Methotrexate and sulphasalazine as combination therapy in rheumatoid arthritis. The Effectiveness of Early Treatment with Second-Line Antirheumatic Drugs Combination leflunomide and methotrexate (MTX) therapy for patients with active rheumatoid arthritis failing MTX monotherapy: open-label extension of a randomized, double-blind, placebo controlled trial. Longterm combination therapy of refractory and destructive rheumatoid arthritis with methotrexate (MTX) and intramuscular gold or other disease modifying antirheumatic drugs compared to MTX monotherapy. Combination therapy with methotrexate and chloroquine in rheumatoid arthritis. A multicenter randomized placebo-controlled trial. Sustained remission and reduced radiographic progression with combination disease modifying antirheumatic drugs in early rheumatoid arthritis. Combination treatment with methotrexate, cyclosporine, and intraarticular betamethasone compared with methotrexate and intraarticular betamethasone in early active rheumatoid arthritis: an investigator-initiated, multicenter, randomized, double-blind, parallel-group, placebo-controlled study. Development and validation of the European League Against Rheumatism response criteria for rheumatoid arthritis. Comparison with the preliminary American College of Rheumatology and the World Health Organization/International League Against Rheumatism Criteria. Combination therapy versus monotherapy for the treatment of patients with rheumatoid arthritis. Combination therapy in early rheumatoid arthritis: a randomised, controlled, double blind 52 week clinical trial of sulphasalazine and methotrexate compared with the single components Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. Radiographic progression in early rheumatoid arthritis: a 12-month randomized controlled study comparing the combination of cyclosporin and methotrexate with methotrexate alone. Comparison of azathioprine, methotrexate, and the combination of both in the treatment of rheumatoid arthritis. A controlled clinical trial. Treatment continuation rate in relation to efficacy and toxicity in long-term therapy with low-dose methotrexate, sulfasalazine, and bucillamine in 1,358 Japanese patients with rheumatoid arthritis. Combination treatment of rheumatoid arthritis using azathioprine and methotrexate: a 48 week controlled clinical trial. Comparison of azathioprine, methotrexate, and the combination of the two in the treatment of rheumatoid arthritis. A forty-eight-week controlled clinical trial with radiologic outcome assessment. Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial Safety and efficacy of hydroxychloroquine as maintenance therapy for rheumatoid arthritis after combination therapy with methotrexate and hydroxychloroquine. Efficacy of triple DMARD therapy in patients with RA with suboptimal response to methotrexate. Combination of methotrexate and sulphasalazine vs methotrexate alone: a randomized open clinical trial in rheumatoid arthritis patients resistant to sulphasalazine therapy. Preliminary evidence for a structural benefit of the new bisphosphonate zoledronic acid in early rheumatoid arthritis. Methotrexate and leflunomide combination therapy for patients with active rheumatoid arthritis. Combination therapy with hydroxychloroquine and methotrexate in rheumatoid arthritis. Treatment of early seropositive rheumatoid arthritis: doxycycline plus methotrexate versus methotrexate alone. Efficacy of sulphasalazine plus methotrexate in rheumatoid arthritis. Treatment of rheumatoid arthritis with methotrexate alone, sulfasalazine and hydroxychloroquine, or a combination of all three medications. Concomitant Leflunomide Therapy in Patients with Active Rheumatoid Arthritis despite Stable Doses of Methotrexate 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 A 48-week, randomized, double-blind, double-observer, placebo-controlled multicenter trial of combination methotrexate and intramuscular gold therapy in rheumatoid arthritis: results of the METGO study. Levofloxacin Treatment in Patients with Rheumatoid Arthritis Receiving Methotrexate Comparison of Treatment Strategies in Early Rheumatoid Arthritis Long term structural effects of combination therapy in patients with early rheumatoid arthritis: five year follow up of a prospective double blind controlled study Combination therapy with cyclosporine and methotrexate in severe rheumatoid arthritis. The Methotrexate-Cyclosporine Combination Study Group. Combination of sulphasalazine and methotrexate versus the single components in early rheumatoid arthritis: a randomized, controlled, double-blind, 52 week clinical trial.
Sulphasalazine ( SASP ) and methotrexate ( MTX ) are well-established treatments for RA but the use of these drugs in combination has been avoided as both have antifolate activity . In this paper we report our experience with 32 patients treated with the combination MTX/SASP and compare the toxicity and tolerability of the combination with 63 patients treated with MTX alone .  The median duration of exposure to the combination was 23 months . Nineteen patients have continued this regime for over 18 months . Five patients on MTX/SASP combination discontinued MTX , in four cases due to toxicity and in one because MTX/SASP was ineffective . In 17 patients on MTX alone  , the drug was withdrawn permanently . In seven cases the cause was toxicity including two patients with severe reactions . In patients known to tolerate SASP alone , the combination of MTX/SASP is also well tolerated . In our experience of 48 patient-years of such combination therapy , there is no increase in toxicity compared to therapy with MTX alone in RA In recent years , therapeutic strategies for patients with rheumatoid arthritis have been discussed in detail [ 1 - 8 ] . Traditional therapy , usually referred to as the pyramid model , begins with nonsteroidal anti-inflammatory drugs ( NSAIDs ) . If these are insufficiently effective , they are later replaced or supplemented with second-line antirheumatic drugs , which are distinguished from NSAIDs primarily by their assumed disease-modifying potential and delayed onset of action . These second-line drugs are also referred to as slow-acting antirheumatic drugs ( SAARDs ) or disease-modifying antirheumatic drugs ( DMARDs ) . Traditionally , the SAARDs of first choice have been hydroxychloroquine or intramuscular gold followed by D-penicillamine , methotrexate , or azathioprine . The traditional therapeutic pyramid is based on the principle of primum non nocere : Because of their potential toxicity , SAARDs should only be given when milder therapies have failed . Recently , the beneficial effects of the pyramid strategy have been question ed because the long-term outcome of rheumatoid arthritis continues to be disappointing . Patients with rheumatoid arthritis have increased mortality [ 9 , 10 ] , and their quality of life is seriously affected by functional impairment and loss of employment [ 11 , 12 ] . The pyramid model might be undesirable because