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Comparative efficacy of biologics as monotherapy and in combination with methotrexate on patient reported outcomes (PROs) in rheumatoid arthritis patients with an inadequate response to conventional DMARDs--a systematic review and network meta-analysis.

ABSTRACT: To compare biologics as monotherapy or in combination with methotrexate (MTX) in terms of patient reported outcomes (PROs) in RA patients with an inadequate response to conventional DMARDs (DMARD-IR).With a systematic literature review 17 RCTs were identified that evaluated adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, abatacept, anakinra or tocilizumab. Treatment effects in terms of pain (0-100 mm), patient's global assessment of disease activity (PGA; 0-100 mm), Health Assessment-Questionnaire (HAQ) disability index (DI; 0-3), and the physical component summary (PCS) of the SF36 Health Survey (0-100) at 24 weeks were combined by means of Bayesian network meta-analyses.With tocilizumab monotherapy, greater improvements in pain (difference?=?-11.1; (95% Credible Interval -21.3, -0.1)) and PGA (-10.3 (-20.4, 0.8)) were observed than with aTNF monotherapy. Tocilizumab was at least as efficacious as aTNF in HAQ-DI improvements (-0.16; (-0.37, 0.05)). aTNF?+?MTX (-17.9 (-23.1, -13.0) & -19.1 (-24.2, -14.4)), abatacept?+?MTX (-23.0 (-47.3, 1. 5) & -13.6 (-28.4, 2.0)) and tocilizumab?+?MTX (-16.0 (-26.3, -6.3) & -15.1 (-25.1, -5.7)) showed comparable reductions in pain and PGA relative to MTX. Efficacy of anakinra?+?MTX was much smaller as compared to other biologics. The greatest improvements in HAQ-DI relative to MTX were observed with aTNF?+?MTX (-0.30 (-0.37, -0.22)) and tocilizumab?+?MTX (-0.27 (-0.42, -0.12)), followed by abatacept?+?MTX (-0.21 (-0.37, -0.05)) and anakinra?+?MTX (-0.11 (-0.26, 0.05)). The improvements in SF36-PCS with abatacept?+?MTX, aTNF?+?MTX and tocilizumab?+?MTX were comparable. There is a >90% probability that aTNF?+?MTX results in a greater improvement in pain (-12.4), PGA (-16.1) and HAQ-DI (-0.21) than aTNF as monotherapy. Efficacy of tocilizumab?+?MTX showed comparable improvements in PROs as tocilizumab monotherapy.Based on a network meta-analysis involving indirect comparison of trial findings, the following observations were made for DMARD-IR patients. In monotherapy, tocilizumab was associated with a greater improvement in pain and self-reported disease activity than aTNF, and was at least as efficacious regarding functional ability. The improvements in PROs with aTNF, abatacept and tocilizumab in combination with MTX were comparable. Improvements in PROs with tocilizumab as monotherapy were similar to that of tocilizumab?+?MTX, whereas aTNF as monotherapy was likely to be less efficacious than aTNF?+?MTX.

SUBMITTER: Jansen JP

PROVIDER: S-EPMC4101713 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Comparative efficacy of biologics as monotherapy and in combination with methotrexate on patient reported outcomes (PROs) in rheumatoid arthritis patients with an inadequate response to conventional DMARDs--a systematic review and network meta-analysis.

Jansen Jeroen P JP Buckley Felicity F Dejonckheere Fred F Ogale Sarika S

Health and quality of life outcomes 20140703

<h4>Objective</h4>To compare biologics as monotherapy or in combination with methotrexate (MTX) in terms of patient reported outcomes (PROs) in RA patients with an inadequate response to conventional DMARDs (DMARD-IR).<h4>Methods</h4>With a systematic literature review 17 RCTs were identified that evaluated adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, abatacept, anakinra or tocilizumab. Treatment effects in terms of pain (0-100 mm), patient's global assessment of disease ac ...[more]

