A Trial of Etanercept, a Recombinant Tumor Necrosis Factor Receptor:Fc Fusion Protein, in Patients with Rheumatoid Arthritis Receiving Methotrexate
Michael E. Weinblatt, M.D., Joel M. Kremer, M.D., Arthur D. Bankhurst, M.D., Ken J. Bulpitt, M.D., Roy M. Fleischmann, M.D., Robert I. Fox, M.D., Christopher G. Jackson, M.D., Mary Lange, M.S., and Daniel J. Burge, M.D.
Background Patients treated with methotrexate for rheumatoidarthritis often improve but continue to have active disease.This study was undertaken to determine whether the additionof etanercept, a soluble tumor necrosis factor receptor (p75):Fcfusion protein (TNFR:Fc), to methotrexate therapy would provideadditional benefit to patients who had persistent rheumatoidarthritis despite receiving methotrexate.
Methods In a 24-week, double-blind trial, we randomly assigned89 patients with persistently active rheumatoid arthritis despiteat least 6 months of methotrexate therapy at a stable dose of15 to 25 mg per week (or as low as 10 mg per week for patientsunable to tolerate higher doses) to receive either etanercept(25 mg) or placebo subcutaneously twice weekly while continuingto receive methotrexate. The primary measure of clinical responsewas the American College of Rheumatology criteria for a 20 percentimprovement in measures of disease activity (ACR 20) at 24 weeks.
Results The addition of etanercept to methotrexate therapy resultedin rapid and sustained improvement. At 24 weeks, 71 percentof the patients receiving etanercept plus methotrexate and 27percent of those receiving placebo plus methotrexate met theACR 20 criteria (P<0.001); 39 percent of the patients receivingetanercept plus methotrexate and 3 percent of those receivingplacebo plus methotrexate met the ACR 50 criteria (for a 50percent improvement) (P<0.001). Patients receiving etanerceptplus methotrexate had significantly better outcomes accordingto all measures of disease activity. The only adverse eventsassociated with etanercept were mild injection-site reactions,and no patient withdrew from the study because of adverse eventsassociated with etanercept.
Conclusions In patients with persistently active rheumatoidarthritis, the combination of etanercept and methotrexate wassafe and well tolerated and provided significantly greater clinicalbenefit than methotrexate alone.
Among the disease-modifying drugs used to treat rheumatoid arthritis,methotrexate is increasingly regarded as the agent of firstchoice, because of its early onset of action and superior efficacyand tolerability.1 Clinical benefit with methotrexate may beseen as early as three weeks after initiating treatment,2 andthe maximal improvement is generally achieved by six months.3Although methotrexate can have toxic effects, making carefulmonitoring of patients necessary, most rheumatologists believethe benefits outweigh the risks. Methotrexate can diminish theactivity of rheumatoid arthritis, but many patients have persistentdisease even when treated with methotrexate. When this occurs,rheumatologists usually add another disease-modifying drug.
Tumor necrosis factor (TNF) is a proinflammatory cytokine thathas a complex role in the pathogenesis of rheumatoid arthritis.4,5,6,7,8,9,10,11Etanercept (Enbrel, Immunex, Seattle), a genetically engineeredfusion protein consisting of two identical chains of the recombinanthuman TNF-receptor p75 monomer fused with the Fc domain of humanIgG1, binds and inactivates TNF. Two previous randomized, double-blind,placebo-controlled trials showed that etanercept treatment yieldedsignificant clinical benefit, with minimal toxicity, in patientswith rheumatoid arthritis who had inadequate responses to otherdisease-modifying drugs.12,13 We undertook the present studyto determine whether etanercept combined with methotrexate couldfurther diminish disease activity in patients who still hadactive rheumatoid arthritis despite long-term methotrexate treatment.
