Treatment of Rheumatoid Arthritis with Methotrexate Alone, Sulfasalazine and Hydroxychloroquine, or a Combination of All Three Medications
James R. O'Dell, M.D., Claire E. Haire, R.N., M.S.N., Nils Erikson, M.D., Walter Drymalski, M.D., William Palmer, M.D., P. James Eckhoff, M.D., Vernon Garwood, M.D., Pierre Maloley, Pharm.D., Lynell W. Klassen, M.D., Steven Wees, M.D., Harry Klein, M.D., and Gerald F. Moore, M.D.
Background Rheumatoid arthritis is a common disease that causessubstantial morbidity and mortality. The responses of patientswith rheumatoid arthritis to treatment with a single so-calleddisease-modifying drug, such as methotrexate, are often suboptimal.Despite limited data, many patients are treated with combinationsof these drugs.
Methods We enrolled 102 patients with rheumatoid arthritis andpoor responses to at least one disease-modifying drug in a two-year,double-blind, randomized study of treatment with methotrexatealone (7.5 to 17.5 mg per week), the combination of sulfasalazine(500 mg twice daily) and hydroxychloroquine (200 mg twice daily),or all three drugs. The dose of methotrexate was adjusted inan attempt to achieve remission in all patients. The primaryend point of the study was the successful completion of twoyears of treatment with 50 percent improvement in compositesymptoms of arthritis and no evidence of drug toxicity.
Results Fifty of the 102 patients had 50 percent improvementat nine months and maintained at least that degree of improvementfor two years without evidence of major drug toxicity. Amongthem were 24 of 31 patients treated with all three drugs (77percent), 12 of 36 patients treated with methotrexate alone(33 percent, P<0.001 for the comparison with the three-druggroup), and 14 of 35 patients treated with sulfasalazine andhydroxychloroquine (40 percent, P = 0.003 for the comparisonwith the three-drug group). Seven patients in the methotrexategroup and three patients in each of the other two groups discontinuedtreatment because of drug toxicity.
Conclusions In patients with rheumatoid arthritis, combinationtherapy with methotrexate, sulfasalazine, and hydroxychloroquineis more effective than either methotrexate alone or a combinationof sulfasalazine and hydroxychloroquine.
Rheumatoid arthritis is a common disease1 that causes substantialmorbidity in most patients2 and premature mortality in many.2,3,4Conventional therapy for rheumatoid arthritis includes the administrationof antiinflammatory drugs, followed by disease-modifying antirheumaticdrugs such as methotrexate, hydroxychloroquine, sulfasalazine,and gold in patients with persistent active disease. Short-termstudies5,6,7,8,9,10,11,12,13,14 and meta-analyses15,16 haverepeatedly proved the efficacy of disease-modifying drugs, buttheir long-term effectiveness is less than optimal; therefore,most patients do not take them for more than two to five years,17,18because of either lack of efficacy or toxic effects. Patientstreated with methotrexate have the highest rate of continuedlong-term therapy,19,20,21 and therefore most rheumatologistsconsider it the drug of choice.22 We designed a study to determinewhether disease-modifying drugs were effective as combinationtherapy for rheumatoid arthritis and whether the combinationsstudied had better efficacy than methotrexate alone.
Methods
This study was conducted by the Rheumatoid Arthritis InvestigationalNetwork (RAIN), which brings rheumatologists at the Universityof Nebraska together with rheumatologists in Nebraska, Iowa,South Dakota, Minnesota, and Illinois who are interested inclinical studies of rheumatoid arthritis. All the participatingphysicians were involved not only in enrolling patients andcollecting data, but also in developing the study protocols.
Selection of Patients
We asked patients followed in the rheumatology clinics at theUniversity of Nebraska Medical Center, the Omaha Veterans AffairsMedical Center, or the private offices of physicians in thenetwork who met the criteria for this study to participate.The protocol was approved by the Food and Drug Administrationand the institutional review board at the University of Nebraska,and all the patients gave informed written consent.
The criteria for entry into the study were an age of 19 to 70years; rheumatoid arthritis fulfilling the criteria of the AmericanRheumatism Association23; disease lasting more than six months;and active disease with at least three of the following: erythrocytesedimentation rate >28 mm per hour, morning stiffness lasting45 minutes or more, eight or more tender joints, and three ormore swollen joints. In addition, the patients must have hadpoor responses to treatment with at least one of the following:gold, hydroxychloroquine, penicillamine, sulfasalazine, andmethotrexate. Patients were not eligible for the study if theyhad received combination therapy with two of these drugs; ifthey had stage IV disease24 or were allergic to any of the studydrugs; if they were women of childbearing age who were not usingcontraception; if they had liver, renal, hematologic, pulmonary,or cardiovascular disease; if they had visual difficulties,including a recent decrease in visual acuity, retinal disease,or macular degeneration; or if they had active peptic ulcerdisease.
Study Design
We enrolled 102 patients in this two-year, double-blind, randomized,controlled study. The pharmacy performed the randomization;equal numbers of cards with each group assignment were mixed,drawn, and placed in sequentially numbered envelopes that wereopened as the patients were enrolled. The patients were treatedwith methotrexate alone, the combination of hydroxychloroquineand sulfasalazine, or all three drugs. They received methotrexate(Rheumatrex, Lederle, Pearl River, N.Y.) or placebo in one bottle,sulfasalazine (Azulfidine, Pharmacia, Columbus, Ohio) or placeboin another bottle, and hydroxychloroquine (Plaquenil, SanofiWinthrop, New York) or placebo in a third bottle. The dosesof sulfasalazine and hydroxychloroquine were 500 and 200 mgtwice daily, respectively, and the initial dose of methotrexatewas 7.5 mg per week.
