Combination Therapy with Cyclosporine and Methotrexate in Severe Rheumatoid Arthritis
Peter Tugwell, M.D., Theodore Pincus, M.D., David Yocum, M.D., Michael Stein, M.D., Oscar Gluck, M.D., Gunnar Kraag, M.D., Robert McKendry, M.D., John Tesser, M.D., Philip Baker, B.Sc., George Wells, Ph.D., for The Methotrexate–Cyclosporine Combination Study Group
Background Patients with severe rheumatoid arthritis who aretreated with methotrexate frequently have only partial improvement.
Methods In a six-month randomized, double-blind trial, we comparedcombination therapy with cyclosporine (2.5 to 5 mg per kilogramof body weight per day) and methotrexate (at the maximal tolerateddose) with methotrexate and placebo in 148 patients with rheumatoidarthritis who had residual inflammation and disability despitepartial but substantial responses to prior methotrexate treatment.The primary outcome measure was the change in the number oftender joints.
Results As compared with the placebo group, the patients inthe treatment group had a net improvement in the tender-jointcount of 25 percent, or 4.8 joints (95 percent confidence interval,0.7 to 8.9; P = 0.02), and in the swollen-joint count of 25percent, or 3.8 joints (95 percent confidence interval, 1.3to 6.3; P = 0.005); improvement in overall disease activityas assessed by the physician (19 percent, P<0.001) and thepatient (21 percent, P<0.001); and improvement in joint pain(23 percent, P = 0.04) and in the degree of disability (26 percent,P<0.001). Thirty-six patients (48 percent) in the cyclosporinegroup and 12 patients (16 percent) in the placebo group (P<0.001)met the 1993 criteria for improvement of the American Collegeof Rheumatology (more than 20 percent improvement in the numbersof both swollen and tender joints and improvement in three offive other variables). Serum creatinine concentrations increasedby a mean of 0.14±0.27 mg per deciliter (12±24mmol per liter) in the cyclosporine group and by 0.05±0.19mg per deciliter (4±17 mmol per liter) in the placebogroup (P = 0.02).
Conclusions Patients with severe rheumatoid arthritis and onlypartial responses to methotrexate had clinically important improvementafter combination therapy with cyclosporine and methotrexate.Side effects were not substantially increased. Long-term follow-upof patients treated with this combination is needed.
Rheumatoid arthritis is a chronic, recurrent inflammatory diseasethat leads to substantial disability, loss of productivity,and increased mortality.1,2,3 The traditional4 approach to drugtreatment emphasizes the stepped use of one medication at atime. When first-line agents such as aspirin and other nonsteroidalantiinflammatory drugs fail, slow-acting antirheumatic drugssuch as methotrexate, antimalarial agents, gold salts, penicillamine,or sulfasalazine are considered. Patients treated with cyclosporine,a recent addition to this list, have improvement of similarmagnitude to that of patients given other slow-acting agents.5
Monotherapy for rheumatoid arthritis is being reconsidered becauseof dissatisfaction with its effects,6,7,8 and combination therapyhas attracted increasing attention.9,10,11 In an open study,patients who had partial improvement while receiving gold ormethotrexate had additional improvement when they also receivedlow-dose cyclosporine.12 In a multicenter, placebo-controlled,randomized trial, we assessed combination therapy with cyclosporineand methotrexate for patients with severe rheumatoid arthritis.
Methods
Eligibility
To be eligible for the study, patients had to meet the revisedcriteria of the American Rheumatism Association for rheumatoidarthritis13; had to have had a partial response in symptomssince the start of methotrexate treatment that they consideredimportant and improvement in the number of tender joints, asdetermined by their physicians; had to have been receiving theirmaximal tolerated dose of methotrexate (<15 mg per week)at a stable dosage for a least three months; had to have hadthe same number of tender joints on two assessments one monthapart; had to have active synovitis, defined as six or moreactively inflamed tender or swollen joints; and had to be receivingno more than 10 mg of prednisone per day, a stable dose of nonsteroidalantiinflammatory drugs given for at least four weeks, or both.
Patients were excluded from the study if they had abnormal hepaticor renal function, a platelet count below 100,000 per cubicmillimeter, leukopenia (total white-cell count, <3000 percubic millimeter), cancer or a history of cancer, or concomitanttherapy with any other experimental drug during the month beforeentry. Women of reproductive age were required to take appropriatecontraceptive measures.
Treatment Groups and Monitoring
After providing written informed consent, patients were randomlyassigned to receive cyclosporine or placebo in addition to theirmaximal tolerated dose of methotrexate. The first patient wasenrolled in March 1992, and the last in May 1993. A separaterandomization schedule was generated at each center. Gelatincapsules of cyclosporine (Sandimmune, 25 mg and 100 mg) andplacebo were prepared by Sandoz (Basel, Switzerland); they wereidentical in taste and appearance.