Methods
Patients
Eligible patients were at least 18 years of age and fulfilledthe 1987 criteria for rheumatoid arthritis of the American RheumatismAssociation14; were in functional class I, II, or III accordingto the revised criteria of the American College of Rheumatology(ACR)15; and had active disease, as manifested by at least sixjoints that were swollen and six that were tender at the timeof enrollment. Before receiving the study drugs, all the patientshad been taking methotrexate for at least six months, and ata stable dose of 15 to 25 mg per week for the last four weeks(weekly doses as low as 10 mg were acceptable for patients whocould not tolerate higher doses). All patients received folicacid or folinic acid to mitigate the toxic effects of methotrexate.
In addition, eligible patients had platelet counts of at least125,000 per cubic millimeter, serum creatinine levels of nomore than 2 mg per deciliter (177 µmol per liter), white-cellcounts of at least 3500 per cubic millimeter, serum aspartateand alanine aminotransferase levels no more than 1.2 times thelaboratory's upper limit of normal, hemoglobin levels of atleast 8.5 g per deciliter, stable hemoglobin levels for at leastsix months in patients with levels of less than 10 g per deciliter,and negative serologic results on tests for hepatitis B surfaceantigen and hepatitis C antibody.
The study patients discontinued therapy with sulfasalazine andhydroxychloroquine at least two weeks before starting to takethe study drug and disease-modifying antirheumatic drugs otherthan methotrexate at least four weeks before. Patients who werereceiving nonsteroidal antiinflammatory drugs, prednisone (at10 mg daily or less), or both were eligible if the doses hadbeen stable for at least four weeks before the study periodand continued to be stable during the study period.
Protocol
The protocol was approved by the human research committee ateach study site, and all patients gave written informed consentbefore undergoing a screening evaluation to determine theireligibility. Clinical and laboratory assessments were conductedat screening and on study days 1, 8, and 15; during weeks 4,8, 12, 16, 20, and 24; and 15 and 30 days after the last doseof study drug for patients who withdrew from the study. Themeasurements consisted of a physical examination, measures ofdisease activity, and laboratory tests (hematologic values,serum chemical values, and urinalysis with microscopical evaluation).In addition, serum was obtained for testing for autoantibodies(antibodies to double-stranded DNA, antinuclear antibodies,and IgG and IgM anticardiolipin antibodies) at screening, onday 1, at the end-of-study evaluation (week 24 or on discontinuationof the study drug), and at the 30-day follow-up (if the patientwithdrew prematurely). Serum for testing for antibodies to etanerceptwas collected on day 1 and at the end-of-study evaluation.
The measures of disease activity consisted of evaluations of71 joints for tenderness and 68 joints for swelling, physician'sand patient's global assessment of disease status, patient'sassessment of pain according to a visual-analogue scale,16 patient'sassessment of disability as indicated by responses to the HealthAssessment Questionnaire,17 the erythrocyte sedimentation rate(as measured by the Westergren method), and the C-reactive proteinlevel.16
Adverse events and changes in laboratory values were gradedon a scale derived from the Common Toxicity Criteria of theNational Cancer Institute. The reasons for withdrawal were prespecifiedas lack of efficacy, pregnancy, withdrawal of consent, noncompliance,a decision by an investigator, serious systemic toxic effectsthat were unresponsive to treatment or that recurred on rechallenge,serious infection or hypotension suggestive of impending sepsissyndrome, and interruption of scheduled therapy for more thantwo weeks.
Treatment
A 2:1 randomization scheme was used to increase exposure tothe combination of etanercept and methotrexate. Patients wereassigned to receive etanercept plus methotrexate or to receiveplacebo plus methotrexate. Etanercept was supplied in single-dosevials containing a lyophilized powder consisting of 25 mg ofetanercept, 40 mg of mannitol, 10 mg of sucrose, and 1.2 mgof tromethamine. The placebo had the same ingredients exceptfor the omission of etanercept. The study drug was reconstitutedwith 1.0 ml of bacteriostatic water and injected subcutaneouslytwice weekly for 24 weeks. The patients received stable dosesof oral or subcutaneous methotrexate.