administering SAARDs only after milder regimens prove to be insufficiently effective delays the suppression of inflammation . It is preferable that the disease process be controlled as soon as possible , because radiologic abnormalities appear in the joints early in the course of the disease [ 13 , 14 ] and are related to the extent of inflammation [ 15 , 16 ] . Toxicity indices for NSAIDs and most SAARDs have recently been shown to be similar ; thus , exposure of patients to possible adverse reactions is probably not in itself a reason to withhold treatment with SAARDs [ 17 ] . However , the ability of SAARDs to modify the course of disease and prevent radiologic damage is often question ed [ 18 , 19 ] . The poor long-term outcome of rheumatoid arthritis might be caused not by a delay in effective treatment but by the low disease-modifying power of both first- and second-line drugs . The short courses of SAARDs ( short because of adverse reactions or impatience with a delay in effect ) might also play a role [ 20 , 21 ] . Combinations of SAARDs have not been shown to be superior to single drugs [ 21 , 22 ] . Current clinical practice is shifting toward the earlier introduction of second-line treatment for rheumatoid arthritis , but thus far no clinical trials have shown this strategy to be beneficial . We investigated the consequences of ignoring the treatment pyramid for patients with recent-onset rheumatoid arthritis . In this report , we describe the first-year results of a r and omized clinical trial in which the delayed and the immediate introduction of SAARDs were compared . Effectiveness was measured by disease activity and progression of radiologic abnormalities . The various SAARDs are considered as a single group in this report ; comparisons among the second-line therapies will be reported in detail later . Methods Patients As of January 1990 , all patients with recent-onset rheumatoid arthritis ( diagnosed according to the 1987 American College of Rheumatology criteria [ [ 23 ] ] from six rheumatologic centers in the region of Utrecht , the Netherl and s , were asked to participate in a r and omized , prospect i ve clinical trial . Disease duration had to have been less than 1 year , and most patients were enrolled shortly after diagnosis . The following exclusion criteria were applied : 1 ) age younger than 17 years , 2 ) comorbid conditions that might interfere with one of the therapeutic strategies , 3 ) previous or current treatment with any SAARDs , glucocorticosteroids , or cytotoxic or immunosuppressive therapy , 4 ) the possibility of pregnancy or breast feeding , and 5 ) psychiatric or mental disturbances that would make adherence to the study protocol unlikely . All patients gave informed consent before study entry and were told that the study was intended to compare the unsure outcome of treatment with NSAIDs alone with that of treatment with NSAIDs and a SAARD for rheumatoid arthritis at an early stage . The study design was approved by the ethical committees of all participating hospitals . The baseline characteristics of patients who were eligible for the study but who objected to r and omization were compared with those of r and omly assigned patients to determine whether any selection bias had occurred . Treatment Patients entering the study were r and omly assigned to one of two therapeutic groups . All r and omization procedures were done by drawing sealed envelopes from blocks of 100 with equal numbers of patients for each of the four treatments per hospital ; the person doing the procedures was blinded to treatment assignments . This method was used because eligible patients were not distributed equally among the centers . The assigned therapeutic strategy was continued for at least 1 year . In the non-SAARD group , patients began receiving NSAID therapy , the dose and type of which could be modified at any time . For this group , initiation of SAARD treatment during the study was regarded as discontinuation of the therapeutic strategy . In the SAARD group , patients were r and omly assigned ( by persons blinded to treatment assignments ) to treatment with one of the following SAARDs : hydroxychloroquine ( 400 mg/d ) , intramuscular gold ( aurothioglucose , 50 mg/wk ) , or oral methotrexate ( 7.5 to 15 mg/wk ) . Therapy with the initial SAARD was continued for 12 months unless adverse reactions necessitated discontinuation ; if this occurred , another SAARD was given . Hydroxychloroquine was followed by auranofin ( 6 to 9 mg/d ) ; intramuscular gold was followed by D-penicillamine ( 500 to 750 mg/d ) ; and methotrexate was followed by sulfasalazine ( 2000 to 3000 mg/d ) . Discontinuation of therapy with the second SAARD was regarded as discontinuation of the therapeutic strategy . Use of NSAIDs was allowed in the SAARD group ; as in the non-SAARD group , the dose and type could be changed at any time . Patients were assigned to the non-SAARD group and the SAARD group in a ratio of 1:3 , and power calculations for the primary end point disability ( equals 0.05 ; equals 0.20 ; difference to be detected , 25 % ) indicated that group sizes of 40 and 120 , respectively , would be sufficient . The ratio of 1:3 was chosen to enable later comparisons of results within the SAARD group , which were thought to be similar . The use of analgesics was allowed in both groups ; the use of oral glucocorticosteroids was avoided if possible ; and intraarticular injections were not allowed within 2 months of a scheduled visit . Criteria for discontinuation or dose adjustment of a SAARD because of adverse reactions were described in detail in the study protocol . Discontinuation of any treatment because of sustained disease activity was done only if the patient and the attending physician ( who had to discuss the patient with a colleague ) judged it to be unavoidable . Primary End Points Assessment s were done at the start of the trial and were repeated every 3 months . Clinical variables were assessed by the same physician or research nurse for each patient on each occasion . Primary end points were functional disability , pain , joint score , erythrocyte sedimentation rate , and radiologic abnormalities [ 24 ] . Radiologic abnormalities and erythrocyte sedimentation rate were determined by persons blinded to treatment assignments ; functional disability and pain were self-assessed scores ; and determination of the joint score was not blinded to treatment . Functional disability was assessed using a vali date d Dutch version of the Health Assessment Question naire Disability Score [ 25 - 27 ] . The question naire scores range from 0 to 3 ; 0 is the best score ( no problems ) , and 3 is the worst . Pain was measured on two horizontal visual analog scales of 100 mm ; the mean of the scores for pain during the night and pain during the morning was calculated . The joint score according to Thompson and colleagues [ 28 , 29 ] assessed the simultaneous presence of joint tenderness and swelling in a selection of joints weighed