The initial dose of cyclosporine or placebo was 2.5 mg per kilogramof body weight per day, given in two divided doses at 12-hourintervals. Serum creatinine concentrations and other laboratoryvalues were monitored, and cyclosporine doses adjusted, by aclinician who was aware of the patient's study group but notinvolved in assessing outcomes. The dose of cyclosporine (orplacebo in identical capsules) was increased by 0.5 mg per kilogramper day to a maximum of 5 mg per kilogram at weeks 2, 4, 8,12, and 16 if actively inflamed joints remained. The dosageof cyclosporine was reduced by 0.5 mg per kilogram per day ifthe serum creatinine level increased by 30 percent or more fromthe base-line level. If after seven days the creatinine levelwas more than 30 percent above base line, the dosage was decreasedby an additional 0.5 mg per kilogram per day each week untilthe creatinine level decreased to no more than 30 percent abovebase line. If serum aminotransferase concentrations exceededtwice the upper limit of normal, the white-cell count fell below3000 per cubic millimeter, or the platelet count fell below100,000 per cubic millimeter, methotrexate therapy was discontinueduntil the values became normal. After the base-line assessment,patients were seen twice in the first month and then monthlyuntil the end of the six-month study period.
Clinical Assessments
The patients, primary care physicians, and study investigatorswere unaware of the study-group assignments. Assessments wereperformed by rheumatologists, nurses, or clinical metrologiststrained in making standardized assessments in clinical trials(to minimize intraobserver variation); each patient's conditionwas assessed by the same person throughout the study. Benefitswere evaluated with a standard classification system for assessingclinical outcomes.14 Seven clinical variables were evaluated:the tender-joint count (the number of joints with clinicallyactive disease, as determined by pain on passive movement andtenderness on pressure)15; the swollen-joint count15; pain asrecorded on a 100-mm visual-analogue scale15; the physician'soverall assessment of disease activity15; the patient's overallassessment of disease activity15; the degree of disability,as measured on the Health Assessment Questionnaire16; and theerythrocyte sedimentation rate. The primary outcome measurewas the tender-joint count, as defined by the American Collegeof Rheumatology.15 Blood pressure and the concurrent use ofother medications were recorded at base line and at each follow-upvisit.
Laboratory Assessments and Side Effects
The following tests were performed at base line, every two weeksfor the first month, and monthly thereafter: complete bloodcount; serum determinations of total bilirubin, aspartate aminotransferase,alkaline phosphatase, creatinine, blood urea nitrogen, electrolytes,and uric acid; and urinalysis. The erythrocyte sedimentationrate was obtained by the Westergren method at base line andat the end of months 2 and 6. Rheumatoid factor was measuredat base line and six months. Side effects were monitored ateach clinic visit by asking the patient open-ended questionsto identify any problems that had occurred since the previousvisit.
Statistical Analysis
With the tender-joint count used as the primary outcome, a sampleof 75 patients per group was needed in order to have a 5 percentprobability of a Type I error and a power of 80 percent to detecta difference of 5 tender joints between groups, with a standarddeviation of 9.5,7 and to allow for a 25 percent dropout rate.
All the study patients were included in the primary analysis,with the data on those who did not complete the study extrapolatedfrom the time of their permanent discontinuation of the studytreatment. Changes in continuous variables were compared bythe t-test, and changes in categorical data by the chi-squarestatistic.17 The scores for changes were expressed as a percentageof each group's mean base line score, and relative improvementwas computed by subtracting the percentage of improvement inthe placebo group from that in the cyclosporine group.
Results
Among the consecutive patients who were potentially eligiblefor the study, 148 patients were randomized. Another 36 patientswere screened but not randomized for the following reasons:refusal to participate because of the inconvenience of studyrequirements, an unwillingness to risk potential toxic effects,or the risk of being assigned to placebo (17 patients); abnormalresults on laboratory tests (9); the lack of a stable jointcount at the base-line assessments (8); and a history of cancer(2).
The base-line characteristics of the 148 patients are summarizedin Table 1. There were no substantive differences between thetwo groups with regard to these characteristics. Although themajority of patients had advanced rheumatoid arthritis, 41 (28percent) had had their disease for less than five years. Amongthose enrolled, 117 patients (56 of the 75 in the cyclosporinegroup and 61 of the 73 in the placebo group) completed the six-monthregimen of study medication. Seventeen patients in the cyclosporinegroup and 12 in the placebo group were withdrawn from the studytreatment before six months. The timing and reasons are shownin Table 2. Two patients died, both in the cyclosporine group.Interstitial pneumonitis developed in a 76-year-old woman after15 weeks of therapy, and she died 5 weeks later. The cause ofdeath was thought to be viral pneumonia; methotrexate couldnot be ruled out as a contributing factor. An autopsy showedmild pulmonary fibrosis but no hypersensitivity changes characteristicof pneumonia caused by methotrexate. When cyclosporine therapywas discontinued, the dose was 4.0 mg per kilogram and the creatinineconcentration was 1.39 mg per deciliter (122 µmol perliter), an increase of 16 percent over the base-line value of1.19 mg per deciliter (105 µmol per liter). The otherpatient died in a motor vehicle accident during the fourth weekof the study.