Testing for Antibodies
Testing for antibodies to etanercept has been described previously.12Rheumatoid factor was measured by nephelometry (Beckman, Fullerton,Calif.). Antinuclear antibodies were measured by indirect fluorescentantibody with HEp-2 cell substrate (Kallestad, Chaska, Minn.);a titer of 1:160 or higher was considered positive. Antibodiesto double-stranded DNA were measured with use of a 125I radiobindingassay kit (Dupont Medical Products, Boston); a value of 3.6IU per milliliter or higher was considered positive. IgG andIgM anticardiolipin antibodies were detected by indirect enzyme-linkedimmunosorbent assay (Readds Medical Products, Westminster, Colo.);values of 23 IgG phospholipid units or higher and 11 IgM phospholipidunits or higher were considered positive.
Statistical Analysis
The primary end point with respect to efficacy was the proportionof patients meeting the ACR preliminary criteria for improvementin rheumatoid arthritis (ACR 20) at 24 weeks.16 Patients whomet these criteria had a reduction of at least 20 percent inthe number of both swollen and tender joints and an improvementof at least 20 percent in at least three of the following: thepatient's assessment of pain, the physician's global assessmentof disease status, the patient's global assessment of diseasestatus, the patient's assessment of disability (a domain ofthe Health Assessment Questionnaire17), and values for acute-phasereactants (either the erythrocyte sedimentation rate or thelevel of C-reactive protein).16 Safety was evaluated accordingto the frequency of adverse events, laboratory abnormalities,and antibody formation.
The other efficacy end points were the proportion of patientswho reached the ACR 20 at 12 weeks and the proportions who metthe ACR 50 and ACR 70 (defined in the same manner as ACR 20,but with improvements of 50 percent and 70 percent, respectively,in the various scores) at 12 and 24 weeks. Individual measuresof disease activity, such as numbers of swollen and tender jointsand physician's assessment, were evaluated at 12 and 24 weeks.
The power of the study with respect to the primary efficacyend point (based on the ACR 20) was estimated to be approximately80 percent, on the assumption that the response rates wouldbe 25 percent in the placebo-plus-methotrexate group and 55percent in the etanercept-plus-methotrexate group. At the plannedsample size of 75 patients, if the underlying rate of adverseevents was 5 percent, the probability of observing at leastone adverse event was 92 percent in the etanercept-plus-methotrexategroup (50 subjects) and 72 percent in the placebo-plus-methotrexategroup (25 subjects).
Response rates measured by the ACR 20 and ACR 50 were comparedwith use of the chi-square test. Fisher's exact test (two-tailed)was used for response rates according to the ACR 70 and fordata on safety. With regard to the ACR response measures, patientswho withdrew from the study were considered not to have hada response at all points after withdrawal, irrespective of theclinical response. For individual measures (tender and swollenjoints and global assessments), the last observation was usedin analysis if the patient withdrew. Patients who received intraarticularinjections of corticosteroids during the study were countedas having or not having a response according to their overallevaluation, but the joint or joints injected were counted astender and swollen for the remainder of the study. Patientswho received increased doses of oral corticosteroids were considerednot to have had a response at all time points after the increase.
Results
The base-line demographic and clinical characteristics of thepatients are summarized in Table 1. Fourteen men and 75 womenwere enrolled. The mean age was 50 years (range, 26 to 71),and the mean duration of rheumatoid arthritis was 13 years.The treatment groups were generally well matched. The mean weeklydose of methotrexate per patient was 18 mg in the placebo-plus-methotrexategroup and 19 mg in the etanercept-plus-methotrexate group. Despitelong-term methotrexate therapy, the patients had a median of28 tender and 18 swollen joints at base line.
Table 1. Base-Line Demographic and Clinical Characteristics of the Study Patients.
Of the 59 patients randomly assigned to receive etanercept plusmethotrexate, 57 (97 percent) completed the 24-week study and2 withdrew because of adverse events unrelated to etanercept(abdominal pain due to an incisional hernia from prior surgeryin 1 patient, and traumatic fractures of the shoulder and calcaneusin the other). Of the 30 patients randomly assigned to receiveplacebo plus methotrexate, 24 (80 percent) completed the study,4 withdrew because of lack of efficacy, 1 had a myocardial infarction,and 1 was lost to follow-up. All the patients received at leastone dose of study drug and could be included in the evaluationof the safety and efficacy of the treatment. The mean numberof doses of study drug received was 47 in the etanercept-plus-methotrexategroup and 43 in the placebo-plus-methotrexate group.
