Showing papers by "Peter C. Taylor published in 2015"

Anti-TNF therapy: past, present and future

Abstract: While for a century therapeutics has been dominated by small molecules, i.e. organic chemicals of ~400 Da absorbable via the gut, this is no longer the case. There are now a plethora of important medicines which are proteins and injectable, which have dramatically improved the therapy of many inflammatory diseases and of cancer. Most of these are monoclonal antibodies, some are receptor Ig Fc fusion proteins, others are cytokines or enzymes. The key to this new aspect of therapeutics has been the filling of unmet needs, and the consequent commercial success, which promoted further research and development. The first ‘biologic’ for a common disease, rheumatoid arthritis (RA), was a monoclonal antibody, infliximab, to human tumour necrosis factor (TNF). This was based on our work, which is described in this review, summarizing how TNF was defined as a good target in RA, how it was developed is described here, as well as future indications for anti-TNF and related agents. Biologics are now the fastest growing sector of therapeutics.

Safety and efficacy of baricitinib at 24 weeks in patients with rheumatoid arthritis who have had an inadequate response to methotrexate

Abstract: Objectives To investigate baricitinib (LY3009104, formerly INCB028050), a novel, oral inhibitor of JAK1/JAK2 in patients with moderate to severe rheumatoid arthritis (RA) despite treatment with methotrexate. Methods In this phase IIb study, 301 patients were randomised 2:1:1:1:1 to receive once daily doses of placebo or 1, 2, 4 or 8 mg baricitinib for 12 weeks. Patients assigned to 2, 4 and 8 mg baricitinib continued blinded treatment for an additional 12 weeks. Patients assigned to placebo or 1 mg baricitinib were reassigned to 2 mg twice daily or 4 mg once daily baricitinib between weeks 12–24. The primary endpoint was the proportion of patients in the combined 4 and 8 mg groups achieving an American College of Rheumatology 20% (ACR20) response versus placebo at week 12. Results Significantly more patients in the combined baricitinib 4 and 8 mg groups compared with placebo achieved an ACR20 response at week 12 (76% vs 41%, p Conclusions Baricitinib improved the signs and symptoms of RA in methotrexate inadequate responders with active disease. Baricitinib was well tolerated with no unexpected safety findings through week 24. Trial registration number NCT01185353.

Ultrasound-guided synovial biopsy: a safe, well-tolerated and reliable technique for obtaining high-quality synovial tissue from both large and small joints in early arthritis patients

Abstract: OBJECTIVE: To determine the tolerability, safety and yield of synovial tissue in an early arthritis cohort using a minimally invasive, ultrasound (US)-guided, synovial biopsy technique in small, medium and large joints. METHODS: 93 sequential biopsy procedures were assessed from a total of 57 patients (baseline and 36 repeat biopsies at 6 months) recruited as part of the 'Pathobiology of Early Arthritis Cohort' study. Patients completed a tolerability questionnaire prior to and following the synovial biopsy procedure. The synovial biopsy was performed under US guidance with US images of the joint recorded prior to each procedure. Synovial tissue was harvested for immunohistochemistry and RNA extraction. RESULTS: Five different joint sites were biopsied (knee, elbow, wrist, metacarpal phalangeal and proximal interphalangeal). No significant complications were reported following the procedure. No difference in pain, swelling and stiffness of the biopsied joint from before and after the procedure was demonstrated. A median of 14 biopsy samples was retrieved from each procedure with 93% of biopsy procedures yielding good quality tissue. RNA yield was good in all joints and in repeat biopsies. Multivariant analysis demonstrated a significantly greater yield of RNA and graded tissue in relation to a high prebiopsy, grey-scale synovitis score (0-3, semiquantitative). CONCLUSIONS: A minimally invasive approach to synovial tissue harvesting, using US guidance, is both safe and well-tolerated by patients. Tissue quality/RNA yield is preserved in subsequent biopsies following therapeutic intervention. A high US grey-scale synovitis score is a predictor of good quality/quantity of tissue and RNA.

