Factorial randomised controlled trial of glucocorticoids and combination disease modifying drugs in early rheumatoid arthritis

Transcription

1 Factorial randomised controlled trial of glucocorticoids and combination disease modifying drugs in early rheumatoid arthritis EHSChoy, 1 CMSmith, 1 V Farewell, 2 D Walker, 3 A Hassell, 4 LChau, 1 D L Scott, 1 for the CARDERA (Combination Anti-Rheumatic Drugs in Early Rheumatoid Arhritis) Trial Group 1 Sir Alfred Baring Garrod Clinical Trials Unit, Academic Department of Rheumatology, King s College School of Medicine, Weston Education Centre, Cutcombe Road, London, UK; 2 Medical Research Council Biostatistics Unit, University of Cambridge Institute of Public Health, Cambridge, UK; 3 Department of Rheumatology, Freeman Hospital, Freeman Road, High Heaton, Newcastle upon Tyne, UK; 4 Department of Rheumatology, Hayward Hospital, High Lane, Burslem, Stoke-on-Trent, UK Correspondence to: Dr E H Choy, Sir Alfred Baring Garrod Clinical Trials Unit, Academic Department of Rheumatology, King s College School of Medicine, Weston Education Centre, Cutcombe Road, London SE5 9RJ, UK; ernest.choy@kcl.ac.uk Accepted 26 August 2007 Published Online First 3 September 2007 ABSTRACT Objective: Treating early active rheumatoid arthritis (RA) with disease modifying antirheumatic drug (DMARD) monotherapy achieves incomplete outcomes and intensive treatment seems preferable. As the relative benefits of combining two DMARDs, one DMARD with glucocorticoids and two DMARDs with glucocorticoids are uncertain we defined them in a factorial trial. Methods: A 2-year randomised double-blind factorial trial in patients with RA within 2 years of diagnosis treated with methotrexate studied the benefits of added ciclosporin, 9 months intensive prednisolone or both (triple therapy). The primary outcome was the number of patients with new erosions. Secondary outcomes included Larsen s x-ray scores, disability, quality of life and adverse events. Findings: 1391 patients were screened and 467 randomised. Over 2 years 132 (28%) changed therapy and 88 (19%) were lost to follow-up. The number of patients with new erosions was reduced by nearly half by adding ciclosporin or prednisolone (p = 0.01 and 0.03); both treatments reduced increases in Larsen s x-ray scores by over 2 units (p = and 0.003). A further reduction in erosive damage was seen with combined use of both treatments. Their effects on erosive damage appeared independent. Triple therapy reduced disability and improved quality of life compared with methotrexate; ciclosporin and prednisolone acted synergistically. More patients withdrew because of adverse events with triple therapy, without an increase in serious adverse effects. Conclusions: This study confirms the existence of a window of opportunity in early RA, when intensive combination therapy produces sustained benefits on damage and disability. Although methotrexate prednisolone combinations reduce erosive damage, the synergistic effect of two DMARDs is needed to improve quality of life. There is intense interest in the optimal management of early rheumatoid arthritis (RA). UK and EULAR guidance 12 recommends disease modifying antirheumatic drugs (DMARDs) should be initiated early with intensive management incorporating escalating doses of DMARDs, glucocorticoids and combination therapy. The rationale includes longterm randomised controlled trials (RCTs) and observational studies that show sequential DMARD monotherapy often results in progressive joint damage and high disability scores. 3 7 Intensive therapy in early RA may involve DMARDs or tumour necrosis factor (TNF) inhibitors. Guidance in the UK, 8 9 continental Europe 10 and internationally 11 means TNF inhibitors cannot be used initially. Consequently, intensive early treatment will currently involve conventional DMARDs and glucocorticoids. There is evidence giving two DMARDs or one or more DMARDs with glucocorticoids improves outcome. However, the optimal DMARD combination and the value of glucocorticoids are uncertain. TNF inhibitors alone 28 or, more especially, in combination with methotrexate also improve out come. The benefits of all combination therapies must be weighed against increased adverse events. 33 TNF inhibitors also have specific problems, including high costs and concerns about malignancy. 34 Although there is uncertainty about the relative merits of intensive DMARD therapy and early biologics, 35 the evidence favours early intensive therapy targeting the window of opportunity in early RA We addressed the merits of intensive therapy with conventional drugs in early active RA assessing the relative benefits of two DMARDs, adding prednisolone to one DMARD or using two DMARDs with prednisolone in a factorial-design RCT. Factorial trials usually allow simultaneous evaluation of two interventions in a 262 design. Patients are randomly assigned to one of four groups. One group receives neither intervention, a second group receives one intervention, a third group receives the other intervention and the fourth group receives both interventions. Matching placebos maintain blinding. The effects of each intervention can be compared simultaneously and synergistic or negative interactions between interventions evaluated. Such factorial designs have helped optimise combination therapies in cancer and cardiovascular diseases as outlined by McAlister et al. 44 In our trial all patients received methotrexate as standard treatment. One additional treatment was step-down prednisolone, selected because of its known efficacy and safety in early RA. The other additional treatment was ciclosporin, which was increased incrementally to a pre-defined target dose, was selected because of its combined efficacy with methotrexate 45 and ability to reduce erosions. 46 The factorial trial lasted 2 years, which is often considered the minimal time to show genuine disease modification. PATIENTS AND METHODS Participants Consecutive patients with early RA who were seen in routine rheumatology outpatient clinics at 42 centres in England and Wales were enrolled into the trial. 656 Ann Rheum Dis 2008;67: doi: /ard

