Predictors of Placebo Response to Local (Intra-Articular) Therapy In Osteoarthritis: An Individual Participant Data Meta-Analysis.

OBJECTIVE: We undertook this study to evaluate potential predictors of placebo response with intra-articular (IA) injections for knee/hip osteoarthritis (OA) using individual participant data (IPD) from existing trials. METHODS: Randomized placebo-controlled trials evaluating IA glucocorticoid or hyaluronic acid published to September 2018 were selected. IPD for disease characteristics and outcome measures were acquired. Potential predictors of placebo response included participant characteristics, pain severity, intervention, and trial design. Placebo response was defined as at least a 20% reduction in baseline pain. Logistic regression models and odds ratios were computed as effect measures to evaluate patient and pain mechanisms and then pooled using a random effects model. Generalized mixed-effect models were applied to intervention and trial characteristics. RESULTS: Of 56 eligible trials, 6 shared data, and these were combined with the existing 4 OA Trial Bank studies, yielding 10 studies with IPD of 621 placebo participants for analysis. In the total placebo population, at short-term follow-up, the use of local anesthetic and ultrasound guidance were associated with reduced odds of placebo response. At midterm follow-up, mid- to long-term trial duration was associated with increased odds of placebo response, and worse baseline function scores were associated with reduced odds of a placebo response. CONCLUSION: The administration of local anesthetics or ultrasound guidance may reduce IA placebo response at short-term follow-up. At midterm follow-up, participants with worse baseline function scores may be less likely to respond to IA placebo, and mid- to long-term trial duration may enhance the placebo response. Further studies are required to corroborate these potential predictors of IA placebo response.

Osteoporosis, fracture, osteoarthritis & sarcopenia: A systematic review of circulating microRNA association.

Circulating microRNAs (c-miRs) show promise as biomarkers. This systematic review explores their potential association with age-related fracture/osteoporosis (OP), osteoarthritis (OA) and sarcopenia (SP), as well as cross-disease association. Most overlap occurred between OA and OP, suggesting potentially shared microRNA activity. There was little agreement in results across studies. Few reported receiver operating characteristic analysis (ROC) and many identified significant dysregulation in disease, but direction of effect was commonly conflicting. c-miRs with most evidence for consistency in dysregulation included miR-146a, miR-155 and miR-98 for OA (upregulated). Area under the curve (AUC) for miR-146a biomarker performance was AUC 0.92, p = 0.028. miR-125b (AUC 0.76-0.89), miR-100, miR-148a and miR-24 were consistently upregulated in OP. Insufficient evidence exists for c-miRs in SP. Study quality was typically rated intermediate/high risk of bias. Wide study heterogeneity meant meta-analysis was not possible. We provide detailed critique and recommendations for future approaches in c-miR analyses based on this review.

Clinical and cost-effectiveness of bracing in symptomatic knee osteoarthritis management: protocol for a multicentre, primary care, randomised, parallel-group, superiority trial.

BACKGROUND: Brace effectiveness for knee osteoarthritis (OA) remains unclear and international guidelines offer conflicting recommendations. Our trial will determine the clinical and cost-effectiveness of adding knee bracing (matched to patients' clinical and radiographic presentation and with adherence support) to a package of advice, written information and exercise instruction delivered by physiotherapists. METHODS AND ANALYSIS: A multicentre, pragmatic, two-parallel group, single-blind, superiority, randomised controlled trial with internal pilot and nested qualitative study. 434 eligible participants with symptomatic knee OA identified from general practice, physiotherapy referrals and self-referral will be randomised 1:1 to advice, written information and exercise instruction and knee brace versus advice, written information and exercise instruction alone. The primary analysis will be intention-to-treat comparing treatment arms on the primary outcome (Knee Osteoarthritis Outcomes Score (KOOS)-5) (composite knee score) at the primary endpoint (6 months) adjusted for prespecified covariates. Secondary analysis of KOOS subscales (pain, other symptoms, activities of daily living, function in sport and recreation, knee-related quality of life), self-reported pain, instability (buckling), treatment response, physical activity, social participation, self-efficacy and treatment acceptability will occur at 3, 6, and 12 months postrandomisation. Analysis of covariance and logistic regression will model continuous and dichotomous outcomes, respectively. Treatment effect estimates will be presented as mean differences or ORs with 95% CIs. Economic evaluation will estimate cost-effectiveness. Semistructured interviews to explore acceptability and experiences of trial interventions will be conducted with participants and physiotherapists delivering interventions. ETHICS AND DISSEMINATION: North West Preston Research Ethics Committee, the Health Research Authority and Health and Care Research in Wales approved the study (REC Reference: 19/NW/0183; IRAS Reference: 247370). This protocol has been coproduced with stakeholders including patients and public. Findings will be disseminated to patients and a range of stakeholders. TRIAL REGISTRATION NUMBER: ISRCTN28555470.