The patients were evaluated three months after enrollment byphysicians who were unaware of the treatment-group assignments.If a patient did not meet the criteria for remission,25 we increasedthe dose of methotrexate (or placebo) to 12.5 mg per week. Thepatient was then evaluated at six months. If he or she was notin remission, the dose of methotrexate (or placebo) was increasedto 17.5 mg per week. Since most patients did not meet the criteriafor remission while taking lower doses, over 90 percent received17.5 mg of methotrexate or placebo per week. We evaluated thepatients again after nine months of therapy (i.e., after threemonths of maximal therapy), and if their condition had not improvedby 50 percent we considered the treatment ineffective. If theyhad improved by 50 percent or more, we followed them every threemonths for the remainder of the two-year study period.
Evaluation Criteria
The main end point was whether the patient's condition improvedby at least 50 percent, as determined by whether three of thefollowing requirements had been fulfilled (the modified Pauluscomposite criteria26): morning stiffness of less than 30 minutes'duration, or decreased by 50 percent; joint tenderness decreasedby 50 percent; joint swelling decreased by 50 percent; and anerythrocyte sedimentation rate of less than 30 mm per hour inwomen and less than 20 mm per hour in men. Patients who didnot have this degree of improvement at any of the three-monthevaluations after receiving maximal therapy were consideredto have had treatment failures.
Additional measures of evaluation included estimates of theduration of morning stiffness and scores on a modified Ritchiearticular index,27 in which 38 joints in each patient were scoredon a scale of 0 to 3 with regard to tenderness and swelling.The patient's global status and level of overall pain (as scoredby the patient) and the physician's global assessment were scoredon a visual-analogue scale on which 0 indicated normal and 10indicated severe problems.28
Monitoring of Toxicity
An ophthalmologist examined all the patients every six monthsfor potentially toxic effects of hydroxychloroquine. All thepatients had complete blood counts and measurements of serumaspartate aminotransferase, albumin, and creatinine concentrationsmonthly during the study. Erythrocyte sedimentation rates weremeasured every three months. Patients were excluded from thestudy if their serum aspartate aminotransferase values weremore than twice the upper limit of the normal range on two successiveoccasions.
Concurrent Therapy
We permitted concurrent therapy with systemic corticosteroidsif the dose remained stable throughout the study period andthe patient took no more than 10 mg of prednisone (or its equivalent)per day. We also permitted the use of nonsteroidal antiinflammatorymedications, both as regular therapy and on an as-needed basis.
Statistical Analysis
The primary end point was successful completion of the two-yearstudy. Differences among the three treatment groups in the numberof patients who completed the study and the number who had treatmentfailures were analyzed by both the chi-square test and the log-ranktest.29 We developed a Kaplan–Meier curve for the patientswho completed the study, with all those who did not do so consideredto have had treatment failures. The log-rank test was used tocompare these groups.29 Cox proportional-hazards regressionanalysis was used to adjust for differences among the groupsat study entry.
Differences in the mean values of other outcome variables wereevaluated by two-tailed Student's t-tests, assuming unequalvariance.29 Analysis of covariance was used to adjust for base-linedifferences in the severity of disease among the treatment groups.29
Results
We randomly assigned 36 patients to receive methotrexate, 35patients to receive sulfasalazine and hydroxychloroquine, and31 patients to receive all three drugs. There were no significantdifferences among the groups at study entry (Table 1). Thirteenpatients discontinued the study because of drug toxicity, and37 patients did so because of lack of efficacy. Two patientswere withdrawn from the study for protocol violations (failureto have laboratory studies done). The remaining 50 patientscompleted the two years of the study successfully, having 50percent or greater improvement at nine months and maintainingat least 50 percent improvement for the duration of the study.
Table 1. Base-Line Characteristics of Patients with Rheumatoid Arthritis, According to Study Group.
Toxicity
Treatment with all three drugs did not produce more toxic effectsthan did methotrexate therapy alone. Seven patients in the methotrexategroup discontinued treatment because of toxic effects: two patientshad pneumonia; one patient each had stomatitis, diarrhea, nausea,and vertigo; and one patient had sepsis and subsequently died.Three patients assigned to sulfasalazine and hydroxychloroquinediscontinued treatment because of pneumonia, diarrhea, and Crohn'sdisease, respectively; and three patients in the three-druggroup discontinued treatment because of nausea, cervical cancer,and weight gain, respectively.
No patient had serum aspartate aminotransferase values morethan twice the upper limit of the normal range during the study.The patients in the three-drug group had higher serum creatininevalues than those in the other two groups at nine months (P= 0.03), but this difference was not apparent at two years.
Treatment Outcomes
The 50 patients who had at least 50 percent improvement at ninemonths and maintained that degree of improvement to the endof the two-year treatment period included 24 of the 31 patientsreceiving all three drugs (77 percent), 14 of the 35 patientsreceiving sulfasalazine and hydroxychloroquine (40 percent),and 12 of the 36 patients receiving methotrexate alone (33 percent)(P = 0.003 and P<0.001 for the respective comparisons betweenthe three-drug group and the other two groups). Three patientsin the three-drug group, 18 in the sulfasalazine–hydroxychloroquinegroup, and 16 in the methotrexate group were considered to havehad treatment failures. The remaining patients in each groupdiscontinued the study because of toxic effects or protocolviolations.