2 Inclusion criteria This was determined as active RA by American College of Rheumatology (ACR) criteria of less than 24 months with three of the following: >3 swollen joints, >6 tender joints, >45 min morning stiffness, erythrocyte sedimentation rate (ESR) >28 mm/h. Other inclusion criteria were that patients needed to give informed consent and were aged >18 years. Exclusion criteria These were other inflammatory arthropathies (eg, psoriatic arthritis), current oral glucocorticoids, serious medical disorders (eg, hepatic or cardiac failure), women of child-bearing potential without adequate contraceptive protection, and contraindications for trial drugs. We recorded details of non-recruited patients in line with CONCORD recommendations. Interventions Study drugs These were: (a) open-label methotrexate (starting 7.5 mg weekly, increasing incrementally to target dose of 15 mg/week); (b) step-down prednisolone started with methotrexate (60 mg/day initially, reduced to 7.5 mg at 6 weeks, 7.5 mg daily from 6 to 28 weeks, stopped by 34 weeks); and (c) ciclosporin started 3 months after methotrexate (initial dose 100 mg/day, increased gradually to target dose of 3 mg/kg daily). Prednisolone and ciclosporin were given as active tablets or matching placebos. Study drugs were varied by supervising rheumatologists for: (a) adverse effects; (b) uncontrolled disease activity; (c) intercurrent illnesses/surgery. Central advice (EHSC) recommended changes in ciclosporin dose for renal function and blood pressure. Concomitant therapy Analgesics (paracetamol or co-proxamol) and/or non-steroidal anti-inflammatory drugs were used at standard dosages. Other drugs (eg, hypertensives) were continued as needed. To limit toxicity patients received folate supplements (5 mg/week) and bone protection (calcium and vitamin D supplements and optional bisphosphonates). Intra-articular glucocorticoids (40 mg methylprednisolone with lignocaine) were given ((6 occasions) as required. Intramuscular glucocorticoids were allowed but only three doses of 120 mg of depot methylprednisolone could be given in a year. All intra-particular and intramuscular steroid treatments will be recorded. Safety monitoring National guidelines were followed (monthly blood counts, liver and renal function tests, urinalysis, blood pressure). Patients were asked about adverse events. DEXA scans (spine, hip) were undertaken at 0 and 2 years. Objective Testing the hypothesis combining methotrexate with glucocorticoids and/or ciclosporin in early RA reduced the proportion of patients developing new erosions within 2 years. A clinically relevant reduction was 40% fewer patients developing new erosions. Primary outcome The primary outcome was the development of new erosions in x-rays of hands and feet. Secondary outcomes These comprised changes in total Larsen score for x-ray damage, function, quality of life, disease activity and adverse events. Patients were screened for eligibility then assessed at entry and every 6 months. x-rays of hands and feet These were read chronologically and independently by two observers (DLS, LC) after preliminary studies had ensured comparable scoring of new erosions and modified Larsen scores. 47 These methods were chosen to replicate the methods in the ARC trial of glucocorticoids in early RA. 2 Function The Health Assessment Questionnaire (HAQ) was used to determine function. Quality of life SF-36 (summary physical and mental component scores) and EuroQol were used to determine quality of life. Disease activity Clinical core data (28 swollen and tender joint counts, visual analogue scores for pain, assessors global and patients global assessment, ESR) used to calculate disease activity score (DAS28) for 28 joints and ACR-20, 50 and 70 responder rates. Disease remission is defined as DAS28, Adverse events All events were recorded whether or not they were considered treatment-related. Sample size Previous data from Kirwan 2 indicated 46% of patients receiving one DMARD develop new erosions after 2 years. Sample size calculations were based on a logistic regression model for dual therapy taking a 40% reduction in cases developing new erosions as clinically relevant. In a 262 factorial design with equal group sizes a sample size of 438 is required to achieve 90% power, conservatively assuming triple therapy leads to a 56% reduction. This corresponded to 110 in each group; allowance for 5% of patients who may withdraw consent gave a planned recruitment number of 464. Randomisation The study involved four geographical regions (London, West Midlands, North East and South West). Patients were randomly allocated to one of the four groups stratified by region. Sequence generation, allocation concealment and implementation The allocation sequence was generated by VF (statistician). Randomisation, stratified by region, used random treatment assignment in balanced blocks of 16. Metrologists performed the screening visit and faxed anonymised data to the trial centre. CMS (co-ordinator) assigned consecutive patient numbers (within strata) to patients in chronological order when they passed the screening assessment. The metrologists and coordinator were unaware of the allocation sequence. Treatment assignments were in a locked cabinet in the co-ordinating centre pharmacy for emergency access. Ann Rheum Dis 2008;67: doi: /ard