Efficacy
The etanercept-plus-methotrexate group had significantly superioroutcomes for all end points according to the ACR response criteria(Table 2). The primary efficacy end point, the proportion ofpatients who reached the ACR 20 at 24 weeks, was achieved in71 percent in the etanercept-plus-methotrexate group, as comparedwith 27 percent in the placebo-plus-methotrexate group (P<0.001).The response in the etanercept-plus-methotrexate group was rapidand sustained; at all evaluations, beginning at week 1, a significantlygreater proportion of patients in the etanercept-plus-methotrexategroup achieved the ACR 20. Significantly greater proportionsof patients in the etanercept-plus-methotrexate group achievedthe ACR 50 at one month and at each subsequent evaluation andreached the ACR 70 at three months and at each subsequent evaluation.At base line the patients had a median of 28 tender joints and18 swollen joints. At 24 weeks the median number of tender jointswas 7 in the etanercept-plus-methotrexate group and 17 in theplacebo-plus-methotrexate group (an improvement from base lineof 75 percent and 39 percent, respectively); the median numberof swollen joints was 6 in the etanercept-plus-methotrexategroup and 11 in the placebo-plus-methotrexate group (an improvementfrom base line of 78 percent and 33 percent, respectively) (Figure 1).In addition, patients receiving etanercept plus methotrexatehad significantly greater improvement in all other individualmeasures of disease activity at 12 and 24 weeks (Table 3).
Table 3. Median Values for Measures of Disease and Quality of Life at Base Line and at 12 and 24 Weeks.
The median disability-index score from the Health AssessmentQuestionnaire improved from 1.5 to 0.8 in the etanercept-plus-methotrexategroup, an improvement of 47 percent. The score in the placebo-plus-methotrexategroup did not change significantly (the median base-line valuewas 1.5, and the end-of-study value was 1.1, an improvementof 27 percent).
Acute-phase reactants also improved significantly more in thepatients in the etanercept-plus-methotrexate group. Among patientswith abnormal erythrocyte sedimentation rates at base line,62 percent of those treated with etanercept plus methotrexateand 30 percent of those treated with placebo plus methotrexatehad normal erythrocyte sedimentation rates at their last visits.Among patients with abnormal C-reactive protein levels at baseline, 44 percent of those treated with etanercept plus methotrexateand 13 percent of those treated with placebo plus methotrexatehad normal values at their last visits.
Intraarticular corticosteroids and increasing doses of oralcorticosteroids were used in a small number of patients andmight have affected the study results. However, only one ofthe four patients who received an increased dose of oral corticosteroids(a patient receiving placebo plus methotrexate) would have beenclassified as having a response on the basis of observation.Only one of the four patients who received intraarticular corticosteroids(a patient receiving etanercept plus methotrexate) would havebeen classified as having a response on the basis of observation.Reclassification of these two patients did not alter the conclusionregarding the primary end point (P=0.001).
The combination of etanercept and methotrexate was superiorto the combination of placebo and methotrexate regardless ofthe dose of methotrexate, the duration of methotrexate therapy,or background use of corticosteroids or nonsteroidal antiinflammatorydrugs.
Safety
Etanercept was well tolerated (Table 4). Reactions at the injectionsite were the only events that occurred significantly more oftenin the etanercept-plus-methotrexate group (42 percent vs. 7percent, P<0.001). All injection-site reactions were mild(erythema with or without itching, pain, or swelling), mostresolved without treatment (median duration, three days), andnone required suspension of the study drug. Most patients hadfive or fewer injection-site reactions during the 24-week trial.The difference between the treatment groups in the percentageof patients with injection-site reactions does not appear tohave affected the outcome of the study, because the responserates of patients treated with etanercept who had injection-sitereactions were no different from those of patients treated withetanercept who did not have reactions (72 percent and 71 percent,respectively, met the ACR 20 criteria at 24 weeks). Infectionwas the most common adverse event overall, but there were nosignificant intergroup differences in the incidence or typesof infection. Approximately one third of the infections in bothgroups were upper respiratory infections (colds) or sinusitis.
