ARTHRITIS & RHEUMATISM Vol. 64, No. 9, September 2012, pp 2824–2835 DOI 10.1002/art.34498 © 2012, American College of Rheumatology
A Randomized Comparative Effectiveness Study of Oral Triple Therapy Versus Etanercept Plus Methotrexate in Early Aggressive Rheumatoid Arthritis The Treatment of Early Aggressive Rheumatoid Arthritis Trial Larry W. Moreland,1 James R. O’Dell,2 Harold E. Paulus,3 Jeffrey R. Curtis,4 Joan M. Bathon,5 E. William St.Clair,6 S. Louis Bridges Jr.,4 Jie Zhang,4 Theresa McVie,4 George Howard,4 De´sire´e van der Heijde,7 and Stacey S. Cofield,4 for the TEAR Investigators Objective. To assess whether it is better to intensively treat all patients with early rheumatoid arthritis (RA) using combinations of drugs or to reserve this approach for patients who do not have an appropriate response (as determined by a Disease Activity Score in
28 joints using the erythrocyte sedimentation rate [DAS28-ESR] of >3.2 at week 24) to methotrexate (MTX) monotherapy, and to assess whether combination therapy with MTX plus etanercept is superior to the combination of MTX plus sulfasalazine plus hydroxychloroquine. Methods. The Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) study is a 2-year, randomized, double-blind trial. A 2 ⴛ 2 factorial design was used to randomly assign subjects to 1 of 4 treatment arms: immediate treatment with MTX plus etanercept, immediate oral triple therapy (MTX plus sulfasalazine plus hydroxychloroquine), or step-up from MTX monotherapy to one of the combination therapies (MTX plus etanercept or MTX plus sulfasalazine plus hydroxychloroquine) at week 24 if the DAS28-ESR was >3.2. All treatment arms included matching placebos. The primary outcome was an observed-group analysis of DAS28-ESR values from week 48 to week 102. Results. At week 24 (beginning of the step-up period), subjects in the 2 immediate-treatment groups demonstrated a greater reduction in the DAS28-ESR compared with those in the 2 step-up groups (3.6 versus 4.2; P < 0.0001); no differences between the combination-therapy regimens were observed. Between week 48 and week 102, subjects randomized to the step-up arms had a DAS28-ESR clinical response that was not different from that of subjects who initially received combination therapy, regardless of the treatment arm. There was no significant difference in the DAS28-ESR between subjects randomized to oral triple therapy and those randomized to receive MTX plus
ClinicalTrials.gov identifier: NCT00259610. Supported by Amgen through a grant to the University of Alabama at Birmingham. The study drugs were provided by Amgen (etanercept and placebo), Barr Pharmaceuticals (methotrexate), and Pharmacia (sulfasalazine and placebo). The initial phases of the study were supported by the NIH (planning grant 1-R34-AR-055122 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases to Dr. Moreland). 1 Larry W. Moreland, MD: University of Pittsburgh, Pittsburgh, Pennsylvania; 2James R. O’Dell, MD: University of Nebraska Medical Center at Omaha; 3Harold E. Paulus, MD: University of California at Los Angeles; 4Jeffrey R. Curtis, MD, MS, MPH, S. Louis Bridges Jr., MD, PhD, Jie Zhang, MPH, PhD, Theresa McVie, MS, George Howard, DrPH, Stacey S. Cofield, PhD: University of Alabama at Birmingham; 5Joan M. Bathon, MD: Columbia University, New York, New York; 6E. William St.Clair, MD: Duke University, Durham, North Carolina; 7De´sire´e van der Heijde, MD, PhD: Leiden University Medical Center, Leiden, The Netherlands. Dr. Curtis has received consulting fees, speaking fees, and/or honoraria from Abbott, Bristol-Myers Squibb, Crescendo Bioscience, Pfizer (less than $10,000 each) and from Roche/Genentech, UCB, Centocor, and Amgen (more than $10,000 each). Dr. van der Heijde has received consulting fees from Abbott, Amgen, AstraZeneca, Bristol-Myers Squibb, Centocor, Chugai, Eli Lilly, GlaxoSmithKline, Merck, Novartis, Otsuka, Pfizer, Roche, Sanofi-Aventis, ScheringPlough, UCB, and Wyeth (less than $10,000 each). Dr. Cofield has received consulting fees from Teva Neuroscience (less than $10,000) and receives compensation as a member of the Data and Safety Monitoring Board of Centocor Ortho Biotech Service. Address correspondence to Larry W. Moreland, MD, University of Pittsburgh, Arthritis Institute, 200 Lothrop Street, S711 Biomedical Science Tower South, Pittsburgh, PA 15261. E-mail:
[email protected]. Submitted for publication August 24, 2011; accepted in revised form April 3, 2012. 2824
ORAL TRIPLE THERAPY VERSUS ETANERCEPT PLUS MTX IN EARLY RA
etanercept. By week 102, there was a statistically significant difference in the change in radiographic measurements from baseline between the group receiving MTX plus etanercept and the group receiving oral triple therapy (0.64 versus 1.69; P ⴝ 0.047). Conclusion. There were no differences in the mean DAS28-ESR during weeks 48–102 between subjects randomized to receive MTX plus etanercept and those randomized to triple therapy, regardless of whether they received immediate combination treatment or step-up from MTX monotherapy. At 102 weeks, immediate combination treatment with either strategy was more effective than MTX monotherapy prior to the initiation of step-up therapy. Initial use of MTX monotherapy with the addition of sulfasalazine plus hydroxychloroquine (or etanercept, if necessary, after 6 months) is a reasonable therapeutic strategy for patients with early RA. Treatment with the combination of MTX plus etanercept resulted in a statistically significant radiographic benefit compared with oral triple therapy. The treatment of rheumatoid arthritis (RA) has changed dramatically over the past decade and now includes 5 US Food and Drug Administration–approved biologic therapies that block tumor necrosis factor (TNF) (1–7). Disease-modifying antirheumatic drugs (DMARDs) have long been the cornerstone of RA therapy (8,9), and among traditional oral DMARDs, methotrexate (MTX) has emerged as the preferred first-line agent (10,11). There are no blinded data directly comparing an oral DMARD combination (MTX plus sulfasalazine [SSZ] plus hydroxychloroquine [HCQ]) (8,12) with the combination of an anti-TNF agent plus MTX (13,14) in early RA. Because oral triple therapy with DMARDs has major cost advantages over biologic therapy, the comparative efficacy of these 2 treatments is of interest (15,16). The traditional approach to the management of early RA is a “step-up” method in which initial treatment with MTX is incrementally supplemented with treatment with other biologic or nonbiologic DMARDs in patients with persistent disease. Early “immediate” treatment with the combination of a biologic agent and DMARDs reduces the proportion of patients in whom disease progresses to severe disability (5,13,17). However, this approach requires the use of multiple DMARDs in all patients, including those who might have responded to MTX monotherapy (13,18,19). It remains to be determined whether step-up DMARD therapy can provide clinical and radiographic benefits