Safety and Tolerability of Subcutaneous Methotrexate in Routine Clinical Practice.

OBJECTIVE: To show the safety and efficacy of subcutaneous (SC) methotrexate (MTX) compared to oral MTX, alternative disease-modifying antirheumatic drugs (DMARDs) monotherapy, biologic monotherapy, and combinations (conventional and biologic combination groups) in routine clinical practice. METHODS: Clinical and laboratory data were retrospectively analyzed for rheumatology clinic attendances at a large Northeast England hospital trust between January 2014 and January 2018. Rates of adverse events and stop events (transaminitis [serum alanine aminotransferase level of >80 units/liter] or neutropenia [neutrophil count of <2.0 × 109 /liter]) were calculated, with adjustment for duration of DMARD exposure. RESULTS: In the present study, 8,394 patients received DMARDs, with 2,093 patients receiving oral MTX and 949 patients receiving SC MTX. The median dose was 15 mg (interquartile range [IQR] 10-20 mg) for oral MTX, and 20 mg (IQR 15-25 mg) for SC MTX (P < 0.0001). Continuation rates were higher for SC MTX therapy when adjusted for follow-up duration, with a rate ratio (RR) of 1.54 (95% confidence interval [95% CI] 1.40-1.70) (P < 0.0001). For the time period assessed, 2,382 patients experienced 4,358 adverse events, with 1,711 incidents of transaminitis and 2,647 incidents of neutropenia recorded. Significantly fewer adverse events were observed in patients who received SC MTX monotherapy versus those who received biologic and combination DMARD therapies (P < 0.01). Compared to oral MTX, SC MTX was associated with a nonsignificant trend toward lower rates of neutropenia, but only a slightly higher rate of transaminitis (RR 1.26 [95% CI 1.07-1.48]) (P = 0.006), despite significantly higher doses of MTX. CONCLUSION: Subcutaneous MTX is safe in routine clinical practice. This is the largest study yet reported on SC MTX and provides observational data that SC MTX is continued longer and better tolerated in patients compared to other therapy groups, especially oral MTX.

Pain trajectory defines knee osteoarthritis subgroups: a prospective observational study.

Knee osteoarthritis (OA) is a heterogeneous disease, and identification of its subgroups/phenotypes can improve patient treatment and drug development. We aimed to identify homogeneous OA subgroups/phenotypes using pain development over time; to understand the interplay between pain and functional limitation in time course; and to investigate subgroups' responses to available pharmacological and surgical treatments. We used group-based trajectory modelling to identify pain trajectories in the phase-3 VIDEO trial (n = 474, 3-year follow-up) and also in the Osteoarthritis Initiative cohort study (n = 4796, 9-year follow-up). We extended trajectory models by (1) fitting dual trajectories to investigate the interplay between pain and functional limitation over time, and (2) including analgesic use as a time-varying covariate. Also, we investigated the relationship between trajectory groups and knee replacement in regression models. We identified 4 pain trajectory groups in the trial and 6 in the cohort. These overlapped and led us to define 4 OA phenotypes: low-fluctuating, mild-increasing, moderate-treatment-sensitive, and severe-treatment-insensitive pain. Over time, functional knee limitation followed the same trajectory as pain with almost complete concordance (94.3%) between pain and functional limitation trajectory groups. Notably, we identified a phenotype with severe pain that did not benefit from available treatments, and another one most likely to benefit from knee replacement. Thus, knee OA subgroups/phenotypes can be identified based on patients' pain experiences in studies with long and regular follow-up. We provided a robust approach, reproducible between different study designs, which informs clinicians about symptom development and delivery of treatment options and opens a new avenue toward personalized medicine in OA.