The proportions of patients who completed the two-year treatmentperiod successfully are shown in Figure 1. In the figure, allthe patients who did not complete the study are counted as havinghad treatment failures, including the 13 with toxic effects,the 37 with treatment failures, and the 2 who were withdrawnfrom the study because of protocol violations. The comparisonbetween the three-drug group and each of the other groups withrespect to good responses (Figure 1) was statistically significant(P = 0.003 by the log-rank test). To ensure that these divergentresults were not caused by differences in the severity of diseaseat base line, we performed an adjusted analysis of the timeto treatment failure, using the presence of rheumatoid factor,the erythrocyte sedimentation rate, the duration of disease,the number of previous disease-modifying drugs taken, the patient'sglobal status, the physician's global assessment, and the totaljoint score as variables. The sedimentation rate, the patient'sglobal status, and the total joint score all had weak but statisticallysignificant effects on the time to treatment failure. However,the difference between the three-drug group and the methotrexategroup remained significant after this adjustment (P = 0.009).
Figure 1. Patients with Good Responses to the Assigned Study Treatment.
Other Measures of Efficacy
Table 2 shows the other clinical measurements of arthritis activityat base line, after nine months, and after two years of therapy.We chose nine months because that was the point at which thedecision to retain the patient in the study (on the basis ofat least 50 percent improvement) was made. There were trendstoward clinical improvement in the three-drug group as comparedwith the other two groups on all measures of efficacy. The resultsat two years were particularly impressive, considering thatall these patients had already been selected as those who weredoing well (i.e., who had at least 50 percent improvement).
Table 2. Changes in Joint Symptoms and Measures of Activity in the Study Patients, According to Treatment Group.
Discussion
With the disease-modifying therapy currently available, completeremissions of rheumatoid arthritis are disappointingly rare.25,30Therefore, most clinicians have resorted to using combinationsof drugs to treat a substantial subgroup of patients.22,31 Thereare few data to suggest that combinations of drugs are betterthan therapy with single drugs, however. A recent meta-analysisof combination therapy in rheumatoid arthritis concluded thatthere is little evidence to support the use of combination therapy,32but few studies have been done, and only two have included methotrexate.33,34In one of these, the dose in the methotrexate-plus-azathioprinegroup was only half the dose in the methotrexate-alone group,34making comparison difficult or impossible. In the other studyusing methotrexate, the maximal dose was only 7.5 mg per week.33Three studies in the meta-analysis included oral gold or penicillamine,33,35,36medications that are now seldom used by rheumatologists.22
Our double-blind, controlled, randomized study demonstratesthe tolerability and the benefit of combination therapy withmethotrexate, hydroxychloroquine, and sulfasalazine as comparedwith methotrexate alone. This enhanced efficacy occurred withno increase in toxicity. We believe that our results are particularlypertinent to clinicians for several reasons. The study designincluded a combination of the three most widely used disease-modifyingdrugs. We compared this combination therapy with methotrexatealone, currently the gold standard of treatment for rheumatoidarthritis. The goal of the study was to induce remission, andthe dose of methotrexate was increased (to up to 17.5 mg perweek) to try to achieve this goal. The dose of the other drugsremained the same in the two groups that received them, andtherefore we can directly compare the treatment groups withrespect to efficacy. Our study lasted two years, making it oneof the longer controlled trials of any therapy, combinationor otherwise, in patients with rheumatoid arthritis. Finally,the main end point was 50 percent or greater improvement ratherthan 20 percent improvement, as is frequently used. Fifty percentimprovement is a clinically relevant end point because patientsand treating physicians can readily observe this degree of improvement.
We sought to design and conduct a study that would reflect clinicalpractice and yield results applicable to patients with rheumatoidarthritis and their physicians. Therefore, we allowed patientsto continue taking nonsteroidal antiinflammatory drugs and prednisoneif the dose was relatively low.
Some will question the fact that only a small percentage ofpatients in the methotrexate group completed the two-year studysuccessfully. Most clinicians believe that methotrexate is moreeffective than our results suggest, and in open-label studieslasting three to five years 50 to 65 percent of patients werereported to have sustained improvement.19,20,21 Reconcilingthese seemingly disparate results requires acknowledging thatthe measure of efficacy we used (50 percent improvement) differsfrom the measures used in routine clinical practice and otherlongitudinal studies. In one clinic, for example, 64 percentof patients were still taking methotrexate after five years,19,37but only 35 percent had at least 50 percent improvement.37 Thepercentage of patients who dropped out of our study becauseof side effects was higher because of the double-blind natureof this study. These side effects would often not have precludedthe continuation of methotrexate therapy if the patients hadbeen followed in clinical practice or an open-label study.
We are indebted to Lederle, Sanofi Winthrop, and Pharmacia forproviding the study drugs and placebos; to Ms. Lucie Case fordata entry and assistance in the preparation of the manuscript;to Mr. David Nicklin for expert review of the manuscript; toMuriel Block, R.N., and Rayla Otto, P.A., for assistance withdata collection; to Michael Reece, B.S., for assistance in dispensingthe study medications; and to James Anderson, Ph.D., and KashPatil, Ph.D., for statistical assistance.
Source Information
From the University of Nebraska Medical Center and the Omaha Veterans Affairs Medical Center, Omaha (J.R.O., C.E.H., P.M., L.W.K., G.F.M.), and affiliated Rheumatoid Arthritis Investigational Network clinics (N.E., W.D., W.P., P.J.E., V.G., S.W., H.K.).
Address reprint requests to Dr. O'Dell at the University of Nebraska Medical Center, Department of Internal Medicine, 600 S. 42nd St., Omaha, NE 68198-3025.
