EXTENDED REPORT

Intensive combination treatment regimens, includingprednisolone, are effective in treating patients withearly rheumatoid arthritis regardless of additionaletanercept: 1-year results of the COBRA-lightopen-label, randomised, non-inferiority trialMarieke M ter Wee,1 Debby den Uyl,1 Maarten Boers,1,2 Pit Kerstens,2,3

Mike Nurmohamed,1,2 Dirkjan van Schaardenburg,1,2 Alexandre E Voskuyl,1

Willem F Lems1,2

Handling editor Tore K Kvien

▸ Additional material ispublished online only. To viewplease visit the journal online(http://dx.doi.org/10.1136/annrheumdis-2013-205143).1Department of Rheumatology,VU University Medical Center,Amsterdam, Noord Holland,The Netherlands2Department of Rheumatology,Jan van Breemen ResearchInstitute Reade, Amsterdam,Noord Holland,The Netherlands3Westfriesgasthuis, Hoorn,Noord Holland,The Netherlands

Correspondence toM M ter Wee,Department of Rheumatology,VU University Medical Center,Room 3A52, De Boelelaan1117, Amsterdam 1081 HV,The Netherlands;m.terwee@vumc.nl

Received 23 December 2013Revised 1 April 2014Accepted 13 April 2014

To cite: ter Wee MM, denUyl D, Boers M, et al. AnnRheum Dis Published OnlineFirst: [please include DayMonth Year] doi:10.1136/annrheumdis-2013-205143

ABSTRACTBackground Recently, we documented the likelynon-inferiority of Combinatietherapie Bij ReumatoïdeArtritis (COBRA)-light therapy (methotrexate increased to25 mg/week with initial prednisolone 30 mg/day)compared with the original COBRA therapy(methotrexate 7.5 mg/week, sulfasalazine 2 g/day, withinitial prednisolone 60 mg/day) after 26 weeks inpatients with early active rheumatoid arthritis (RA).Objective To assess the non-inferiority of COBRA-lightversus COBRA after 1 year in terms of disease activity(DAS44), functional outcome (Health AssessmentQuestionnaire (HAQ)) and radiographic progression(Sharp/van der Heijde score (SHS)), and to assess theeffect of adding etanercept.Methods An open-label, randomised controlled, non-inferiority trial of 162 patients with active early RA,following a treat-to-target protocol incorporating theaddition of etanercept if DAS44 ≥1.6 at weeks 26 or 39.Results Both groups showed major improvements inDAS44 after 52 weeks: mean (SD) −2.41 (1.2) in theCOBRA and −2.02 (1.0) in the COBRA-light group (p=ns).In both groups, functional ability improved and radiologicalprogression of joints was minimal. At least one adverseevent was reported in 96% of the patients in both groups.In total, 25 serious adverse events occurred: 9 vs 16 inCOBRA and COBRA-light, respectively. Treatment actuallyinstituted was often less intensive than required by theprotocol: of the total population, 108 patients (67%)required etanercept (more in the COBRA-light group), butonly 67 of these (62%) actually received it.Conclusions Intensive COBRA or COBRA-light therapyhas major, comparably favourable effects on diseaseactivity, functional ability and radiological outcome after1 year in patients with early RA. Protocolised addition ofetanercept was often not implemented by treatingrheumatologists, and patients receiving it appeared to havelimited added benefit, probably because of low diseaseactivity levels at its initiation.Trial registration number: ISRCTN55552928.

INTRODUCTIONTreatment with disease-modifying anti-rheumaticdrugs (DMARDs) has proven to be effective in the

treatment of rheumatoid arthritis (RA) in improv-ing disease activity and physical functioning andpreventing joint progression.1–7 Patients with earlyRA are usually treated with methotrexate (MTX),often combined with glucocorticoids, with sulfa-salazine and/or hydroxychloroquine as alterna-tives.8 A very effective strategy is COBRA therapy(COmbinatietherapie Bij Reumatoïde Artritis(COBRA)) in which patients receive MTX (7.5 mg/week), sulfasalazine (2 g/day) and initially high-doseprednisolone (60 mg/day). In the BeSt trial, thisstrategy proved to be as effective and safe as thecombination of high-dose MTX (25 mg/week) andanti-tumour necrosis factor (TNF) treatment (inflix-imab).9–11 Despite this, rheumatologists have reser-vations in prescribing COBRA therapy for severalreasons, including concerns over the possible sideeffects of high-dose or prolonged glucocorticoidexposure.12 13 Therefore, we recently introducedCOBRA-light therapy, combining MTX (25 mg/week) with an initially lower dose of prednisolone(30 mg/day). Our first report of the COBRA-lighttrial, in which both therapies were applied intreat-to-target strategies for patients with early RA,suggested that COBRA-light was non-inferior toCOBRA in clinical outcomes, safety and efficacyafter 26 weeks of treatment.14

The COBRA-light trial protocol specified 1 yearof treatment, in which patients were to start etaner-cept if they did not reach minimal disease activityat week 26 or 39. This report describes clinical andradiological outcomes at 1 year.