PMID: 24988902

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Project description:Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis.In this 6-month, phase 3, randomized, placebo-controlled trial, 611 patients with inadequate response to disease-modifying anti-rheumatic drugs (DMARD-IR) were randomized 4:4:1:1 to receive: tofacitinib 5 mg BID or tofacitinib 10 mg BID for the duration of the study, or placebo for 3 months followed by tofacitinib 5 mg BID or tofacitinib 10 mg BID. Patient-reported outcomes (PROs) included: Patient Global Assessment of Disease Activity (PtGA); Patient Assessment of Pain (Pain); Health Assessment Questionnaire-Disability Index (HAQ-DI); Medical Outcomes Survey (MOS) Short Form-36 (SF-36); Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F); and MOS Sleep Scale. Time-to-event data (PtGA and Pain) were collected using an interactive voice response system daily diary (baseline through day 14).At month 3, tofacitinib 5 and 10 mg BID demonstrated statistically significant improvements versus placebo in PtGA (both p < 0.0001), Pain (both p < 0.0001), HAQ-DI (both p < 0.0001), SF-36 Physical (p < 0.0001) and Mental (p < 0.05 [5 mg BID] and p < 0.0001 [10 mg BID]), Component Summary scores and all domain scores (p < 0.05-p < 0.0001) and FACIT-F (both p < 0.0001). Statistically significant changes from baseline in MOS Sleep Scale were reported for 10 mg BID (p < 0.05). Benefits of tofacitinib treatment were rapid in onset and significant improvements were reported at week 2 for PtGA, Pain and HAQ-DI, and differentiation from baseline was seen as early as 3 days after treatment initiation for interactive voice response system (IVRS) PtGA and IVRS Pain. The numbers needed to treat for patients to report changes greater than or equal to the minimum clinically important difference in PtGA, Pain, HAQ-DI, SF-36 Physical Component Summary score and FACIT-F ranged between 4.0-6.1 (5 mg BID) and 3.2-5.0 (10 mg BID).Tofacitinib monotherapy in DMARD-IR patients resulted in statistically significant and clinically meaningful improvements in multiple PROs versus placebo at month 3, with sustained improvements over 6 months.Clinicaltrials.gov registration NCT00814307 , registered 22 December 2008.

Project description:BackgroundSarilumab is a human monoclonal antibody directed against the alpha subunit of the interleukin-6 receptor complex. In the MOBILITY phase III randomized controlled trial (RCT), sarilumab + methotrexate (MTX) treatment resulted in clinical improvements at 24 weeks that were maintained at 52 weeks in adults with rheumatoid arthritis (RA), who have inadequate response to MTX (MTX-IR). These analyses indicate the effects of sarilumab + MTX versus placebo on patient-reported outcomes (PROs) in this RCT.MethodsPatients (n = 1197) were randomized to receive placebo, sarilumab 150 or 200 mg subcutaneously + MTX every 2 weeks for 52 weeks; after 16 weeks, patients without ≥20 % improvement from baseline in swollen or tender joint counts on two consecutive assessments were offered open-label treatment. PROs included patient global assessment of disease activity (PtGA), pain, health assessment questionnaire disability index (HAQ-DI), Short Form-36 Health Survey (SF-36), and functional assessment of chronic illness therapy-fatigue (FACIT-F). Changes from baseline at weeks 24 and 52 were analyzed using a mixed model for repeated measures. Post hoc analyses included percentages of patients reporting improvements equal to or greater than minimal clinically important differences (MCID) and normative values in the FACIT-F and SF-36. Pearson correlation between observed PRO scores and clinical measures of disease activity was tested at week 24.ResultsBoth doses of sarilumab + MTX vs placebo + MTX resulted in improvement from baseline by week 24 in PtGA, pain, HAQ-DI, SF-36 and FACIT-F scores (p < 0.0001) that was clinically meaningful, and persisted until week 52. In post hoc analyses, the percentages of patients with improvement equal to or greater than the MCID across all PROs were greater with sarilumab than placebo (p < 0.05), with differences ranging from 11.6 to 26.2 %, as were those reporting equal to or greater than normative scores.ConclusionsIn this RCT in patients with MTX-IR RA, sarilumab + MTX resulted in sustained improvement in PROs that were clinically meaningful, greater than placebo + MTX, and complement the previously reported clinical efficacy and safety of sarilumab.Trial registrationClinicalTrials.gov. NCT01061736 . February 2, 2010.