References
Hochberg MC. Adult and juvenile rheumatoid arthritis: current epidemiologic concepts. Epidemiol Rev 1981;3:27-44. [Free Full Text]
Scott DL, Symmons DPM, Coulton BL, Popert AJ. Long-term outcome of treating rheumatoid arthritis: results after 20 years. Lancet 1987;1:1108-1111. [CrossRef][Medline]
Pincus T, Brooks RH, Callahan LF. Prediction of long-term mortality in patients with rheumatoid arthritis according to simple questionnaire and joint count measures. Ann Intern Med 1994;120:26-34. [Free Full Text]
Wolfe F, Mitchell DM, Sibley JT, et al. The mortality of rheumatoid arthritis. Arthritis Rheum 1994;37:481-494. [Medline]
Sigler JW, Bluhm GB, Duncan H, Sharp JT, Ensign DC, McCrum WR. Gold salts in the treatment of rheumatoid arthritis: a double-blind study. Ann Intern Med 1974;80:21-26.
Dixon AJ, Davies J, Dormandy TL, et al. Synthetic D(-)penicillamine in rheumatoid arthritis: double-blind controlled study of a high and low dosage regimen. Ann Rheum Dis 1975;34:416-421. [Free Full Text]
The Multicentre Trial Group. Controlled trial of D(-)penicillamine in severe rheumatoid arthritis. Lancet 1973;1:275-280. [Medline]
Pinals RS, Kaplan SB, Lawson JG, Hepburn B. Sulfasalazine in rheumatoid arthritis: a double-blind, placebo-controlled trial. Arthritis Rheum 1986;29:1427-1434. [Erratum, Arthritis Rheum 1987;30:459.] [Medline]
Williams HJ, Ward JR, Dahl SL, et al. A controlled trial comparing sulfasalazine, gold sodium thiomalate, and placebo in rheumatoid arthritis. Arthritis Rheum 1988;31:702-713. [Medline]
Hannonen P, Mottonen T, Hakola M, Oka M. Sulfasalazine in early rheumatoid arthritis: a 48-week double-blind, prospective, placebo-controlled study. Arthritis Rheum 1993;36:1501-1509. [Medline]
Weinblatt ME, Coblyn JS, Fox DA, et al. Efficacy of low-dose methotrexate in rheumatoid arthritis. N Engl J Med 1985;312:818-822. [Abstract]
Ward JR, Williams HJ, Egger MJ, et al. Comparison of auranofin, gold sodium thiomalate, and placebo in the treatment of rheumatoid arthritis: a controlled clinical trial. Arthritis Rheum 1983;26:1303-1315. [Medline]
Anderson PA, West SG, O'Dell JR, Via CS, Claypool RG, Kotzin BL. Weekly pulse methotrexate in rheumatoid arthritis: clinical and immunologic effects in a randomized, double-blind study. Ann Intern Med 1985;103:489-496.
Williams HJ, Willkens RF, Samuelson CO Jr, et al. Comparison of low-dose oral pulse methotrexate and placebo in the treatment of rheumatoid arthritis: a controlled clinical trial. Arthritis Rheum 1985;28:721-730. [Medline]
Felson DT, Anderson JJ, Meenan RF. The comparative efficacy and toxicity of second-line drugs in rheumatoid arthritis: results of two metaanalyses. Arthritis Rheum 1990;33:1449-1461. [Medline]
Felson DT, Anderson JJ, Meenan RF. Use of short-term efficacy/toxicity tradeoffs to select second-line drugs in rheumatoid arthritis: a metaanalysis of published clinical trials. Arthritis Rheum 1992;35:1117-1125. [Medline]
Wolfe F, Hawley DJ, Cathey MA. Termination of a slow acting antirheumatic therapy in rheumatoid arthritis: a 14-year prospective evaluation of 1017 consecutive starts. J Rheumatol 1990;17:994-1002. [Medline]
Morand EF, McCloud PI, Littlejohn GO. Life table analysis of 879 treatment episodes with slow acting antirheumatic drugs in community rheumatology practice. J Rheumatol 1992;19:704-708. [Erratum, J Rheumatol 1992;19:1998.] [Medline]
Weinblatt ME, Kaplan H, Germain BF, et al. Methotrexate in rheumatoid arthritis: a five-year prospective multicenter study. Arthritis Rheum 1994;37:1492-1498. [Medline]
Kremer JM, Phelps CT. Long-term prospective study of the use of methotrexate in the treatment of rheumatoid arthritis: update after a mean of 90 months. Arthritis Rheum 1992;35:138-145. [Medline]
Alarcon GS, Tracy IC, Blackburn WD Jr. Methotrexate in rheumatoid arthritis: toxic effects as the major factor in limiting long-term treatment. Arthritis Rheum 1989;32:671-676. [Medline]
O'Dell JR, Case L. The treatment of rheumatoid arthritis in 1995: results of a survey. Arthritis Rheum 1995;38:Suppl:S366-S366.abstract
Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31:315-324. [Medline]
Steinbrocker O, Traeger CH, Batterman RC. Therapeutic criteria in rheumatoid arthritis. JAMA 1949;140:659-662. [Free Full Text]
Pinals RS, Masi AT, Larsen RA, Subcommittee for Criteria of Remission in Rheumatoid Arthritis of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Preliminary criteria for clinical remission in rheumatoid arthritis. Arthritis Rheum 1981;24:1308-1315. [Medline]
Paulus HE, Egger MJ, Ward JR, Williams HJ. Analysis of improvement in individual rheumatoid arthritis patients treated with disease-modifying antirheumatic drugs, based on the findings in patients treated with placebo. Arthritis Rheum 1990;33:477-484. [Medline]