3 Figure 1 CONSORT flowchart of patients in the trial. RA, rheumatoid arthritis; FU, follow-up; ACR, American College of Rheumatology; MTX, methotrexate. Blinding The study was fully blinded with matching placebos for oral glucocorticoids and ciclosporin. x-rays were read independently by DLS and LC without knowledge of the treatments. HAQ, SF-36 and EuroQol were completed by patients and scored independently of supervising clinicians. Disease activity was assessed by the visiting metrologist without knowledge of treatments. Statistical methods Data were analysed on an intention to treat basis at the end of the trial. The primary outcome was evaluated by logistic regression analysis, stratified by region. Odds ratios (ORs) and Table 1 Demographic and initial clinical assessments n = 117 ciclosporin n = 119 prednisolone n = 115 Triple therapy n = 116 Mean age (range) 54 (21 80) 53 (20 89) 54 (27 84) 55 (20 78) Sex (F/M) 78/39 79/40 90/25 78/38 Rheumatoid factor 76 (66%) 77 (65%) 76 (66%) 83 (72%) positive Rheumatoid arthritis 27 (23%) 38 (32%) 20 (17%) 18 (16%) nodules Mean disease duration 2.7 (3.8) 4.2 (5.7) 5.1 (5.8) 3.9 (5.2) in months (SD) Previous DMARDs 14 (12%) 17 (14%) 16 (14%) 18 (16%) Mean DAS28 (SD) 5.8 (1.2) 5.9 (1.3) 5.8 (1.4) 5.6 (1.3) Erosive changes on 37 (32%) 44 (37%) 34 (30%) 39 (34%) x-rays Median Larsen score 7 (3, 15) 8 (3, 23) 6 (2, 20) 5 (2, 14) (IQR) Mean HAQ (SD) 1.5 (0.7) 1.7 (0.7) 1.6 (0.7) 1.6 (0.7) Median SF-36 PCS (IQR) 30 (9) 29 (8) 30 (10) 30 (9) Mean values (SD) or median values with IQRs are shown. IQRs, interquartile ranges; DMARDs, disease modifying anti-rheumatic drugs; HAQ, Health Assessment Questionnaire; SF-36 PCS, Short-Form Physical Component Summary; DAS28, Disease Activity Score including a 28-joint count. confidence intervals (CIs) were calculated for the main effects of prednisolone and ciclosporin. Information on interaction effects was examined, although the study was not powered for this analysis. Secondary outcomes were analysed in a comparable fashion using a general linear model and analysis of variance. These analyses were also used to calculate number needed to treat (NNT) and number needed to harm (NNH). Missing data were imputed through last observations carried forward (LOCF). Pre-planned subgroup analysis examined the effects of age, sex, region, rheumatoid factor and disease activity using logistic and linear regression. Ethics review The trial was approved by the South East Multicentre Research Ethics Committee and local research ethics committees at each centre. Trial registration The trial was registered by the sponsor (Medical Research Council) at as ISRCTN no (accessed 28 December 2006). RESULTS Participants and recruitment A total of 1391 patients were screened at 42 rheumatology units: 587 patients were ineligible and 804 patients were eligible; 337 of these 804 eligible patients declined to participate and 467 were randomised (fig 1). Patients were recruited from 2000 to 2002, follow-up was completed in 2004 and data validated in Baseline data A total of 312 (67%) patients were rheumatoid factor positive, 103 (22%) had rheumatoid nodules and 154 (33%) erosive damage. Sixty-five (14%) had previously received DMARDs. Mean (95% CI) clinical assessments comprised 11.8 (11.1, 12.5) 658 Ann Rheum Dis 2008;67: doi: /ard

4 Table 2 Outcomes at 2 years Initial groups Ciclosporin Prednisolone Significance (n = 117) Added ciclosporin (n = 119) Added prednisone (n = 115) Triple therapy (n = 116) Control (n = 232) Active (n = 235) Control (n = 236) Active (n = 231) Prednisolone Ciclosporin Interaction Cases with new 34 (29%) 19 (17%) 19 (16%) 15 (13%) 53 (23%) 34 (15%) 53 (23%) 34 (15%) erosions (%) Mean change in Larsen score (SE) 7.41 (0.99) 4.53 (0.88) 4.70 (0.69) 2.99 (0.51) 6.07 (0.61) 3.77 (0.51) 5.95 (0.67) 3.83 (0.83) Mean change in HAQ (SE) (0.07) (0.06) (0.07) (0.06) (0.06) (0.06) (0.06) (0.07) Mean change in SF-36 PCS (SE) 5.8 (1.0) 3.9 (1.1) 3.5 (1.0) 8.0 (1.2) 4.8 (0.8) 5.7 (0.8) 4.6 (0.8) 6.0 (0.8) Mean change in DAS28 (SE) (0.17) (0.15) (0.15) (0.15) (0.12) (0.11) (0.11) (0.11) HAQ, Health Assessment Questionnaire; SF-36 PCS, Short-Form Physical Component Summary; DAS28, Disease Activity Score including a 28-joint count. tender joints, 9.9 (9.3, 10.4) swollen joints, ESR (mm/h) 41 (38, 44), assessor global (VAS mm) 48 (46, 50), patient global (VAS mm) 55 (53, 57) and pain (VAS mm) 48 (45, 50). The groups were well matched (table 1). Cases analysed A total of 247 (53%) patients continued allocated treatment for 2 years, 88 (19%) were lost to follow-up and 132 (28%) changed treatment. At 24 months, results were available in 379 (81%); data from the