Project description:ObjectiveTo evaluate the effect of upadacitinib (UPA) monotherapy vs MTX on patient-reported outcomes (PROs) in patients with RA who were MTX-naïve or who had an inadequate response to MTX (MTX-IR).MethodsPROs from the SELECT-EARLY and SELECT-MONOTHERAPY randomized controlled trials were evaluated at Weeks 2 and 12/14. Patients were ≥18 years of age with RA symptoms for ≥6 weeks (SELECT-EARLY, MTX-naïve) or diagnosed RA for ≥3 months (SELECT-MONOTHERAPY, MTX-IR) and received UPA monotherapy (15 or 30 mg) or MTX. PROs included Patient Global Assessment of Disease Activity (PtGA), pain visual analogue scale, HAQ Disability Index (HAQ-DI), morning stiffness duration/severity, Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue (SELECT-EARLY), health-related quality of life (HRQOL) by the 36-iem Short Form Health Survey and Work Productivity and Activity Impairment (WPAI; SELECT-EARLY). Least square mean (LSM) changes and proportions of patients reporting improvements greater than or equal to the minimum clinically important differences and normative values were determined.ResultsIn 945 MTX-naïve and 648 MTX-IR patients, UPA monotherapy (15 mg, 30 mg) vs MTX resulted in greater reported LSM changes from baseline at Weeks 12/14 in PtGA, pain, HAQ-DI, morning stiffness duration/severity, FACIT-F (SELECT-EARLY), HRQOL and WPAI (SELECT-EARLY). These changes were statistically significant with both doses of UPA vs MTX at Weeks 12/14 in both RCTs. Improvements were reported as early as week 2. Compared with MTX, more UPA-treated MTX-naïve and MTX-IR patients reported improvements greater than or equal to the minimum clinically important differences and scores greater than or equal to normative values.ConclusionAmong MTX-naïve and MTX-IR patients with active RA, UPA monotherapy at 15 or 30 mg for 12/14 weeks resulted in statistically significant and clinically meaningful improvements in pain, physical function, morning stiffness, HRQOL and WPAI compared with MTX alone.Clinical trial registration numberSELECT-EARLY (NCT02706873) and SELECT-MONOTHERAPY (NCT02706951) are registered with ClinicalTrials.gov.

Project description:BACKGROUND AND OBJECTIVE:Early seronegative rheumatoid arthritis (RA) is considered a specific entity, especially regarding diagnostic issues and prognosis. Little is known about its potentially different initial clinical presentation and outcome. We aimed to determine predictors of good response to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) in seronegative RA patients with early inflammatory arthritis. PATIENTS AND METHODS:Patients from the ESPOIR cohort with early inflammatory arthritis fulfilling the 2010 ACR/EULAR classification criteria for RA despite negativity for both rheumatoid factor and anti-CCP antibodies. The primary endpoint was a good or moderate EULAR response assessed after 1?year of follow-up, given at least 3?months of treatment with a csDMARD. Secondary objectives were to compare the early therapeutic response to methotrexate (MTX) and leflunomide (LEF) versus other csDMARDs (hydroxychloroquine, sulfasalazine) and to identify factors associated with functional disability (Health Assessment Questionnaire-Disability Index [HAQ-DI]?>?0.5 at 1?year) and structural progression (van der Heijde-modified total Sharp score >?1 and >?5 points at 1?year). Logistic regression analysis was used to determine independent predictors of outcomes. RESULTS:One hundred seventy-two patients were analyzed. Overall, 98/172 (57%) patients received MTX during the first year of follow-up. A good or moderate EULAR response at 1?year was associated with early use of csDMARDs (i.e., within 3?months after the first joint swelling) on univariate and multivariable analysis (odds ratio?=?2.41 [95% confidence interval 1.07-5.42], p =?0.03). Response rates were not affected by other classical prognostic factors (i.e., baseline DAS28). Presence of erosions at baseline was associated with Sharp score progression >?1 point and >?5 points (both p =?0.03) at 1?year. HAQ-DI ??1 at inclusion and active smoking were significantly associated with HAQ-DI?>?0.5 at 1?year. CONCLUSION:Our results suggest that delay in initiation of csDMARD more than baseline clinical, biological, or imaging features predominantly affects the outcome in early seronegative RA. These findings confirm that the usual therapeutic concepts in RA (early treatment, tight control, and treat-to-target) should be applied similarly to both seropositive and seronegative disease forms. TRIAL REGISTRATION:ClinicalTrials.gov: NCT03666091. Registered September 11, 2018.