Mixed methods study of a new model of care for chronic disease: co-design and sustainable implementation of group consultations into clinical practice.

OBJECTIVES: Group consultations are used for chronic conditions, such as inflammatory arthritis, but evidence of efficacy for treatment to target or achieving tight control is lacking. Our aim was to establish whether group consultation is a sustainable, co-designed routine care option and to explore factors supporting spread. METHODS: The study used mixed methods, observational process/outcome data, plus qualitative exploration of enabling themes. It was set in two community hospitals, in 2008-19, with a third hospital from 2016, and was triangulated with primary care qualitative data. There was a total of 3363 arthritis patient attendances at 183 clinics during 2008-19. The early arthritis cohort comprised 46 patients, followed monthly until the treatment target was achieved, during 2016-19. Focus groups included 15 arthritis and 11 osteoporosis group attendees. Intervention was a 2 h group consultation, attended monthly for early/active disease and annually for stable disease. Measurements included attendance, DAS, satisfaction and enabling themes. RESULTS: There was a mean number of 18.4 patients per clinic (n = 16, 2010-15; n = 18, 2016; n = 20, 2017; n = 23, 2018-19). Forty per cent (1161/2874) of patients with DAS data reached low disease activity (DAS < 3.2) or remission (DAS < 2.6). Forty-six early arthritis patients followed monthly until they achieved remission responded even better: 50% remission; and 89% low disease activity/remission by 6 months. Qualitative analysis derived five main enabling themes (efficiency, empathy, education, engagement and empowerment) and five promotors to translate these themes into practice (prioritization, personalization, participation, personality and pedagogy). Limitations included the prospectively collected observational data and pragmatic design susceptible to bias. CONCLUSION: Co-designed group consultations can be sustainable, clinically effective and efficient for monthly review of early active disease and annual review of stable disease. Promoting factors may support effective training for chronic disease group consultations.

Cost-Effectiveness of Combination Disease-Modifying Antirheumatic Drugs Versus Tumor Necrosis Factor Inhibitors in Active Rheumatoid Arthritis: A Pragmatic, Randomized, Multicenter Trial.

OBJECTIVE: To determine whether intensive combinations of conventional synthetic disease-modifying antirheumatic drugs (csDMARDS) achieve similar clinical benefits more cheaply than high-cost biologics such as tumor necrosis factor inhibitors (TNFi) in patients with active rheumatoid arthritis (RA) whose illness has failed to respond to methotrexate and another DMARD. METHODS: We used within-trial cost-effectiveness and cost-utility analyses from health and social care and 2 societal perspectives. Participants were recruited into an open-label, 12-month, pragmatic, randomized, multicenter, 2-arm, noninferiority trial in 24 rheumatology clinics in England and Wales. Costs were linked with the Health Assessment Questionnaire (HAQ; primary outcome) and quality-adjusted life years derived from 2 measures (Short-Form 36 health survey and EuroQol 5-domain 3-level instrument). RESULTS: In total, 205 participants were recruited, 104 in the csDMARD arm and 101 in the TNFi arm. Participants in the csDMARD arm with poor response at 6 months were offered TNFi; 46 participants (44%) switched. Relevant cost and outcome data were available for 93% of participants at 6-month follow-up and for 91-92% of participants at 12-month follow-up. The csDMARD arm had significantly lower total costs from all perspectives (6-month health and social care adjusted mean difference -£3,615 [95% confidence interval (95% CI) -4,104, -3,182]; 12-month health and social care adjusted mean difference -£1,930 [95% CI -2,599, -1,301]). The HAQ score showed benefit to the csDMARD arm at 12 months (-0.16 [95% CI -0.32, -0.01]); other outcomes/follow-ups showed no differences. CONCLUSION: Starting treatment with csDMARDs, rather than TNFi, achieves similar outcomes at significantly lower costs. Patients with active RA and who meet the National Institute for Health and Care Excellence criteria for expensive biologics can be treated with combinations of intensive csDMARDs in a cost-effective manner.