Patient Expectations and Perceptions of Goal-setting Strategies for Disease Management in Rheumatoid Arthritis

Abstract: Objective To identify how patients perceive the broad effect of active rheumatoid arthritis (RA) on their daily lives and indicate how RA disease management could benefit from the inclusion of individual goal-setting strategies. Methods Two multinational surveys were completed by patients with RA. The “Good Days Fast” survey was conducted to explore the effect of disease on the daily lives and relationships of women with RA. The “Getting to Your Destination Faster” survey examined RA patients’ treatment expectations and goal-setting practices. Results Respondents from all countries agreed that RA had a substantial negative effect on many aspects of their lives (work productivity, daily routines, participation in social and leisure activities) and emotional well-being (loss of self-confidence, feelings of detachment, isolation). Daily pain was a paramount issue, and being pain- and fatigue-free was considered the main indicator of a “good day.” Setting personal, social, and treatment goals, as well as monitoring disease progress to achieve these, was considered very beneficial by patients with RA, but discussion of treatment goals seldom appeared to be a part of medical appointments. Conclusion Many patients with RA feel unable to communicate their disease burden and treatment goals, which are critically important to them, to their healthcare provider (HCP). Insights gained from these 2 surveys should help to guide patients and HCP to better focus upon mutually defined goals for continued improvement of management and achievement of optimal care in RA.

Anti-tumour necrosis factor treatment increases circulating T helper type 17 cells similarly in different types of inflammatory arthritis.

Abstract: We investigated changes in circulating T helper type 17 (Th17) cells following anti-tumour necrosis factor (TNF) in rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) patients. Peripheral blood mononuclear cells (PBMC) were isolated from 25 RA, 15 AS and eight PsA patients at baseline 4 and 12 weeks after treatment, and Th17 cell frequencies were analysed using interleukin (IL)-17 enzyme-linked immunospot (ELISPOT) and flow cytometry. A significant increase in IL-17-producing cells was observed by ELISPOT in RA and AS patients at 12 weeks. Flow cytometry confirmed significant increases in CD4(+) IL-17(+) cells at 12 weeks in RA and AS and 4 weeks in PsA patients. Anti-TNF treatment increases circulating Th17 cells in three different diseases.

The biology of IL-23 and IL-17 and their therapeutic targeting in rheumatic diseases

Abstract: Purpose of reviewInterleukin (IL)-23 and the related cytokine IL-17 play vital roles in immune-mediated inflammatory pathology. In the years since its discovery, IL-23 has been implicated as a central pathogenic factor in multiple rheumatic conditions and has been shown to act via a wide range of im

Combination cytokine blockade: the way forward in therapy for rheumatoid arthritis?