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similar to those observed with the initial use of combination DMARD therapy. Designed in 2000 and implemented in 2004, the investigator-initiated Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) study aimed to assess 2 clinically important questions concerning early aggressive RA as determined by the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR) (20). First, is immediate combination therapy (either MTX plus etanercept or MTX combined with HCQ plus SSZ [oral triple therapy]) more effective than MTX monotherapy with the step-up approach? Second, what is the comparative efficacy of these treatments (MTX plus etanercept or oral triple therapy) in patients with early RA? PATIENTS AND METHODS Research design and methods. The 2 ⫻ 2 factorial design called for 4 treatment arms: immediate treatment with MTX plus etanercept, immediate treatment with MTX combined with SSZ plus HCQ (triple therapy), step-up from MTX to MTX plus etanercept if the DAS28-ESR was ⱖ3.2 at week 24, and step-up from MTX to triple therapy if the DAS28-ESR was ⱖ3.2 at week 24 (Figure 1). It is important to note that no participant was randomized to an MTX monotherapy arm for the full length of the 102-week trial. Randomization to the step-up arms occurred at baseline, and all participants in the 2 step-up arms were eligible to step up to active therapy if their DAS28-ESR was ⱖ3.2. Those who did not step up at week 24 were included in their assigned treatment group for analysis, regardless of step-up status. Randomization to the step-up arms was performed at baseline for 2 reasons: 1) to alleviate site and participant burden at week 24 by allowing for the appropriate step-up kits to be available on-site for the week 24 visit and 2) to allow for the use of a 2 ⫻ 2 factorial design during analysis. All subjects and site personnel (including the treating rheumatologists) were blinded (for the length of the trial) to treatment assignment and change to active medication at the step-up period. The TEAR study was approved by local institutional review board committees. Members of the TEAR study group are shown in Appendix A. Participants. At the time of enrollment, the entry criteria were as follows: disease duration of ⬍3 years from the time of diagnosis; age ⱖ18 years; a diagnosis of RA according to the 1987 American College of Rheumatology (ACR) criteria (21); active disease (at least 4 swollen joints and 4 tender joints, using a 28-joint count); positivity for rheumatoid factor (RF) or anti–cyclic citrullinated peptide (anti-CCP) antibodies, or if seronegative, the presence of ⱖ2 erosions on radiographs of the hands/wrists/feet, as determined by the site investigator; for those receiving corticosteroids, the dosage (ⱕ10 mg/day of prednisone) had to be stable for at least 2 weeks prior to screening; for those receiving nonsteroidal antiinflammatory drugs, the dosage had to be stable for at least 1 week prior to screening. Exclusion criteria were contraindi-
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Figure 1. Disposition of the participants. TB ⫽ tuberculosis; ENT ⫽ etanercept; TT ⫽ triple therapy; DAS28 ⫽ Disease Activity Score in 28 joints; Tx ⫽ treatment; I ⫽ immediate; S ⫽ step-up; IE ⫽ immediate methotrexate (MTX) plus etanercept; IT ⫽ immediate triple therapy (MTX plus sulfasalazine [SSZ] plus hydroxychloroquine [HCQ]); SE ⫽ step-up from MTX to MTX plus etanercept; ST ⫽ step-up from MTX to triple disease-modifying antirheumatic drug therapy (MTX plus SSZ plus HCQ); RA ⫽ rheumatoid arthritis.
ORAL TRIPLE THERAPY VERSUS ETANERCEPT PLUS MTX IN EARLY RA
cations to study medications, prior use of biologic therapy of any type at any dosage, corticosteroid injections during the 4 weeks prior to study entry, and diagnosis of a serious infection (including a positive result of skin testing for tuberculosis). Prior use of leflunomide, HCQ, and SSZ for no more than 2 months was permitted, as was a total dose of ⱕ40 mg of MTX. Study protocol. All baseline assessments were performed at the screening visit; the period of time between the screening and baseline visits was minimal (⬍3 days). Treatment was allocated via a computerized data entry system at a 2:1 ratio for etanercept versus triple therapy, using a standard permuted block approach, by site, with block sizes of 6 or 12. The data entry system masked both participants and investigators to the study medication arm, where medication kits were assigned to participants by using a blinded drug distribution system. Investigators and participants remained blinded to the treatment assignment until the end of year 2. Matching placebos were used throughout the trial, including during the step-up period, when all participants were dispensed a step-up kit even if he or she was already receiving immediate therapy (step-up medication kits contained all active medication) or was not stepping up to active therapy (step-up medication kits contained all placebo medication). After informed consent was obtained, participants were screened for eligibility by rheumatologists at 44 centers. Following randomization, participants were monitored for 102 weeks. Joint assessments were performed every 6 weeks during the first 48 weeks and every 12 weeks thereafter. Radiographs of the hands, wrists, and feet were acquired at baseline and at weeks 48 and 102. Study medications. All participants received oral MTX, which was escalated to a dosage of 20 mg/week or to a lower dosage if treatment resulted in no active tender/painful or swollen joints by week 12. Immediate triple therapy with SSZ and HCQ (IT) was administered as follows: SSZ at a dosage of 500 mg twice daily, escalated (if tolerated) to 1,000 mg twice daily at 6 weeks, plus HCQ at a dosage of 200 mg twice daily. Immediate therapy with etanercept (IE) was administered subcutaneously at a dosage of 50 mg/week. At the 24-week time point, participants in the 2 step-up arms who had a DAS28-ESR of ⱖ3.2 continued to receive the same dosage of MTX, and placebo was switched to either active etanercept (SE) or SSZ plus HCQ (ST). Participants in the 2 step-up arms with a DAS28-ESR of ⬍3.2 continued to receive the same dosage of MTX and placebo. All participants were given folic acid at a dosage of 1 mg per day. Corticosteroid treatment. Among participants who were receiving daily oral corticosteroids at the time of study entry, the dosage was tapered if improvement in disease activity was observed prior to week 24. For participants whose DAS28-ESR was ⬍3.2, the dosage of prednisone could be reduced by 1 mg/month or 2.5 mg/month. Corticosteroid tapering could not be changed within 4 weeks of the week 24 visit. If participants had a disease flare while receiving a reduced dosage of corticosteroids, treatment with the previous (baseline) dosage was resumed. A single intraarticular injection of corticosteroids was allowed during the study; the injected joint was considered to be nonevaluable for subsequent study visits. Toxicity and event monitoring. In patients in whom toxicity secondary to MTX treatment developed, either the drug was discontinued or the dosage was decreased at the