Table 4. Adverse Events Observed in at Least 5 Percent of Patients.
No patients died during the study or within 30 days after receivingthe last dose of study drug. Two patients in each treatmentgroup were hospitalized during the study. In the placebo-plus-methotrexategroup, one patient had a myocardial infarction and discontinuedthe study, and one patient was hospitalized for gastrointestinalbleeding due to a gastric ulcer. In the etanercept-plus-methotrexategroup, one patient withdrew from the study before undergoingsurgery to relieve abdominal pain (due to an incisional herniafrom prior surgery) and intertrigo (due to a large abdominalpanniculus). After surgery the patient was readmitted to thehospital twice because of infection at the incision site. Anotherpatient who was receiving etanercept and methotrexate was admittedto the hospital for idiopathic pancreatitis that was treatedsymptomatically and resolved spontaneously, without interruptionof etanercept-and-methotrexate therapy.
Most laboratory abnormalities in both groups were mild; moreserious laboratory abnormalities included lymphocytopenia (fewerthan 500 cells per cubic millimeter) in two patients from eachgroup, hyponatremia (116 to 124 mmol of sodium per liter) inone patient receiving placebo plus methotrexate, and anemia(less than 6.5 g of hemoglobin per deciliter) secondary to gastrointestinalbleeding in another patient receiving placebo plus methotrexate.No other serious laboratory abnormalities were noted in theetanercept-plus-methotrexate group.
Non-neutralizing antibodies to etanercept were detected in onlyone patient during the study, at the 24-week evaluation of apatient in the etanercept-plus-methotrexate group. This patienthad a rapid and sustained response to therapy, with an 84 percentreduction in the number of tender joints and a 100 percent reductionin the number of swollen joints by week 24. This patient hadno injection-site reactions or other adverse events.
Before receiving the study drugs, 1 of the 30 patients assignedto placebo plus methotrexate (3 percent) and 4 of the 59 patientsassigned to etanercept plus methotrexate (7 percent) had positiveresults on assays for antibodies to double-stranded DNA. At24 weeks or at the last visit before discontinuation, one additionalpatient assigned to placebo plus methotrexate and four additionalpatients assigned to etanercept plus methotrexate had positivetests for antibodies to double-stranded DNA. Of the patientswho had positive tests for antibodies to double-stranded DNAat any time, half in each group had negative results for antinuclearantibodies at the time of the positive results for anti–double-strandedDNA antibodies, and only one patient in each group had a positiveantinuclear antibody titer at the end of the study. With regardto the levels of antinuclear antibodies and anticardiolipinantibodies, a small number of patients in each group shiftedfrom positive to negative or from negative to positive testresults. There were no significant differences between the groupsin the proportions of patients undergoing these shifts. Moreover,no patients had new connective-tissue disorders, thromboticevents, or thrombocytopenia.
Discussion
Over the past decade, methotrexate has emerged as the main treatmentfor rheumatoid arthritis. However, in many patients methotrexatealone does not result in satisfactory control of the disease,and therefore methotrexate in combination with other drugs hasbeen tested. After six months of therapy, 48 percent of patientsreceiving cyclosporine plus methotrexate and 16 percent of thosereceiving placebo plus methotrexate met the ACR 20 criteria.18Also among these patients, 1 percent of those receiving thecombination and none receiving only methotrexate met the ACR70 criteria. The ACR 70 criteria are important because theyhave been proposed by the Food and Drug Administration (FDA)as the preliminary criteria for a major clinical response.19According to modified Paulus response criteria, triple therapywith methotrexate, sulfasalazine, and hydroxychloroquine wassuperior to methotrexate alone or the combination of sulfasalazineand hydroxychloroquine.20 However, even with these combinations,patients continue to have active rheumatoid arthritis.