Table 2. Reasons for Early Withdrawal of Patients from the Study, According to Study Group.
The mean (±SD) dose of cyclosporine at the time of thefinal treatment was 2.97±1.02 mg per kilogram per day.The mean serum creatinine concentration increased from baseline to six months by 0.14±0.27 mg per deciliter (12±24µmol per liter) in the cyclosporine group and 0.05±0.19mg per deciliter (4±17 µmol per liter) in the placebogroup (P = 0.02). The mean diastolic blood pressure in the cyclosporinegroup rose from 77.6 mm Hg to 78.2 mm Hg at six months, as comparedwith a decrease from 77.0 to 76.8 mm Hg in the placebo group(P = 0.219). Eight patients in the cyclosporine group and 10in the placebo group had readings of diastolic pressure above95 mm Hg and of systolic pressure above 165 mm Hg on at leasttwo occasions. Other adverse events reported included hypertrichosis(in 10 patients in the cyclosporine group, as compared withnone in the placebo group), tremors (in 4 and 1, respectively),paresthesia (in 8 and 3), nausea (in 21 and 12), diarrhea (in13 and 12), dyspepsia (in 3 and 3), gum hyperplasia (in 1 and2), and mouth ulcers (in 14 and 11). Many of the reported gastrointestinaland neurologic symptoms were not severe enough for the patientsto be withdrawn prematurely from the study, and many symptomsimproved over time.
The main study outcomes are summarized in Figure 1 and Table 3.There were statistically significant differences betweenthe treatment groups on all clinical measures. As compared withthose in the placebo group, the patients in the treatment grouphad a mean improvement in the tender-joint count of 25 percent,or 4.8 joints (95 percent confidence interval, 0.7 to 8.9; P= 0.02), and in the swollen-joint count of 25 percent, or 3.8joints (95 percent confidence interval, 1.3 to 6.3, P = 0.005);improvement in overall disease activity as assessed by the physician(19 percent, P<0.001) and the patient (21 percent, P<0.001);and improvement in joint pain (23 percent, P = 0.04) and inthe degree of disability, as measured on the Health AssessmentQuestionnaire (26 percent, P<0.001). The mean erythrocytesedimentation rate increased by 4.2 mm per hour in the cyclosporinegroup and decreased by 4.8 mm per hour in the placebo group(P = 0.006). Forty-eight patients (64 percent) in the cyclosporinegroup improved by at least 25 percent, and 34 (45 percent) byat least 50 percent, in the number of tender joints, as comparedwith 34 patients (47 percent, P = 0.033) and 20 patients (27percent, P = 0.023), respectively, in the placebo group.
Figure 1. Percentage of Patients with Rheumatoid Arthritis Who Had 20 Percent Improvement in the Number of Tender and Swollen Joints and Improvement in Other Variables.
The American College of Rheumatology defines improvement as improvement in at least three of five variables (degree of disability, pain, patient's global assessment, physician's global assessment, and erythrocyte sedimentation rate) in addition to 20 percent improvement in the number of tender and swollen joints.
Table 3. Outcomes of Treatment during Six Months of Study in Patients with Rheumatoid Arthritis.
The proportions of patients in each group who met the preliminarycriteria of the American College of Rheumatology for improvementin rheumatoid arthritis19 are shown in Figure 1. These criteriarequire that patients improve by 20 percent in the numbers ofboth swollen and tender joints and in three of the five remainingend points (pain, the patient's global assessment, the physician'sglobal assessment, the degree of disability, and the erythrocytesedimentation rate).14 Thirty-six patients (48 percent) in thecyclosporine group met these criteria, as compared with 12 (16percent) in the placebo group (P<0.001).