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discretion of the treating physician. If discontinuing MTX therapy or reducing the dosage of MTX for 2 weeks resolved the toxicity, then MTX therapy was continued using a tolerable dosage. A similar strategy was used in making dosage adjustments for suspected SSZ toxicity. Drug toxicity was assessed at 6-week intervals, using laboratory measures and evaluation of adverse events (AEs). Study outcomes. The primary end point for the trial was an observed-group analysis of the DAS28-ESR between week 48 and week 102 (22,23), with secondary end points defined by the ACR criteria for 20% improvement in disease activity (ACR20) (24), the ACR50, and the ACR70; physical disability (as determined using the modified Health Assessment Questionnaire [M-HAQ] [25]); and joint damage (radiographic assessments [26]). Radiographic progression was evaluated in the hands, wrists, and feet. The radiographs were scored by 2 independent readers, according to the modified Sharp/van der Heijde method (27). The readers scored all of the films grouped per patient but blinded for time sequence and clinical data. The mean score of the 2 readers was used for the analysis (intraclass correlation 0.96). Statistical analysis. Statistical analysis was performed using the intent-to-treat approach, including participants in the groups to which they were randomized, regardless of compliance with drug therapy during the trial. The primary outcome of the study was analyzed using a two-way, repeated-measures, mixed-models analysis with the DAS28-ESR from week 48 to week 102 (24), to allow for assessment of change over the entire year 2 period. The effects considered were treatment (MTX plus etanercept and MTX combined with SSZ plus HCQ), timing of treatment (immediate and step-up), and the interaction between treatment and timing creating the 4 treatment groups (IE, IT, SE, and ST). If the significance level for the interaction did not correspond to an alpha value of 0.10 or less for Type I error, we planned to remove the interaction term of treatment-by-timing from the random-effects regression models and assess the differences between treatment groups. The study was not powered for the interaction but rather for the 2 main-effect comparisons. Weeks 48–102 were included to allow sufficient time for those receiving step-up medication at week 24 to experience maximal efficacy. A subject had to participate until week 48 to be included in the primary analysis; however, a subsequent analysis for the entire 102-week period is also presented. A priori covariate-adjusted models were also considered in order to reduce error variance and thereby improve precision rather than to adjust the potential confounding effect of the covariates. Secondary outcomes included assessment of treatment differences in the following: the DAS28-ESR pattern between week 0 and week 102; radiographic disease progression between baseline and week 102 (27); ACR20, ACR50, and ACR70 responses between week 48 and week 102; discontinuation of treatment because of lack of efficacy; major clinical response (participants who achieved an ACR70 response on 2 consecutive 3-month visits between week 48 and week 102); DAS28-ESR of ⬍2.6 between week 48 and week 102 (23); functional status between week 48 and week 102; and healthrelated quality of life between week 48 and week 102 as assessed by the Short Form 12 health survey (28).
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Results were presented as all observed data without imputation for missing values, as data from only the participants who completed 102 weeks, or as a nonresponders analysis as indicated. Data are reported as the mean ⫾ SD or the number (%) for descriptive analyses. We analyzed differences in the pattern of outcomes over time using the repeatedmeasures, mixed-models approach (29), using Tukey-Kramer adjustment for multiple comparisons with unbalanced treatment arms. This approach allows for use of all observed data without imputation for missing values. The intent-to-treat design was maintained for all analyses regardless of the data imputation method used. For function and disability changes from baseline to year 2, cross-sectional differences at specific time points between treatment groups were assessed using an analysis of covariance (ANCOVA) approach, where the difference was assessed after adjustment for covariates assumed a priori to be associated with outcome. The following covariates were used to reduce error variance and increase precision: age, sex, race/ethnicity, duration of disease, prior DMARD use, RF status, DAS28-ESR, and body mass index at screening. Tests were performed at the 0.05 significance level (unless noted otherwise) utilizing SAS version 9 or JMP version 8 software. Radiographic changes were analyzed using an ANCOVA approach, where the differences between the mean progression scores of the treatment groups at 2 years were assessed after adjustment for the baseline radiographic score. In addition, ANCOVA using ranks of the modified Sharp progression scores with baseline ranks as a covariate was also
MORELAND ET AL
considered, as were repeated-measures mixed models for analysis of changes over the 2-year period. Chi-square tests were used to assess differences in the proportion of participants meeting the ACR criteria at months 6, 12, and 24 (with dropouts considered failures, i.e., nonresponder imputation) and for comparison of treatment discontinuations due to lack of efficacy. Lack of efficacy was defined by individual participants who chose “perceived lack of benefit” as the reason for termination. Power and sample size estimation. The study was designed to have 80% power to detect a 0.30-unit difference in the DAS28-ESR between treatment arms with 675 participants, pooled across timing arms (step-up versus immediate). Assuming a 10% withdrawal rate, the target sample size for recruitment was 750. The trial was designed with a 2:1 treatment allocation to the etanercept and triple-therapy arms to allow for sufficient power to compare the IE group with the SE group with respect to radiographic outcomes. Study organization. The Clinical Coordinating Center and Statistical and Data Management Center for the study were located at the University of Alabama at Birmingham. The protocol was developed in 2003. Recruitment began in May 2004 and concluded in January 2007 under protocol Amendment 4, with no substantial changes to eligibility criteria. One center with 5 participants was closed for administrative reasons due to failure of protocol adherence at the center level; the site was closed prior to any of the 5 participants reaching the step-up period, and these participants were excluded from all analyses. All centers received local institutional review board or Western Institutional Review Board approval.