PATIENTS AND METHODSFromMarch 2008 to April 2011, 164 DMARD-naïveDutch patients with recent-onset RAwere included inthe COBRA-light trial. This study was a multicentre,randomised, open-label trial (http://www.controlled-trials.com; ISRCTN55552928). Patients were rando-mised to the COBRA-light or COBRA strategy (asapplied in the BeSt trial), to determine the non-inferiority of COBRA-light therapy. The treatmentgoal was minimal disease activity (at that time definedas clinical remission: Disease Activity Score in 44joints (DAS44) <1.6), and treatment intensification of

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MTX and addition of etanercept to reach this goal was protocolisedup to 52 weeks (see online supplementary file appendix 1).Patient-selection criteria, the randomisation process and studydesign have been reported previously.14

Medical ethics committees at each participating centreapproved the protocol; patients gave written informed consentbefore inclusion, and the study was conducted in accordancewith the Declaration of Helsinki/Good Clinical Practice.

Clinical assessmentsOutcome measures were disease activity variables, factors to cal-culate different response and remission criteria, and severalpatient-reported outcomes, including the changed and achievedstate in physical functioning as measured by the Dutch versionof the Health Assessment Questionnaire (NL-HAQ).15–18

Medication use was ascertained by self-report of the patientsthrough patient diaries and from patient medical records.14

Intra-articular and intramuscular glucocorticoid injectionswere allowed. To correct for possible influence of these injec-tions on disease activity assessment, the score of joints injectedin the 12 weeks before a study visit was set to swollen andpainful (Ritchie articular index score 1), if no score wasrecorded. The DAS44 score of patients receiving an intramuscu-lar injection in the 4 weeks before a study visit was set tomissing.

All adverse events and protocol violations were reported ateach visit by active solicitation.14 An independent committee oftwo rheumatologists who were not involved in the execution ofthe study evaluated all adverse events to identify serious adverseevents (SAEs) according to the standard of the Directive 2001/20/EC of 4 April 2001,19 and assessed their potential relation-ship to treatment. This same committee classified all protocolviolations as major or minor and confirmed protocolised treat-ment deviations. A major protocol violation was defined as anymodification from protocol, design or procedure that couldaffect the completeness, accuracy, reliability or integrity of thestudy data. These violations were further classified as lack ofcompliance of the physician or the patient, administrative mis-takes, and other reasons. Minor violations were defined as smallor temporary alterations in treatment deemed not to affect thestudy data. Protocolised treatment deviations were changes inprotocol treatment (dose reduction or cessation) due to adverseevents or secondary ineligibility (eg, the desire to becomepregnant).

RadiologyRadiographs were obtained at baseline, week 26 and at 1 year offollow-up, and scored by two independent trained assessorsaccording to the Sharp/van der Heijde score (SHS).20 The asses-sors were blinded to group allocation and patient identification,but were aware of time order, as reading in chronological orderwas carried out; this is most sensitive for detecting progressionand leads to less bias.21 If assessors differed by more than 5points in the SHS, a third assessor (DvS) was consulted to reacha consensus. The intraclass correlation coefficient agreementbetween the two assessors was 0.90 (95% CI 0.8 to 1.0),assessed on a test sample of 30 patients. The mean of the twoobservers’ scores was reported. If radiographs were missing atweek 26, and scores at baseline and week 52 remained stable,the same score was imputed at week 26. For missing radio-graphs at week 52, SHS was extrapolated with linear imput-ation, using scores at baseline and week 26. Missing baselinescores (n=1) were imputed by retrograde extrapolation fromscores at week 26 and 52.

Anti-TNF therapyThe protocol required treatment intensification with etanerceptfor patients who did not reach a DAS44 <1.6 at week 26 or 39.In the COBRA group, MTX dose was initially increased to25 mg/week in 2-weekly steps, followed by etanercept 50 mgonce weekly subcutaneously if minimal disease activity had notbeen achieved at the next assessment (see online supplementaryfile appendix 1). In the COBRA-light group, the initial step wasthe possibility of switching to subcutaneous MTX followed byetanercept. Patients received etanercept until week 52 (periodof 3–6 months depending on start date). During etanercept use,DMARD dosages were kept stable, except in the case of adverseevents and in cases of minimal disease activity, when prednisol-one was tapered to 0 mg/day.