Discussion
Patients with rheumatoid arthritis who had only partial responsesto methotrexate had clinically important improvement when cyclosporinewas added to their treatment. As shown in Figure 1 and Table 3,the benefits were consistent for all clinical end points,including both measurable and detectable physical signs of inflammation,such as joint swelling and tenderness, and information reportedby patients, such as pain and disability. The lack of a beneficialeffect of the combination of methotrexate and cyclosporine onthe erythrocyte sedimentation rate was consistent with the findingsin studies of cyclosporine therapy alone.5
In rheumatoid arthritis, treatment with a single slow-actingagent rarely results in true remission. Clinical studies ofother combinations (such as that of antimalarial agents withgold or penicillamine, or that of methotrexate with azathioprineor auranofin) have shown equivocal benefits.9,11 Favorable experiencewith combination therapy in transplantation and oncology encouragedus to study two relatively potent agents, methotrexate and cyclosporine.Methotrexate is effective in controlling clinical signs of inflammationin patients with rheumatoid arthritis, has an effect that continuessubstantially longer than those of other slow-acting drugs,20,21and is considered by many rheumatologists to be the second-linedrug of first choice.22 Cyclosporine is effective as a singleagent in patients with rheumatoid arthritis.5 The two drugstogether have been shown to be more effective than either usedalone.23 An open study12 suggested that the combination of cyclosporineand methotrexate was more effective than methotrexate alonein patients with partial responses to methotrexate. Methotrexateand cyclosporine may work through different mechanisms: methotrexatethrough interleukin-1, macrophages, and monocytes,24 and cyclosporinethrough interleukin-2 and T lymphocytes.25,26,27
A randomized, controlled trial design is particularly importantto ensure that patients' improvement is not due to the naturalhistory of the disease or to treatment with methotrexate alone.Other trials of combination therapy in patients with rheumatologicdiseases require that the drugs be studied alone as well astogether. However, when two therapeutic agents are comparedin rheumatoid arthritis, there is often a high rate of spontaneousimprovement in the placebo group (due to regression to the mean).10It is difficult to discern differences between groups withoutenrolling large numbers of patients and evaluating long periodsof therapy. This problem may explain the equivocal results ofprevious studies of drug combinations in rheumatoid arthritis,such as that of methotrexate with auranofin or azathioprine.28,29Our protocol, in which a combination of two drugs was comparedwith a single drug plus placebo, provided a statistically efficientway of evaluating the efficacy and safety of the combination.Such protocols are commonly used in oncology to evaluate theearly efficacy of combination chemotherapy.
The frequency and causes of adverse events were similar to thosein prior trials of methotrexate30 and cyclosporine5 used alone.Unacceptable toxic effects (e.g., gastrointestinal intoleranceand bone marrow suppression) found with other drug combinations11did not occur in this trial. Although both drugs affect thekidneys, deterioration of renal function was not a clinicalproblem. Because the threshold for dose reduction was a 30 percentincrease in the serum creatinine concentration, the mean doseof cyclosporine in this study (2.97±1.02 mg per kilogram)was lower than that in our previous placebo-controlled trialof cyclosporine alone31 (3.8 mg per kilogram), in which thethreshold for dose reduction was a 50 percent increase in thecreatinine level. The finding of efficacy with lower doses isreassuring, since the risk of structural damage to the kidneysfrom cyclosporine is dose-dependent.32
The long-term risk of cancer with the combination of methotrexateand cyclosporine requires further study. Patients with rheumatoidarthritis have a risk of cancer 20 to 30 times higher than peoplein general, whether or not they have taken second-line agents.Those who take such agents have a risk 10 times higher thanthose who do not. Although these relative risks are high, theymay be acceptable to many patients and physicians, since theabsolute risk of cancer is less than 0.1 percent per year.33Reversible lymphomas have occurred in patients with rheumatoidarthritis who have received either methotrexate or cyclosporinealone.34,35 The Sandoz Corporation maintains a registry of lymphomasreported in patients who have ever received cyclosporine; asof June 1994, four lymphomas and one lung cancer had been reportedin 2327 patients with rheumatoid arthritis who were so treated.
The usefulness of the type of combination therapy we studiedcan be evaluated from several perspectives. Symptoms and signsof inflammation lessened to a clinically important degree.36Rheumatoid arthritis severe enough to warrant second-line therapy,as assessed by the number of tender joints and the degree ofdisability, carries a substantially increased risk of long-termdisability and a reduced life expectancy.37,38 Further studiesshould assess whether this combination therapy decreases disabilityand reduces mortality in such patients.36 Many believe thatthese goals are more likely to be achieved by treating the patientaggressively early in the course of disease — that is,beginning less than two years after diagnosis.9 Long-term follow-upof patients treated with this combination should also assesswhether the benefit is maintained, whether the use of the drugsmight be discontinued temporarily or permanently, and whetherlong-term toxicity is increased.
Supported by Sandoz Canada and Sandoz Pharmaceuticals, U.S.A.Dr. Tugwell, Dr. Pincus, Dr. Yocum, and Dr. Stein have receivedhonorariums for talks from Sandoz.
We are indebted to Ms. Diane Gagnon for assistance in the preparationof the manuscript.
* Additional members of the Methotrexate–Cyclosporine StudyGroup are listed in the Appendix.
Source Information
From the Department of Medicine and the Clinical Epidemiology Unit, University of Ottawa, Ottawa, Ont., Canada (P.T., G.K., R.M., P.B., G.W.); the Division of Rheumatology and Immunology, Vanderbilt University, Nashville (T.P., M.S.); the Division of Rheumatology and Immunology, University of Arizona, Tucson (D.Y.); and the Arizona Rheumatology Center, Phoenix (O.G., J.T.).