Abstract: Two decades ago, patients presenting with the heterogeneous condition termed rheumatoid arthritis (RA), best thought of as a syndrome, had a variable, but often poor, prognosis. Since that time, however, the outlook for the majority of contemporary patients meeting classification criteria for RA has improved dramatically. This is in part because of advances in the optimal use of conventional synthetic disease-modifying antirheumatic drugs, but in particular, because of the research leading up to approval of biologic therapies targeting proinflammatory cytokines—initially, tumor necrosis factor (TNF) (1). These advances came about because of two concurrent developments: 1) the availability of reagents that allowed TNF to be measured and strongly implicated in the pathogenesis of RA, and 2) advances in protein engineering that enabled pharmacologic blockade of the putative therapeutic target. Clinical trials followed, which confirmed the validity of TNF as a target, with the best efficacy achieved when a biologic TNF inhibitor is used together with methotrexate. Perhaps one of the most striking benefits of biologic TNF inhibition to emerge from early trials was the magnitude of inhibition of structural damage to joints as assessed radiographically, reflecting the importance of the TNF-mediated pathway in modulation of both RANKL and enzymes degrading bone and cartilage. As a consequence of this structural preservation and the magnitude of clinical efficacy, observational studies confirm that most patients benefit from maintained physical function over time. However, in spite of the clinical successes, the observed magnitude of clinical responses to anti-TNF treatment is variable, with the majority of patients with established disease exhibiting only partial response. Biologic therapies targeting other mechanisms of action were developed soon after anti-TNF, and—similar to results observed with anti-TNF—while beneficial in most patients, very few of these newer therapies provide complete restoration of immune homeostasis. Furthermore, the proportion of patients achieving a given categorical response level is remarkably consistent between approved biologic agents targeting different mechanisms of action. This ceiling effect observed with direct inhibition of a single cytokine and other inflammatory targets strongly suggests that for most patients with RA-pattern disease expression, achievement of more profound clinical responses will require modulation of the dysregulated immune system at more than one point. The challenge, however, is how to accomplish this with the goal of restoring immune homeostasis with its clinical correlate of health, but without rendering the patient immunosuppressed and vulnerable to the associated complications. Appetite for clinical trials of combination biologic agents has been tempered by the failure to demonstrate increased efficacy with combination TNF and costimulation blockade and combination interleukin-1 (IL-1) and TNF blockade, and worse, with an unacceptably high rate of infectious complications, as noted in the report by Fischer et al (2) that is discussed in further detail below. Th17 cells are a highly proinflammatory subset of CD4 T helper cells and are known to contribute to arthritis pathogenesis (3,4). Their signature cytokine, Dr. Williams’ work was supported by the Kennedy Trust for Rheumatology Research and the European Union Seventh Framework Programme (project PRIAT; 305309). Peter C. Taylor, MA, PhD, MD, FRCP: Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, and Botnar Research Centre, Oxford, UK; Richard O. Williams, PhD: Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, and University of Oxford, Oxford, UK. Dr. Taylor has received consulting fees, speaking fees, and/or honoraria from UCB, Merck, Abbott/AbbVie, Roche, Pfizer, and AstraZeneca (less than $10,000 each). Dr. Williams has received grant support from Merck. Address correspondence to Peter C. Taylor, MA, PhD, MD, FRCP, Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Botnar Research Centre, Windmill Road, Headington, Oxford OX3 7L, UK. E-mail: peter.taylor@kennedy.ox.ac.uk. Submitted for publication September 8, 2014; accepted in revised form September 23, 2014.

TNFα regulates cortisol metabolism in vivo in patients with inflammatory arthritis

Abstract: Objective To determine the relationship between inflammation and glucocorticoid metabolism in vivo, in a clinical study of patients with inflammatory arthritis treated with anti-TNFα therapy. Methods Urine samples were collected from patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA) as part of a multicentre study assessing responses to infliximab and etanercept. Systemic measures of glucocorticoid metabolism were assessed by gas chromatography/mass spectrometry at weeks 0 (baseline), 4 and 12 after anti-TNFα therapy. Clinical data including DAS28 and C-reactive protein were also collected. Results Systemic measures of 11β-HSD1 activity in patients with inflammatory arthritis decreased significantly following anti-TNFα therapy in patients with RA and PsA. Additionally, the activity of the glucocorticoid inactivating enzyme 5α-reductase appeared to increase significantly. Conclusions This study demonstrates, for the first time, that the increased 11β-HSD1 activity seen in patients with inflammatory arthritis is mediated through TNFα. Furthermore, the changes in related glucocorticoid metabolising enzymes suggest that there is a coordinated change in glucocorticoid metabolism which promotes higher tissue glucocorticoid levels.