for joint size ( range , 0 to 534 ) [ 28 , 29 ] . Erythrocyte sedimentation rate ( mm/h ) was measured using Westergren method . Radiography of h and s and feet was done at the start of the study and at 12 months . A modified version of the method of Sharp and coworkers [ 30 , 31 ] was used to score radiologic abnormalities . According to this method , erosions and joint space narrowing in h and and foot joints are scored and added together to obtain a total radiologic damage score ( range , 0 to 448 ) . All radiographs were evaluated by two investigators who were blinded to treatment assignments . The scores of the first investigator were used in the analyses , and the scores of the second investigator were used to vali date the scores of the first . Correlation between the two sets of scores was satisfactory ( Spearman correlation coefficients for scores at baseline and at 12 months were 0.84 for both ) ; the second investigator was found to have given lower scores ( means at baseline were 4.2 and 3.4 , respectively ; means at 12 months were 11.2 and 9.7 , respectively ) . Therefore , in individual cases , differences in total scores of 25 % or more were discussed until an agreement was reached on the appropriate score . That score was then used in the analyses . Additional Assessment s Secondary end points were grip strength ( mean of three measurements of each h and with a vigorimeter [ Martin , Tuttlingen , Germany ] in kPa ) , duration of morning stiffness ( maximum , 720 min ) , and general well-being ( horizontal visual analog scale of 100 mm ) . Additional laboratory variables were serum level of C-reactive protein ( mg/L ) , hemoglobin concentration ( mmol/L ) , and platelet count ( times 109/L ) . Rheumatoid factor status was determined to be positive or negative , as indicated by either the OBJECTIVE To obtain additional safety and efficacy data on leflunomide ( LEF ) treatment in combination with methotrexate ( MTX ) therapy in an open-label extension study in patients with rheumatoid arthritis ( RA ) . METHODS Following a 24 week , r and omized , double-blind trial of adding placebo ( PLA ) or LEF to stable MTX therapy , patients could enter a 24 week extension . Subjects r and omized to LEF and MTX  continued treatment [ ( LEF/LEF ) + MTX ] . Subjects r and omized to PLA and MTX switched to LEF ( 10 mg/day , no loading dose ) and MTX [ ( PLA/LEF ) + MTX ] . The double-blind regarding initial r and omization was maintained . RESULTS For subjects in the extension phase , American College of Rheumatology 20 % ( ACR20 ) responder rates for the ( LEF/LEF ) + MTX group were maintained from Week 24 ( 57/96 , 59.4 % ) to Week 48 ( 53/96 , 55.2 % ) . ACR20 responder rates improved in patients switched to LEF from PLA at Week 24 [ ( PLA/LEF ) + MTX ] from 25.0 % ( 24/96 ) at Week 24 to 57.3 % ( 55/96 ) at Week 48 . Patients in the extension who switched from PLA to LEF without a loading dose exhibited a lower incidence of elevated transaminases compared to patients initially r and omized to LEF . Diarrhea and nausea were less frequent during the open-label extension in patients who did not receive a LEF loading dose . CONCLUSION Response to therapy was maintained to 48 weeks of treatment in patients who continued to receive LEF and MTX during the extension . Importantly , ACR20 response rates after 24 weeks of LEF therapy were similar between patients switched from PLA to LEF without loading dose , and those who received a loading does of LEF ( 100 mg/day x 2 days ) at r and omization . Fewer adverse events were reported in patients switched to LEF without a loading dose OBJECTIVE To evaluate tolerability and efficacy of combination therapy with methotrexate (MTX)/parenteral gold or MTX/other disease modifying antirheumatic drug ( DMARD , d-penicillamine or chloroquine ) in comparison with MTX monotherapy in patients with longst and ing destructive active rheumatoid arthritis ( RA ) . METHODS In an open prospect i ve trial all consecutive MTX-naive patients with active RA starting MTX treatment alone or in combination between January 1980 and December 1987 , after failing one or more DMARD , were followed at regular intervals up to 108 months . Evaluations included the number of swollen joints ( 0 - 32 ) , grip strength , patient assessment of pain and mobility , erythrocyte sedimentation rate ( ESR ) , C-reactive protein ( CRP ) , and hemoglobin . Group 1 , treated with MTX monotherapy ( n = 97 ) , was compared with Group 2 , with combination therapy MTX/parenteral gold ( n = 126 ) and Group 3 with MTX + other DMARD ( n = 48 ) . RESULTS There were no significant differences between the groups in mean age ( 59/57/56 yrs ) , disease duration ( 9.6/7.7/8.3 yrs ) , seropositivity ( 80/88/82 % ) , or ACR anatomical disease stage ( 2/3 in stage III and IV ) . The number of swollen joints ( 16.8/19.3/16.1 of 32 ) and the CRP ( 4.4/5.1/4.7 mg/dl ) was significantly greater in Group 2 ; other disease activity variables were not significantly different . The mean  MTX dose at baseline ( mostly parenteral ) was 16.8/17.0/12.8 mg and could be reduced to around 12 mg ( predominantly oral ) in the 3 groups . Frequency of adverse events ( 80/83/88 % ) , nature of clinical ( nausea , hair loss , stomatitis ) and laboratory ( liver enzyme elevation , slight proteinuria ) side effects , and withdrawal rate for side effects ( 20.6/15.0/12.5 % ) were not significantly different between the groups . After 5 years 54/54/80 % of patients continued their treatment . All efficacy variables improved significantly ( p < 0.001 ) in all groups without significant intergroup difference . Improvement > 50 % in the ESR was achieved in 63/68/41 % and in the swollen joint count in 70/85/48 % of patients after 3 years . The number of patients taking oral steroids decreased from 63/59/65 % to 22/31/48 % after 3 years . In half the patients hemoglobin increased by at least 1 g/dl . CONCLUSION Combination therapy of MTX with parenteral gold or other DMARD is effective in reducing clinical and biochemical disease activity in patients with longst and ing destructive RA with no greater risk of toxicity compared with MTX alone ; our study however , did not show clear advantages of combination therapy versus monotherapy for effectiveness To compare the efficacy of the combination therapy Methotrexate ( MTX ) and Chloroquine ( CHLO ) with MTX and Placebo ( PLA ) in the treatment of Rheumatoid Arthritis . A total of 82 patients with Rheumatoid Arthritis ( RA ) , diagnosed according to the American College of Rheumatology criteria , received orally either MTX 7.5 mg/week and CHLO 250 mg/day or MTX 7.5 mg/week and PLA 1 tablet/day . Adverse effects ( AE ) were monitored monthly and disease activity was assessed at 0 , 2 , 4 and 6 months . Sixty-eight patients completed the study . All outcome measures improved significantly in both treatment groups . Patients receiving MTX/CHLO ended the study with a significantly lower joint count , greater grip strength and better functional