Address reprint requests to Dr. Tugwell at the Department of Medicine, University of Ottawa and Ottawa General Hospital, 501 Smyth Rd., Rm. LM12, Ottawa, ON K1H 8L6, Canada.
References
Harris ED Jr. Clinical features of rheumatoid arthritis. In: Kelley WN, Harris ED Jr, Ruddy S, Sledge CB, eds. Textbook of rheumatology. 4th ed. Vol. 1. Philadelphia: W.B. Saunders, 1993:874-911.
Gordon DA, Hastings DE. Rheumatoid arthritis clinical features. In: Klippel JH, Dieppe PA, eds. Rheumatology. St. Louis: C.V. Mosby, 1994:3.4.1-3.4.14.
Pincus T, Callahan LF. What is the natural history of rheumatoid arthritis? Rheum Dis Clin North Am 1993;19:123-151. [Medline]
Williams JH. Rheumatoid arthritis: treatment. In: Schumacher HR Jr, ed. Primer on rheumatic diseases. 10th ed. Atlanta: The Arthritis Foundation, 1993:96-9.
Wells G, Tugwell P. Cyclosporin A in rheumatoid arthritis: overview of efficacy. Br J Rheumatol 1993;32:Suppl 1:51-56.
Wilske KR, Healey LA. Remodelling the pyramid -- a concept whose time has come. J Rheumatol 1989;16:565-567. [Medline]
Bensen WG, Bensen W, Adachi JD, Tugwell PX. Remodelling the pyramid: the therapeutic target of rheumatoid arthritis. J Rheumatol 1990;17:987-989. [Medline]
Pincus T, Callahan LF. Remodeling the pyramid or remodeling the paradigms concerning rheumatoid arthritis -- lessons from Hodgkin's disease and coronary artery disease. J Rheumatol 1990;17:1582-1585. [Medline]
Tugwell P, Boers M. Long-acting drug combinations in rheumatoid arthritis: updated overview. In: Wolfe F, Pincus T, eds. Rheumatoid arthritis: pathogenesis, assessment, outcome, and treatment. New York: Marcel Dekker, 1994:357-71.
Paulus HE. The use of combinations of disease-modifying antirheumatic agents in rheumatoid arthritis. Arthritis Rheum 1990;33:113-120. [Medline]
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]
Bensen W, Tugwell P, Roberts R, et al. Combination therapy of cyclosporine with methotrexate and gold in rheumatoid arthritis (2 pilot studies). J Rheumatol 1994;21:2034-2038. [Medline]
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]
The OMERACT Committee. Conference on Outcome Measures in Rheumatoid Arthritis Clinical Trials, Maastricht, the Netherlands, April 29-May 3, 1992. J Rheumatol 1993;20:527-591. [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]
Fries JF, Spitz PW, Young DY. The dimensions of health outcomes: the Health Assessment Questionnaire, disability and pain scales. J Rheumatol 1982;9:789-793. [Medline]
Steinbrocker O, Traeger CH, Batterman RC. Therapeutic criteria in rheumatoid arthritis. JAMA 1949;140:659-662. [Free Full Text]
Felson DT. American College of Rheumatology preliminary criteria for improvement in rheumatoid arthritis trials. Arthritis Rheum (in press).
Wolfe F, Hawley DJ, Cathey MA. Termination of slow acting antirheumatic therapy in rheumatoid arthritis: a 14-year prospective evaluation of 1017 consecutive starts. J Rheumatol 1990;17:994-1002. [Medline]
Pincus T, Marcum SB, Callahan LF. Longterm drug therapy for rheumatoid arthritis in seven rheumatology private practices. II. Second-line drugs and prednisone. J Rheumatol 1992;19:1885-1894. [Medline]
Cash JM, Klippel JH. Second-line drug therapy for rheumatoid arthritis. N Engl J Med 1994;330:1368-1375. [Free Full Text]
Brahn E, Peacock DJ, Banquerigo ML. Suppression of collagen-induced arthritis by combination cyclosporin A and methotrexate therapy. Arthritis Rheum 1991;34:1282-1288. [CrossRef][Medline]
Kremer JM, Petrillo GF, Lawrence DA. Methotrexate (MTX) induces significant changes in IL-1, IL-2, IL-6 and IL-8 but not lymphocyte markers in patients (PTS) with rheumatoid arthritis (RA). Arthritis Rheum 1993;36:Suppl:S77-S77.abstract
Reem GH, Cook LA, Vilcek J. Gamma interferon synthesis by human thymocytes and T lymphocytes inhibited by cyclosporin A. Science 1983;221:63-65. [Free Full Text]
Kronke M, Leonard WJ, Depper JM, et al. Cyclosporin A inhibits T-cell growth factor gene expression at the level of mRNA transcription. Proc Natl Acad Sci U S A 1984;81:5214-5218. [Free Full Text]
Palacios R. Cyclosporin A inhibits antigen- and lectin-induced but not constitutive production of interleukin-3. Eur J Immunol 1985;15:204-206. [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]
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]
Tugwell P, Bennett K, Gent M. Methotrexate in rheumatoid arthritis: indications, contraindications, efficacy, and safety. Ann Intern Med 1987;107:358-366.