Egger MJ, Huth DA, Ward JR, Reading JC, Williams HJ. Reduced joint count indices in the evaluation of rheumatoid arthritis. Arthritis Rheum 1985;28:613-619. [Medline]
Felson DT, Anderson JJ, Boers M, et al. The American College of Rheumatology preliminary core set of disease activity measures for rheumatoid arthritis clinical trials. Arthritis Rheum 1993;36:729-740. [Medline]
Alarcon GS, Blackburn WE Jr, Calvo A, Castaneda O. Evaluation of the American Rheumatism Association preliminary criteria for remission in rheumatoid arthritis: a prospective study. J Rheumatol 1987;14:93-96. [Medline]
Cash JM, Klippel JH. Second-line drug therapy for rheumatoid arthritis. N Engl J Med 1994;330:1368-1375. [Free Full Text]
Felson DT, Anderson JJ, Meenan RF. The efficacy and toxicity of combination therapy in rheumatoid arthritis: a meta-analysis. Arthritis Rheum 1994;37:1487-1491. [Medline]
Williams HJ, Ward JR, Reading JC, et al. Comparison of auranofin, methotrexate, and the combination of both in the treatment of rheumatoid arthritis: a controlled clinical trial. Arthritis Rheum 1992;35:259-269. [Medline]
Willkens RF, Urowitz MB, Stablein DM, et al. Comparison of azathioprine, methotrexate, and the combination of both in the treatment of rheumatoid arthritis: a controlled clinical trial. Arthritis Rheum 1992;35:849-856. [Medline]
Gibson T, Emery P, Armstrong RD, Crisp AJ, Panayi GS. Combined D-penicillamine and chloroquine treatment of rheumatoid arthritis -- a comparative study. Br J Rheumatol 1987;26:279-284. [Free Full Text]
Taggart AJ, Hill J, Astbury C, Dixon JS, Bird HA, Wright V. Sulphasalazine alone or in combination with D-penicillamine in rheumatoid arthritis. Br J Rheumatol 1987;26:32-36. [Free Full Text]
Weinblatt ME. Methotrexate (MTX) in rheumatoid arthritis (RA): a 5 year multicenter prospective trial. Arthritis Rheum 1993;36:Suppl:S79-S79.abstract
Treatment of Rheumatoid Arthritis
Stohl W., Arkfeld D. G., Zurier R. B., DeMarco D. M., Liu N. Y., Schinagl E. F., Strauss P. C., O'Dell J. R.
Extract |
Full Text
N Engl J Med 1996;
335:821-823, Sep 12, 1996.
Correspondence
This article has been cited by other articles:
Rachapalli, S. M., Williams, R., Walsh, D. A., Young, A., Kiely, P. D. W., and, , Choy, E. H., on behalf of the Early Rheumatoid Arthritis Networ,
(2009). First-line DMARD choice in early rheumatoid arthritis--do prognostic factors play a role?. Rheumatology (Oxford)
0: kep389v1-kep389
[Abstract][Full Text]
Schipper, L. G., Fransen, J., Barrera, P., den Broeder, A. A., Van Riel, P. L. C. M.
(2009). Methotrexate therapy in rheumatoid arthritis after failure to sulphasalazine: to switch or to add?. Rheumatology (Oxford)
48: 1247-1253
[Abstract][Full Text]
van TUYL, L. H.D., PLASS, A. M. C., LEMS, W. F., VOSKUYL, A. E., KERSTENS, P. J.S.M., DIJKMANS, B. A.C., BOERS, M.
(2009). Facilitating the Use of COBRA Combination Therapy in Early Rheumatoid Arthritis: A Pilot Implementation Study. The Journal of Rheumatology
36: 1380-1386
[Abstract][Full Text]
Visser, K, Katchamart, W, Loza, E, Martinez-Lopez, J A, Salliot, C, Trudeau, J, Bombardier, C, Carmona, L, van der Heijde, D, Bijlsma, J W J, Boumpas, D T, Canhao, H, Edwards, C J, Hamuryudan, V, Kvien, T K, Leeb, B F, Martin-Mola, E M, Mielants, H, Muller-Ladner, U, Murphy, G, Ostergaard, M, Pereira, I A, Ramos-Remus, C, Valentini, G, Zochling, J, Dougados, M
(2009). Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative. Ann Rheum Dis
68: 1086-1093
[Abstract][Full Text]
Katchamart, W, Trudeau, J, Phumethum, V, Bombardier, C
(2009). Efficacy and toxicity of methotrexate (MTX) monotherapy versus MTX combination therapy with non-biological disease-modifying antirheumatic drugs in rheumatoid arthritis: a systematic review and meta-analysis. Ann Rheum Dis
68: 1105-1112
[Abstract][Full Text]
Schipper, L. G., Fransen, J., Barrera, P., Van Riel, P. L. C. M.
(2009). Methotrexate in combination with sulfasalazine is more effective in rheumatoid arthritis patients who failed sulfasalazine than in patients naive to both drugs. Rheumatology (Oxford)
48: 828-833
[Abstract][Full Text]
van der Kooij, S M, Goekoop-Ruiterman, Y P M, de Vries-Bouwstra, J K, Guler-Yuksel, M, Zwinderman, A H, Kerstens, P J S M, van der Lubbe, P A H M, de Beus, W M, Grillet, B A M, Ronday, H K, Huizinga, T W J, Breedveld, F C, Dijkmans, B A C, Allaart, C F
(2009). Drug-free remission, functioning and radiographic damage after 4 years of response-driven treatment in patients with recent-onset rheumatoid arthritis. Ann Rheum Dis
68: 914-921
[Abstract][Full Text]
van Tuyl, L. H. D., Plass, A. M. C., Lems, W. F., Voskuyl, A. E., Kerstens, P. J. S. M., Dijkmans, B. A. C., Boers, M.