Statistical analysisNon-inferiority was defined as a difference in ΔDAS44 betweenthe two groups of 0.5 points or less. All patients who receivedat least one medication dose were included in the modifiedintention-to-treat (ITT) protocol. Data are presented as mean±SD, or as median (IQR) in the case of skewed distribution.

All disease activity outcome measures with Gaussian distributionwere analysed with Generalised Estimating Equation (GEE) toassess differences between treatment strategies over time and tocorrect for repeated measures. Baseline measures were included inall analyses to correct for regression to the mean. Change inDAS44 over time was analysed as outcome, treatment group andbaseline DAS44 as explanatory measures. Measures with a skewedcontribution were first log-transformed (natural logarithm) andthen analysed with GEE. A linear regression model was used toassess difference in radiological progression and for resultsexpressed as area under the curve. Differences in proportions ofpatients achieving remission and starting etanercept wereexpressed as relative risks (RRs). χ2 for trend analyses were per-formed on American College of Rheumatology (ACR) response(ACR20 but not ACR50, ACR50 but not ACR70, and ACR70)and European League against Rheumatism (EULAR) response(non-responder, moderate responder but not good responder,good responder).22 All statistical analyses were conducted usingIBM SPSS statistics V.20. A two-sided p<0.05 was considered sig-nificant. For the primary outcome (change in DAS44), non-inferiority of COBRA-light can be declared if the upper limit ofthe 95% CI (two-sided) around the difference between the groupsis <0.5.23 24 For all other outcomes, acceptance of the nullhypothesis was deemed to document non-inferiority.

RESULTSA total of 164 patients were included: 81 receiving COBRAtherapy and 83 COBRA-light therapy (figure 1). Two patientsdid not start treatment because of withdrawal of informedconsent immediately after randomisation. These patients werenot included in the ITTanalyses. Baseline demographic and clin-ical characteristics for the two groups were similar, except for asmall difference in baseline DAS44: mean (SD) 4.09 (0.7) forCOBRA and 3.96 (0.9) for COBRA-light, as shown in table 1.14

Half of all patients were positive for both rheumatoid factorand anti-cyclic citrullinated peptide.

Seven patients dropped out during the trial: three in theCOBRA group and four in the COBRA-light group (figure 1). Tenpatients (COBRA, 3; COBRA-light, 7) received an intra-articularinjection, five in the 12 weeks before an assessment. Nine patientsreceived an intramuscular glucocorticoid injection (COBRA, 4;COBRA-light, 5), one within 4 weeks of an assessment.

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Clinical outcomesBoth groups showed major improvements in disease activitybetween baseline and week 26 as reported previously,14 with sta-bilisation in the second 6 months; COBRA-light remained non-inferior to COBRA. Longitudinal change over time in DAS44between baseline and week 52 was −2.41 (1.2) in the COBRAgroup and −2.02 (1.0) in the COBRA-light group (adjustedβ=0.19 (0.1), 95% CI −0.07 to 0.45, p=0.15; table 1, figure 2).At this time point, the CI of difference in ΔDAS44 does notinclude the predefined clinically relevant threshold of 0.5.Minimal disease activity (DAS44 <1.6) was reached in 38% ofthe patients in COBRA and 31% in COBRA-light (ACR/EULARremission in 15% vs 17%, respectively) (table 1).

The two strategies had an almost equally positive effect onfunctional ability: decrease of 0.79 and 0.76 (0.7) points on theHAQ for COBRA and COBRA-light, respectively, and showedconsistent patterns in single disease activity measures over time,except for a larger erythrocyte sedimentation rate (ESR)decrease for COBRA (table 1). At week 26 and 39, ∼40% of thepatients in both groups could taper prednisolone to 0 mg/day.

No significant differences were found in any of the other out-comes, supporting non-inferiority. Differences in proportions ofpatients reaching EULAR response, ACR20, ACR50 and ACR70improvement were small and did not favour one treatment

group (table 1). At week 52, 6% of the patients were EULARnon-responders in both groups. This proportion increased whenthe cut-off point for non-responders was set as HAQ score ≥1.0at week 52: 17% in COBRA and 30% in COBRA-light.Non-responders (DAS44 ≥2.4 or HAQ score ≥1.0 or ΔSHS ≥5)had a somewhat higher baseline DAS44 than responders (∼4.2vs 3.9, respectively). This was mostly driven by a high visualanalogue scale (more than 65 points) and approximately 23tender joints (data not shown).