Tugwell P, Bombardier C, Gent M, et al. Low-dose cyclosporin versus placebo in patients with rheumatoid arthritis. Lancet 1990;335:1051-1055. [CrossRef][Medline]
International Kidney Biopsy Registry of Cyclosporin (Sandimmun) in Autoimmune Diseases. Renal morphology after cyclosporin A therapy in rheumatoid arthritis patients. Br J Rheumatol 1993;32:Suppl 1:65-71.
Morse ML, LeRoy AA, Strom BL. COMPASS: a population-based postmarketing drug surveillance system. In: Inman WHW, ed. Monitoring for drug safety. Philadelphia: J.B. Lippincott, 1986:237-54.
Shiroky JB, Frost A, Shelton JD, Haegert DG, Newkirk MM, Neville C. Complications of immunosuppression associated with weekly low dose methotrexate. J Rheumatol 1991;18:1172-1175. [Medline]
Arellano F, Krupp P. Malignancies in rheumatoid arthritis patients treated with cyclosporin A. Br J Rheumatol 1993;32:Suppl 1:72-75.
Edmonds JP, Scott DL, Furst DE, Brooks P, Paulus HE. Antirheumatic drugs: a proposed new classification. Arthritis Rheum 1993;36:336-339. [Medline]
Pincus T, Callahan LF. The side effects of rheumatoid arthritis: joint destruction, disability and early mortality. Br J Rheumatol 1993;32:Suppl 1:28-37.
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]
Appendix
The following members of the Methotrexate–CyclosporineCombination Study Group participated in this trial: R. Goldstein,M.D., P. Morassut, M.D., C. Shamess, M.D., and J. Thomson, M.D.(Ottawa center), coinvestigators; R. Brooks, B.S. (Nashvillecenter), M. Cornett, B.Sc.N. (Tucson center), and P. Dale andJ. Groh (Ottawa center), research coordinators; L. Yetisir,M.Sc. (Ottawa center), biostatistician; and T. Croft (Ottawacenter), data-entry manager.
Cyclosporine and Methotrexate for Severe Rheumatoid Arthritis
Schlesinger N., Huppert A., Hoch S., Malleson P., Steinberg A. D., Rosh J. R., Birnbaum A. H., van de Rijn M., Kamel O. W., Storb R., Thomas E. D., Tugwell P., Yocum D., Pincus T., Wells G.
Extract |
Full Text
N Engl J Med 1995;
333:1567-1569, Dec 7, 1995.
Correspondence
Etanercept in Rheumatoid Arthritis
Cook D. A., Dimick J. B., Gallagher D. C., Escalante A., del Rincón I., Ferraccioli G.F., Di Poi E., Weinblatt M. E., Burge D. J.
Extract |
Full Text
N Engl J Med 1999;
340:2000-2001, Jun 24, 1999.
Correspondence
This article has been cited by other articles:
Griffiths, B., Emery, P., Ryan, V., Isenberg, D., Akil, M., Thompson, R., Maddison, P., Griffiths, I. D., Lorenzi, A., Miles, S., Situnayake, D., Teh, L. S., Plant, M., Hallengren, C., Nived, O., Sturfelt, G., Chakravarty, K., Tait, T., Gordon, C.
(2010). The BILAG multi-centre open randomized controlled trial comparing ciclosporin vs azathioprine in patients with severe SLE. Rheumatology (Oxford)
0: kep396v1-kep396
[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]
Isaacs, J. D.
(2008). Therapeutic T-cell manipulation in rheumatoid arthritis: past, present and future. Rheumatology (Oxford)
47: 1461-1468
[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]
Haupl, T., Ostensen, M., Grutzkau, A., Burmester, G.-R., Villiger, P. M.
(2008). Interaction between rheumatoid arthritis and pregnancy: correlation of molecular data with clinical disease activity measures. Rheumatology (Oxford)
47: iii19-iii22
[Abstract][Full Text]
Choy, E H S, Smith, C M, Farewell, V, Walker, D, Hassell, A, Chau, L, Scott, D L, for the CARDERA (Combination Anti-Rheumatic Drugs,
(2008). Factorial randomised controlled trial of glucocorticoids and combination disease modifying drugs in early rheumatoid arthritis. Ann Rheum Dis
67: 656-663
[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]
Aletaha, D, Strand, V, Smolen, J S, Ward, M M
(2008). Treatment-related improvement in physical function varies with duration of rheumatoid arthritis: a pooled analysis of clinical trial results. Ann Rheum Dis
67: 238-243
[Abstract][Full Text]
Guyatt, G. H., Ferrans, C. E., Halyard, M. Y., Revicki, D. A., Symonds, T. L., Varricchio, C. G., Kotzeva, A., Valderas, J. M., Alonso, J. L., Clinical Significance Consensus Meeting Group,
(2007). Exploration of the Value of Health-Related Quality-of-Life Information From Clinical Research and Into Clinical Practice. Mayo Clin Proc.