Table 1. Demographic and baseline clinical characteristics of the randomized population (n ⫽ 755), according to treatment group*
No. of participants (% of total) Age, mean ⫾ SD years Female sex Race/ethnicity White African American Hispanic Body mass index, mean ⫾ SD kg/m2 Disease duration, mean ⫾ SD months RF positive RF negative and anti-CCP antibody positive Anti-CCP antibody negative/not tested, with 2 erosions Prior DMARD use Etanercept† Infliximab† Anakinra† HCQ SSZ MTX MTX dose ⬎40 mg total† Low-dose corticosteroid treatment at screening Corticosteroid dose at screening, mean ⫾ SD mg prednisone/day
IE
IT
SE
ST
244 (32.3) 50.7 ⫾ 13.4 181 (74.2)
132 (17.5) 48.8 ⫾ 12.7 101 (76.5)
255 (33.8) 48.6 ⫾ 13.0 176 (69.0)
124 (16.4) 49.3 ⫾ 12.0 87 (70.2)
188 (77.1) 31 (12.7) 26 (10.7) 29.3 ⫾ 7.0 3.5 ⫾ 6.4 216 (88.5) 8 (3.3) 20 (8.2) 68 (27.9) 0 1 (0.4) 1 (0.4) 5 (2.1) 1 (0.4) 60 (24.6) 3 (1.2) 105 (43.0) 3.4 ⫾ 4.3
107 (81.1) 11 (8.3) 17 (12.9) 30.0 ⫾ 8.2 4.1 ⫾ 7.2 121 (91.7) 4 (3.0) 7 (5.3) 30 (22.7) 0 0 0 3 (2.3) 0 27 (20.5) 1 (0.8) 58 (43.9) 3.4 ⫾ 4.2
200 (78.4) 29 (11.4) 32 (12.6) 30.0 ⫾ 6.7 2.9 ⫾ 5.6 232 (91.0) 9 (3.5) 14 (5.5) 58 (22.8) 1 (0.4) 0 1 (0.4) 4 (1.6) 0 52 (20.4) 3 (1.2) 111 (43.5) 3.4 ⫾ 4.3
106 (85.5) 14 (11.3) 10 (8.1) 29.2 ⫾ 7.3 4.5 ⫾ 7.6 108 (87.1) 4 (3.2) 12 (9.7) 22 (17.7) 0 0 0 3 (2.4) 1 (0.8) 18 (14.5) 3 (2.4) 41 (33.1) 2.6 ⫾ 4.1
* No significant differences between the treatment arms were observed. Except where indicated otherwise, values are the number (%). IE ⫽ immediate methotrexate (MTX) plus etanercept; IT ⫽ immediate triple therapy (MTX plus sulfasalazine [SSZ] plus hydroxychloroquine [HCQ]); SE ⫽ step-up from MTX to MTX plus etanercept; ST ⫽ step-up from MTX to triple disease-modifying antirheumatic drug (DMARD) therapy (MTX plus SSZ plus HCQ); RF ⫽ rheumatoid factor; anti-CCP ⫽ anti–cyclic citrullinated peptide. † Protocol exception/violation.
IE (n ⫽ 244)
IT (n ⫽ 132)
SE (n ⫽ 255)
Baseline (n ⫽ 755) ST (n ⫽ 124)
Characteristics of the participants at baseline and followup*
IE (n ⫽ 159)
IT (n ⫽ 76)
SE (n ⫽ 166)
Baseline ST (n ⫽ 75)
IE (n ⫽ 159)
SE (n ⫽ 166)
Year 2 IT (n ⫽ 76)
Week 102 completers (n ⫽ 476)
ST (n ⫽ 75)
* Except where indicated otherwise, values are the mean ⫾ SD. M-HAQ ⫽ modified Health Assessment Questionnaire; ESR ⫽ erythrocyte sedimentation rate; DAS28-ESR ⫽ Disease Activity Score in 28 joints using the ESR. † The numbers of subjects assessed were as follows: at baseline, 227 in the immediate methotrexate (MTX) plus etanercept (IE) group, 125 in the immediate triple therapy (MTX plus sulfasalazine [SSZ] plus hydroxychloroquine [HCQ]) (IT) group, 237 in the step-up from MTX to MTX plus etanercept (SE) group, and 117 in the step-up from MTX to triple disease-modifying antirheumatic drug therapy (MTX plus SSZ plus HCQ) (ST) group; among completers, 151 in the IE group, 73 in the IT group, 154 in the SE group, and 71 in the ST group. ‡ At baseline, 243 subjects in the IE group, 131 subjects in the IT group, 255 subjects in the SE group, and 124 subjects in the ST group were assessed. § The maximum possible score (total score) is 448 (168 for joint space narrowing and 280 for erosions).