(2008). Discordant perspectives of rheumatologists and patients on COBRA combination therapy in rheumatoid arthritis. Rheumatology (Oxford)
47: 1571-1576
[Abstract][Full Text]
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
[Abstract][Full Text]
Saleem, B, Mackie, S, Quinn, M, Nizam, S, Hensor, E, Jarrett, S, Conaghan, P G, Emery, P
(2008). Does the use of tumour necrosis factor antagonist therapy in poor prognosis, undifferentiated arthritis prevent progression to rheumatoid arthritis?. Ann Rheum Dis
67: 1178-1180
[Abstract][Full Text]
Kravitz, R. L., Duan, N., White, R. H.
(2008). N-of-1 Trials of Expensive Biological Therapies: A Third Way?. Arch Intern Med
168: 1030-1033
[Abstract][Full Text]
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
(2008). Avonex Combination Trial in relapsing--remitting MS: rationale, design and baseline data. Mult Scler
14: 370-382
[Abstract]
Donahue, K. E., Gartlehner, G., Jonas, D. E., Lux, L. J., Thieda, P., Jonas, B. L., Hansen, R. A., Morgan, L. C., Lohr, K. N.
(2008). Systematic Review: Comparative Effectiveness and Harms of Disease-Modifying Medications for Rheumatoid Arthritis. ANN INTERN MED
148: 124-134
[Abstract][Full Text]
Wasko, M. C. M., Hubert, H. B., Lingala, V. B., Elliott, J. R., Luggen, M. E., Fries, J. F., Ward, M. M.
(2007). Hydroxychloroquine and Risk of Diabetes in Patients With Rheumatoid Arthritis. JAMA
298: 187-193
[Abstract][Full Text]
Goekoop-Ruiterman, Y. P.M., de Vries-Bouwstra, J. K., Allaart, C. F., van Zeben, D., Kerstens, P. J.S.M., Hazes, J. M. W., Zwinderman, A. H., Peeters, A. J., de Jonge-Bok, J. M., Mallee, C., de Beus, W. M., de Sonnaville, P. B.J., Ewals, J. A.P.M., Breedveld, F. C., Dijkmans, B. A.C.
(2007). Comparison of Treatment Strategies in Early Rheumatoid Arthritis: A Randomized Trial. ANN INTERN MED
146: 406-415
[Abstract][Full Text]
O'Dell, J. R.
(2007). The BeSt Way to Treat Early Rheumatoid Arthritis?. ANN INTERN MED
146: 459-460
[Full Text]
Capell, H. A, Madhok, R., Porter, D. R, Munro, R. A L, McInnes, I. B, Hunter, J. A, Steven, M., Zoma, A., Morrison, E., Sambrook, M., Wui Poon, F., Hampson, R., McDonald, F., Tierney, A., Henderson, N., Ford, I.
(2007). Combination therapy with sulfasalazine and methotrexate is more effective than either drug alone in patients with rheumatoid arthritis with a suboptimal response to sulfasalazine: results from the double-blind placebo-controlled MASCOT study. Ann Rheum Dis
66: 235-241
[Abstract][Full Text]
Russell, A S, Wallenstein, G V, Li, T, Martin, M C, Maclean, R, Blaisdell, B, Gajria, K, Cole, J C, Becker, J-C, Emery, P
(2007). Abatacept improves both the physical and mental health of patients with rheumatoid arthritis who have inadequate response to methotrexate treatment. Ann Rheum Dis
66: 189-194
[Abstract][Full Text]
Fraenkel, L., Rabidou, N., Dhar, R.
(2006). Are rheumatologists' treatment decisions influenced by patients' age?. Rheumatology (Oxford)
45: 1555-1557
[Abstract][Full Text]
Douglas, K M J, Ladoyanni, E, Treharne, G J, Hale, E D, Erb, N, Kitas, G D
(2006). Cutaneous abnormalities in rheumatoid arthritis compared with non-inflammatory rheumatic conditions. Ann Rheum Dis
65: 1341-1345
[Abstract][Full Text]
Weinblatt, M E, Keystone, E C, Furst, D E, Kavanaugh, A F, Chartash, E K, Segurado, O G
(2006). Long term efficacy and safety of adalimumab plus methotrexate in patients with rheumatoid arthritis: ARMADA 4 year extended study. Ann Rheum Dis
65: 753-759
[Abstract][Full Text]
Pincus, T., Sokka, T.
(2006). Should aggressive therapy for rheumatoid arthritis require early use of weekly low-dose methotrexate, as the first disease-modifying anti-rheumatic drug in most patients?. Rheumatology (Oxford)
45: 497-499
[Full Text]
Lev-Ari, S., Strier, L., Kazanov, D., Elkayam, O., Lichtenberg, D., Caspi, D., Arber, N.
(2006). Curcumin synergistically potentiates the growth-inhibitory and pro-apoptotic effects of celecoxib in osteoarthritis synovial adherent cells. Rheumatology (Oxford)
45: 171-177
[Abstract][Full Text]
Choy, E. H. S., Smith, C., Dore, C. J., Scott, D. L.