82: 1229-1239
[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]
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]
Combe, B, Landewe, R, Lukas, C, Bolosiu, H D, Breedveld, F, Dougados, M, Emery, P, Ferraccioli, G, Hazes, J M W, Klareskog, L, Machold, K, Martin-Mola, E, Nielsen, H, Silman, A, Smolen, J, Yazici, H
(2007). EULAR recommendations for the management of early arthritis: report of a task force of the European Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis
66: 34-45
[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]
Yoo, S.-A., Park, B.-H., Park, G.-S., Koh, H.-S., Lee, M.-S., Ryu, S. H., Miyazawa, K., Park, S.-H., Cho, C.-S., Kim, W.-U.
(2006). Calcineurin Is Expressed and Plays a Critical Role in Inflammatory Arthritis. J. Immunol.
177: 2681-2690
[Abstract][Full Text]
Aletaha, D, Ward, M M
(2006). Duration of rheumatoid arthritis influences the degree of functional improvement in clinical trials. Ann Rheum Dis
65: 227-233
[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]
Suresh, E, Lambert, C M
(2005). Combination treatment strategies in early rheumatoid arthritis. Ann Rheum Dis
64: 1252-1256
[Abstract][Full Text]
Waters, V., Sokol, S., Reddy, B., Soong, G., Chun, J., Prince, A.
(2005). The Effect of Cyclosporin A on Airway Cell Proinflammatory Signaling and Pneumonia. Am. J. Respir. Cell Mol. Bio.
33: 138-144
[Abstract][Full Text]
Fraser, A D, van Kuijk, A W R, Westhovens, R, Karim, Z, Wakefield, R, Gerards, A H, Landewe, R, Steinfeld, S D, Emery, P, Dijkmans, B A C, Veale, D J
(2005). A randomised, double blind, placebo controlled, multicentre trial of combination therapy with methotrexate plus ciclosporin in patients with active psoriatic arthritis. Ann Rheum Dis
64: 859-864
[Abstract][Full Text]
Dougados, M, Emery, P, Lemmel, E M, Zerbini, C A F, Brin, S, van Riel, P
(2005). When a DMARD fails, should patients switch to sulfasalazine or add sulfasalazine to continuing leflunomide?. Ann Rheum Dis
64: 44-51
[Abstract][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]
Fiehn, C., Muller-Ladner, U., Gay, S., Krienke, S., Freudenberg-Konrad, S., Funk, J., Ho, A. D., Sinn, H., Wunder, A.
(2004). Albumin-coupled methotrexate (MTX-HSA) is a new anti-arthritic drug which acts synergistically to MTX. Rheumatology (Oxford)
43: 1097-1105
[Abstract][Full Text]
Yocum, D. E., Furst, D. E., Bensen, W. G., Burch, F. X., Borton, M. A., Mengle-Gaw, L. J., Schwartz, B. D., Wisememandle, W., Mekki, Q. A.
(2004). Safety of tacrolimus in patients with rheumatoid arthritis: long-term experience. Rheumatology (Oxford)
43: 992-999
[Abstract][Full Text]
O'Dell, J. R.
(2004). Therapeutic Strategies for Rheumatoid Arthritis. NEJM
350: 2591-2602
[Full Text]
Strand, V., Cohen, S., Crawford, B., Smolen, J. S., Scott, D. L.
(2004). Patient-reported outcomes better discriminate active treatment from placebo in randomized controlled trials in rheumatoid arthritis. Rheumatology (Oxford)
43: 640-647
[Abstract][Full Text]
Brennan, A., Bansback, N., Reynolds, A., Conway, P.
(2004). Modelling the cost-effectiveness of etanercept in adults with rheumatoid arthritis in the UK. Rheumatology (Oxford)
43: 62-72
[Abstract][Full Text]
Marchesoni, A., Battafarano, N., Arreghini, M., Panni, B., Gallazzi, M., Tosi, S.
(2003). Radiographic progression in early rheumatoid arthritis: a 12-month randomized controlled study comparing the combination of cyclosporin and methotrexate with methotrexate alone. Rheumatology (Oxford)
42: 1545-1549
[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]
Osiri, M, Suarez-Almazor, M E, Wells, G A, Robinson, V, Tugwell, P
(2003). Number needed to treat (NNT): implication in rheumatology clinical practice. Ann Rheum Dis
62: 316-321
[Abstract][Full Text]
Gause, A.