Project description:Despite recommendations suggesting that biological and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) should be used in combination with methotrexate in the treatment of rheumatoid arthritis (RA), up to one-third of patients with RA are treated with monotherapy. The objective of the systematic literature review reported here was to evaluate the clinical evidence regarding the efficacy of b/tsDMARDs as monotherapy in the treatment of RA. MEDLINE®, Embase®, and the Cochrane Central Trials Register (to April 11, 2017) and the American College of Rheumatology and European League Against Rheumatism conference proceedings (2010-2016) were searched for randomized controlled trials evaluating the efficacy of b/tsDMARDs as monotherapy for RA in adults. Forty-four monotherapy studies of abatacept, adalimumab, baricitinib, certolizumab pegol, etanercept, sarilumab, sirukumab, tocilizumab, and tofacitinib reported in 71 publications were identified. Tocilizumab had the most studies (14), followed by etanercept (10) and adalimumab (9). These b/tsDMARDs were consistently shown to be efficacious treatments, regardless of whether patients were intolerant of or had never used conventional synthetic (cs) DMARDs. However, better treatment outcomes were usually achieved with combination therapy, and this was observed for all b/tsDMARDs assessed by this review. Only a few studies provided a head-to-head comparison between b/tsDMARD treatments or between b/tsDMARD monotherapy and combination therapy, and as many were initial RA treatments they were not generalizable to usual care. In conclusion, evidence from randomized trials suggests that the b/tsDMARDs studied are effective as monotherapy. In general, some patient responses seem better with combination therapy and the durability of monotherapy is less than combination therapy. There is, however, a need for longer-term head-to-head trials to establish positioning of these interventions in the treatment algorithm for RA. FUNDING:Pfizer.Plain Language Summary: Plain language summary available on the journal website.

Project description:BackgroundTo evaluate the effect of upadacitinib on patient-reported outcomes (PROs) in patients with RA who had an inadequate response to csDMARDs.MethodsPatients in SELECT-NEXT, a randomised controlled trial, were on a background of csDMARDs and received upadacitinib 15 mg and 30 mg or placebo daily for 12 weeks. PROs included Patient Global Assessment of Disease Activity (PtGA), pain, Health Assessment Questionnaire-Disability Index (HAQ-DI), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), duration and severity of morning (AM) joint stiffness, Short Form 36 Health Survey (SF-36), and Work Instability Scale for RA (RA-WIS). Least squares mean (LSM) changes were based on mixed-effect repeated measure models. Percentages of patients reporting improvements ≥ minimum clinically important differences (MCIDs) and scores ≥ normative values and number needed to treat (NNT) were determined; group comparisons used chi-square tests.ResultsData from 661 patients were analysed. Compared with placebo, patients receiving upadacitinib reported statistically significant improvements (both doses, P < 0.05) in PtGA, pain, HAQ-DI, FACIT-F, duration and severity of AM stiffness, SF-36 (PCS and 6/8 domains), and RA-WIS at week 12. Significantly, more upadacitinib-treated patients (both doses, P < 0.05) reported improvements ≥ MCID in PtGA, pain, HAQ-DI, FACIT-F, AM stiffness, SF-36 (PCS and 4 or 7/8 domains), and RA-WIS and scores ≥ normative values in HAQ-DI, FACIT-F, and SF-36 (PCS and 4 or 5/8 domains). For most PROs, the incremental NNT with upadacitinib to report clinically meaningful improvement from baseline ranged from 4 to 8 patients.ConclusionsUpadacitinib 15 mg or 30 mg daily for 12 weeks resulted in significant and clinically meaningful improvements in global disease activity, pain, physical function, fatigue, duration and severity of AM stiffness, HRQOL, and work instability among csDMARD-IR patients with RA.Trial registrationClinicaltrials.gov, NCT02675426. Retrospectively registered 5 February 2016.

Dataset Information

Comparative efficacy of biologics as monotherapy and in combination with methotrexate on patient reported outcomes (PROs) in rheumatoid arthritis patients with an inadequate response to conventional DMARDs--a systematic review and network meta-analysis.

Publications

Comparative efficacy of biologics as monotherapy and in combination with methotrexate on patient reported outcomes (PROs) in rheumatoid arthritis patients with an inadequate response to conventional DMARDs--a systematic review and network meta-analysis.

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