Virtual group consultations offer continuity of care globally during Covid-19.

Covid-19 has led to virtual care (mainly telephone consultations) becoming a default worldwide, despite well-documented shortcomings. Published evidence on virtual group consultations is limited, although interest and front-line experience have grown substantially since pandemic onset. Unpublished data are summarised showing feasibility of transitioning care to this model across different countries, care settings and conditions. An international webinar series has supported development and sharing of best practice and representative data on spread and utilisation of virtual groups. This model of care creates time and space for more questions and answers, so once engaged patients become staunch advocates. Group care supports personalised care and lifestyle medicine, which is growing very rapidly. In the current context, even healthcare providers under pressure can implement virtual group consultations. Most virtual group consultations have a facilitator, so this allows roles to be extended and support education of both students and new team members. These can confer greater access, continuity of care, peer support and timely information about Covid-19 and may result in better health outcomes. Given the rapid and widespread implementation of virtual care during this pandemic, data should be shared effectively and methodologically sound observational studies and clinical trials to test safety and effectiveness should be promoted now.

PROCESS AND SYSTEMS: A systems approach to embedding group consultations in the NHS.

Group consultations are an important care option that is -starting to gain traction in the USA and Australia. This review summarises the likely benefits accruing from a systems -approach to implementing group consultations widely in the NHS and other socialised healthcare systems. Existing evidence is mapped to five distinct systems approaches: (1) development; (2) different age groups; (3) patient-centred pathway of care; (4) NHS system changes; and (5) education. Implications are discussed for patients and staff, who both benefit from group consultations once embedded; ranging from improved access and efficiency to more enjoyable multidisciplinary team working, improved resource management, and maintained/better outcomes. Moreover, even patients who don't attend group consultations can benefit from system effects of long-term implementation. Changing behaviour and health systems is challenging, but change requires systematic experimentation and documentation of evidence. We conclude that group consultations have unique potential for delivering system-wide benefits across the NHS.

Developing a toolkit for the assessment and monitoring of musculoskeletal ageing.

The complexities and heterogeneity of the ageing process have slowed the development of consensus on appropriate biomarkers of healthy ageing. The Medical Research Council-Arthritis Research UK Centre for Integrated research into Musculoskeletal Ageing (CIMA) is a collaboration between researchers and clinicians at the Universities of Liverpool, Sheffield and Newcastle. One of CIMA's objectives is to 'Identify and share optimal techniques and approaches to monitor age-related changes in all musculoskeletal tissues, and to provide an integrated assessment of musculoskeletal function'-in other words to develop a toolkit for assessing musculoskeletal ageing. This toolkit is envisaged as an instrument that can be used to characterise and quantify musculoskeletal function during 'normal' ageing, lend itself to use in large-scale, internationally important cohorts, and provide a set of biomarker outcome measures for epidemiological and intervention studies designed to enhance healthy musculoskeletal ageing. Such potential biomarkers include: biochemical measurements in biofluids or tissue samples, in vivo measurements of body composition, imaging of structural and physical properties, and functional tests. This review assesses candidate biomarkers of musculoskeletal ageing under these four headings, details their biological bases, strengths and limitations, and makes practical recommendations for their use. In addition, we identify gaps in the evidence base and priorities for further research on biomarkers of musculoskeletal ageing.

Hydroxychloroquine Effectiveness in Reducing Symptoms of Hand Osteoarthritis: A Randomized Trial.