(2003). Progress in the treatment of rheumatic disease. Nephrol Dial Transplant
18: 13-16
[Full Text]
Morgan, C, Lunt, M, Brightwell, H, Bradburn, P, Fallow, W, Lay, M, Silman, A, Bruce, I N
(2003). Contribution of patient related differences to multidrug resistance in rheumatoid arthritis. Ann Rheum Dis
62: 15-19
[Abstract][Full Text]
Isnard Bagnis, C., Tezenas du Montcel, S., Beaufils, H., Jouanneau, C., Jaudon, M. C., Maksud, P., Mallet, A., LeHoang, P., Deray, G.
(2002). Long-Term Renal Effects of Low-Dose Cyclosporine in Uveitis-Treated Patients: Follow-Up Study. J. Am. Soc. Nephrol.
13: 2962-2968
[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]
Scott, D. L., Strand, V.
(2002). The effects of disease-modifying anti-rheumatic drugs on the Health Assessment Questionnaire score. Lessons from the leflunomide clinical trials database. Rheumatology (Oxford)
41: 899-909
[Abstract][Full Text]
Kvien, T K, Zeidler, H K, Hannonen, P, Wollheim, F A, Forre, O, Hafstrom, I, Kaltwasser, J P, Leirisalo-Repo, M, Manger, B, Laasonen, L, Prestele, H, Kurki, P
(2002). Long term efficacy and safety of cyclosporin versus parenteral gold in early rheumatoid arthritis: a three year study of radiographic progression, renal function, and arterial hypertension. Ann Rheum Dis
61: 511-516
[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]
Hochberg, M C, Tracy, J K, Flores, R H
(2001). ""Stepping-up"" from methotrexate: a systematic review of randomised placebo controlled trials in patients with rheumatoid arthritis with an incomplete response to methotrexate. Ann Rheum Dis
60: iii51-54
[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]
Griffiths, B, Emery, P
(2001). The treatment of lupus with cyclosporin A. Lupus
10: 165-170
[Abstract]
Verhoeven, A C, Boers, M, van der Linden, S
(2000). Responsiveness of the core set, response criteria, and utilities in early rheumatoid arthritis. Ann Rheum Dis
59: 966-974
[Abstract][Full Text]
Feldmann, M., Miotla, J., Paleolog, E., Williams, R., Malfait, A.-M., Taylor, P., Brennan, F. M, Maini, R. N
(2000). Future prospects for anti-cytokine treatment. Ann Rheum Dis
59: i119-122
[Abstract][Full Text]
Smolen, J. S., Graninger, W. B., Emery, P.
(2000). Leflunomide, a new disease-modifying anti-rheumatic drug and the never ending rheumatoid arthritis story. Rheumatology (Oxford)
39: 689-692
[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]
Hurst, N. P.
(1999). Combination therapy in rheumatoid arthritis. Rheumatology (Oxford)
38: 789-789
[Full Text]
Cook, D. A., Dimick, J. B., Gallagher, D. C., Escalante, A., del Rincon, I., Ferraccioli, G.F., Di Poi, E., Weinblatt, M. E., Burge, D. J.
(1999). Etanercept in Rheumatoid Arthritis. NEJM
340: 2000-2001
[Full Text]
Veale, D J, Reece, R J, Parsons, W, Radjenovic, A, O'Connor, P J, Orgles, C S, Berry, E, Ridgway, J P, Mason, U, Boylston, A W, Gibbon, W, Emery, P
(1999). Intra-articular primatised anti-CD4: efficacy in resistant rheumatoid knees. A study of combined arthroscopy, magnetic resonance imaging, and histology. Ann Rheum Dis
58: 342-349
[Abstract][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]
Guyatt, G. H., Naylor, C. D., Juniper, E., Heyland, D. K., Jaeschke, R., Cook, D. J.
(1997). Users' Guides to the Medical Literature: XII. How to Use Articles About Health-Related Quality of Life. JAMA
277: 1232-1237
[Abstract]
Schlesinger, N., Huppert, A., Hoch, S., Malleson, P., Steinberg, A. D., Rosh, J. R., Birnbaum, A. H., van de Rijn, M., Kamel, O. W., Storb, R., Thomas, E. D., Tugwell, P., Yocum, D., Pincus, T., Wells, G.
(1995). Cyclosporine and Methotrexate for Severe Rheumatoid Arthritis. NEJM
333: 1567-1569
[Full Text]
(1995). Cyclosporine and Corticosteroids for Rheumatoid Arthritis. Journal Watch Dermatology
1995: 18-18
[Full Text]
(1995). CYCLOSPORINE AND CORTICOSTEROIDS FOR RHEUMATOID ARTHRITIS. JWatch General
1995: 1-1
[Full Text]
Breedveld, F. C.
(1995). New Perspectives on Treating Rheumatoid Arthritis. NEJM
333: 183-184
[Full Text]