Two previous trials showed that etanercept was effective againstrheumatoid arthritis and had no serious toxic effects. In onetrial, 75 percent of patients receiving 16 mg of etanerceptper square meter of body-surface area twice weekly had at leastan ACR 20 response, as compared with only 14 percent of thosereceiving placebo.12 A fixed dose of 25 mg of etanercept wasused in a second trial, and 62 percent of the etanercept-treatedpatients had at least an ACR 20 response, as compared with only23 percent of the patients receiving placebo.13
Because of the prominent role of methotrexate in the treatmentof rheumatoid arthritis and the efficacy of etanercept alone,it is important to study the combination of the two. This studywas designed to determine whether the combination was safe andwhether additional benefit could be achieved in patients whohad active disease despite therapeutic doses of methotrexate.
In this six-month study in patients who had persistent diseaseactivity despite methotrexate therapy, the addition of etanerceptprovided additional benefit without potentiating the toxic effectsof methotrexate or inducing dose-limiting toxic effects of itsown. At 24 weeks, the ACR 20 criteria were met in 71 percentof patients receiving etanercept and methotrexate and 27 percentof those receiving placebo and methotrexate. The ACR 50 criteriawere met in 39 percent and 3 percent of the patients in thetwo groups, respectively. The ACR 70 criteria (proposed by theFDA as the criteria for a major clinical response) were metby 15 percent of the etanercept-plus-methotrexate group andnone of the placebo-plus-methotrexate group.
With the exception of injection-site reactions in the etanercept-plus-methotrexategroup, no significant differences were found between the treatmentgroups in the incidence or types of adverse events reported,including those characteristic of methotrexate therapy. Moreover,the adverse events seen in this trial were similar to thoseseen with methotrexate alone in patients with rheumatoid arthritis.21,22Specifically, gastrointestinal side effects, hematologic effects,and headaches were not increased by the addition of etanercept.
The combination of methotrexate plus etanercept is a novel therapyfor rheumatoid arthritis. A long-term study23 has demonstratedthe efficacy and safety of etanercept therapy continued formore than 18 months. We are continuing to follow the patientsin this study in order to evaluate the safety and efficacy ofthe etanercept-plus-methotrexate combination. Another trialis currently comparing etanercept with methotrexate, and onthe basis of these results, an additional study comparing etanerceptwith etanercept plus methotrexate would be valuable. The combinationof etanercept and methotrexate offers a promising new alternativefor patients who have persistently active rheumatoid arthritisdespite treatment with methotrexate.
Supported by Immunex.
Drs. Weinblatt and Fleischmann have served as ad hoc consultantsto Immunex.
We are indebted to Bonnie L. Bermas, M.D., Jonathan S. Coblyn,M.D., Simon M. Helfgott, M.D., and Agnes Maier, B.A. (Brighamand Women's Hospital, Boston); Sheila M. Kelly, M.D., PatrickJ. Mroczkowski, M.D., Martin Morell, M.D., and Vilma Byrne,R.N. (Albany Medical College, Albany, N.Y.); Wilmer L. Sibbitt,M.D., Mary Ann Brewington, R.N., Marilyn Salas, R.N., and SharonWilson, R.N. (University of New Mexico School of Medicine, Albuquerque);Philip J. Clements, M.D., Harold E. Paulus, M.D., and Rita Jepson,B.S. (University of California at Los Angeles); Stanley B. Cohen,M.D., Thomas Geppert, M.D., Robert Neil Jenkins, M.D., Ph.D.,Sharad Lakhanpal, M.D., Leatha Harrell, R.N., Kaye Harrison-Whitehead,R.N., and Sandra Rankin, L.S.W. (Metroplex Clinical ResearchCenter, Dallas); Ken D. Pischel, M.D., Lauren McBride, and theDepartment of Academic Affairs (Scripps Clinic, La Jolla, Calif.);Sara Anderson, M.D., Michael J. Battistone, M.D., Daniel O.Clegg, M.D., Grant W. Cannon, M.D., Allen D. Sawitzke, M.D.,H. James Williams, M.D., and Sidney Hughes (University of UtahMedical Center, Salt Lake City); and Bette Glass and Linda Melvin(Immunex, Seattle).