ability the patients in the MTX/PLA group , respectively ; 4.5 vs 7.5 ( P < 0.05 ) , 113.3 vs 89.1 ( P < 0.05 ) and 0.636 vs 0.811 ( P < 0.05 ) . Mild AE were more frequently observed in the MTX/CHLO , 17 events in 15 patients , compared to 9 events in 8 patients in the MTX/PLA group ( NS ) . These data indicate that MTX/CHLO is slightly more efficacious and toxic than is MTX/PLA in the treatment of RA OBJECTIVE To study sustainability of remission and good treatment response , and the association of both with radiographic progression , in early rheumatoid arthritis ( RA ) in the Finnish Rheumatoid Arthritis Combination Therapy trial ( FIN-RACo ) . METHODS Patients were r and omized to receive either a combination of disease modifying antirheumatic drugs ( DMARD ; COMBI , n = 97 ) or a single DMARD ( SINGLE , n = 98 ) . Remission was defined according to modified American College of Rheumatology ( ACR ) remission criteria and Disease Activity Score 28 joint count ( DAS28 ) < or = 2.6 , and sustained remission as presence of remission at 6 , 12 , and 24 months . Good treatment response was defined as DAS28 ( 3/4 ) 3.2 and decrease of DAS28 > 1.2 . RESULTS In 169 patients with complete data , 33 ( 42 % ) COMBI and 18 ( 20 % ) SINGLE patients achieved modified ACR remission at 2 years , which was sustained in 11 ( 14 % ) COMBI and 3 ( 3 % ) SINGLE patients . Fifty-four ( 68 % ) COMBI and 37 ( 41 % ) SINGLE patients were in DAS28 remission at 2 years , which was sustained in 40 ( 51 % ) COMBI and 14 ( 16 % ) SINGLE patients . Good treatment response was sustained in 67 % of COMBI and 27 % of SINGLE patients . Over 2 years , the Larsen score increased by a median of 1 ( 95 % CI 0 - 2 ) in patients in sustained DAS28 remission compared to 4 ( 95 % CI 2 - 16 ) in patients who were in DAS28 remission at 6 months but lost it later ; and by 6 ( 95 % CI 2 - 10 ) in patients who were not in remission at 6 months . CONCLUSION A remarkable proportion of patients with early RA treated with combinations of DMARD were in remission at 2 years , and remission was more often sustained compared to patients treated with a single DMARD . Sustained remission protects against radiographic joint damage OBJECTIVE To investigate whether disease control can be achieved in early active rheumatoid arthritis ( RA ) by treatment with methotrexate and intraarticular betamethasone , and whether the addition of cyclosporine to the regimen has any additional effect . METHODS Patients ( n = 160 ) were r and omized to receive methotrexate 7.5 mg/week plus cyclosporine 2.5 mg/kg of body weight/day ( combination therapy ) or methotrexate plus placebo-cyclosporine ( monotherapy ) . At weeks 0 , 2 , 4 , 6 , and 8 and every 4 weeks thereafter , betamethasone was injected into swollen joints ( maximum 4 joints or 4 ml per visit ) . Beginning at week 8 , if synovitis was present , the methotrexate dosage was increased stepwise up to 20 mg/week , with a subsequent stepwise increase in the cyclosporine or placebo-cyclosporine dosage up to 4 mg/kg . RESULTS At 52 weeks , 20 % improvement according to the American College of Rheumatology criteria ( ACR20 ) was achieved in 85 % of the combination therapy group versus 68 % of the monotherapy group ( P = 0.02 ) . The median individual overall ACR response ( ACR-N ) in the 2 groups was 80.0 % ( interquartile range 40.1 - 91.8 % ) and 54.5 % ( interquartile range 2.4 - 87.8 % ) , respectively ( P = 0.025 ) . At 48 and 52 weeks , ACR remission criteria were met in 35 % of the combination therapy group and 28 % of the monotherapy group . Progression in the Larsen score at 52 weeks was -0.2 + /- 6.5 and 0.4 + /- 6.9 ( mean + /- SD ) in the combination therapy and monotherapy groups , respectively . Serum creatinine levels increased by 7 % , and hypertrichosis was more prevalent , in the combination therapy group . CONCLUSION Combined treatment with methotrexate and intraarticular glucocorticoid showed excellent disease control and stopped the progression of erosions in patients with early active RA , who had a poor prognosis . Addition of cyclosporine improved the ACR20 and ACR-N responses , whereas the ACR50 and ACR70 responses , remission rates , and radiographic changes did not differ between the 2 study groups OBJECTIVE To vali date the European League Against Rheumatism ( EULAR ) , the American College of Rheumatology ( ACR ) , and the World Health Organization (WHO)/International League Against Rheumatism ( ILAR ) response criteria for rheumatoid arthritis ( RA ) . METHODS EULAR response criteria were developed combining change from baseline and level of disease activity attained during follow up . In a trial comparing hydroxychloroquine and sulfasalazine , we studied construct ( radiographic progression ) , criterion ( functional capacity ) , and discriminant validity . RESULTS EULAR response criteria had good construct , criterion , and discriminant validity , ACR and WHO/ILAR criteria showed only good criterion validity . CONCLUSION EULAR response criteria showed better construct and discriminant validity than did the ACR and the WHO/ILAR response criteria for RA OBJECTIVE The response to single disease modifying antirheumatic drug ( DMARD ) is often suboptimal in patients with rheumatoid arthritis ( RA ) . Thus , despite the limited data on the therapeutic efficacy of combination therapies , many patients are currently treated with a combination of DMARDs . METHODS We studied prospect ively the efficacy of combination therapy with DMARDs . The study was design ed as a r and omized trial and a single DMARD or two or three DMARD combinations were administered to 180 consecutive , age- and sex-matched patients with active RA , each of whom was followed up for a period of 2 years under treatment . Patients were divided into 3 groups which did not differ with regard to demographic , clinical and laboratory parameters . Patients in group I were treated with a single DMARD [ methotrexate ( MTX ) 7.5 - 15 mg/week or sulfasalazine ( SSZ ) 1 - 2 g/day or hydroxychloroquine ( HCQ ) 200 mg/day ] , group II with MTX + SSZ or MTX + HCQ , and group III with a combination of all three drugs . Patients were re-evaluated at regular intervals by means of clinical and biochemical tests design ed to detect specific rheumatic activity . Radiological assessment s were also performed and scored according to Larsen by the same radiologist who was blinded to the treatment groups . RESULTS At the end of the trial there were significant improvements in the clinical and laboratory parameters in all 3 groups . However , improvements were greater and much more significant in the patients who were given combination therapies . The combination of MTX + SSZ + HCQ was more effective than both monotherapy and the two-drug combinations . CONCLUSION In conclusion , we suggest that patients with RA should be treated with combinations of DMARDs OBJECTIVES To investigate the potential clinical benefit of a combination therapy . METHODS 205 patients fulfilling the