M-HAQ score† 1.1 ⫾ 0.4 1.0 ⫾ 0.4 1.0 ⫾ 0.4 1.0 ⫾ 0.4 1.1 ⫾ 0.4 1.0 ⫾ 0.3 1.0 ⫾ 0.4 1.0 ⫾ 0.4 1.0 ⫾ 0.3 1.0 ⫾ 0.3 0.9 ⫾ 0.3 0.9 ⫾ 0.3 M-HAQ pain score‡ 5.3 ⫾ 2.6 5.3 ⫾ 2.5 5.2 ⫾ 2.4 5.1 ⫾ 2.5 5.4 ⫾ 2.6 5.3 ⫾ 2.4 5.0 ⫾ 2.5 4.9 ⫾ 2.3 2.1 ⫾ 2.3 2.3 ⫾ 2.3 2.3 ⫾ 2.5 2.3 ⫾ 2.5 Patient’s global assessment 6.0 ⫾ 2.3 6.2 ⫾ 2.2 5.9 ⫾ 2.3 6.0 ⫾ 2.1 6.0 ⫾ 2.2 6.2 ⫾ 2.3 5.7 ⫾ 2.3 5.7 ⫾ 1.9 3.0 ⫾ 2.2 3.1 ⫾ 2.0 3.0 ⫾ 2.1 3.1 ⫾ 2.0 (0–10 scale) Physician’s global assessment 6.4 ⫾ 1.7 6.6 ⫾ 1.8 6.4 ⫾ 1.7 6.5 ⫾ 1.8 6.4 ⫾ 1.7 6.6 ⫾ 1.8 6.3 ⫾ 1.7 6.5 ⫾ 1.8 2.1 ⫾ 1.6 2.3 ⫾ 1.6 2.5 ⫾ 1.8 2.3 ⫾ 1.6 (0–10 scale) No. of swollen joints 12.7 ⫾ 5.8 12.1 ⫾ 5.8 13.1 ⫾ 6.2 13.1 ⫾ 6.1 12.7 ⫾ 5.6 12.5 ⫾ 5.8 12.5 ⫾ 5.9 13.1 ⫾ 5.5 2.2 ⫾ 3.9 2.3 ⫾ 3.3 4.4 ⫾ 3.1 4.4 ⫾ 2.8 No. of tender joints 14.3 ⫾ 6.6 14.1 ⫾ 6.8 14.2 ⫾ 6.9 14.6 ⫾ 7.0 13.6 ⫾ 6.4 14.1 ⫾ 6.8 13.7 ⫾ 6.8 13.8 ⫾ 7.0 3.3 ⫾ 5.5 2.6 ⫾ 4.5 3.6 ⫾ 5.8 2.6 ⫾ 4.4 ESR, mm/hour 33.6 ⫾ 26.8 33.1 ⫾ 27.0 32.4 ⫾ 27.0 32.4 ⫾ 25.5 37.1 ⫾ 26.9 33.7 ⫾ 25.4 35.0 ⫾ 28.3 32.5 ⫾ 24.9 17.2 ⫾ 15.8 17.2 ⫾ 15.1 17.7 ⫾ 18.6 15.5 ⫾ 19.4 DAS28-ESR 5.8 ⫾ 1.1 5.8 ⫾ 1.1 5.8 ⫾ 1.1 5.8 ⫾ 1.1 5.9 ⫾ 1.1 5.8 ⫾ 1.1 5.8 ⫾ 1.1 5.8 ⫾ 1.0 3.0 ⫾ 1.4 2.9 ⫾ 1.5 3. ⫾ 1.4 2.8 ⫾ 1.3 No. of patients with radiographs 208 115 211 110 141 74 139 63 141 74 139 63 Sharp score§ Erosions 3.3 ⫾ 6.5 3.3 ⫾ 6.7 2.5 ⫾ 3.5 3.6 ⫾ 7.5 3.2 ⫾ 7.0 2.6 ⫾ 3.5 2.4 ⫾ 3.4 2.6 ⫾ 3.4 3.6 ⫾ 7.4 3.3 ⫾ 3.9 3.0 ⫾ 3.9 3.3 ⫾ 4.4 Joint space narrowing 3.5 ⫾ 9.3 3.7 ⫾ 8.4 1.9 ⫾ 4.3 3.6 ⫾ 10.3 3.3 ⫾ 9.8 2.7 ⫾ 6.0 1.6 ⫾ 3.7 2.2 ⫾ 4.5 3.7 ⫾ 9.8 3.9 ⫾ 10.6 2.1 ⫾ 4.4 2.6 ⫾ 5.0 Total 6.8 ⫾ 14.8 6.9 ⫾ 14.2 4.4 ⫾ 7.2 7.2 ⫾ 17.0 6.5 ⫾ 16.1 5.4 ⫾ 8.4 4.1 ⫾ 6.4 4.8 ⫾ 7.0 7.0 ⫾ 16.6 7.3 ⫾ 13.3 4.8 ⫾ 7.2 6.2 ⫾ 8.9
Table 2.