Scientific rationale behind the development and approval of biosimilar infliximab (CT-P13) in Europe

Abstract: Biosimilars are drugs developed to be highly similar to their originator biologic (or 'reference medicinal product') with no clinically meaningful differences in purity, efficacy or safety. Production of biologics and biosimilars is highly complex and sensitive, with any change in manufacturing process having a potential impact on efficacy and safety. This review provides an overview of the manufacturing process for these drugs and considers the implications of any process changes. The scientific rationale underlying the regulatory comparability exercise for process-changed reference medicinal products and biosimilars is also discussed, as is the issue of 'switchability' from a reference medicinal product to its biosimilar. CT-P13 (Remsima(®), Inflectra(®)), a biosimilar of infliximab, is used as a case study to discuss these issues.

Most Trial Eligibility Criteria and Patient Baseline Characteristics Do Not Modify Treatment Effect in Trials Using Targeted Therapies for Rheumatoid Arthritis: A Meta-Epidemiological Study

Abstract: Objective To determine if variations in trial eligibility criteria and patient baseline characteristics could be considered effect modifiers of the treatment response when testing targeted therapies (biological agents and targeted synthetic disease modifying antirheumatic drugs (DMARDs)) for rheumatoid arthritis (RA). Methods We conducted a meta-epidemiological study of all trials evaluating a targeted therapy approved by regulatory authorities for treating RA. The database search was completed on December 11th 2013. Eligible trials reported ACR20 data at months 3–6 and used an add-on design. Odds ratios (ORs) were calculated from the response rates and compared among the trial eligibility criteria/patient baseline characteristics of interest. Comparisons are presented as the Ratio of Odds Ratios (ROR). Results Sixty-two trials (19,923 RA patients) were included in the primary analyses using ACR20 response. Overall, targeted therapies constituted an effective treatment (OR 3.96 95% confidence interval (CI) 3.41 to 4.60). The majority of the trial eligibility criteria and patient baseline characteristics did not modify treatment effect. The added benefit of targeted therapies was lower in trials including "DMARD-naive" patients compared with trials including "DMARD inadequate responders" (ROR = 0.45, 95%CI 0.31 to 0.66) and trials including "targeted therapy inadequate responders" (0.50, 95%CI 0.29 to 0.87), test for interaction: p = 0.0002. Longer mean disease duration was associated with a higher likelihood of responding to treatment (β = 1.05, 95%CI 1.00 to 1.11 OR’s per year; p = 0.03). Analyses conducted using DAS28-remission as the outcome supported the above-mentioned findings. Conclusion Our results suggest that a highly selective inclusion is not associated with greater treatment effect, as might otherwise be expected. The added benefit of a targeted therapy was lower in trials including patients who were DMARD-naive and trials including patients with shorter disease durations.

Early metacarpal bone mineral density loss using digital x-ray radiogrammetry and 3-tesla wrist MRI in established rheumatoid arthritis: a longitudinal one-year observational study.

Abstract: Objectives. Early change in rheumatoid arthritis (RA) is characterised by periarticular osteopenia. We investigated the relationship of early metacarpal digital X-ray radiogrammetry bone mineral density (DXR-BMD) change rate (RC-BMD, mg/cm2/month) to longitudinal changes in hand and feet radiographic and wrist MRI scores over 1 year. Materials and Methods. 10 RA patients completed the study and had wrist 3T-MRI and hand and feet X-rays at various time points over 1 year. MRI was scored by RAMRIS, X-ray was done by van der Heijde modified Sharp scoring, and RC-BMD was analysed using dxr-online. Results. There was good correlation amongst the two scorers for MRI measures and ICC for erosions: 0.984, BME: 0.943, and synovitis: 0.657. Strong relationships were observed between RC-BMD at 12-week and 1-year change in wrist marrow oedema (BME) (r = 0.78, P = 0.035) but not with erosion, synovitis, or radiographic scores. Conclusion. Early RC-BMD correlates with 1-year wrist BME change, which is a known predictor of future erosion and joint damage. However, in our pilot study, early RC-BMD did not show relationships to MRI erosion or radiographic changes over 1 year. This may reflect a slower kinetic in the appearance of MRI/radiographic erosions, generating the hypothesis that RC-BMD may be a more sensitive and early structural prognostic marker in RA follow-up.

