients were randomized 4:3:4 to MTX administered once weekly (N = 210), baricitinib monotherapy (4 mg once daily (QD), N = 159), or combination of baricitinib (4 mg QD) and MTX (baricitinib + MTX, N = 215). PROs included the Patient's Global Assessment of Disease Activity (PtGA), patient's assessment of pain, Health Assessment Questionnaire-Disability Index (HAQ-DI), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), duration of morning joint stiffness (MJS), worst joint pain, worst tiredness, Work Productivity and Activity Impairment-Rheumatoid Arthritis (WPAI-RA), Short Form 36 version 2, Acute (SF-36); and EuroQol 5-Dimensions (EQ-5D) Health State Profile. Comparisons were assessed with analysis of covariance (ANCOVA) and logistic regression models.ResultsCompared to MTX, patients in both baricitinib groups reported greater improvement (p ≤ 0.01) in HAQ-DI, PtGA, pain, fatigue, worst join pain, SF-36 physical component score, and EQ-5D at weeks 24 and 52. For the SF-36 mental component score, patients in both baricitinib groups reported statistically significant improvements (p ≤ 0.01) at week 52 compared to MTX-treated patients. Statistically significant improvements (p ≤ 0.05) were observed with the WPAI-RA for the baricitinib groups vs. MTX at week 24 and for the WPAI-RA daily activity and work productivity measures for baricitinib + MTX at week 52.ConclusionsIn this study, baricitinib alone or in combination with MTX, when used as initial therapy, resulted in significant improvement compared to MTX in the majority of the pre-specified PRO measures.Trial registrationClinicalTrials.gov, NCT01711359 . Registered on 18 October 2012.

Project description:ObjectiveTo compare methotrexate based disease modifying antirheumatic drug (DMARD) treatments for rheumatoid arthritis in patients naive to or with an inadequate response to methotrexate.DesignSystematic review and Bayesian random effects network meta-analysis of trials assessing methotrexate used alone or in combination with other conventional synthetic DMARDs, biologic drugs, or tofacitinib in adult patients with rheumatoid arthritis.Data sourcesTrials were identified from Medline, Embase, and Central databases from inception to 19 January 2016; abstracts from two major rheumatology meetings from 2009 to 2015; two trial registers; and hand searches of Cochrane reviews.Study selection criteriaRandomized or quasi-randomized trials that compared methotrexate with any other DMARD or combination of DMARDs and contributed to the network of evidence between the treatments of interest.Main outcomesAmerican College of Rheumatology (ACR) 50 response (major clinical improvement), radiographic progression, and withdrawals due to adverse events. A comparison between two treatments was considered statistically significant if its credible interval excluded the null effect, indicating >97.5% probability that one treatment was superior.Results158 trials were included, with between 10 and 53 trials available for each outcome. In methotrexate naive patients, several treatments were statistically superior to oral methotrexate for ACR50 response: sulfasalazine and hydroxychloroquine ("triple therapy"), several biologics (abatacept, adalimumab, etanercept, infliximab, rituximab, tocilizumab), and tofacitinib. The estimated probability of ACR50 response was similar between these treatments (range 56-67%), compared with 41% with methotrexate. Methotrexate combined with adalimumab, etanercept, certolizumab, or infliximab was statistically superior to oral methotrexate for inhibiting radiographic progression, but the estimated mean change over one year with all treatments was less than the minimal clinically important difference of 5 units on the Sharp-van der Heijde scale. Triple therapy had statistically fewer withdrawals due to adverse events than methotrexate plus infliximab. After an inadequate response to methotrexate, several treatments were statistically superior to oral methotrexate for ACR50 response: triple therapy, methotrexate plus hydroxychloroquine, methotrexate plus leflunomide, methotrexate plus intramuscular gold, methotrexate plus most biologics, and methotrexate plus tofacitinib. The probability of response was 61% with triple therapy and ranged widely (27-70%) with other treatments. No treatment was statistically superior to oral methotrexate for inhibiting radiographic progression. Methotrexate plus abatacept had a statistically lower rate of withdrawals due to adverse events than several treatments.ConclusionsTriple therapy (methotrexate plus sulfasalazine plus hydroxychloroquine) and most regimens combining biologic DMARDs with methotrexate were effective in controlling disease activity, and all were generally well tolerated in both methotrexate naive and methotrexate exposed patients.