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RESULTS Characteristics of the participants and study completion. A total of 895 participants were screened for the study, and 755 were enrolled and randomized. The characteristics of participants at baseline are shown in Table 1, and their disease status is shown in Table 2. There were no significant differences between the groups in terms of pretreatment characteristics or baseline disease activity, including prior treatment with DMARDs and corticosteroids. The withdrawal rate was 32.1%, with 67.9% of participants completing the 2-year trial, including 168 (68.8%) in the IE group, 82 (62.1%) in the IT group, 182 (71.4%) in the SE group, and 81 (65.3%) in the ST group. There was no differential dropout across the 4 treatment arms (P ⫽ 0.73), the timing of treatment (for immediate versus step-up, P ⫽ 0.61), or the type of medication (for etanercept plus MTX versus triple therapy, SE ⫽ 0.18). DAS28-ESR results for the 596 participants in whom the DAS28-ESR was determined at least once between years 1 and 2 were included in the primary analysis according to the prespecified analysis plan. Forty-two percent of the withdrawals (n ⫽ 100) were based on the decision of the participant; the most common reasons for withdrawal were a perceived lack of efficacy (n ⫽ 31) and unspecified reason/lost to followup (n ⫽ 29). Among participants who withdrew early, there were no differences across the 4 treatment arms in the DAS28-ESR at the time of termination, the mean number of days in the study, reason for termination, demographics, or proportion that terminated early; therefore, the missing observations were assumed to be missing at random in the analysis. We performed the analysis using several different missing-data approaches, and regardless of the method used, there were no differences in the results (see Supplementary tables S1 and S2, available on the Arthritis & Rheumatism web site at http://onlinelibrary. wiley.com/journal/10.1002/(ISSN)1529-0131). However, of the 513 subjects who participated for 2 years, only 476 had sufficient data to determine the DAS28-ESR at week 102. Compliance was measured by self-report at 10 study visits after baseline, as follows: excellent (patient reports taking medication as directed [takes medications 99% of time]), good (missed ⱕ2 doses of the oral medication or 1 dose of the weekly injection), fair (missed ⱕ2 doses of the oral medication and ⱕ2 of the weekly injections), poor (missed ⱖ2 doses of the oral medication and ⱖ2 of the weekly injections), and uncer-
tain. At no point during the trial was there a difference in compliance between any of the treatment arms by timing of medication (for immediate versus step-up S, P ⫽ 0.74) or type of medication (for MTX plus etanercept versus triple therapy, P ⫽ 0.76), with good or excellent compliance reported at 94% of all study visits. There were no statistically significant differences between the treatment groups in the mean weekly MTX doses at week 102; for all 4 groups, the mean dosage was 19.1 mg/week at week 102. Likewise, there were no statistically significant differences between groups in the mean daily steroid dose at week 102. The dosage of SSZ was very homogeneous (dosage of ⬍2,000 mg/day at ⬍3% of the study visits). Efficacy. DAS28-ESR and remission. The primary outcome of this study was the mean DAS28-ESR from week 48 to week 102 (Figure 2). At week 24, 28% of the subjects who were initially in the 2 MTX-only arms (SE and ST) had a DAS28-ESR of ⱕ3.2 and thus did not step up, resulting in 72% of participants stepping up to active etanercept or SSZ plus HCQ as determined at randomization. In comparison, 41% of the group assigned to receive immediate treatment with MTX plus etanercept and 43% of those assigned to the immediate triple-therapy group had a DAS28-ESR of ⱕ3.2 by week 24. The 2 immediate-treatment groups demonstrated a larger reduction in the DAS28-ESR at week 24 compared with the step-up groups (3.6 versus 4.2; P ⬍ 0.0001). However, the SE and ST groups showed improvement in the mean DAS28-ESR by week 36, and by week 48, the mean DAS28-ESR was similar in all groups. The analysis of the primary outcome showed no significant differences across the 4 treatment groups in the DAS28-ESR between week 48 and week 102 (P ⫽ 0.28), by medication received (for MTX plus etanercept versus triple therapy, P ⫽ 0.48), or treatment regimen (for immediate versus step-up therapy, P ⫽ 0.55). Fiftysix percent of all participants achieved DAS28-ESR remission, defined as a DAS28-ESR of ⬍2.6, at some point during followup. There were no differences across the 4 treatment arms in the proportion achieving DAS28-ESR remission (56.6% in the IE group, 59.1% in the IT group, 52.9% in the SE group, and 56.5% in the ST group; P ⫽ 0.93), nor was there a difference according to timing of treatment (for immediate versus step-up, P ⫽ 0.36) or medication received (for MTX plus etanercept versus triple therapy, P ⫽ 0.43). ACR response and major clinical response. ACR responses were evaluated using a nonresponders analysis. Participants who withdrew early were assumed not to have achieved an ACR response at subsequent visits.
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Figure 2. Observed DAS28 using the erythrocyte sedimentation rate (ESR). Values are the mean ⫹ upper 95% confidence interval. DMARDs ⫽ disease-modifying antirheumatic drugs; BL ⫽ baseline (see Figure 1 for other definitions).
The percentage of subjects in each treatment arm with an ACR20, ACR50, or ACR70 response is shown in Figure 3. At month 6, both immediate-treatment groups had a higher proportion of subjects achieving ACR20, ACR50, and ACR70 responses compared with the step-up groups (all P ⬍ 0.0001), with no difference observed between treatment received (MTX plus etanercept or triple therapy). By year 2, there was no
difference in the proportion of participants meeting ACR20 and ACR50 criteria according to timing of treatment (immediate versus step-up); the only significant treatment difference at week 102 was between the etanercept and triple-therapy groups for an ACR70 response (18.2% versus 11.3%; P ⫽ 0.01). Function and disability. Based on data for participants who completed 102 weeks, all treatment groups
Figure 3. Percentage of participants achieving American College of Rheumatology 20% response (ACR20), ACR50, and ACR70 at the time of initiation of step-up therapy (6 months) and at the 2-year conclusion of the study, with nonresponder imputation (i.e., subjects who withdrew were considered treatment failures). E ⫽ etanercept; T ⫽ triple therapy (see Figure 1 for other definitions).