Methods and system for determining the disease status of a subject

Abstract: A method of determining the osteoarthritis, inflammatory arthritis or joint injury status in a subject, and a panel of test biomarkers for use in determining same is disclosed. In particular, the method comprise the steps of determining the expression levels of at least three test biomarkers in a sample of bodily fluid obtained from the subject; conducting a statistical analysis of the correlation and relative expression levels between the at least three biomarkers; calculating a statistical score based on the statistical analysis; and comparing the statistical score with reference statistical scores generated from at least three reference group expression profiles to predict, diagnose, monitor or determine one or more of osteoarthritis, inflammatory arthritis or joint injury. For both the method and panel the test biomarkers typically contains at least PIIANP. By analysis of the test biomarkers, the disease status of a subject may be determined.

A scientific update on biosimilar infliximab (CT-P13) in rheumatic diseases

Abstract: The development of biologic drugs has undoubtedly enhanced the spectrum of treatments available for immune-mediated inflammatory rheumatic diseases such as rheumatoid arthritis. However, despite their clear clinical benifits, use of biologics is often hindered by their high costs. The manufacture and subsequent approval of more cost-effective 'biosimilar' versions of these drugs may address this issue and improve patient access. CT-P13 (Remsima(®), Inflectra(®)), a biosimilar of infliximab (Remicade(®)), has shown comparable efficacy, safety and pharmacokinetics to its originator drug in clinical studies. The articles in this supplement present a scientific update on the development and use of biosimilars in rheumatic disorders, with specific focus on CT-P13. The information discussed highlights the predicted positive clinical and economic impact of biosimilars on the management of rheumatic diseases.

THU0363 A Structured Literature Review of the Burden of Illness and Unmet Needs in Patients with Rheumatoid Arthritis: A Current Perspective

Abstract: Background Despite improvements in the attainable clinical and health outcomes for patients with rheumatoid arthritis (RA), the goals of remission or low disease activity still remain difficult to achieve in a substantial proportion of patients. While rheumatologists have focussed on attainment of these goals, for many patients, particularly those who do not achieve these targets, additional treatment goals are control over pain and fatigue, as well as maintaining physical function and quality of life (QoL). Objectives To examine patients9 treatment aspirations and to identify the unmet needs for patients with RA receiving ongoing treatment and the associated humanistic and economic burden. Methods Searches were performed using MEDLINE, Embase, PsycINFO and Econlit literature databases for articles published from 2004–2014 in the English language. Published literature was screened to identify articles reporting the burden of RA in patients receiving ongoing treatment. Core search terms included those related to the condition of study and treatment, and were combined with search terms related to humanistic and economic burden. Results A total of 3212 articles were identified. After removing conference abstracts and duplicates and screening titles and abstracts, 77 publications that reported on the humanistic (68 articles) and economic burden (9 articles) of RA were selected for full text review. Despite clinically meaningful improvements in pain with the introduction of effective treatment algorithms, patient scores remained below the acceptable threshold in those receiving biologic therapy (1), whereas patients with RA receiving ongoing treatment with conventional disease-modifying antirheumatic drugs continued to experience moderate pain (2). Other health outcomes such as physical disability persisted above the threshold that patients would consider acceptable (3, 4) and mental health needs were also insufficiently met in a large proportion of patients with RA receiving ongoing treatment (5). In Europe, the health burden of RA was associated with an economic burden of € 45.3 billion, affecting patients, their families and society (6). Conclusions Despite ongoing advances in the treatment of RA, many patients receiving currently available therapies continue to experience substantial disability and suboptimal QoL. RA is a multifaceted disease that can impact on individual patients in a variety of ways, some objectively evident and others known only to the patient themselves. Although a broad range of available pharmaco-therapeutic and management options are currently available, novel treatments and approaches are needed to address the associated unmet needs. References Fleischmann R. Open Access Rheumatology Research and Reviews. 2009;1:95–106. Gronning K, Rodevand E, Steinsbekk A. Clin Rheumatol. 2010;29:1317–1322. Westhovens R, Cole JC, Li T, et al. Rheumatology (Oxford). 2006;45:1238–1246. Wells GA, Tugwell P, Kraag GR, Baker PRA, Groh J, Redelmeier DA. The Journal of Rheumatology. 1993;20:557–560. Strand V, Singh JA. Drugs. 2010;70:121–145. Lundkvist J, Kastang F, Kobelt G. Eur J Health Econ. 2008;Suppl 2:S49–60. Acknowledgements Medical writing support was provided by Neel Misra of Engage Scientific Solutions and was funded by Pfizer Inc. Disclosure of Interest P. Taylor Consultant for: Pfizer, A. Moore: None declared, R. Vasilescu Shareholder of: Pfizer, Employee of: Pfizer, J. Alvir Shareholder of: Pfizer, Employee of: Pfizer, M. Tarallo Shareholder of: Pfizer, Employee of: Pfizer