(2005). A meta-analysis of the efficacy and toxicity of combining disease-modifying anti-rheumatic drugs in rheumatoid arthritis based on patient withdrawal. Rheumatology (Oxford)
44: 1414-1421
[Abstract][Full Text]
Irvine, S, Capell, H C
(2005). Great expectations of modern RA treatment. Ann Rheum Dis
64: 1249-1251
[Full Text]
Suresh, E, Lambert, C M
(2005). Combination treatment strategies in early rheumatoid arthritis. Ann Rheum Dis
64: 1252-1256
[Abstract][Full Text]
Cronstein, B. N.
(2005). Low-Dose Methotrexate: A Mainstay in the Treatment of Rheumatoid Arthritis. Pharmacol. Rev.
57: 163-172
[Abstract][Full Text]
Roberts, L. J., Kalil, A. C., Messori, A., Santarlasci, B., Vaiani, M.
(2004). New Drugs for Rheumatoid Arthritis. NEJM
351: 2659-2661
[Full Text]
Lee, S J, Kavanaugh, A
(2004). A need for greater reporting of socioeconomic status and race in clinical trials. Ann Rheum Dis
63: 1700-1701
[Full Text]
Choy, E. H.
(2004). Two is better than one? Combination therapy in rheumatoid arthritis. Rheumatology (Oxford)
43: 1205-1207
[Full Text]
O'Dell, J. R.
(2004). Therapeutic Strategies for Rheumatoid Arthritis. NEJM
350: 2591-2602
[Full Text]
Breedveld, F C, Kalden, J R
(2004). Appropriate and effective management of rheumatoid arthritis. Ann Rheum Dis
63: 627-633
[Abstract][Full Text]
Matteson, E. L., Weyand, C. M., Fulbright, J. W., Christianson, T. J. H., McClelland, R. L., Goronzy, J. J.
(2004). How aggressive should initial therapy for rheumatoid arthritis be? Factors associated with response to 'non-aggressive' DMARD treatment and perspective from a 2-yr open label trial. Rheumatology (Oxford)
43: 619-625
[Abstract][Full Text]
Maillefert, J F, Combe, B, Goupille, P, Cantagrel, A, Dougados, M
(2003). Long term structural effects of combination therapy in patients with early rheumatoid arthritis: five year follow up of a prospective double blind controlled study. Ann Rheum Dis
62: 764-766
[Abstract][Full Text]
Gerards, A H, Landewe, R B M, Prins, A P A, Bruijn, G A W, Goei The, H S, Laan, R F J M, Dijkmans, B A C
(2003). Cyclosporin A monotherapy versus cyclosporin A and methotrexate combination therapy in patients with early rheumatoid arthritis: a double blind randomised placebo controlled trial. Ann Rheum Dis
62: 291-296
[Abstract][Full Text]
Gause, A.
(2003). Progress in the treatment of rheumatic disease. Nephrol Dial Transplant
18: 13-16
[Full Text]
Canvin, J. M. G., Bernatsky, S., Hitchon, C. A., Jackson, M., Sowa, M. G., Mansfield, J. R., Eysel, H. H., Mantsch, H. H., El-Gabalawy, H. S.
(2003). Infrared spectroscopy: shedding light on synovitis in patients with rheumatoid arthritis. Rheumatology (Oxford)
42: 76-82
[Abstract][Full Text]
Kremer, J. M., Genovese, M. C., Cannon, G. W., Caldwell, J. R., Cush, J. J., Furst, D. E., Luggen, M. E., Keystone, E., Weisman, M. H., Bensen, W. M., Kaine, J. L., Ruderman, E. M., Coleman, P., Curtis, D. L., Kopp, E. J., Kantor, S. M., Waltuck, J., Lindsley, H. B., Markenson, J. A., Strand, V., Crawford, B., Fernando, I., Simpson, K., Bathon, J. M.
(2002). Concomitant Leflunomide Therapy in Patients with Active Rheumatoid Arthritis despite Stable Doses of Methotrexate: A Randomized, Double-Blind, Placebo-Controlled Trial. ANN INTERN MED
137: 726-733
[Abstract][Full Text]
Temekonidis, T I, Georgiadis, A N, Alamanos, Y, Bougias, D V, Voulgari, P V, Drosos, A A
(2002). Infliximab treatment in combination with cyclosporin A in patients with severe refractory rheumatoid arthritis. Ann Rheum Dis
61: 822-825
[Abstract][Full Text]
Ferraccioli, G. F., Gremese, E., Tomietto, P., Favret, G., Damato, R., Di Poi, E.
(2002). Analysis of improvements, full responses, remission and toxicity in rheumatoid patients treated with step-up combination therapy (methotrexate, cyclosporin A, sulphasalazine) or monotherapy for three years. Rheumatology (Oxford)
41: 892-898
[Abstract][Full Text]
Machein, U., Buss, B., Spiller, I., Braun, J., Rudwaleit, M., Faerber, L., Sieper, J.
(2002). Effective treatment of early rheumatoid arthritis with a combination of methotrexate, prednisolone and cyclosporin. Rheumatology (Oxford)
41: 110-111
[Full Text]
Pisetsky, D. S., St.Clair, E. W.
(2001). Progress in the Treatment of Rheumatoid Arthritis. JAMA
286: 2787-2790
[Full Text]
Lai, J.-H., Ho, L.-J., Lu, K.-C., Chang, D.-M., Shaio, M.-F., Han, S.-H.
(2001). Western and Chinese Antirheumatic Drug-Induced T Cell Apoptotic DNA Damage Uses Different Caspase Cascades and Is Independent of Fas/Fas Ligand Interaction. J. Immunol.
