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Similar short-term clinical response to high-dose versus low-dose methotrexate in monotherapy and combination therapy in patients with rheumatoid arthritis.

ABSTRACT: Aiming at rapid decrease of disease activity, there has been a trend to start with higher doses of methotrexate (MTX) in patients newly diagnosed with rheumatoid arthritis (RA), both as monotherapy and in combination with other antirheumatic drugs. We aimed to study the relationship between clinical response and MTX dose as monotherapy or combination therapy in patients with early RA.Disease-modifying anti-rheumatic drug (DMARD)-naive patients with early RA, from a large international observational database, the METEOR database, were selected if MTX was part of their initial treatment. Patients were divided into four groups: MTX monotherapy, MTX?+?convention synthetic (cs)DMARDs, MTX?+?glucocorticoids or MTX?+?biologic (b)DMARDs. MTX dose was dichotomized: low dose ?10 mg/week; high dose ?15 mg/week. Linear mixed model analyses for the Disease Activity Score (DAS), DAS in 28 joints (DAS28) and Health Assessment Questionnaire (HAQ) were performed in each medication group, with MTX dose and time as covariates. Outcomes were assessed from baseline until 3-6 months follow up. Associations were adjusted for potential confounding by indication using propensity score (PS) modelling.For patients starting MTX monotherapy (n?=?523), MTX?+?csDMARDs (n?=?266) or MTX?+?glucocorticoids (n?=?615), the PS-adjusted effects of MTX dose (high versus low) on the DAS, DAS28 and HAQ were small and not clinically meaningful. Patients starting MTX?+?bDMARDs were disregarded due to low numbers (n =11).In patients newly diagnosed with RA, no clinical benefit of high compared to low initial MTX doses was found for MTX monotherapy or for MTX combination therapy with csDMARDs or glucocorticoids.

SUBMITTER: Bergstra SA

PROVIDER: S-EPMC5700534 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Similar short-term clinical response to high-dose versus low-dose methotrexate in monotherapy and combination therapy in patients with rheumatoid arthritis.

Bergstra Sytske Anne SA Allaart Cornelia F CF van den Berg Rosaline R Chopra Arvind A Govind Nimmisha N Huizinga Tom W J TWJ Landewe Robert B M RBM

Arthritis research & therapy 20171122 1

<h4>Background</h4>Aiming at rapid decrease of disease activity, there has been a trend to start with higher doses of methotrexate (MTX) in patients newly diagnosed with rheumatoid arthritis (RA), both as monotherapy and in combination with other antirheumatic drugs. We aimed to study the relationship between clinical response and MTX dose as monotherapy or combination therapy in patients with early RA.<h4>Methods</h4>Disease-modifying anti-rheumatic drug (DMARD)-naive patients with early RA, fr ...[more]

PMID: 29166919

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Project description:OBJECTIVE:To compare the efficacy and toxicity of cyclosporin A (CsA) monotherapy with CsA plus methotrexate (MTX) combination therapy in patients with early rheumatoid arthritis (RA). PATIENTS AND METHODS:120 patients with active RA, rheumatoid factor positive and/or erosive, were randomly allocated to receive CsA with MTX (n=60) or CsA with placebo (n=60). Treatment with CsA was started in all patients at 2.5 mg/kg/day and increased to a maximum of 5 mg/kg/day in 16 weeks. MTX was started at 7.5 mg/week and increased to a maximal dose of 15 mg/week at week 16. Primary outcomes were clinical remission (Pinals criteria) and radiological damage (Larsen score), at week 48. RESULTS:Treatment was discontinued prematurely in 27 patients in the monotherapy group (21 because of inefficacy, and six because of toxicity) and in 26 patients in the combination therapy group (14 and 12, respectively). At week 48, clinical remission was achieved in four patients in the monotherapy group and in six patients in the combination therapy group (p=0.5). The median Larsen score increased to 10 (25th, 75th centiles: 3.5; 13.3) points in the monotherapy group and to 4 (1.0; 10.5) points in the combination therapy group (p=0.004). 28/60 (47%) of patients in the monotherapy group v 34/60 (57%) of patients in the combination therapy group had reached an American college of Rheumatology 20% (ACR20) response (p=0.36) at week 48; 15/60 (25%) v 29/60 (48%) of patients had reached an ACR50 response (p=0.013); and 7 (12%) v 12 (20%) of patients had reached an ACR70 response (p=0.11). Their was a tendency towards more toxicity in the combination therapy group. CONCLUSIONS:In patients with early RA, neither CsA plus MTX combination therapy nor CsA monotherapy is very effective in inducing clinical remission. Combination therapy is probably better at improving clinical disease activity, and definitely better at slowing radiological progression. Combination therapy should still be compared with methotrexate monotherapy.