ACR criteria for rheumatoid arthritis ( RA ) , not treated with disease modifying anti-rheumatoid drugs previously , with an early ( ⩽1 year duration ) , active ( Disease Activity Score ( DAS ) > 3.0 ) , rheumatoid factor and /or HLA DR 1/4 positive disease were r and omised between sulphasalazine ( SASP ) 2000 ( maximum 3000 ) mg daily ( n = 68 ) , or methotrexate ( MTX ) 7.5 ( maximum 15 ) mg weekly ( n = 69 ) or the combination ( SASP + MTX ) of both ( n = 68 ) . RESULTS The mean changes in the DAS during the one year follow up of the study was −1.15 , −0.87 , −1.26 in the SASP , MTX , and SASP + MTX group respectively ( p = 0.019 ) . However , there was no statistically significant difference in terms of either EULAR good responders 34 % , 38 % , 38 % or ACR criteria responders 59 % , 59 % , 65 % in the SASP , MTX , and SASP + MTX  group respectively . Radiological progression evaluated by the modified Sharp score was very modest in the three groups : mean changes in erosion score : + 2.4 , + 2.4 , + 1.9 , in narrowing score : + 2.3 , + 2.1 , + 1.6 and in total damage score : + 4.6 , + 4.5 , + 3.5 , in the SASP , MTX , and SASP +  MTX groups respectively . Adverse events occurred more frequently in the SASP + MTX group 91 % versus 75 % in the SASP and MTX group ( p = 0.025 ) . Nausea was the most frequent side effect : 32 % , 23 % , 49 % in the SASP , MTX , and SASP + MTX groups respectively ( p = 0.007 ) . CONCLUSION This study suggests that an early initiation therapy of disease modifying drug seems to be of benefit . However , this study was unable to demonstrate a clinical ly relevant superiority of the combination therapy although several outcomes were in favour of this observation . The tolerability of the three treatment modalities seems acceptable OBJECTIVE Several treatment strategies have proven value in the amelioration of rheumatoid arthritis ( RA ) , but the optimal strategy for preventing long-term joint damage and functional decline is unclear . We undertook this study to compare clinical and radiographic outcomes of 4 different treatment strategies , with intense monitoring in all patients . METHODS In a multicenter , r and omized clinical trial , 508 patients were allocated to 1 of 4 treatment strategies : sequential disease-modifying antirheumatic drug monotherapy ( group 1 ) , step-up combination therapy ( group 2 ) , initial combination therapy with tapered high-dose prednisone ( group 3 ) , and initial combination therapy with the tumor necrosis factor antagonist infliximab ( group 4 ) . Treatment adjustments were made every 3 months in an effort to obtain low disease activity ( a Disease Activity Score in 44 joints of < or = 2.4 ) . RESULTS Initial combination therapy including either prednisone ( group 3 ) or infliximab ( group 4 ) result ed in earlier functional improvement than did sequential monotherapy ( group 1 ) and step-up combination therapy ( group 2 ) , with mean scores at 3 months on the Dutch version of the Health Assessment Question naire ( D-HAQ ) of 1.0 in groups 1 and 2 and 0.6 in groups 3 and 4 ( P < 0.001 ) . After 1 year , mean D-HAQ scores were 0.7 in groups 1 and 2 and 0.5 in groups 3 and 4 ( P = 0.009 ) . The median increases in total Sharp/Van der Heijde radiographic joint score were 2.0 , 2.5 , 1.0 , and 0.5 in groups 1 - 4 , respectively ( P < 0.001 ) . There were no significant differences in the number of adverse events and withdrawals between the groups . CONCLUSION In patients with early RA , initial combination therapy including either prednisone or infliximab result ed in earlier functional improvement and less radiographic damage after 1 year than did sequential monotherapy or step-up combination therapy OBJECTIVE To determine whether patients with early rheumatoid arthritis ( RA ) treated with cyclosporin A ( CsA ) and methotrexate ( MTX ) in combination for 12 months show a lower rate of radiographic deterioration than those treated with MTX alone . METHODS In this controlled and r and omized single-blind trial , 61 consecutive patients with untreated RA of less than 2 yr duration were treated with either CsA + MTX combination therapy ( n = 30 ) or MTX alone ( n = 31 ) . The primary end-point was radiographic progression after 12 months , measured using the damage score ( DS ) of the Sharp and van der Heijde method . RESULTS Although there was a significant difference between the mean baseline and 12-month DS in both treatment groups ( MTX/CsA , 1.93 + /- 0.90 ; MTX , 7.47 + /- 2.03 ) , it was significantly less in the combination arm ( P = 0.018 ) . Of the 30 evaluable CsA + MTX patients , 16 ( 53 % ) were ACR20 responders , 15 ( 50 % ) ACR50 and 14 ( 47 % ) ACR70 ; the corresponding figures in the MTX arm were 19 ( 61 % ) , 13 ( 44 % ) and 6 ( 19 % ) . Toxicity was acceptable in both groups . CONCLUSIONS In patients with early RA , CsA + MTX combination therapy led to a significantly lower rate of 12-month radiographic progression , was effective on inflammatory articular symptoms , and was well tolerated OBJECTIVE To compare the relative safety and efficacy of azathioprine ( AZA ) , methotrexate ( MTX ) , and the combination of both in the treatment of active rheumatoid arthritis ( RA ) . METHODS Two hundred twelve patients with active RA were entered into a 24-week prospect i ve , controlled , double-blind , multicenter trial and were r and omly assigned to 1 of 3 treatment groups . RESULTS One hundred fifty-eight patients finished 24 weeks of the study . There were no remissions seen but response rates were greater than 30 % for all outcome measures . Combination therapy was not statistically superior to MTX therapy alone , but both combination therapy and MTX alone were superior to AZA alone when patients were analyzed by intent-to-treat and with withdrawals treated as therapy failures . If only patients who continued taking the therapy were analyzed , the mean improvement was greater for AZA therapy than for MTX , while the combination remained the most active . Adverse effects on the gastrointestinal tract and elevations of liver enzyme levels were the most frequent causes for discontinuations . CONCLUSION Both combination therapy and MTX alone were superior to therapy with AZA alone for active RA but were not statistically different in their effect on outcome assessment OBJECTIVE To evaluate the effectiveness of disease-modifying antirheumatic drugs , namely , methotrexate ( MTX ) , sulfasalazine ( SSZ ) and bucillamine ( BUC ) at low-doses ( 4 , 6 or 8 mg MTX , 500 or 1,000 mg SSZ , and 100 or 200 mg BUC ) in 1,358 patients with a follow-up of at least 12 months and more than 120 months . METHODS Clinical assessment s were based on the number of painful joints ( NPJ ) and that of swollen joints ( NSJ ) , CRP level , erythrocyte sedimentation rate , rheumatoid factor level and morning stiffness before and after treatment . Results were evaluated on the basis of the duration of treatment for each drug with inefficacy or inadequate efficacy as one endpoint for discontinuation and adverse drug reactions ( ADRs ) as the other in single agent and combination therapy . The incidence and nature of ADRs in single and combination treatment are described . RESULTS The effects of MTX , SSZ and BUC on clinical parameters were monitored over the first three months , and in particular , NPJs and NSJs were found to decrease significantly during single agent MTX or BUC treatment over 108 months . CRP levels remained significantly improved for more than 120 months with MTX . In the single and combination long-term treatments , continuation rate with inefficacy or inadequate efficacy as the end point achieved for each of the treatments were 83.1 % for MTX , 76.0 % for BUC , 68.5 % for SSZ , and in the case of the combination treatments , these rates were 83.3 % for MTX + BUC and 71.0 % for MTX+SSZ .  