RadiologyIn 18 patient sets, the two assessors differed by at least 5 points,and the score of the third assessor was applied. The intraclasscorrelation coefficient agreement, based on the mean total SHSat baseline between the two assessors in this dataset (excludingpatients with a consensus score), was 0.91 (95% CI 0.88 to0.93). At baseline, the SHS was 2.66 (6.5) for COBRA and 1.61(4.0) for COBRA-light (table 1); erosive disease, as defined bythe 2010 ACR/EULAR criteria,25 was present in 7% vs 2% inCOBRA and COBRA-light, respectively. At week 52, theincrease in SHS was 0.49 (1.6) and 0.59 (1.4) points forCOBRA and COBRA-light, respectively (p=0.42), with no dif-ference in the score components. In COBRA, 6% had erosivedisease, compared with 7% in COBRA-light. An increase indamage of 5 points or more occurred in only 5% of the patients(figure 3).

Anti-TNF therapyPer protocol (DAS44 ≥1.6) at either week 26 or 39, fewerCOBRA than COBRA-light patients needed treatment intensifica-tion with etanercept: 47 (59%) vs 61 (75%) (RR 1.67, 95% CI1.05 to 2.65, p=0.03). If the protocol cut-off had been set atDAS44 ≥2.4 (‘low disease activity’, corresponding to DAS28≥3.2), 38% versus 49%, respectively, would have needed intensi-fication to etanercept (p=0.04). However, owing to protocolisedtreatment deviations and/or protocol violations, only 27 of 47(57%) COBRA patients versus 40 of 61 (66%) COBRA-lightpatients actually started etanercept (p=0.04). In the COBRAgroup, 16 and 11 patients started at week 26 and 39, respect-ively; one patient started at week 30 because of a rapid increasein disease activity between week 26 and 39. In the COBRA-lightgroup, 28 and 10 patients started at week 26 and 39, respectively.In addition, two patients started at week 13 because of highdisease activity (DAS44=6.0 and 4.5). The two groups had thesame minimal progression of ΔSHS as the total group and wererandomly distributed on the probability plot in figure 3 (data notshown). Etanercept was, in general, well tolerated: at week 39,adverse events had occurred in 24% of etanercept users com-pared with 13% of non-users. At week 52, proportions were26% vs 14%, respectively. The 22 COBRA patients and 21COBRA-light patients who were etanercept non-starters hadsomewhat lower disease activity than actual starters, as evidencedby DAS44. These differences were only statistically significant inthe COBRA-light group (table 2). In addition, in 60% of thesecases, the physician assessed the disease activity to be lower thandid the research nurse (data based on remarks of physiciansduring collection of protocol violations).

Thirteen weeks after the indication to start etanercept, themean disease activity had decreased in all groups regardless ofwhether etanercept was actually started: in the COBRA group,DAS44 had decreased by 0.57 (0.8) and 0.23 (0.5) points foractual starters and non-starters, respectively (adjusted β=0.29(0.24), 95% CI −0.21 to 0.78, p=0.25); in the COBRA-lightgroup, it had decreased by 0.55 (0.8) and 0.29 (0.9) points,

Figure 1 Flow chart of Combinatietherapie Bij Reumatoïde Artritis(COBRA)-light therapy trial. In the COBRA group, one patientdiscontinued at week 13 (myocardial infarction), one at week 26(intolerance of medication), and one at week 39 (bilateral pulmonaryembolism). In the COBRA-light group, one patient discontinued at week13 (poor compliance with treatment) and three patients at week 26(manic episode, desire to become pregnant, poor compliance withtreatment). All patients were alive at week 52 of the trial. The ninepatients who did not start or prematurely stopped the trial were older(mean (SD) 59 (12.3) years), had a shorter disease duration (median13 weeks, IQR 6–18.5), a lower Disease Activity Score in 44 joints(3.94 (0.4)) and a higher Health Assessment Questionnaire score(median 1.88, IQR 1.32–2.13) at baseline compared with the patientswith complete follow-up.

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Table 1 Demographic and disease activity measures at baseline and at 52 weeksDemographic and disease activityat baseline COBRA (n=81) COBRA-light (n=81)

Female, n (%) 54 (66) 58 (69)

Age, years 53 (13) 51 (12)

Disease duration, weeks 22 (17) 25 (22)

Rheumatoid factor, n (%) 47 (58) 49 (59)

Anti-CCP positive, n (%) 50 (61) 55 (66)

DAS44 4.09 (0.7) 3.96 (0.9)

DAS44-CRP 4.44 (1.0) 4.21 (1.2)

DAS28 5.55 (1.1) 5.32 (1.2)

Tender joints 15.7 (7.0) 14.6 (7.9)

Swollen joints 14.1 (5.1) 12.4 (5.4)

HAQ 1.36 (0.7) 1.37 (0.7)

SHS 2.66 (6.5) 1.61 (4.0)