remaining 88 (19%) were imputed using LOCF. Observed case analysis was also carried out to check the impact of the LOCF assumption. Primary outcome With methotrexate monotherapy, 34 (29%) patients developed new erosions (table 2). Logistic regression analysis showed reductions with prednisolone (OR 0.59 (95% CI 0.36, 0.96), p = 0.03) and ciclosporin (OR 0.54 (95% CI 0.33, 0.88), p = 0.01). Least new erosions were seen with triple therapy (15 of 116, 13%), regression analysis showed no multiplicative effects (p = 0.32), although sample size of the study was not powered to detect interaction. Analyses omitting patients with missing data at 2 years gave estimated ORs of 0.55 (p = 0.02) and 0.56 (p = 0.02) for ciclosporin and prednisolone. Figure 2 Mean increases (SE) in Larsen scores and Health Assessment Questionnaire (HAQ) over 2 years in all patients by treatment.ˆ, control; N, active treatment. Ann Rheum Dis 2008;67: doi: /ard

5 stopping steroid therapy. At 24 months the mean increase in Larsen score was 7.41 (95% CI 5.47, 9.33) with methotrexate monotherapy. Stratified factorial analysis estimated reductions of 2.33 and 2.11 with ciclosporin and prednisolone respectively (p = and 0.008) with no significant interaction (p = 0.45) between prednisolone and ciclosporin (table 2). Observed case data at 24 months gave estimated reductions of 2.39 for ciclosporin and prednisolone (both p = 0.004). Disability HAQ scores decreased with all treatments by 6 months (fig 2): with methotrexate monotherapy and added ciclosporin mean HAQ scores fell by 0.21 and 0.23; with added prednisolone and triple therapy they fell by 0.53 and At 24 months HAQ scores showed a mean fall of 0.29 with methotrexate monotherapy. Stratified factorial analysis showed a significant synergistic interaction between therapies (p = 0.01); estimated mean changes in HAQ were 20.20, and with additional ciclosporin, additional prednisolone, and triple therapy compared with methotrexate alone (table 2). An observed case analysis gave similar results. Quality of life SF-36 PCS showed similar changes to HAQ (table 2). Mean increases at 24 months were 5.8 with methotrexate; adding ciclosporin or prednisolone alone gave no benefits but with triple therapy the mean increase was 8.0. Stratified factorial analysis showed no significant reductions in SD-36 PCS at 24 months with ciclosporin or prednisolone, but a significant interaction with triple therapy (p,0.01). There were no differences in SF-36 Mental Component scores or with EuroQol. Observed case analyses gave comparable results. Figure 3 Changes in American College of Rheumatology (ACR) responders (20, 50 and 70) and mean DAS28, Disease Activity Score (including a 28-joint count; DAS28) scores (SE) in patients receiving methotrexate or triple therapy. O, control; N, active treatment. Based on the estimated ORs from the stratified factorial analysis, and an assumed baseline rate of new erosions of 29% (from the methotrexate arm), the number needed to treat (NNT) to stop erosive progression was 11 (95% CI 6, 120) with added prednisolone and 10 (95% CI 6, 39) with added ciclosporin. The estimated NNT for triple therapy was 6 (95% CI 4, 14). Secondary outcomes Larsen scores These increased most with methotrexate monotherapy, though the rate of increase declined with time (fig 2). Ciclosporin reduced progression throughout the 2-year period. Prednisolone showed a rapid initial effect without a rebound increase after Disease activity Disease activity fell in all groups by 6 months: with methotrexate monotherapy and added ciclosporin mean falls in DAS28 were 1.14 and 1.49 and 9% and 14% were in DAS28 remission; with added prednisolone and triple therapy mean falls were 1.81 and 1.84 with 36% and 31% in DAS28 remission. At 24 months mean falls in DAS28 were 1.42 with methotrexate monotherapy (table 2) and with triple therapy mean DAS28 scores fell by 1.67; stratified factorial analysis showed no significant differences between treatment arms. DAS28 remission at 24 months occurred in 21 of 117 (18%) patients receiving methotrexate, 27 of 119 (10%) and 23 of 115 (20%) receiving added ciclosporin and added prednisolone and 32 of 116 (28%) on triple therapy. Detailed changes in disease activity (ACR responders and mean DAS28 scores) over time are shown for methotrexate monotherapy and triple therapy in fig 3. Triple therapy reduced all assessments of disease activity by 6 months compared with methotrexate monotherapy but thereafter the number of responders in the patients initially randomised to receive methotrexate increased and by 24 months the groups were similar. Adverse events and withdrawals Adverse events A total 81 (17%) patients had serious adverse events (table 3), including five deaths (one ovarian cancer, one cerebrovascular accident, three sudden/unexpected). Three patients had strokes, three angina, three myocardial infarctions and 16 infections (two tuberculosis and three pneumonias). These serious adverse events were unrelated to treatment group. 660 Ann Rheum Dis 2008;67: doi: /ard