Continuation rates using ADRs as the end point were 88 % for SSZ , 79.6 % for BUC and 79.4 % for MTX . The incidences of ADRs for the various treatments were : MTX 22.2 % , SSZ 11.0 % , BUC 20.6 % , MTX + BUC 30.0 % and MTX + SSZ 31.2 % . CONCLUSION MTX showed the highest efficacy even though it was administrated at a low dose ( 6 - 8 mg ) , as a single agent or in combination with other treatment . However , in combination treatments , the continuous duration of treatment ending in ADRs as the end point were lower than those in single treatments with MTX , SSZ and BUC To assess the relative efficacy of methotrexate ( MTX ) , azathioprine ( AZA ) , and their combination in the treatment of rheumatoid arthritis ( RA ) , a double blind , prospect i ve , multicenter , controlled trial was carried out . Two hundred nine patients with active RA were treated with escalating doses of MTX ( 5 - 15 mg/week ) , AZA ( 50 - 150 mg/day ) , or combination ( 5/50 - 7.5/100 ) with opportunity to increase dosage at 6 week intervals . Patients were evaluated for clinical and laboratory improvement and assessed for radiologic progression at 48 weeks . One hundred ten patients remained on the initial , r and omly assigned therapy . Response was defined as 30 % or greater improvement in at least 3 of 4 variables , and occurred in the following : 38 % on the combination arm , 26 % on AZA , and 45 % on MTX ( p = 0.06 ) . A trend for decreased radiologic progression was seen in the MTX group . Adverse experiences and treatment termination occurred more frequently in the combination and AZA arms relative to the MTX group . The most frequent causes for treatment discontinuations were lack of effectiveness , gastrointestinal adverse effects and liver enzyme elevation . This study establishes that the combination of MTX and AZA in the dosages employed is not associated with more toxicity than treatment with single agents , but enhanced efficacy is not seen . A trend toward decreased radiographic progression was noted in the MTX treated patients OBJECTIVE To assess the relative efficacy of methotrexate ( MTX ) , azathioprine ( AZA ) , and their combination in the treatment of rheumatoid arthritis ( RA ) in a double-blind , prospect i ve , multicenter , controlled trial . METHODS Two hundred nine patients with active RA were treated with escalating doses of MTX ( 5 - 15 mg/week ) , AZA ( 50 - 150 mg/day ) , or combination ( 5 mg MTX/week plus 50 mg AZA/day-7.5 mg MTX/week plus 100 mg AZA/day ) , with opportunity to increase the dosage at 6-week intervals . The patients were evaluated for significant clinical and laboratory improvement and assessed for radiologic progression at 48 weeks . RESULTS One hundred ten patients remained on the initial , r and omly assigned therapeutic regimen . The percentage of patients who were responders , defined as those who had 30 % or greater improvement in at least 3 of 4 variables , was 38 % for the combination treatment , 26 % for AZA , and 45 % for MTX ( P = 0.06 ) . A trend toward decreased radiologic progression was seen in the MTX-treated patients . Termination of treatment due to adverse experience occurred more frequently with combination and AZA treatments than with MTX treatment . Lack of effectiveness , adverse gastrointestinal effects , and liver enzyme elevation were the most frequent causes of treatment discontinuation . CONCLUSION This study establishes that the combination of MTX and AZA in the dosages utilized is not associated with more toxicity than treatment with single agents ; however , enhanced efficacy is also not seen . There is a trend toward decreased radiologic progression in patients treated with MTX BACKGROUND The treatment of rheumatoid arthritis should aim at clinical remission . This multicentre , r and omised trial with 2-year follow-up sought evidence on the efficacy and tolerability of combination therapy ( sulphasalazine , methotrexate , hydroxychloroquine , and prednisolone ) compared with treatment with a single disease-modifying antirheumatic drug , with or without prednisolone , in the treatment of early rheumatoid arthritis . METHODS 199 patients were r and omly assigned to two treatment groups . 195 started the treatment ( 97 received combination and 98 single drug therapy ) . Single-drug therapy in all patients started with sulphasalazine ; in 51 patients methotrexate was later substituted . Oral prednisolone was required by 63 patients . The primary outcome measure was induction of remission . Analyses were intention to treat . FINDINGS 87 patients in the combination group and 91 in the  single-therapy  group completed the trial . After a year , remission was achieved in 24 of 97 patients with combination therapy , and 11 of 98 with single-drug therapy ( p=0.011 ) . The remission frequencies at 2 years were 36 of 97 and 18 of 98 ( p=0.003 ) . Clinical improvement ( American College of Rheumatology criteria of 50 % clinical response ) was achieved after 1 year in 68 ( 75 % ) patients with combination therapy , and in 56 ( 60 % ) using single-drug therapy ( p=0.028 ) , while at the 2-year visit 69 and 57 respectively ( 71 % vs 58 % , p=0.058 ) had clinical ly improved . The frequencies of adverse events were similar in both treatment groups . INTERPRETATION Combination therapy was better and not more hazardous than single treatment in induction of remission in early rheumatoid arthritis . The combination strategy as an initial therapy seems to increase the efficacy of the treatment in at least a proportion of patients with early rheumatoid arthritis OBJECTIVE To evaluate the ability of hydroxychloroquine sulfate ( HCQ ) to extend the response to combination therapy with HCQ and methotrexate ( MTX ) and the safety of longterm HCQ maintenance therapy in patients with active rheumatoid arthritis ( RA ) . METHODS Two-part study consisting of an open label segment evaluating combination HCQ/MTX therapy followed by a double blind segment evaluating maintenance therapy for a total of 60 weeks . First , all patients were treated with HCQ 400 mg/day and MTX 7.5 to 15 mg/week for 24 weeks . Then , responders were r and omized into 3 groups : ( 1 ) HCQ with MTX as needed for disease