ESR, mm/h 27.0 (14.5 to 44.5) 27.0 (12.0 to 48.0)

CRP, mg/L 13.0 (4.5 to 27.0) 13.0 (4.0 to 30.5)

Patient assessment disease activity, by VAS, mm 60.2 (21.6) 65.6 (23.5)

Patient assessment of pain, by VAS, mm 60.1 (22.9) 57.8 (25.4)

Patient global assessment, by VAS, mm 60.5 (21.9) 58.3 (25.3)

Physician assessment disease activity, by VAS, mm 51.2 (14.5) 48.2 (16.6)

Disease activity and response at week 52* β (95% CI) p Value

DAS44 1.70 (1.0) 1.88 (1.0) 0.19 (−0.07 to 0.45) 0.15

DAS44-CRP 1.71 (1.2) 1.69 (1.1) 0.03 (−0.27 to 0.33) 0.74

DAS28 2.49 (1.3) 2.71 (1.3) 0.24 (−0.08 to 0.57) 0.15

Tender joints 5.3 (7.2) 5.0 (6.0) −0.17 (−1.99 to 1.64) 0.85

Swollen joints 2.6 (3.6) 2.3 (2.6) −0.79 (−2.12 to 0.55) 0.25

HAQ 0.57 (0.5) 0.61 (0.6) 0.07 (−0.08 to 0.21) 0.35

ESR, mm/h† 6.0 (2.5 to 1.0) 2.5 (1.0 to 4.3) 0.42 (0.20 to 0.64) <0.01

CRP, mg/L† 2.5 (2.0 to 4.0) 7.5 (3.0 to 16.0) 0.05 (−0.17 to 0.26) 0.65

Patient assessment disease activity, by VAS, mm 30.1 (27.2) 26.1 (26.0) −5.78 (−11.89 to 0.34) 0.06

Patient assessment of pain, by VAS, mm 29.3 (26.4) 24.9 (25.5) −3.55 (−9.38 to 2.28) 0.23

Patient global assessment, by VAS, mm 31.2 (26.2) 28.8 (26.2) −0.96 (−6.71 to 4.79) 0.74

Physician assessment disease activity, by VAS, mm 18.5 (16.2) 16.7 (14.7) −0.58 (−4.32 to 3.16) 0.76

Differences in outcome after 52 weeks‡

ΔDAS44 −2.41 (1.2) −2.02 (1.1) 0.21 (−0.09 to 0.52) 0.17

AUC DAS44 104 (76 to 124) 108 (74 to 135) 0.00 (−0.00 to 0.00) 0.33

ΔSHS 0.49 (1.6) 0.59 (1.4) 0.18 (−0.27 to 0.63) 0.42

ΔErosion 0.18 (0.4) 0.30 (0.8) 0.19 (0.00 to 0.37) 0.05

ΔJSN 0.31 (1.5) 0.27 (0.8) −0.05 (−0.43 to 0.33) 0.80

Response measures at week 52 RR (95% CI) p Value

Remissions, n (%)§

Clinical remission (DAS44 <1.6) 38 (47) 31 (38) 0.85 (0.64 to 1.13) 0.18

ACR/Boolean remission 12 (15) 14 (17) 1.03 (0.90 to 1.18) 0.67

EULAR response, n (%)¶

Non-responders 5 (6) 5 (6) 1.00 (0.53 to 1.90) 1.00

Moderate responder, but not good responders 16 (50) 23 (28)

Good responders 56 (69) 49 (60)

ACR response, n (%)¶

ACR non-responders 19 (23) 20 (25) OR 1.03 (0.71 to 1.49) 0.73

ACR20, but not ACR50 12 (15) 15 (18)

ACR50, but not ACR70 20 (25) 14 (17)

ACR70 25 (31) 28 (35)

Data are expressed as mean (SD) unless otherwise stated. Significance between groups was tested with Generalised Estimating Equation (GEE) analyses, linear regression and relativerisk. All regression analyses were corrected for baseline values.*GEE analyses.†Analyses based on lnESR and lnCRP.‡Linear regression analyses.§Relative risk analyses.¶χ2 for trend analyses.ACR, American College of Rheumatology; anti-CCP, anti-cyclic citrullinated peptide; AUC, area under the curve; COBRA, COmbinatietherapie Bij Reumatoïde Artritis; CRP, C-reactive protein;DAS28, 28-joint count Disease Activity Score; DAS44, 44-joint count Disease Activity Score; DAS44-CRP, 44-joint count Disease Activity Score based on CRP; ESR, erythrocyte sedimentation rate;EULAR, European League against Rheumatism; HAQ, Health Assessment Questionnaire; JSN, joint space narrowing; RR, relative risk; SHS, Sharp/ van der Heijde score; VAS, visual analogue scale.