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:ObjectiveAssociations between rheumatoid arthritis (RA) and effect of treatment at the tissue levels are poorly understood. We investigated the scope of released extracellular matrix (ECM) metabolites as a consequence of tissue remodelling in patients treated with methotrexate (MTX) and tocilizumab (TCZ) compared to placebo.MethodsTissue metabolites from 387 RA patients treated with either TCZ (8 mg/kg) or MTX monotherapy (7.5-20 mg/kg) were measured at baseline and 8 weeks sera by validated ELISA assays. The levels of collagen biomarkers (C1M, C2M, C3M and C4M) together with C-reactive protein (CRP) and CRP metabolite (CRPM) were investigated. Baseline levels of biomarkers have been compared with 72 age- and gender-matched healthy controls. Comparison between treatment and response groups were done by ANCOVA, Spearman's correlation and logistic regression adjusted for age, gender, BMI and disease duration.ResultsC1M and C3M were significantly (P < 0.05) inhibited by TCZ and C3M by MTX (P < 0.01) compared to placebo. C1M and C3M inhibition with TCZ was respectively 23% and 16% greater than that of MTX (P < 0.01 and P < 0.0001). C4M was inhibited by TCZ and MTX, but the effect of TCZ was 22% greater than MTX (P < 0.0001). TCZ and MTX had minimal effect on C2M levels. MTX had no effect on CRP and CRPM, whereas TCZ reduced their levels to 69% and 27% from baseline. Investigated biomarkers revealed a significant (P < 0.05) difference in biomarker profiles of MTX ACR50 treatment responders and non-responders. Change to week 8 in levels of C3M, C4M, CRP and CRPM in MTX patients correlated significantly (rho = 0.41 to 0.18, P < 0.0001 to 0.039) with change in disease activity (DAS28) at weeks 8, 16 and 24, whereas only CRP in TCZ patients (rho = 0.32 to 0.21, P < 0.0001 to 0.01).ConclusionPatients receiving TCZ treatment for 8 weeks had higher suppression of tissue remodelling and inflammatory biomarkers over patients treated with MTX. Measured biomarkers enabled for a discrimination of biomarker profiles of ACR50 treatment responding patients and identification of those who benefit at the early time point. Week 8 change in levels of C3M, C4M, CRP and CRPM significantly predicted clinical response to treatment and correlated with DAS28 at all time points.Trial registrationClinicalTrials.gov, NCT00109408 . Date of registration: July 2005. Name of the registry: A Study to Assess the Safety and Efficacy of Tocilizumab in Patients with Active Rheumatoid Arthritis.

Project description:ObjectiveTo compare the effects of preventing radiographic progression (in its 3 components) of tocilizumab (TCZ) monotherapy with those of TCZ and methotrexate (MTX) in combination therapy (TCZ + MTX), and to evaluate possible effect modifiers in this model.MethodsRandomized trials that compared TCZ monotherapy to TCZ + MTX combination therapy for differences in radiographic progression were analyzed on an individual patient data level using mixed-effects models, and data were collected from 820 subjects with either early rheumatoid arthritis (RA) or established RA. Outcomes were classified as the absence of radiographic progression after 2 years (i.e., preventing radiographic progression) as measured by total Sharp/van der Heijde score (SHS), erosion score, and joint space narrowing (JSN) score. Effect modification by baseline joint damage, disease duration, and Disease Activity Score in 28 joints (DAS28) was studied.ResultsOverall, TCZ + MTX combination therapy was more effective in preventing radiographic progression compared to TCZ monotherapy, which was measured by total SHS score. However, in patients with early RA who had more joint damage compared to those with less joint damage at baseline (relative risk [RR] 1.02 versus RR 0.91, respectively) or in patients with a lower DAS28 score compared to those with a higher DAS28 score (RR 1.04 versus RR 0.92, respectively) at baseline, this advantage disappeared. In patients with established RA, the advantage of TCZ + MTX versus TCZ alone in the prevention of radiographic progression disappeared with a longer disease duration at baseline (RR 1.04 versus 0.83). Results of erosion scores as an outcome were in line with these findings, though findings for JSN scores were less clear.ConclusionCombination therapy with TCZ + MTX is more effective in preventing radiographic progression compared to TCZ monotherapy, but the effectiveness of TCZ monotherapy may approximate the effectiveness of TCZ + MTX in patients with early RA who have more joint damage and/or a lower DAS28 at baseline and in patients with established RA who have longer disease duration.

Dataset Information

Similar short-term clinical response to high-dose versus low-dose methotrexate in monotherapy and combination therapy in patients with rheumatoid arthritis.

Publications

Similar short-term clinical response to high-dose versus low-dose methotrexate in monotherapy and combination therapy in patients with rheumatoid arthritis.

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