flare ( n = 40 ) , ( 2 ) HCQ 400 mg/day ( n = 41 ) , or ( 3 ) placebo with MTX as needed for disease flare ( n = 40 ) , each for 36 weeks . RESULTS Clinical disease and laboratory variables improved significantly during initial combination therapy with HCQ and MTX . After MTX withdrawal , HCQ-containing maintenance regimens delayed the onset of disease flare ( p = 0.023 ) . There were no unexpected adverse events at any time or between-group differences in the distribution of adverse events during the double blind segment . CONCLUSION Combination of HCQ and MTX appeared to be effective and well tolerated for 24 weeks . After withdrawal of MTX , HCQ extended the response seen with combination therapy and was well tolerated for 36 weeks . Initial therapy with HCQ and MTX , followed by maintenance HCQ , may be a useful alternative for the treatment of RA Rheumatoid arthritis ( RA ) has a profound effect on patients , producing significant morbidity and in some cases mortality . Because of this , most rheumatologists are moving to disease modifying antirheumatic drug ( DMARD ) therapy earlier in the course of RA . Methotrexate ( MTX ) has become the initial DMARD of choice for most rheumatologists . Unfortunately , treatment of RA with a single DMARD , including MTX , often results in a suboptimal response . Therefore , most rheumatologists are now using combinations of DMARD to treat patients with RA who have had incomplete responses to single DMARD therapy . The Rheumatoid Arthritis Investigational Network ( RAIN ) reported the results of a double blind , controlled comparison of triple drug therapy ( MTX-sulfasalazine-hydroxychloroquine ) against MTX alone , and against the combination of hydroxychloroquine and sulfasalazine .  Twenty-eight patients who had suboptimal responses to MTX or the combination of sulfasalazine and hydroxychloroquine  were then treated with triple therapy in an open label study . Fourteen had previously failed MTX therapy , and 14 had previously failed combination therapy with sulfasalazine and hydroxychloroquine . Both groups had statistically significant improvements in sedimentation rates , morning stiffness , swollen joint scores , tender joint scores , patient global status assessment , and physician global status assessment . Statistical significance was reached for all these variables for patients in both groups , but improvement was greater for the patients in the sulfasalazine-hydroxychloroquine group . Patients with RA who have had suboptimal responses to MTX  , or to the combination of sulfasalazine-hydroxychloroquine , show both statistical and clinical ly significant improvement in multiple clinical variables when treated with the combination of MTX 17.5 mg/week , sulfasalazine 500 mg bid , and hydroxychloroquine 200 mg bid To compare efficacy , toxicity , and the pharmacokinetics of the combination of sulphasalazine ( SASP ) and methotrexate ( MTX ) vs MTX alone in the treatment of SASP-resistant RA we conducted a controlled open clinical trial . Forty RA patients with active arthritis despite adequate SASP therapy , were allocated r and omly to regimes of either SASP+MTX or MTX alone . The patients were evaluated openly by a single observer for 24 weeks . In the first 15 patients using the combination , pharmacokinetics of MTX without and with SASP were studied . Thirty-eight patients completed the trial . The mean decrease in the disease activity score in the group of patients receiving the combination was significantly greater than in the MTX group ( -2.6 vs -1.3 respectively ) . The same pattern was seen concerning the other efficacy variables . There was no difference in the occurrence of toxicity .  SASP had no influence on the pharmacokinetics of MTX .  In conclusion in this open study the efficacy of the combination of MTX and SASP seems to be superior to MTX alone , the toxicity of both therapies was similar . This effect was not explained by the pharmacokinetics of MTX which were not altered by concomitant SASP administration OBJECTIVE Bisphosphonates inhibit osteoclast activity , which is central to the development of bone damage in rheumatoid arthritis ( RA ) . The aim of this study was to assess whether treatment with zoledronic acid , compared with placebo , could achieve a > or = 50 % reduction in the development of new erosions on magnetic resonance imaging ( MRI ) in patients with early RA . METHODS In this proof-of-concept study , 39 patients with early RA and clinical synovitis of the h and /wrist were r and omized to receive infusions with either zoledronic acid ( 5 mg ) or placebo , administered at baseline and week 13 . Patients in both groups received methotrexate ( MTX ) at a dosage of 7.5 - 20 mg/week . MRI and plain radiography were performed at baseline and week 26 . RESULTS At week 26 , the mean + /- SD change in MRI h and and wrist erosions was 61 % lower in the zoledronic acid group compared with the placebo group ( 0.9 + /- 1.63 versus 2.3 + /- 3.09 ; P = 0.176 ) . The mean + /- SD increase in the number of h and and wrist bones with erosions was 0.3 + /- 0.75 for zoledronic acid compared with 1.4 + /- 1.77 for placebo ( P = 0.029 ) . The proportion of patients in whom new MRI-visualized bone edema developed was smaller in the zoledronic acid group compared with the placebo group ( 33 % versus 58 % ; P = 0.121 ) . The zoledronic acid group had a mean change in the number of radiographic erosions of 0.1 compared with 0.5 for the placebo group ( P = 0.677 ) . The safety profile of zoledronic acid was similar to that of placebo . CONCLUSION The results of this study suggest a structural benefit associated with zoledronic acid therapy in patients with RA , as demonstrated by consistent results in structural end points in favor of zoledronic acid plus MTX compared with MTX alone An open-label , one-year study was conducted to evaluate the safety and clinical response to  leflunomide and methotrexate combination therapy for rheumatoid arthritis . Study results revealed tolerable safety , no significant pharmacokinetic interactions between methotrexate and leflunomide , and suggested improved clinical response with combination therapy The aim of the study was to compare the efficacy of hydroxychloroquine ( HCQ ) alone and in combination with methotrexate ( MTX ) in a r and omized placebo-controlled study lasting 6 months . Forty patients with rheumatoid arthritis participated in the study and were r and omly assigned to two groups--20 patients were treated with HCQ ( 200 mg daily ) and placebo , 20 patients with HCQ and MTX ( 7.5 mg ) once a week . Patients were assessed at regular intervals of 1 month up to 6 months using six clinical and five laboratory tests and one radiological measure . All six clinical variables and two laboratory variables were favorably influenced by combination therapy during the 6-month period . HCQ alone significantly influenced only three clinical variables and none of the laboratory parameters . There was a greater number of patients without