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respectively (adjusted β=−0.05 (0.23), 95% CI −0.51 to 0.41,p=0.83) (figure 4). Of the actual starters, 27% could taperprednisolone to 0 compared with 35% of the non-starters(p=ns).

A total of 46 patients received etanercept for 26 weeks (16 inthe COBRA group and 30 in the COBRA-light group); in thisgroup, DAS44 had increased again between week 39 and 52,resulting in a net decrease of 0.31 points in COBRA and 0.36points in COBRA-light therapy over the total 6-month period.

Protocol violations and adverse eventsAfter 52 weeks of treatment, nearly all patients reported at leastone adverse event after active solicitation: 96% in both groups.The most commonly reported were skin problems, mild gastro-intestinal problems, and infections; their incidence did notdiffer between the two groups (see online supplementary fileappendix 2). Patients in both groups gained ∼1.0 kg in weight(p=0.89). In total, 16 patients (20%) in the COBRA arm hadan increase of >5 kg in weight compared with 11 patients(14%) in the COBRA-light arm (p=0.31). Only one patient wasnewly diagnosed with diabetes mellitus type II and needed treat-ment with oral antidiabetic drugs (COBRA group). Ninepatients needed treatment for hypertension (five in the COBRAgroup and four in the COBRA-light group), and eight patientsneeded treatment for dyslipidaemia (three and five in theCOBRA and COBRA-light groups, respectively).

In total, 25 SAEs occurred: nine and sixteen in COBRAand COBRA-light patients, respectively. The COBRA patientsexperienced the following SAEs: myocardial infarction, pul-monary embolism, hospitalisation for pneumonia, plannedcataract surgery on both eyes (2×), planned surgery of thecervical spine, attempted suicide due to depression, fibulafracture caused by MTX osteopathy, and a pelvis fracture.SAEs in the COBRA-light patients included lung carcinoma(2×), planned knee replacement surgery (2×), plannedhallux valgus surgery, planned varicose vein surgery, plannedcontrol coloscopy for diverticulitis, hospitalisation forarrhythmia, manic episode, replacement and hospitalisationfor a retina bleeding, planned surgery for cyst removal, hospi-talisation for anaemia caused by duodenal ulcers, plannedcholecystectomy, surgery for an inguinal hernia, hospitalisa-tion and surgery for a hip fracture after a fall, and surgery forchronic synovitis.

Over the year, there were one or more protocol violations/deviations for more than half of the patients: 49 in COBRAand 47 in COBRA-light. More major violations occurred inthe COBRA than the COBRA-light group: 68 vs 48 (seeonline supplementary file appendix 2). Most of these viola-tions were due to non-compliance of the physician with theprotocol, and most of the violations led to a decrease inintensity of the therapy.

Figure 2 Mean change in outcomes of treatment. Data areexpressed as mean (SD). Black line, COBRA therapy; grey line,COBRA-light therapy. N=74 or greater at all time points. COBRA,COmbinatietherapie Bij Reumatoïde Artritis; CRP, C-reactive protein;DAS44, Disease Activity Score for 44 joints; ESR, erythrocytesedimentation rate; HAQ, Health Asessment Questionnaire.

Figure 3 Probability plot Sharp/vander Heijde score (SHS). Black circles,COBRA therapy; grey circles,COBRA-light therapy. COBRA,COmbinatietherapie Bij ReumatoïdeArtritis.

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DISCUSSIONThis study confirms that, in patients with early RA, COBRA andCOBRA-light therapy are similarly efficacious in suppressingclinical disease activity and improving functional ability. In add-ition, both strategies have been shown to effectively suppressprogression of joint damage after 52 weeks of treatment. Theaddition of the TNF-blocking agent, etanercept, to the treat-ment had limited added benefit in decreasing disease activity.

The present effects are comparable to other treat-to-targetstudies in patients with early RA.3 6 10 26 In the BeSt trial, thegoal of low disease activity (DAS44 ≤2.4) was reached in 71%of the patients receiving COBRA therapy; in the present study,73% reached this goal compared with 67% receivingCOBRA-light therapy. Mean rates of damage progression wereonly slightly above zero, and this must be interpreted in light ofthe method of reading in a known sequence. This methodresults in slightly higher rates than with random reading, themethod used in most trials of biological agents.27