Background: Synovitis is believed to play a role in producing symptoms in persons with hand osteoarthritis, but data on slow-acting anti-inflammatory treatments are sparse. Objective: To determine the effectiveness of hydroxychloroquine versus placebo as an analgesic treatment of hand osteoarthritis. Design: Randomized, double-blind, placebo-controlled clinical trial with 12-month follow-up. (ISRCTN registry number: ISRCTN91859104). Setting: 13 primary and secondary care centers in England. Participants: Of 316 patients screened, 248 participants (82% women; mean age, 62.7 years) with symptomatic (pain ≥4 on a 0- to 10-point visual analogue scale) and radiographic hand osteoarthritis were randomly assigned and 210 (84.7%) completed the 6-month primary end point. Intervention: Hydroxychloroquine (200 to 400 mg) or placebo (1:1) for 12 months with ongoing usual care. Measurements: The primary end point was average hand pain during the previous 2 weeks (on a 0- to 10-point numerical rating scale [NRS]) at 6 months. Secondary end points included self-reported pain and function, grip strength, quality of life, radiographic structural change, and adverse events. Baseline ultrasonography was done. Results: At 6 months, mean hand pain was 5.49 points in the placebo group and 5.66 points in the hydroxychloroquine group, with a treatment difference of -0.16 point (95% CI, -0.73 to 0.40 point) (P = 0.57). Results were robust to adjustments for adherence, missing data, and use of rescue medication. No significant treatment differences existed at 3, 6, or 12 months for any secondary outcomes. The percentage of participants with at least 1 joint with synovitis was 94% (134 of 143) on grayscale ultrasonography and 59% on power Doppler. Baseline structural damage or synovitis did not affect treatment response. Fifteen serious adverse events were reported (7 in the hydroxychloroquine group [3 defined as possibly related] and 8 in the placebo group). Limitation: Hydroxychloroquine dosage restrictions may have reduced efficacy. Conclusion: Hydroxychloroquine was no more effective than placebo for pain relief in patients with moderate to severe hand pain and radiographic osteoarthritis. Primary Funding Source: Arthritis Research UK.

Total and Visceral Adiposity Are Associated With Prevalent Vertebral Fracture in Women but Not Men at Age 62 Years: The Newcastle Thousand Families Study.

Low body weight is an established risk factor for osteoporosis and fracture, but the skeletal risks of higher adiposity are unclear and appear sex-specific and site-dependent. The aim of this study was to investigate associations of total fat mass (TFM), visceral adipose tissue (VAT), and C-reactive protein (CRP) with bone mineral density (BMD) and prevalent vertebral fracture (VF) in men and women aged 62 years. A total of 352 men and women aged 62.5 ± 0.5 years from the Newcastle Thousand Families Study cohort received dual-energy X-ray absorptiometry (DXA) evaluations of femoral neck and lumbar spine BMD, of the lateral spine for vertebral fracture assessment, and of the whole body for TFM and VAT (GE Lunar CoreScan, Madison, WI, USA). Plasma CRP, FRAX scores, falls in the last 12 months, and occupation at age 50 years were also included in the analysis. Vertebral fractures were less prevalent in women than in men (odds ratio [OR] = 0.33, p < 0.001) and BMD or FRAX scores did not differ between participants with and without VF. Women with VF were heavier and had higher TFM, VAT, and CRP than women without (p < 0.001). In women, greater (+1 SD) TFM and VAT increased the odds of any grade VF (TFM: OR = 1.06, p = 0.001; VAT: OR = 2.50, p = 0.002), and greater VAT mass increased the odds of prevalent mild VF (OR = 2.60, p = 0.002). In contrast, there were no associations in men. In both sexes, after controlling for body weight, neither VAT nor CRP were associated with BMD. In conclusion, irrespective of BMD, total and visceral adiposity were associated with prevalent VF in women but not in men. High fat mass, particularly if visceral, should be considered when assessing VF risk in women. Risk factors for VF in men require further investigation, particularly given their high prevalence. © 2017 American Society for Bone and Mineral Research.

Paracetamol: not as safe as we thought? A systematic literature review of observational studies.