A7.17 Effects of baricitinib on multibiomarker disease activity scores and their components in a phase 2b study in moderate-to-severe rheumatoid arthritis patients

Abstract: Background Baricitinib, an oral inhibitor of JAK1 and JAK2 signaling, improved the signs and symptoms in patients with active rheumatoid arthritis (RA) who were methotrexate inadequate responders (MTX-IR) in a double-blind, placebo (PBO) controlled study1. Objectives To investigate how a quantitative, multibiomarker disease activity score (MBDA) and its individual components are affected by treatment with baricitinib 4 mg (n=50) once daily compared to PBO (n=79) during a 12 week treatment period in moderate-to-severe RA patients. Methods Serum samples collected at baseline and Weeks 4 and 12 from patients in the study1 were shipped frozen to Crescendo Biosciences for analysis2. MBDA scores and changes in individual MBDA components were subjected to post-hoc statistical analyses. Results At baseline, the proportion of patients with low, moderate, and high MBDA scores were similar in the 2 groups, as were median MBDA scores (PBO=44 vs. baricitinib 4 mg=47). Unlike PBO-treated patients, baricitinib 4 mg patients had decreased MBDA scores at 4 and 12 weeks compared to baseline (baricitinib 4 mg =35.5 and 37.0 (p 0.05) changes for baricitinib-treated patients at either timepoint for epidermal growth factor (EGF), MMP-1, or vascular endothelial growth factor-A (VEGF-A). For baricitinib-treated patients versus PBO, at 4 but not 12 weeks, Interleukin-6 (IL-6) and resistin were significantly decreased and at 12 but not 4 weeks, leptin was significantly increased. Conclusions Consistent with other indices of disease activity1, the treatment of MTX-IR patients with baricitinib 4 mg once daily resulted in a reduction in the MBDA scores, apparent by 4 weeks. Decreases in MBDA scores and the components were present at both 4 and 12 weeks. Reduction in the levels of inflammatory markers beyond those associated with an acute phase response is apparent in these patients. References Keystone E et al., Ann Rheum Dis 2015;74(2):333-340. Curtis JR et al., Art Care Res 2012:64(12):1794-1803. Disclosure of Interest P. Taylor Consultant for: Pfizer, Eli Lilly & Company, M. Genovese Grant/research support from: Abbvie, Astellas, Eli Lilly & Company, Galapagos, Pfizer, Vertex, Consultant for: Abbvie, Astellas, Eli Lilly & Company, Galapagos, Pfizer, Vertex, E. Keystone Grant/research support from: Abbott Laboratories, Amgen Inc., AstraZeneca Pharmaceuticals LP, Bristol-Meyers Squibb, F. Hoffman-La Roche Inc., Janssen Inc., Eli Lilly & Company, Novartis Pharmaceuticals, Pfizer Pharmaceuticals, Sanofi-Aventis, UCB, Consultant for: Abbott Laboratories, AstraZeneca Pharmaceuticals LP, Biotest, Bristol-Meyers Squibb, F. Hoffman-La Roche Inc., Genentech, Janssen Inc., Eli Lilly & Company, Merck, Pfizer Pharmaceuticals, UCB, Speakers bureau: Abbott Laboratories, Astrazeneca LP, Bristol-Meyers Squibb Canada, F. Hoffman-La Roche Inc., Janssen Inc., Pfizer Pharmaceuticals, UCB, Amgen, M. Weinblatt Grant/research support from: Bristol-Meyers Squibb, Crescendo Bioscience, UCB, Consultant for: Abbvie, Amgen, Astra Zeneca, Bristol-Meyers Squibb, Crescendo Bioscience, Eli Lilly & Company, Pfizer, Roche, UCB, J. Rancourt Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, E. Nantz Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, D. Schlichting Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, S. Zuckerman Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, W. Macias Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company