Source Information
From Brigham and Women's Hospital, Boston (M.E.W.); Albany Medical College, Albany, N.Y. (J.M.K.); the University of New Mexico School of Medicine, Albuquerque (A.D.B.); the University of California at Los Angeles, Los Angeles (K.J.B.); Metroplex Clinical Research Center, Dallas (R.M.F.); Scripps Clinic, La Jolla, Calif. (R.I.F.); the University of Utah Medical Center, Salt Lake City (C.G.J.); and Immunex Corporation, Seattle (M.L., D.J.B.).
Address reprint requests to Dr. Weinblatt at Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115.
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Etanercept in Rheumatoid Arthritis
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340:2000-2001, Jun 24, 1999.
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67: 1444-1447
[Abstract][Full Text]
Karanikolas, G., Charalambopoulos, D., Vaiopoulos, G., Andrianakos, A., Rapti, A., Karras, D., Kaskani, E., Sfikakis, P. P.
(2008). Adjunctive anakinra in patients with active rheumatoid arthritis despite methotrexate, or leflunomide, or cyclosporin-A monotherapy: a 48-week, comparative, prospective study. Rheumatology (Oxford)
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van Riel, P L C M, Freundlich, B, MacPeek, D, Pedersen, R, Foehl, J R, Singh, A, on behalf of ADORE study investigators,
(2008). Patient-reported health outcomes in a trial of etanercept monotherapy versus combination therapy with etanercept and methotrexate for rheumatoid arthritis: the ADORE trial. Ann Rheum Dis
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(2008). B lymphocyte stimulator expression in patients with rheumatoid arthritis treated with tumour necrosis factor {alpha} antagonists: differential effects between good and poor clinical responders. Ann Rheum Dis
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Bruyn, G A W, Tate, G, Caeiro, F, Maldonado-Cocco, J, Westhovens, R, Tannenbaum, H, Bell, M, Forre, O, Bjorneboe, O, Tak, P P, Abeywickrama, K H, Bernhardt, P, van Riel, P L C, for the RADD study group,
(2008). Everolimus in patients with rheumatoid arthritis receiving concomitant methotrexate: a 3-month, double-blind, randomised, placebo-controlled, parallel-group, proof-of-concept study. Ann Rheum Dis
67: 1090-1095
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Morjaria, J B, Chauhan, A J, Babu, K S, Polosa, R, Davies, D E, Holgate, S T
(2008). The role of a soluble TNF{alpha} receptor fusion protein (etanercept) in corticosteroid refractory asthma: a double blind, randomised, placebo controlled trial. Thorax
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Hyrich, K. L., Lunt, M., Dixon, W. G., Watson, K. D., Symmons, D. P. M., on behalf of the BSR Biologics Register,
(2008). Effects of switching between anti-TNF therapies on HAQ response in patients who do not respond to their first anti-TNF drug. Rheumatology (Oxford)
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Yazici, Y., Adler, N. M., Yazici, H.