OBJECTIVES: We conducted a systematic literature review to assess the adverse event (AE) profile of paracetamol. METHODS: We searched Medline and Embase from database inception to 1 May 2013. We screened for observational studies in English, which reported mortality, cardiovascular, gastrointestinal (GI) or renal AEs in the general adult population at standard analgesic doses of paracetamol. Study quality was assessed using Grading of Recommendations Assessment, Development and Evaluation. Pooled or adjusted summary statistics were presented for each outcome. RESULTS: Of 1888 studies retrieved, 8 met inclusion criteria, and all were cohort studies. Comparing paracetamol use versus no use, of two studies reporting mortality one showed a dose-response and reported an increased relative rate of mortality from 0.95 (0.92 to 0.98) to 1.63 (1.58 to 1.68). Of four studies reporting cardiovascular AEs, all showed a dose-response with one reporting an increased risk ratio of all cardiovascular AEs from 1.19 (0.81 to 1.75) to 1.68 (1.10 to 2.57). One study reporting GI AEs reported a dose-response with increased relative rate of GI AEs or bleeds from 1.11 (1.04 to 1.18) to 1.49 (1.34 to 1.66). Of four studies reporting renal AEs, three reported a dose-response with one reporting an increasing OR of ≥30% decrease in estimated glomerular filtration rate from 1.40 (0.79 to 2.48) to 2.19 (1.4 to 3.43). DISCUSSION: Given the observational nature of the data, channelling bias may have had an important impact. However, the dose-response seen for most endpoints suggests a considerable degree of paracetamol toxicity especially at the upper end of standard analgesic doses.

Diagnosis and management of polymyalgia rheumatica.

Polymyalgia rheumatica (PMR) is a common inflammatory condition of unknown aetiology with a prevalence of 1 in 133 in the over 50s, and a female to male ratio of 2:1. Symptoms develop over a matter of weeks; typically bilateral shoulder or pelvic girdle pain and stiffness, that is worse in the mornings. Associated symptoms include low-grade fever, malaise, fatigue, low mood, poor appetite, and weight loss. There is no specific diagnostic test for PMR but the usual pattern is a commensurate rise in CRP and ESR. A small proportion of PMR patients will have normal inflammatory markers. PMR is associated with giant cell arteritis (GCA). Half of patients with GCA will have some PMR symptoms and up to one fifth of patients with PMR will have evidence of GCA. Other conditions that can mimic PMR include: rheumatic disease in the elderly e.g. rheumatoid arthritis; inflammatory muscle diseases; thyroid disease; malignancy; infection; bilateral shoulder capsulitis; osteoarthritis, Parkinsonism and depressive illness. At diagnosis and each follow-up visit it is imperative to consider the potential for associated GCA. The patient should be asked about headaches, jaw claudication and visual disturbance. If there is any suspicion of GCA, urgent discussion with the rheumatologist should take place that day.

Pain reduction with oral methotrexate in knee osteoarthritis, a pragmatic phase iii trial of treatment effectiveness (PROMOTE): study protocol for a randomized controlled trial.

BACKGROUND: Osteoarthritis (OA) is the fastest growing cause of disability worldwide. Current treatments for OA are severely limited and a large proportion of people with OA live in constant, debilitating pain. There is therefore an urgent need for novel treatments to reduce pain. Synovitis is highly prevalent in OA and is associated with pain. In inflammatory arthritides such as rheumatoid arthritis, methotrexate (MTX) is the gold standard treatment for synovitis and has a well-known, acceptable toxicity profile. We propose that using MTX to treat patients with symptomatic knee OA will be a practical and safe treatment to reduce synovitis and, consequently, pain. METHODS/DESIGN: Pain Reduction with Oral Methotrexate in knee Osteoarthritis, a pragmatic phase III trial of Treatment Effectiveness (PROMOTE) is an investigator-initiated, multi-centre, randomized, double-blind, pragmatic placebo-controlled trial. A total of 160 participants with symptomatic knee OA will be recruited across primary and secondary care sites in the United Kingdom and randomized on a 1:1 basis to active treatment or placebo, in addition to usual care, for 12 months. As is usual practice for MTX, dosing will be escalated over six weeks to 25 mg (or maximum tolerated dose) weekly for the remainder of the study. The primary endpoint is change in average knee pain during the past week (measured on an 11-point numerical rating scale) between baseline and six months. Secondary endpoints include other self-reported pain, function and quality-of-life measures. A health economics analysis will also be performed. A magnetic resonance imaging substudy will be conducted to provide an explanatory mechanism for associated symptom change by examining whether MTX reduces synovitis and whether this is related to symptom change. Linear and logistic regression will be used to compare changes between groups using univariable and multivariable modelling analyses. All analyses will be conducted on an intention-to-treat basis. DISCUSSION: The PROMOTE trial is designed to examine whether MTX is an effective analgesic treatment for OA. The MRI substudy will address the relationship between synovitis and symptom change. This will potentially provide a much needed new treatment for knee OA. TRIAL REGISTRATION: Current Controlled Trials identifier: ISRCTN77854383 (registered: 25 October 2013).