THU0126 Added-Value of Combining Methotrexate with a Biological Agent Compared to Biological Monotherapy in Patients with Rheumatoid Arthritis: A Systematic Review and Meta-Analysis of Randomised Trials

Abstract: Background Methotrexate (MTX) is considered the anchor drug in rheumatoid arthritis (RA) treatment, based on efficacy, safety, and its ability to increase the efficacy of biologic agents when used in combination. Both the “American College of Rheumatology” (ACR) and the “European League Against Rheumatism” (EULAR) recommend the use of biologic agents with concomitant MTX in RA. However, analyses from health care claims suggest that the MTX prescribed in conjunction with a biologic disease-modifying antirheumatic drug (bDMARD), is not collected at the pharmacy by more than half of the patients. Despite claims from pivotal trial data, the empirical evidence supporting combination MTX plus bDMARD in terms of the actual benefit-harm has not been evaluated extensively. Objectives To review the evidence for benefit and harm associated with combining MTX with a biologic agent in RA patients. Methods A systematic review and meta-analysis of randomised controlled trials (RCTs) was performed to identify all trials relating treatment of RA with MTX in combination with bDMARD compared to a bDMARD in monotherapy. Random-effects models were applied for meta-analyses with risk ratio and 95% confidence intervals (RR, 95%CI) and inconsistency (I 2 , %) estimated using Review Manager. According to the protocol the major outcomes were ACR50 for benefit and withdrawals due to adverse events (AEs) for harm (PROSPERO: CRD42014014633). Results From the 4,405 identified references, 14 trials were eligible for inclusion in the meta-analysis. The overall likelihood of responding to therapy (ie, RR according to ACR50) was 1.36 [1.24 to 1.49] - with a low degree of inconsistency (28%) - in favour of concomitant use of MTX when treating with a biologic (P Conclusions This systematic review and meta-analysis of RCTs provides empirical evidence about the clinical value of combining the prescribed bDMARD with the recommended concomitant use of MTX. Combination therapy increases the probability of achieving treatment success at the level of ACR50 by approximately 40% compared to patients using biologics in monotherapy. Although the precision around the estimate of concomitant MTX use does not rule out an increased risk of clinically important harms, these findings justify the recommendation that all patients prescribed biologics should be encouraged to continue MTX therapy. Acknowledgements This study was supported by unrestricted grants from The Oak foundation, and AbbVie (Denmark). Disclosure of Interest T. S. Jorgensen Grant/research support from: has received research grants paid to institute: AbbVie and Roche, S. Tarp: None declared, D. E. Furst: None declared, A. Dossing: None declared, P. Taylor: None declared, H. Bliddal Grant/research support from: has received research grants paid to institute: AbbVie and Roche, R. Christensen Grant/research support from: has received research grants paid to institute: AbbVie and Roche