The treatment goal in this trial was set at DAS44 <1.6; witha combination of traditional DMARDs, 47% and 38% ofpatients for COBRA and COBRA-light therapy, respectively,achieved this, compared with 32% in the BeSt trial. Remarkably,although 67% of our study population required etanercepttreatment according to the protocol, only 62% of those patientsactually received it. It is possible that our predefined goal wastoo stringent compared with daily practice, where lack of lowdisease activity or severe disease activity (threshold DAS28≥3.2, corresponding to DAS44 ≥2.4) is used as an indication tostart biological agents. We also noticed that treating physicianssometimes did not agree with the DAS44 assessors. Therefore,treatment was not intensified, either because physicians assessedpatients with less active disease or both patient and physicianwere willing to accept low disease activity balanced against therisk and costs of biological agents—for instance, TNF-blockingagents. This was also observed earlier in the DREAM study.28

Our data show that a low DAS44 threshold in treat-to-targetprotocols poses challenges in clinical practice, because themeasure is not reliable in patients with low disease activity,mostly because of its sensitivity to small changes in ESR andglobal health scores, when joint scores are low or zero.29 Oneoption may be to add a biomarker in the assessment of diseaseactivity. For example, in a pilot trial that added a biomarker in

Table 2 Etanercept dataTotal population

COBRA (n=81) COBRA-light (n=81) RR (95% CI)* p Value

Etanercept start required, total patients (DAS44 ≥1.6), n (%) 47 (59) 61 (75) 1.67 (1.05 to 2.65) 0.03Based on DAS44 ≥1.6 and <2.4, n (%) 29 (62) 31 (51) 1.03 (0.81 to 1.31) 0.79Based on DAS44 ≥2.4, n (%) 18 (38) 30 (49) 1.23 (1.00 to 1.51) 0.04

Actual started, total (DAS44 ≥1.6), n (%) 27 (57) 40 (66) 1.30 (0.82 to 2.08) 0.04Based on DAS44 ≥1.6 and <2.4, n (%) 15 (56) 18 (45) 0.88 (0.54 to 1.42) 0.59Based on DAS44 ≥2.4, n (%) 12 (44) 22 (55) 1.24 (0.76 to 2.00) 0.40

Activity at intended start: etanercept actual starters vs non-starters

COBRA (n=50) COBRA-light (n=61)

Starters (n=27) Non-starters (n=22) p Value Starters (n=40) Non-starters (n=21) p Value

DAS44 2.44 (0.7) 2.24 (0.6) 0.30 2.66 (0.9) 2.05 (0.5) <0.01Tender joints 8.5 (5.9) 9.3 (11.9) 0.77 9.4 (9.5) 2.8 (1.6) <0.01Swollen joints 5.0 (4.0) 4.2 (9.4) 0.73 6.4 (7.5) 1.6 (1.8) <0.01HAQ† 0.87 (0.7) 0.69 (0.6) 0.45 0.98 (0.7) 0.61 (0.6) 0.10ESR, mm/h, median (IQR) 6.0 (3.0–9.0) 8.5 (4.0–14.0) 0.10 13.0 (3.3 to 22.8) 18.5 (6.5 to 24.5) 0.43CRP, mg/L, median (IQR) 2.8 (1.8–5.5) 2.5 (2.0–9.0) 0.90 4.0 (1.0 to 10.0) 2.8 (1.8 to 5.0) 0.43Patient global assessment, by VAS, mm 41.4 (23.4) 46.7 (24.0) 0.45 43.3 (25.5) 28.7 (22.3) 0.03

Data are expressed as mean (SD) unless otherwise stated.*RR analyses.†HAQ score was only assessed at week 26.COBRA, Combinatietherapie Bij Reumatoïde Artritis; CRP, C-reactive protein; DAS44, 44-joint count Disease Activity Score; ESR, erythrocyte sedimentation rate; HAQ, Health AssessmentQuestionnaire; RR, relative risk; VAS, visual analogue scale.

Figure 4 Mean change in Disease Activity Score in 44 joints (DAS44)for treatment in etanercept-intended vs actual starters. Data areexpressed as mean (SD). Black line, COBRA therapy; grey line,COBRA-light therapy. Etanercept starters (closed circles): n=27 and40 for COBRA and COBRA-light respectively. Etanercept nonstarters(open circles): n=13 and 10 respectively. COBRA, COmbinatietherapieBij Reumatoïde Artritis.