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Table 3. Safety summary by treatment group*
Participants with any AE or SAE No. of events, mean ⫾ SD (range) Participants with an SAE No. of events, mean ⫾ SD (range) Deaths† Total no. of SAEs, including death‡ Blood and lymphatic system Cardiac Eye Gastrointestinal General and administration site Immune system Infections and infestations§ Injury and poisoning Metabolism and nutrition Musculoskeletal and connective tissue Neoplasms, benign and malignant¶ Nervous system Pregnancy, puerperium and perinatal Psychiatric Reproductive system and breast Respiratory, thoracic and mediastinal Surgical and medical procedures Vascular
IE (n ⫽ 244)
IT (n ⫽ 132)
SE (n ⫽ 255)
ST (n ⫽ 124)
Total (n ⫽ 755)
193 (79.1) 3.6 ⫾ 3.0 (1⫺22) 35 (14.3) 1.3 ⫾ 0.6 (1⫺3) 1 44 1 5 0 2 1 1 9 2 0 1 5 2 0 3 0 5 6 0
101 (76.5) 3.3 ⫾ 2.4 (1⫺11) 18 (13.6) 1.3 ⫾ 0.6 (1⫺3) 1 24 1 2 0 5 0 0 4 0 0 0 1 1 1 0 0 0 5 3
187 (73.3) 4.1 ⫾ 3.1 (1⫺18) 32 (12.5) 1.2 ⫾ 0.4 (1⫺2) 2 38 0 4 0 0 2 0 7 1 0 4 0 3 1 0 3 3 7 2
92 (74.2) 3.4 ⫾ 2.9 (1⫺13) 16 (12.9) 1.3 ⫾ 0.5 (1⫺2) 0 21 1 5 1 0 0 0 3 1 2 0 1 2 0 1 0 1 1 0
573 (75.9) 3.7 ⫾ 2.9 (1⫺22) 101 (13.4) 1.3 ⫾ 0.5 (1⫺3) 4 127 3 (2.4) 16 (12.6) 1 (⬍1) 7 (5.5) 3 (2.4) 1 (⬍1) 23 (18.1) 4 (3.1) 2 (1.6) 5 (3.9) 7 (5.5) 8 (6.3) 2 (1.6) 4 (3.1) 3 (2.4) 9 (7.1) 19 (15.0) 5 (3.9)
* Except where indicated otherwise, values are the number (%). IE ⫽ immediate methotrexate (MTX) plus etanercept; IT ⫽ immediate triple therapy (MTX plus sulfasalazine [SSZ] plus hydroxychloroquine [HCQ]); SE ⫽ step-up from MTX to MTX plus etanercept; ST ⫽ step-up from MTX to triple disease-modifying antirheumatic drug (DMARD) therapy (MTX plus SSZ plus HCQ); AE ⫽ adverse event; SAE ⫽ serious adverse event. † Three deaths due to cardiac disorders (general [unattended death], coronary heart failure, and ventricular septal defect) and 1 death due to respiratory failure. ‡ For each participant, ⬎1 event could be reported. § Nine serious infections in the IE group, 4 in the IT group, 7 in the SE group, and 3 in the ST group, 9 cases of pneumonia (3 in the IE group, 1 in the IT group, 4 in the SE group, and 1 in the ST group), 3 cases of cellulitis (all in the IE group), 2 cases of bronchitis (both in the IT group), and 9 other types of infection (3 in the IE group, 1 in the IT group, 3 in the SE group, and 2 in the ST group). ¶ Two breast cancers (1 each in the IE and IT groups), 3 lung cancers (2 in the IE group and 1 in the ST group), 1 prostate cancer (IE group), and 1 renal carcinoma (IE group). Breast cancers are reported as “Neoplasms, benign and malignant” and not as reproductive system and breast disorders.
showed decreases in the M-HAQ and M-HAQ pain scores at year 2 (Table 2). All groups demonstrated similar improvement at year 1 and year 2, with no statistically significant differences between treatment and timing of treatment. For all available observed M-HAQ pain and M-HAQ scores, there were no statistically significant differences in the timing (immediate versus step-up) or the treatment regimen (etanercept versus triple therapy). Radiography results. The mean ⫾ SD Sharp scores at weeks 0 and 102 are shown in Table 2. There was no difference in the change in week 102 scores from baseline when comparing step-up therapy with immediate combination therapy, regardless of the assigned treatment (for immediate versus step-up, P ⫽ 0.74). When the immediate and step-up groups were combined into 2 groups, the group assigned to receive MTX plus etanercept had a smaller increase in Sharp scores com-
pared with those receiving triple therapy (0.64 versus 1.69; P ⫽ 0.047). Radiographic progression was defined as a change of ⬎0.5 from week 0 to week 102. Using this definition, 33.6% of participants showed radiographic progression. The percentages of subjects without radiographic progression were as follows: 79.4% of the IE group, 64.9% of the IT group, 71.1% of the SE group, and 68.3% of the ST group (P ⫽ 0.33). Although there was no difference in the proportion of subjects without radiographic progression across the 4 treatment arms (P ⫽ 0.33) or the timing of treatment (74.4% for immediate versus 72.3% for step-up; P ⫽ 0.56), a difference was noted in this radiographic outcome for subjects receiving MTX plus etanercept compared with those receiving oral triple therapy (76.8% versus 66.4%; P ⫽ 0.02). A single participant had a change in the total Sharp score of 78.5. A rank regression analysis was performed to attenuate the effect of this outlier, result-
ORAL TRIPLE THERAPY VERSUS ETANERCEPT PLUS MTX IN EARLY RA
ing in a nominal difference between the group receiving MTX plus etanercept and the group receiving triple therapy (P ⫽ 0.069). Glucocorticoid use. As shown in Table 1, there were no differences across treatment groups in steroid treatment at study entry. In addition, no differences for steroid treatment during the trial were observed (see Supplementary Table S1, available on the Arthritis & Rheumatism web site at http://onlinelibrary.wiley.com/ journal/10.1002/(ISSN)1529-0131), either according to the number of participants discontinuing after enrollment, the number of participants using rescue steroids during the trial, or the frequency or number of intraarticular injections administered. Safety and tolerability. There was no difference across treatment groups in the number of participants experiencing any AE or serious AE (SAE) (Table 3) (P ⫽ 0.47). There was no difference in the mean number of events for those participants reporting at least 1 AE and/or SAE (P ⫽ 0.13). There was no difference across treatment groups in the number of participants experiencing an SAE (P ⫽ 0.94). DISCUSSION The TEAR study is the only randomized, doubleblind study to compare oral triple DMARD therapy with the combination of MTX plus etanercept. The primary outcome analysis revealed no differences between the 2 treatment approaches. Additionally, 28% of participants had an excellent clinical response to MTX monotherapy and achieved low disease activity by 6 months, consistent with other recently published results (13,18,19). Here, we report the prespecified analyses of the TEAR trial, i.e., a comparison of initial treatment strategies for patients with early, aggressive RA and an evaluation of the outcomes after 2 years. All subjects randomized initially to the step-up strategies were analyzed as a group, including the 28% of subjects initially randomized to SE or ST who received only MTX monotherapy (because they achieved a DAS28 of ⱕ3.2 after 6 months) throughout the 2-year study. However, a post hoc analysis of “responders” to MTX monotherapy (DAS28 of ⬍3.2 at 6 months) versus “nonresponders” (those that stepped up to either anti-TNF or SSZ and HCQ) is possible. The clinically important question of what baseline characteristics differentiate patients with early aggressive RA who will respond to MTX at 6 months from those who will not respond will be explored in other studies, along with a comparison of 2-year outcomes of a pooled MTX monotherapy group.