(2008). Most tumour necrosis factor inhibitor trials in rheumatology are undeservedly called 'efficacy and safety' trials: a survey of power considerations. Rheumatology (Oxford)
47: 1054-1057
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Cohen, J., Calabresi, P., Chakraborty, S., Edwards, K., Eickenhorst, T., Felton, W. III, Fisher, E., Fox, R., Goodman, A., Hara-Cleaver, C., Hutton, G., Imrey, P., Ivancic, D., Mandell, B., Perryman, J., Scott, T., Skaramagas, T., Zhang, H. for the AC
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(2008). Efficacy and safety of the selective co-stimulation modulator abatacept following 2 years of treatment in patients with rheumatoid arthritis and an inadequate response to anti-tumour necrosis factor therapy. Ann Rheum Dis
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(2008). Clinical identification and treatment of a rapidly progressing disease state in patients with rheumatoid arthritis. Rheumatology (Oxford)
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van der Heijde, D, Burmester, G, Melo-Gomes, J, Codreanu, C, Mola, E M., Pedersen, R, Freundlich, B, Chang, D J, for the Etanercept Study 400 Investigators,
(2008). The safety and efficacy of adding etanercept to methotrexate or methotrexate to etanercept in moderately active rheumatoid arthritis patients previously treated with monotherapy. Ann Rheum Dis
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(2007). Regulators of cytokine signalling in rheumatoid arthritis. Rheumatology (Oxford)
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(2007). The efficacy of anti-TNF in rheumatoid arthritis, a comparison between randomised controlled trials and clinical practice. Ann Rheum Dis
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Plenge, R. M., Seielstad, M., Padyukov, L., Lee, A. T., Remmers, E. F., Ding, B., Liew, A., Khalili, H., Chandrasekaran, A., Davies, L. R.L., Li, W., Tan, A. K.S., Bonnard, C., Ong, R. T.H., Thalamuthu, A., Pettersson, S., Liu, C., Tian, C., Chen, W. V., Carulli, J. P., Beckman, E. M., Altshuler, D., Alfredsson, L., Criswell, L. A., Amos, C. I., Seldin, M. F., Kastner, D. L., Klareskog, L., Gregersen, P. K.
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(2007). Combination Immunosuppressive Therapies: The Promise and the Peril. Arch Dermatol
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(2007). Open-label, pilot protocol of patients with rheumatoid arthritis who switch to infliximab after an incomplete response to etanercept: the opposite study. Ann Rheum Dis
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(2007). The efficacy of inhibiting tumour necrosis factor {alpha} and interleukin 1 in patients with rheumatoid arthritis: a meta-analysis and adjusted indirect comparisons. Rheumatology (Oxford)
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(2007). The BeSt Way to Treat Early Rheumatoid Arthritis?. ANN INTERN MED
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Lequerre, T., Jouen, F., Brazier, M., Clayssens, S., Klemmer, N., Menard, J.-F., Mejjad, O., Daragon, A., Tron, F., Le Loet, X., Vittecoq, O.
(2007). Autoantibodies, metalloproteinases and bone markers in rheumatoid arthritis patients are unable to predict their responses to infliximab. Rheumatology (Oxford)
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Klareskog, L, Gaubitz, M, Rodriguez-Valverde, V, Malaise, M, Dougados, M, Wajdula, J, for The Etanercept Study 301 Investigators,
(2006). A long-term, open-label trial of the safety and efficacy of etanercept (Enbrel) in patients with rheumatoid arthritis not treated with other disease-modifying antirheumatic drugs. Ann Rheum Dis
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(2006). Detailed analysis of the cell infiltrate and the expression of mediators of synovial inflammation and joint destruction in the synovium of patients with psoriatic arthritis: implications for treatment. Ann Rheum Dis
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(2006). Etanercept 50 mg once weekly is as effective as 25 mg twice weekly in patients with ankylosing spondylitis. Ann Rheum Dis
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Hyrich, K. L., Watson, K. D., Silman, A. J., Symmons, D. P. M., The BSR Biologics Register,
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van Riel, P L C M, Taggart, A J, Sany, J, Gaubitz, M, Nab, H W, Pedersen, R, Freundlich, B, MacPeek, D, for the ADORE (Add Enbrel or Replace Methotrexate),
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(2006). Adalimumab and methotrexate is more effective than adalimumab alone in patients with established rheumatoid arthritis: results from a 6-month longitudinal, observational, multicentre study. Ann Rheum Dis
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Deng, A., Harvey, V., Sina, B., Strobel, D., Badros, A., Junkins-Hopkins, J. M., Samuels, A., Oghilikhan, M., Gaspari, A.
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Ledingham, J., Deighton, C., on behalf of the British Society for Rheumatology,
(2005). Update on the British Society for Rheumatology guidelines for prescribing TNF{alpha} blockers in adults with rheumatoid arthritis (update of previous guidelines of April 2001). Rheumatology (Oxford)
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Dougados, M, Emery, P, Lemmel, E M, Zerbini, C A F, Brin, S, van Riel, P
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