6 Table 3 Adverse effects, changes in DEXA scores, withdrawals and concomitant steroid therapy (n = 117) Added ciclosporin (n = 119) Added prednisolone (n = 115) Triple therapy (n = 116) Serious adverse events Total Deaths Malignancies Myocardial infarctions, angina, strokes Upper gastrointestinal Infections Common adverse events (.5% cases) Respiratory track infection Nausea or vomiting Headache Mouth ulcer Elevated blood pressure Dizziness Diarrhoea Paraesthesia Cough Abdominal pain Transient creatine elevation Changes in DEXA scores Median spine 20.8 (23.7, 1.2) 20.1 (23.4, 2.8) 21.1 (24.0, 2.2) 0.1 (24.5, 3.2) T score (IQR) Median hip 20.5 (24.3, 1.5) 21.2 (23.1, 2.6) 21.9 (24.7, 0.9) 21.6 (24.4, 0.8) T score (IQR) Withdrawals All Exclusively for toxicity Toxicity implicated Exclusively for lack of effect Lack of effect implicated IQR, interquartile range. Prednisolone resulted in hypertension (OR 2.16; 95% CI 1.07, 4.36) and larger falls in hip DEXA scores (p = 0.03). Ciclosporin also resulted in hypertension (3.35; 1.57, 7.12), mouth ulcers and headaches were commoner, and many patients had transient creatinine elevations (OR 9.13; 95% CI 4.32, 19.30) that did not persist beyond 2 years. Withdrawals Seventy-one (15%) patients withdrew for toxicity and the same number for inefficacy. Toxicity was implicated in more withdrawals, prednisolone, ciclosporin and triple therapy. Based on a factorial analysis, which showed no evidence of an interaction (p = 0.95), and an assumed baseline rate of withdrawals due to toxicity of 9% (from the methotrexate arm), the NNH for any adverse event leading to withdrawal was 20 (95% CI 8, 1280) with added ciclosporin and 14 (95% CI 6, 65) with added prednisolone. The estimated NNH for triple therapy, based only on data from patients receiving this therapy was 6 (95% CI 3, 23). DISCUSSION Our results show combining step-down prednisolone or ciclosporin with methotrexate reduces erosive damage in active early RA. Prednisolone and ciclosporin have independent, additive effects on erosive damage. Prednisolone exerts its effects on erosive damage early. Ciclosporin has less prominent early effects on erosive damage; its benefits extended over 2 years. Triple therapy shows synergistic long-term effects on disability and health status. With both prednisolone and ciclosporin the NNT for stopping erosive progression (8) is substantially less than the NNH for an adverse effect resulting in withdrawal (12 and 14 respectively). With triple therapy the NNT and NNH are both 6, but this more intensive treatment has additional sustained benefits on disability and quality of life. Our results confirm previous RCTs showing glucocorticoids given either with or without DMARDs reduce progressive erosive damage in early RA, which has also been confirmed in a systematic review. 51 Theoretically DMARD co-prescribing could mask this benefit of glucocorticoids. 52 Our results confirm previous RCTs showing adding ciclosporin to methotrexate without glucocorticoids reduces erosive damage; though other DMARD combinations may not reduce erosive damage Overall RCTs of intensive therapy suggest two DMARDs and glucocorticoids is the optimal conventional treatment for early RA. Most trials use the COBRA 12 regimen of high dose/rapidly tailing glucocorticoids rather than low-dose glucocorticoids. 2 Such step down prednisolone gives lower overall cumulative 2-year doses (3740 mg vs 5475 mg with 7.5 mg daily) without the resumption in erosive damage after stopping glucocorticoids seen with low-dose glucocorticoids. 53 Nevertheless the optimal steroid regimen in early RA remains undecided. An additional issue is the optimal dose of methotrexate; although we used up to 25 mg per week, which is widely recommended, 1 there is evidence more intensive treatment regimens may give better results. 54 Ann Rheum Dis 2008;67: doi: /ard

7 RCTs have compared TNF inhibitors plus methotrexate against DMARD monotherapy alone and also against both intensive DMARD/steroid combinations and DMARD monotherapy. Overall, TNF inhibitors with methotrexate show comparable improvements in disease activity and disability to intensive DMARD/steroid combinations in a head-to-head RCT and a comparative meta-analysis. 55 However, TNF inhibitors with methotrexate may give greater reductions in radiological progression. RCTs in early RA use varying x-ray assessments. We used Larsen scores, which were used in RCTs by Kirwan 3 and other investigators and comparable observational studies Other RCTs use Sharp scores; one used both Rattingen (Larsen variant) and Sharp scores. 22 The relative utility of different x-ray scores is contentious RCTs vary in recording patients considered for entry; we recorded details of non-recruited patients following CONCORD recommendations; 42% of patients screened were ineligible and 24% declined. The number of patients with mild RA reflected the numbers of patients in the Norfolk Arthritis Register who did not need DMARDs. 55 Other early RA RCTs do not reported this screening information. Though evidence favours intensive treatment in early RA, it is rarely used in routine care often because of concerns about glucocorticoids, which persists despite reassurance An associated issue is the increased toxicity of intensive treatment regimens. 