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The number of participants who did not complete the study was higher than we had originally expected. However, the rate was similar to that observed in other long-term (1–2 years) RA studies (13,18). Most of the withdrawals occurred within the first year of the study (33% by week 48 and 37% by week 102). Although the mixed-models approach allowed for inclusion of all observed values, several alternative statistical approaches (completers, last observation carried forward, mean imputation) were used to account for missing data, and all suggested that the missing data for participants who withdrew did not significantly influence the overall conclusions. There were no differences in radiographic changes when comparing immediate DMARD therapy with the step-up approaches. Radiographic data at week 102 showed a small, statistically significant (P ⫽ 0.047) difference between the mean progression of joint damage in subjects who received the combination of MTX plus etanercept compared with those receiving triple therapy with DMARDs. There are limited data on the significance of erosions and/or joint space narrowing in terms of physical disability, which might inform the clinical relevance of the radiographic changes we observed. Smolen et al (30) previously presented an approach to estimate the numerical relationship between the HAQ score and radiographic damage, in which 0.01 HAQ unit corresponds to 1 total Sharp score unit. Thus, the minimal differences in radiographic progression did not translate into clinically meaningful changes in disability over the 2-year period of observation. The accumulation of erosions after 2 years of observation and its potential impact on disability were not addressed in this study. In terms of the applicability of the TEAR study results to clinical practice, there were similar 2-year improvements in outcomes in functional status and pain across groups and relatively little difference in radiographic progression among groups. These data strongly suggest that the cost-effectiveness of less expensive triple therapy may be positive relative to that of anti-TNF therapy. We chose a 6-month time point for step-up from MTX monotherapy, mainly to allow for the potential for a lag time of drug effects. However, at 12 weeks, all 4 treatment groups seemed to have stabilized in terms of a DAS28 response, thus suggesting that for many patients in clinical practice, 12 weeks is a reasonable threshold of time for making decisions to change treatment doses or medications. The TEAR study has several strengths. The double-blind, randomized aspects reduce bias due to contamination between treatment arms by patients who
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might preferentially withdraw if they knew they were not in a biologic treatment arm. The 2-year outcomes and the ability to change therapy at 6 months based on clinical response within the blinded trial are pragmatic. This was a study of early disease (mean disease duration 3.6 months). The TEAR study also has limitations. For example, there are clinical situations in which MTX is not the ideal choice for initial DMARD therapy. Additionally, the TEAR study was performed in patients with a more severe phenotype (anti-CCP antibody– and/or RFpositive or erosive disease). Thus, the results may not be generalizable to patients with less active disease, those who are autoantibody negative, and/or patients with a longer disease duration. In conclusion, the TEAR study, a blinded, placebo-controlled, investigator-initiated study involving patients with early active RA, demonstrated that triple therapy with MTX plus oral DMARDs and treatment with MTX plus etanercept resulted in comparable clinical outcomes and small radiographic differences after 2 years of therapy. Initial MTX monotherapy with step-up to combination therapy after 6 months, if necessary, may result in only a slight delay in attaining the same 48-week to 102-week outcomes as those achieved with immediate combination therapies. ACKNOWLEDGMENTS We thank the members of the Data Safety Monitoring Board (Michael Weinblatt, MD, Brigham and Women’s Hospital; David Wofsy, MD, University of California at San Francisco; Mark Genovese, MD, Stanford University; and Barbara Tilley, PhD, Medical University of South Carolina) and the external medical safety monitor, Gene Ball, MD (Birmingham, AL). We appreciate the support of all of the clinical investigators, their staff, and all of the patient participants. Editing assistance was provided by Douglas W. Chew, University of Pittsburgh. AUTHOR CONTRIBUTIONS All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Moreland had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study conception and design. Moreland, O’Dell, Paulus, Bathon, St.Clair, Bridges Jr., Howard, van der Heijde, Cofield. Acquisition of data. Moreland, O’Dell, Paulus, Bathon, St.Clair, Bridges Jr., Zhang, Howard, van der Heijde, Cofield. Analysis and interpretation of data. Moreland, O’Dell, Paulus, Curtis, Bathon, St.Clair, Bridges Jr., McVie, Howard, van der Heijde, Cofield.
ROLE OF THE STUDY SPONSOR This was an investigator-initiated trial. The funding organizations had no role in the design and conduct of the study, in the
collection, analysis, and interpretation of the data, or in the preparation, review, or approval of the manuscript. The authors were solely responsible for all data collection, data management, and statistical analysis, and the decision to publish these results. Publication of this article was not contingent upon approval by the study sponsor.
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APPENDIX A: THE TEAR INVESTIGATORS The investigators who participated in the TEAR study, in addition to the authors, are as follows: C. Adams (Opelika, AL); J. Aelion (Jackson, TN); C. Bingham (Baltimore, MD); K. Blakely (Kearney, NE); D. Bong, M. Sparling, T. Karplus (Vancouver, WA); C. Boniske (Visalia, CA); R. Brasington (St. Louis, MO); M. Burnette (Tampa, FL); W. Chatham (Birmingham, AL); M. Churchill (Lincoln, NE); S. Cohen (Dallas, TX); D. Conn (Atlanta, GA); J. Fanciullo (Sioux Falls, SD); J. Fiechtner (Lansing, MI); A. Goel (Portland, OR); M. Greenwald (Palm Desert, CA); C. Jackson (Salt Lake City, UT); B. Jonas (Chapel Hill, NC); J. Kaine (Sarasota, FL); A. Kivitz (Duncansville, PA); K. Kolba (Santa Maria, CA); G. Krick (Tacoma, WA); R. Leff (Duluth, MN); M. Lundberg (Sandy, UT); J. Molitor (Seattle, WA); K. Oelke (Glendale, WI); W. Palmer (Omaha, NE); C. CharlesSchoeman (Los Angeles, CA); L. Peterson (Bismarck, ND); C. Ritchlin (Rochester, NY); P. Rosenthal (New York, NY); E. Ruderman (Chicago, IL); J. Shanahan, G. Falasca (Camden, NJ); E. Smith (Charleston, SC); R. Tierney (Minneapolis, MN); C. Weaver (Rapid City, SD); C. Wiesenhutter (Coeur d’Alene, ID).