Project description:IntroductionSome patients with rheumatoid arthritis (RA) using tumor necrosis factor inhibitors (TNFi) experience inefficacy or lack of tolerability and hence switch to another TNFi (cycling) or to a therapy with another mode of action (switching). This study examined patient characteristics, prescribing patterns and treatment practice for RA in the United States.MethodsData were from the Adelphi Disease Specific Programme (Q2-Q3 2016). Rheumatologists completed a survey and patient record forms for adult patients with RA who had received ≥ 1 targeted therapy. Patients were grouped by class of first-used targeted therapy, and monotherapy vs. combination therapy. TNFi patients who received ≥ 1 targeted therapy were classified as cyclers or switchers. Univariate analyses compared patient characteristics and physician factors across the analysis groups.ResultsOverall, 631 patients received ≥ 1 targeted therapy; 535 were prescribed a TNFi as first targeted therapy, 53 a nonTNFi biologic disease-modifying antirheumatic drug (bDMARD), and 43 tofacitinib. Of 577 patients with known conventional synthetic (cs) DMARD status, 18.7% were prescribed monotherapy and 81.3% combination therapy. Combination therapy patients received significantly more concomitant medications prior to initiation of first targeted therapy than monotherapy patients (P < 0.05). The top reason for physicians to prescribe first use targeted therapy was strong overall efficacy (79.9%). Of 163 patients who progressed to second targeted therapy, 60.7% were cyclers. A lower proportion of cyclers persisted on their first use targeted therapy versus switchers (P = 0.03). The main reason physicians gave for switching patients at this stage was worsening condition (46.6%).ConclusionsMost patients were prescribed a TNFi as their first targeted therapy; over half then cycled to another TNFi. This suggests other factors may influence second use targeted treatment choice and highlights the need for greater understanding of outcomes associated with subsequent treatment choices and potential benefits of switching.

Project description:BackgroundAdvances in Disease-Modifying Antirheumatic Drugs (DMARDs) have expanded the treatment landscape for Rheumatoid Arthritis (RA). Guidelines recommend adding either conventional synthetic (cs), biologic (b), or targeted synthetic (ts) DMARDs to methotrexate (MTX) for managing RA. Limited evidence exists regarding the factors that contribute to adding a DMARD agent to the MTX regimen. This study examined the factors associated with adding the first DMARD in RA patients initiating MTX.MethodsThis retrospective cohort study utilized the MarketScan data (2012-2014) involving adults (aged ≥18) with RA initiating an MTX (index date) between Jul 1, 2012 and Dec 30, 2013, and with continuous enrollment for the 6-month pre-index period. The combination therapy users received the first treatment addition of DMARD starting from day 30 after the index MTX over one year period. The study focused on the addition of csDMARDs, Tumor Necrosis Factor Inhibitors (TNFi) bDMARDs, non-TNFi bDMARDs, or tsDMARDs. Baseline covariates were measured in the 6-month pre-index and grouped into predisposing, enabling, and need factors, as per the Andersen Behavior Model. Multivariable logistic regression examined the factors associated with the addition of TNFi compared to adding a csDMARD. An additional regression model evaluated the factors associated with adding any biologic (combining TNFi and non-TNFi biologics).ResultsAmong 8350 RA patients starting MTX, 31.92% (n = 2665) initiated any DMARD within the 1-year post-index period. Among RA patients initiating a DMARD prescription after starting MTX, 945 (11.32%) received combination therapy with treatment addition of a DMARD to MTX regimen; majority added TNFi (550, 58%), followed by csDMARD (352, 37%); non-TNF biologic (40, 4%), or tsDMARD (3, 0.3%). The tsDMARD group was limited and was not included for further analysis. The multivariable model found Preferred Provider Organization insurance coverage (odds ratio [OR], 1.43; 95% confidence interval (CI), 1.06-1.93), chronic pulmonary disease (OR, 1.98; 95% CI, 1.14-3.44), liver disease (OR, 5.24; 95% CI, 1.77-15.49), and Elixhauser score (OR, 0.91; 95% CI, 0.86-0.97) were significantly associated with the addition of TNF-α inhibitors. The separate multivariable model additionally found that patients from metropolitan areas (OR, 1.50; 95% CI, 1.04-2.16) were positively associated with adding any biological agent.ConclusionsTNFi are often added to MTX for managing RA. Enabling and need factors contribute to the prescribing of a TNFi add-on therapy in RA. Future research should examine the impact of these combination therapies on RA management.

Dataset Information

Baricitinib, Methotrexate, or Combination in Patients With Rheumatoid Arthritis and No or Limited Prior Disease-Modifying Antirheumatic Drug Treatment.

Publications

Baricitinib, Methotrexate, or Combination in Patients With Rheumatoid Arthritis and No or Limited Prior Disease-Modifying Antirheumatic Drug Treatment.

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