33 Although the benefits of intensive treatment outweigh its risks, and combinations such as the COBRA regimen seem less toxic, 12 patients continue to have greater concerns about adverse events than about treatment benefits; 64 consequently, many patients may prefer a conservative approach. Such concerns may be partially allayed by choosing combinations with less long-term toxicity than ciclosporin. In addition there are important roles for patient education in implementing intensive treatments such as step-down in routine clinical practice, and the optimal ways to enhance such education merits further investigation. Intensive treatment is not yet ideal. Over 30% of our patients receiving triple therapy had active DAS28 >5.1 after 12 months; RCTs of other intensive treatment give comparable results. The ultimate goal is identify ways of increasing the efficacy of intensive initial treatment without enhancing its toxicity. Acknowledgements: Trial Steering Committee: Professor Roger Sturrock (Chair); Professor Vern Farewell (Statistician); Dr David Walker, Dr Andrew Hassell, Dr Adam Young and Professor David Blake (Regional Collaborators); Professor Paul Bacon and Professor David Isenberg (Independent members); Neil Betteridge (Patients Advocate); Professor Ian Harvey (Advisor on Clinical Trials); Dr Alison Carr (Advisor on Health Status); Dr Luke Archard (Advisor on Health Economics). Data Monitoring and Ethics Committee: Professor DGI Scott (Chair), Professor Bryan Williams, Dr Alex MacGregor, and Janice Mooney; Rheumatologists: London region: Dr O Duke and Dr SR Patel (St Helier); Dr TR Price, Dr AL Dolan and Dr G Coakley (Queen Elizabeth, Woolwich); Professor K Chakravarty (Harold Wood); Dr D MacFarlane and Dr Warr (Pembury); Dr A Hammond (Maidstone); Dr N Gendi (Basildon); Dr MS Irani (Ashford); Dr B Dasgupta and Dr Wong (Southend); Dr N Cheung (Queen Mary s, Sidcup); Dr J Wojtuleskwi (Eastbourne); Dr PL Williams (Medway); Dr C Erhardt (Bromley); Dr AB Bhanji (Homerton); Professor C Pitzalis and Dr T Garood (King s College); Dr GH Kingsley and Dr V Hajela (Lewisham); Dr P Pitt (Orpington); Dr D Doyle (Whipps Cross); Dr C Kelsey (Oldchurch); Dr M Lloyd (Frimley Park); Professor G Panayi (Guy s); Dr SM Griffiths (East Surrey); Dr J Griffin and Dr D Fishman (Chase Farm); Dr A Jawad (Royal London); and Dr R Sturge and Dr C Smith (Barnet). West Midlands region: Dr P Dawes, Dr MF Shadforth and Dr EM Hay (Haywood); Dr D Mulherin and Dr T Price (Cannock Chase); Professor D Symmons and Dr SM Knight (Macclesfield); Dr R Butler (Oswestry); Dr AJ Farrell (Leighton); Dr M Allen (Walsgrave); Dr I Pande (Nottingham); and Dr G Kitas (Dudley). North East region: Dr LJ Kay, Dr I Griffiths, Dr P Platt and Dr ML Grove (Freeman/North Tyneside); Dr M Plant and Dr J Fordham (James Cook University Hospital); Dr AJ Chuck (Dryburn); Dr C Kelly (Queen Elizabeth, Gateshead); and Dr P Crook (Ashington). South West region: Dr NL Cox (Royal Hampshire County Hospital and the Royal National Hospital for Rheumatic Diseases); Dr SM Jones (University Hospital of Wales); Dr P Creamer and Dr Hollingworth (Southmead); Dr M Davis, Professor A Woolf and Dr D Hutchinson (Royal Cornwall); and Dr S Richards and Professor PW Thompson (Poole). Funding: This trial was funded by the Medical Research Council, UK. Competing interests: None. REFERENCES 1. Luqmani R, Hennell S, Estrach C, Birrell F, Bosworth A, Davenport G, et al. British Society for Rheumatology and British Health Professionals in Rheumatology Guideline for the Management of Rheumatoid Arthritis (The first 2 years). Rheumatology 2006;45: Combe B, Landewe R, Lukas C, Bolosiu HD, Breedveld F, Dougados M, et al. EULAR recommendations for the management of early arthritis: report of a task force of the European Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 2007;66: Kirwan JR. The effect of glucocorticoids on joint destruction in rheumatoid arthritis. The Arthritis and Rheumatism Council Low-Dose Glucocorticoid Study Group. N Engl J Med 1995;333: Grigor C, Capell H, Stirling A, McMahon AD, Lock P, Vallance R, et al. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet 2004;364: Symmons DP, Silman AJ. The Norfolk Arthritis Register (NOAR). Clin Exp Rheumatol 2003;21(5 Suppl 31):S Young A, Dixey J, Cox N, Davies P, Devlin J, Emery P, et al. How does functional disability in early rheumatoid arthritis (RA) affect patients and their lives? Results of 5 years of follow-up in 732 patients from the Early RA Study (ERAS). Rheumatology 2000;39: Dixey J, Solymossy C, Young A. Early RA study. Is it possible to predict radiological damage in early rheumatoid arthritis (RA)? A report on the occurrence, progression, and prognostic factors of radiological erosions over the first 3 years in 866 patients from the Early RA Study (ERAS). J Rheumatol Suppl 2004;69: (accessed 4 August 2007). 9. Ledingham J, Deighton C. Update on the British Society for Rheumatology guidelines for prescribing TNF-alpha blockers in adults with rheumatoid arthritis. Rheumatology 2005;44: Fautrel B, Constantin A, Morel J, Vittecoq O, Cantagrel A, Combe B, et al. Recommendations of the French Society for Rheumatology. TNFalpha antagonist therapy in rheumatoid arthritis. Joint Bone Spine 2006;73: Furst DE, Breedveld FC, Kalden JR, Smolen JS, Burmester GR, Bijlsma JW, et al. Updated consensus statement on biological agents, specifically tumour necrosis factor {alpha} (TNF{alpha}) blocking agents and interleukin-1 receptor antagonist (IL-1ra), for the treatment of rheumatic diseases, Ann Rheum Dis 2005;64(Suppl 4):iv Boers M, Verhoeven AC, Markusse HM, van de Laar MA, Westhovens R, van Denderen JC, et al. Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis. Lancet 1997;350: Landewe RB, Boers M, Verhoeven AC, Westhovens R, van de Laar MA, Markusse HM, et al. COBRA combination therapy in patients with early rheumatoid arthritis: long-term structural benefits of a brief intervention. Arthritis Rheum 2002;46: Haagsma CJ, van Riel PL, de Jong AJ, van de Putte LB. Combination of sulphasalazine and methotrexate versus the single components in early rheumatoid arthritis: a randomized, controlled, double-blind, 52 week clinical trial. Br J Rheumatol 1997;36: Mottonen T, Hannonen P, Leirisalo-Repo M, Nissila M, Kautiainen H, Korpela M, et al. Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial. FIN-RACo trial group. Lancet 1999;353: Dougados M, Combe B, Cantagrel A Goupille P, Olive P, Schattenkirchner M, et al. Combination therapy in early rheumatoid arthritis: a randomised, controlled, double blind 52 week clinical trial of sulphasalazine and methotrexate compared with the single components. Ann Rheum Dis 1999;58: Proudman SM, Conaghan PG, Richardson C, Griffiths B, Green MJ, McGonagle D, et al. Treatment of poor-prognosis early rheumatoid arthritis. A randomized study of treatment with methotrexate, cyclosporin A, and intraarticular corticosteroids compared with sulfasalazine alone. Arthritis Rheum 2000;43: Marchesoni A, Battafarano N, Arreghini M, Panni B, Gallazzi M, Tosi S. Radiographic progression in early rheumatoid arthritis: a 12-month randomized controlled study comparing the combination of cyclosporin and methotrexate with methotrexate alone. Rheumatology 2003;42: Gerards AH, Landewe RB, Prins AP, Bruyn GA, Goei The HS, Laan RF, et al. Cyclosporin A monotherapy versus cyclosporin A and methotrexate combination therapy in patients with early rheumatoid arthritis: a double blind randomised placebo controlled trial. Ann Rheum Dis 2003;62: Miranda JM, Alvarez-Nemegyei J, Saavedra MA, L, Galvan-Villegas F, Garcia- Figueroa J, et al. A randomized, double-blind, multicenter, controlled clinical trial of cyclosporine plus chloroquine vs. cyclosporine plus placebo in early-onset rheumatoid arthritis. Arch Med Res 2004;35: Sarzi-Puttini P, D Ingianna E, Fumagalli M, Scarpellini M, Fiorini T, Cherie-Ligniere EL, et al. An open, randomized comparison study of cyclosporine A, cyclosporine 662 Ann Rheum Dis 2008;67: doi: /ard

8 A+methotrexate and cyclosporine A+hydroxychloroquine in the treatment of early severe rheumatoid arthritis. Rheumatol Int 2005;25: Wassenberg S, Rau R, Steinfeld P, Zeidler H. Very low-dose prednisolone in early rheumatoid arthritis retards radiographic progression over two years: a multicenter, double-blind, placebo-controlled trial. Arthritis Rheum 2005;52: Svensson B, Boonen A, Albertsson K, van der Heijde D, Keller C, Hafstrom I. Lowdose prednisolone in addition to the initial disease-modifying antirheumatic drug in patients with early active rheumatoid arthritis reduces joint destruction and increases the remission rate: a two-year randomized trial. Arthritis Rheum 2005;52: Hetland ML, Stengaard-Pedersen K, Junker P, Lottenburger T, Ellingsen T, Andersen LS, et al. Combination treatment with methotrexate, cyclosporine, and intraarticular betamethasone compared with methotrexate and intraarticular betamethasone in early active rheumatoid arthritis: an investigator-initiated, multicenter, randomized, double-blind, parallel-group, placebo-controlled study. Arthritis Rheum 2006;54: Capell H, Madhok R, Porter D, Munro RA, McInnes IB, Hunter JA, et al. Combination therapy with sulphasalazine and methotrexate is more effective than either drug alone in rheumatoid arthritis (RA) patients with a suboptimal response to sulphasalazine: results from the double blind placebo controlled mascot study. Ann Rheum Dis 2007;66: Goekoop-Ruiterman YP, De Vries-Bouwstra JK, Allaart CF, van Zeben D, Kerstens PJ, Hazes JM, et al. Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. Arthritis Rheum 2005;52: Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, van Zeben D, Kerstens PJ, Hazes JM, et al. Comparison of treatment strategies in early rheumatoid arthritis: a randomized trial. Ann Intern Med 2007;146: Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH, eystone EC, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med 2000;343: St Clair EW, van der Heijde DM, Smolen JS, Maini RN, Bathon JM, Emery P, et al. Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset Study Group. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial. Arthritis Rheum 2004;50: Klareskog L, van der Heijde D, de Jager JP, Gough A, Kalden J, Malaise M, et al. TEMPO (Trial of Etanercept and with Radiographic Patient Outcomes) study investigators. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet 2004;363: Quinn MA, Conaghan PG, O Connor PJ, Karim Z, Greenstein A, Brown A, et al. Very early treatment with infliximab in addition to methotrexate in early, poor-prognosis rheumatoid arthritis reduces magnetic resonance imaging evidence of synovitis and damage, with sustained benefit after infliximab withdrawal: results from a twelve-month randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2005;52: Breedveld FC, Weisman MH, Kavanaugh AF, Cohen SB, Pavelka K, van Vollenhoven R, et al. The PREMIER study: a multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum 2006;54: Choy EH, Smith C, Dore CJ, Scott DL. A meta-analysis of the efficacy and toxicity of combining disease-modifying anti-rheumatic drugs in rheumatoid arthritis based on patient withdrawal. Rheumatology (Oxford) 