Tumour necrosis factor inhibitors versus combination intensive therapy with conventional disease modifying anti-rheumatic drugs in established rheumatoid arthritis: TACIT non-inferiority randomised controlled trial.

OBJECTIVE: To determine whether intensive combinations of synthetic disease modifying drugs can achieve similar clinical benefits at lower costs to high cost biologics such as tumour necrosis factor inhibitors in patients with active rheumatoid arthritis resistant to initial methotrexate and other synthetic disease modifying drugs. DESIGN: Open label pragmatic randomised multicentre two arm non-inferiority trial over 12 months. SETTING: 24 rheumatology clinics in England. PARTICIPANTS: Patients with rheumatoid arthritis who were eligible for treatment with tumour necrosis factor inhibitors according to current English guidance were randomised to either the tumour necrosis factor inhibitor strategy or the combined disease modifying drug strategy. INTERVENTIONS: Biologic strategy: start tumour necrosis factor inhibitor; second biologic in six month for non-responders. Alternative strategy: start combination of disease modifying drugs; start tumour necrosis factor inhibitors after six months in non-responders. PRIMARY OUTCOME: reduction in disability at 12 months measured with patient recorded heath assessment questionnaire (range 0.00-3.00) with a 0.22 non-inferiority margin for combination treatment versus the biologic strategy. SECONDARY OUTCOMES: quality of life, joint damage, disease activity, adverse events, and costs. Intention to treat analysis used multiple imputation methods for missing data. RESULTS: 432 patients were screened: 107 were randomised to tumour necrosis factor inhibitors and 101 started taking; 107 were randomised to the combined drug strategy and 104 started taking the drugs. Initial assessments were similar; 16 patients were lost to follow-up (seven with the tumour necrosis factor inhibitor strategy, nine with the combined drug strategy); 42 discontinued the intervention but were followed-up (19 and 23, respectively). The primary outcome showed mean falls in scores on the health assessment questionnaire of -0.30 with the tumour necrosis factor inhibitor strategy and -0.45 with the alternative combined drug strategy. The difference between groups in unadjusted linear regression analysis favoured the alternative strategy of combined drugs. The mean difference was -0.14, and the 95% confidence interval (-0.29 to 0.01) was below the prespecified non-inferiority boundary of 0.22. Improvements at 12 months in secondary outcomes, including quality of life and erosive progression, were similar with both strategies. Initial reductions in disease activity were greater with the biologic strategy, but these differences did not persist beyond six months. Remission was seen in 72 patients (44 with biologic strategy; 36 with alternative strategy); 28 patients had serious adverse events (18 and 10, respectively); six and 10 patients, respectively, stopped treatment because of toxicity. The alternative strategy reduced health and social care costs per patient by £3615 (€4930, $5585) for months 0-6 and £1930 for months 6-12. CONCLUSIONS: In patients with active rheumatoid arthritis who meet English criteria for biologics an alternative strategy with combinations of intensive synthetic disease modifying drugs gives non-inferior outcomes to treatment with tumour necrosis factor inhibitors. Costs are reduced substantially.Trial Registration ISRCTN 37438295.