6 ter Wee MM, et al. Ann Rheum Dis 2014;0:1–8. doi:10.1136/annrheumdis-2013-205143

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the assessment of disease activity (measured with DAS28),90% of the patients had reached minimal disease activity(DAS28 <2.6) after 40 weeks of treatment with a modifiedCOBRA strategy followed by infliximab intensification, accord-ing to CTX2 values.30

Nevertheless, the many protocol deviations and violationspreclude a good assessment of the effect of etanercept in theproposed treatment strategy. Of interest, the added benefit ofetanercept in actual starters appeared to be rather limited: bothactual starters and non-starters ended up with a mean DAS44score of 2.2 at week 52. To our knowledge, this study is the firstto assess the effect of adding anti-TNF therapy after 6 or9 months of treatment with intensive combination regimensincluding prednisolone; a study in a real world setting alsofound lack of good outcomes explained by biological agents.31

Other trials starting with an initial treatment with biologicalagents and DMARDs had comparable results.6 10 In theNEO-RACO trial, patients treated with traditional DMARDS andan initial dose of infliximab showed equivalent results on diseasemeasures after 6 months, compared with patients treated withtraditional DMARDs and placebo.6 In the BeSt trial, the inflixi-mab plus MTX treatment arm showed similar results to theCOBRA arm.10 In the SWEFOT trial, infliximab treatment afterinsufficient reaction with 3–4 months of MTX use resulted in asignificant decrease in disease activity levels, as well as in theTEMPO trial with etanercept.32 33 Patients in these trials hadmuch higher disease activity levels at the start of treatment with abiological agent compared with our patients. These data illustratethe well-known phenomenon that anti-TNF therapy is effectivefor treating patients with high disease activity levels, but mighthave limited benefit in patients with low disease activity, as sug-gested in our trial.

This study has limitations. The first is the open-label design:trained research nurses, who are not involved in routine care,assessed all outcomes to minimise any influence on the outcomemeasures. Of course, in classical trial designs, blinding wouldhave limited bias of the results. On the other hand, this designis closer to daily practice, which increases its external validity.Second, power calculations were primarily based on week26 outcome; therefore, the outcome after 52 weeks is a second-ary outcome, but is, nevertheless, clinically very relevant.However, the clinically relevant difference in ΔDAS44 was still<0.5 at week 52, as for the primary outcome time point atweek 26. Therefore, we think our non-inferiority claim stillholds. Several other limitations that have previously been men-tioned14 (eg, non-inferiority, protocol violations) also apply tothis study.

Although most patients responded with both strategies,6% were still EULAR non-responders at week 52. Correspondingproportions of HAQ non-responders (ie, HAQ score ≥1.0) atweek 52 were noted: 17% and 30% for COBRA andCOBRA-light therapy, respectively. In future, these patientsshould be identified earlier, as they probably require differenttreatment from that usually provided.

In conclusion, addition initially of moderate-dose prednisol-one to intensive MTX treatment as proposed in theCOBRA-light therapy yields similar results to the originalCOBRA therapy, with strongly positive effects on disease activ-ity, functional ability and progression of joint damage in earlyRA. Further intensification with etanercept after an inadequateresponse, but mostly in patients with low disease activity, wasoften unacceptable to patients and physicians, leading to non-compliance with the protocol. In patients who actually started

etanercept, its added value appeared to be limited, probablybecause of low disease activity at its initiation.

Acknowledgements We would like to thank all patients, as well as all doctorswho enrolled patients in this study, and all research nurses who were involved inpatient management. We also thank B Blomjous and E Kooijmans, for their workover the past few years entering data into the COBRA-light therapy database,Dr L Burgemeister and Dr M Gerritsen, for their work as an independent committeejudging protocol deviations and SAEs, and Dr K Britsemmer and Dr J van Nies,for scoring all radiographs.

Contributors All authors substantially contributed to the conception or designof the study and the acquisition, analysis and interpretation of data. All revised thearticle critically and approved the final version to be published. All agree to beaccountable for all aspects of the work in ensuring that questions related to theaccuracy or integrity of any part of the work are appropriately investigated andresolved.

Funding This research was performed within the framework of project T1-106 ofthe Dutch Top Institute group, and additionally funded by an unrestricted grant fromPfizer.

Competing interests WFL has received speaker’s fees from Merck, Abbvie, Rocheand Pfizer. MN has received research grants from Abbvie, BMS, MSD, Pfizer, UCB andRoche. He has also acted as a consultant for Abbvie, BMS, Pfizer and Roche.Furthermore, he has participated in speaker bureaus for Abbvie, BMS, Pfizer and Roche.

Ethics approval Medical ethics committees at each participating centre approvedthe protocol; patients gave written informed consent before inclusion, and the studywas conducted in accordance with the Declaration of Helsinki/Good Clinical Practice.

Provenance and peer review Not commissioned; externally peer reviewed.

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doi: 10.1136/annrheumdis-2013-205143 published online May 12, 2014Ann Rheum Dis

 Marieke M ter Wee, Debby den Uyl, Maarten Boers, et al. open-label, randomised, non-inferiority trial1-year results of the COBRA-lightarthritis regardless of additional etanercept: treating patients with early rheumatoidincluding prednisolone, are effective in Intensive combination treatment regimens,

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