2005;44: Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 2006;295: Scott DL, Kingsley GH. Tumor necrosis factor inhibitors for rheumatoid arthritis. N Engl J Med 2006;355: Smolen JS, Aletaha D, Keystone E. Superior efficacy of combination therapy for rheumatoid arthritis: fact or fiction? Arthritis Rheum 2005;52: Huizinga TW, Landewe RB. Early aggressive therapy in rheumatoid arthritis: a window of opportunity? Nat Clin Pract Rheumatol 2005;1: Quinn MA, Emery P. Potential for altering rheumatoid arthritis outcome. Rheum Dis Clin North Am 2005;31: Smolen JS, Aletaha D, Machold KP. Therapeutic strategies in early rheumatoid arthritis. Best Pract Res Clin Rheumatol 2005;19: Kirwan J. Early rheumatoid arthritis: combination therapy with disease-modifying antirheumatic drugs and low-dose glucocorticoids? Nat Clin Pract Rheumatol 2006;2: Finckh A, Liang MH, van Herckenrode CM, de Pablo P. Long-term impact of early treatment on radiographic progression in rheumatoid arthritis: a meta-analysis. Arthritis Rheum 2006;55: Machold KP, Nell VP, Stamm TA, Smolen JS. Aspects of early arthritis. Traditional DMARD therapy: is it sufficient? Arthritis Res Ther 2006;8: Emery P. Treatment of rheumatoid arthritis. BMJ 2006;332: McAlister FA, Straus SE, Sackett DL, Altman DG. Analysis and reporting of factorial trials: a systematic review. JAMA 2003;289: Tugwell P, Pincus T, Yocum D Stein M, Gluck O, Kraag G, et al. Combination therapy with cyclosporine and methotrexate in severe rheumatoid arthritis. The - Cyclosporine Combination Study Group. N Engl J Med 1995;333: Pasero G, Priolo F, Marubini E, Fantini F, Ferraccioli G, Magaro M, et al. Slow progression of joint damage in early rheumatoid arthritis treated with cyclosporin A. Arthritis Rheum 1996;39: Scott DL, Houssien DA, Laasonen L. Proposed modification to Larsen s scoring methods for hand and wrist radiographs. Br J Rheumatol 1995;34: Fransen J, Creemers MC, Van Riel PL. Remission in rheumatoid arthritis: agreement of the disease activity score (DAS28) with the ARA preliminary remission criteria. Rheumatology 2004;43: van Everdingen AA, Jacobs JW, Siewertsz Van Reesema DR, Bijlsma JW. Lowdose prednisone therapy for patients with early active rheumatoid arthritis: clinical efficacy, disease-modifying properties, and side effects: a randomized, double-blind, placebo-controlled clinical trial. Ann Intern Med 2002;136: Jacobs JW, van Everdingen AA, Verstappen SM, Bijlsma JW. Follow up radiographic data on patients with rheumatoid arthritis who participated in a two-year trial of prednisone therapy or placebo. Arthritis Rheum 2006;54: Kirwan JR, Bijlsma JWJ, Boers M, Shea BJ. Effects of glucocorticoids on radiological progression in rheumatoid arthritis. Cochrane Database Syst Rev van Everdingen AA, Siewertsz van Reesema DR, Jacobs JW, Bijlsma JW. The clinical effect of glucocorticoids in patients with rheumatoid arthritis may be masked by decreased use of additional therapies. Arthritis Rheum 2004;51: Hickling P, Jacoby RK, Kirwan JR. Joint destruction after glucocorticoids are withdrawn in early rheumatoid arthritis. Arthritis and Rheumatism Council Low Dose Glucocorticoid Study Group. Br J Rheumatol 1998;37: Verstappen SM, Jacobs JW, van der Veen MJ, Heurkens AH, Schenk Y, Ter Borg EJ, et al. Intensive treatment with methotrexate in early rheumatoid arthritis: aiming for remission. Computer Assisted Management in Early Rheumatoid Arthritis(CAMERA). Ann Rheum Dis 2007;66: Kingsley GH, Saha A, Choy EH, Scott DL. Comparative systematic review of TNFinhibitors and intensive DMARD regimens in ra suggests similar efficacy. Rheumatology 2007;Suppl:in press [abstract] 56. Bukhari MA, Wiles NJ, Lunt M, Harrison BJ, Scott DG, Symmons DP, et al. Influence of disease-modifying therapy on radiographic outcome in inflammatory polyarthritis at five years: results from a large observational inception study. Arthritis Rheum 2003;48: Bruynesteyn K, Van Der Linden S, Landewe R Gubler F, Weijers R, Van Der Heijde D. Progression of rheumatoid arthritis on plain radiographs judged differently by expert radiologists and rheumatologists. J Rheumatol 2004;31: Bruynesteyn K, van der Heijde D, Boers M, Saudan A, Peloso P, Paulus H, et al. Determination of the minimal clinically important difference in rheumatoid arthritis joint damage of the Sharp/van der Heijde and Larsen/Scott scoring methods by clinical experts and comparison with the smallest detectable difference. Arthritis Rheum 2002;46: Guillemin F, Billot L, Boini S, Gerard N, Odegaard S, Kvien TK. Reproducibility and sensitivity to change of 5 methods for scoring hand radiographic damage in patients with rheumatoid arthritis. J Rheumatol 2005;32: Jobanputra P, Wilson J, Douglas K, Burls A. A survey of British rheumatologists DMARD preferences for rheumatoid arthritis. Rheumatology (Oxford) 2004;43: van Tuyl LH, Plass AM, Lems WF, Voskuyl AE, Dijkmans BA, Boers M. Why are Dutch rheumatologists reluctant to use the COBRA treatment strategy in early rheumatoid arthritis? Ann Rheum Dis 2007;66: Carette S. All patients with rheumatoid arthritis should receive corticosteroids as part of their management. J Rheumatol 2007;34: Boers M. Studying the benefit/risk ratio of glucocorticoids in rheumatoid arthritis. J Rheumatol 2007;34: Fraenkel L. Bogardus S. Concato J. Felson D. Risk communication in rheumatoid arthritis. J Rheumatol 2003;30: Ann Rheum Dis 2008;67: doi: /ard