166: 6914-6924
[Abstract][Full Text]
Kim, W-U, Seo, Y-I, Park, S-H, Lee, W-K, Lee, S-K, Paek, S-I, Cho, C-S, Song, H-H, Kim, H-Y
(2001). Treatment with cyclosporin switching to hydroxychloroquine in patients with rheumatoid arthritis. Ann Rheum Dis
60: 514-517
[Abstract][Full Text]
Kremer, J. M.
(2001). Rational Use of New and Existing Disease-Modifying Agents in Rheumatoid Arthritis. ANN INTERN MED
134: 695-706
[Abstract][Full Text]
Zink, A, Listing, J, Niewerth, M, Zeidler, H
(2001). The national database of the German Collaborative Arthritis Centres: II. Treatment of patients with rheumatoid arthritis. Ann Rheum Dis
60: 207-213
[Abstract][Full Text]
Koopman, W. J.
(2001). Prospects for Autoimmune Disease: Research Advances in Rheumatoid Arthritis. JAMA
285: 648-650
[Abstract][Full Text]
Schattner, A.
(2000). A new era in rheumatoid arthritis treatment--time to introduce a modified treatment pyramid. QJM
93: 757-760
[Full Text]
Uitz, E., Fransen, J., Langenegger, T., Stucki, G., , f. t. m. o. t. S. C. Q. M. i. R. A.
(2000). Clinical quality management in rheumatoid arthritis: putting theory into practice. Rheumatology (Oxford)
39: 542-549
[Abstract][Full Text]
Goldring, S. R.
(2000). A 55-Year-Old Woman With Rheumatoid Arthritis. JAMA
283: 524-531
[Full Text]
Bingham, S., Emery, P.
(2000). Resistant rheumatoid arthritis clinics-- a necessary development?. Rheumatology (Oxford)
39: 2-5
[Full Text]
Pincus, T., O'Dell, J. R., Kremer, J. M.
(1999). Combination Therapy with Multiple Disease-Modifying Antirheumatic Drugs in Rheumatoid Arthritis: A Preventive Strategy. ANN INTERN MED
131: 768-774
[Abstract][Full Text]
Verhoeven, A. C., Boers, M., Tugwell, P.
(1999). Combination therapy in rheumatoid arthritis. Rheumatology (Oxford)
38: 789a-790a
[Full Text]
Dougados, M., Combe, B., Cantagrel, A., Goupille, P., Olive, P., Schattenkirchner, M., Meusser, S, Paimela, L, Rau, R., Zeidler, H., Leirisalo-Repo, M., Peldan, K.
(1999). Combination therapy in early rheumatoid arthritis: a randomised, controlled, double blind 52 week clinical trial of sulphasalazine and methotrexate compared with the single components. Ann Rheum Dis
58: 220-225
[Abstract][Full Text]
Weinblatt, M. E., Kremer, J. M., Bankhurst, A. D., Bulpitt, K. J., Fleischmann, R. M., Fox, R. I., Jackson, C. G., Lange, M., Burge, D. J.
(1999). A Trial of Etanercept, a Recombinant Tumor Necrosis Factor Receptor:Fc Fusion Protein, in Patients with Rheumatoid Arthritis Receiving Methotrexate. NEJM
340: 253-259
[Abstract][Full Text]
O'Dell, J. R.
(1999). Anticytokine Therapy -- A New Era in the Treatment of Rheumatoid Arthritis?. NEJM
340: 310-312
[Full Text]
Campbell, S. M., Wernick, R.
(1999). Update in Rheumatology. ANN INTERN MED
130: 135-142
[Full Text]
Porro, G., Bertolini, G., Bonardi, M. A., Giovanetti, E., Lento, P., Leoni, F., Modena, D., Pavich, G., Marcucci, F.
(1998). Diaminic Carbonates, a New Class of Anti-inflammatory Compounds: Their Biological Characterization and Mode of Action. J. Pharmacol. Exp. Ther.
285: 193-200
[Abstract][Full Text]
O'Dell, J. R, Nepom, B. S, Haire, C., Gersuk, V. H, Gaur, L., Moore, G. F, Drymalski, W., Palmer, W., Eckhoff, P J., Klassen, L. W, Wees, S., Thiele, G., Nepom, G. T
(1998). HLA-DRB1 typing in rheumatoid arthritis: predicting response to specific treatments. Ann Rheum Dis
57: 209-213
[Abstract][Full Text]
Harvey, S., Weisman, M., O'Dell, J., Scott, T., Visor, M. K. J., Swindlehurst, C.
(1998). Chondrex: new marker of joint disease. Clin. Chem.
44: 509-516
[Abstract][Full Text]
FERRACCIOLI, G F, CASATTA, L, DI POI, E, DAMATO, R, BARTOLI;, E, O'DELL, J. R
(1997). Combination DMARD therapy for rheumatoid arthritis. Full or low DMARD doses?. Ann Rheum Dis
56: 336a-337
[Full Text]
MASI, A. T, CHROUSOS, G. P
(1997). Dilemmas of low dosage glucocorticoid treatment in rheumatoid arthritis: considerations of timing. Ann Rheum Dis
56: 1-4
[Full Text]
Stohl, W., Arkfeld, D. G., Zurier, R. B., DeMarco, D. M., Liu, N. Y., Schinagl, E. F., Strauss, P. C., O'Dell, J. R.
(1996). Treatment of Rheumatoid Arthritis. NEJM
335: 821-823
[Full Text]
(1996). COMBINING DISEASE-MODIFYING DRUGS FOR RHEUMATOID ARTHRITIS. JWatch General
1996: 4-4
[Full Text]
Previous