radiological progression in the combination group . There was one drop-out in combination group due to general allergic reaction ; otherwise the treatment was well tolerated . The results suggest that a combination of HCQ and MTX is more potent than HCQ alone OBJECTIVE To compare the efficacy of doxycycline plus methotrexate ( MTX ) versus MTX alone in the treatment of early seropositive rheumatoid arthritis ( RA ) , and to attempt to differentiate the antibacterial and antimetalloproteinase effects of doxycycline . METHODS Sixty-six patients with seropositive RA of < 1 year 's duration who had not been previously treated with disease-modifying antirheumatic drugs were r and omized to receive 100 mg of doxycycline twice daily with MTX ( high-dose doxycycline group ) , 20 mg of doxycycline twice daily with MTX ( low-dose doxycycline group ) , or placebo with MTX ( placebo group ) , in a 2-year double-blind study . Treatment was started with an MTX dosage of 7.5 mg/week , which was titrated every 3 months until remission was reached ( maximum dosage of 17.5 mg/week ) . The primary end point was an American College of Rheumatology 50 % improvement ( ACR50 ) response at 2 years . RESULTS ACR50 responses were observed in 41.6 % of patients in the high-dose doxycycline group , 38.9 % of those in the low-dose doxycycline group , and 12.5 % of patients in the placebo group . Results of chi-square analysis of the ACR50 response in the high-dose doxycycline group versus that in the placebo group were significantly different ( P = 0.02 ) . Trend analysis revealed that the ACR20 response and the ACR50 response were significantly different between groups ( P = 0.04 and P = 0.03 , respectively ) . MTX doses at 2 years were not different among groups . Four patients in the high-dose doxycycline group , 2 patients in the low-dose doxycycline group , and 2 patients in the placebo group were withdrawn because of toxic reactions . CONCLUSION In patients with early seropositive RA , initial therapy with MTX plus doxycycline was superior ( based on an ACR50 response ) to treatment with MTX alone . The therapeutic responses to low-dose and high-dose doxycycline were similar , suggesting that the antimetalloproteinase effects were more important than the antibacterial effects . Further studies to evaluate the mechanism of action of tetracyclines in RA are indicated Early intervention with slow acting anti-rheumatic drugs ( SAARDs ) has led to improvement in substantial proportion of rheumatoid arthritis ( RA ) patients . The present open , controlled study was design ed to assess whether a combination of SAARDs offer any added benefit . Fifty-four adult RA patients were r and omly allocated to methotrexate ( MTX ) ( n = 27 ) and MTX plus sulphasalazine ( SSZ ) ( n = 27 ) groups . The subjects were followed-up fortnightly for four weeks then monthly for six months . The disease activity was assessed with the help of 10 clinical and four laboratory indices . The improvement was grade d as : minor , mild decreases in indices , non-steroidal anti-inflammatory drugs ( NSAIDs ) continued , physician 's global assessment ( PGA ) decreased by one ; marked , acceptable decreases in indices , NSAIDs being taken sparingly , PGA decreased by at least 2 , and complete , all indices normalised and patients discontinued NSAIDs completely . The improvement was considered clinical ly important when marked or complete improvement occurred . Adverse drug reactions result ed in withdrawal of 4 subjects from the MTX + SSZ group and 1 from the control groups . Four and three subjects in the combined and MTX groups respectively were lost to follow-up . Subjects in both groups showed significant decline in all indices except hemoglobin and neutrophil count . The differences between the two groups in the pre-treatment and post-treatment values were insignificant . Complete , marked , minor and no improvement occurred in 4 ( 21 % ) , 12 ( 63 % ) , 3 ( 16 % ) & 0 in the MTX and in 11 ( 48 % ) , 7 ( 30 % ) , 4 ( 17 % ) & 1 ( 4 % ) in MTX + SSZ groups respectively . The differences in the rates of complete and clinical ly important improvement between the two groups were insignificant ( P 0.1398 and 0.7092 ) . The incidence of side effects was insignificantly higher in the MTX + SSZ group . Most of them were mild and transient . The combination of SAARDs offered little added advantage in RA . However , the higher rate of complete improvement in the combination group justifies trials including larger sample BACKGROUND Rheumatoid arthritis is a common disease that causes substantial morbidity and mortality . The responses of patients with rheumatoid arthritis to treatment with a single so-called disease-modifying drug , such as methotrexate , are often suboptimal . Despite limited data , many patients are treated with combinations of these drugs . METHODS We enrolled 102 patients with rheumatoid arthritis and poor responses to at least one disease-modifying drug in a two-year , double-blind , r and omized study of treatment with methotrexate alone  ( 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 in an attempt to achieve remission in all patients . The primary and point of the study was the successful completion of two years of treatment with 50 percent improvement in composite symptoms of arthritis and no evidence of drug toxicity . RESULTS Fifty of the 102 patients had 50 percent improvement at nine months and maintained at least that degree of improvement for two years without evidence of major drug toxicity . Among them were 24 of 31 patients treated with all three drugs ( 77 percent ) , 12 of 36 patients treated with methotrexate alone ( 33 percent , P < 0.001 for the comparison with the three-drug group ) , and 14 of 35 patients treated with sulfasalazine and hydroxychloroquine ( 40 percent ) , P = 0.003 for the comparison with the three-drug group ) . Seven patients in the methotrexate group and three patients in each of the other two groups discontinued treatment because of drug toxicity . CONCLUSIONS In patients with rheumatoid arthritis , combination therapy with methotrexate , sulfasalazine , and hydroxychloroquine is more effective than either methotrexate alone or a combination of sulfasalazine , and hydroxychloroquine Context Several disease-modifying antirheumatic drugs ( DMARDs ) slow disease progression in patients with rheumatoid arthritis . Many experts prefer methotrexate , although trials do not uniformly show that it is superior to other DMARDs . It is not known whether combining methotrexate with a second DMARD is better than prescribing methotrexate alone . Contribution This 24-week , r and omized , double-blind , placebo-controlled trial shows that leflunomide added to ongoing stable-dose methotrexate therapy in patients with persistently active rheumatoid arthritis improves clinical outcomes compared with methotrexate alone . Caution s Some adverse effects , such as diarrhea , were more common with combination therapy . All patients receiving DMARD therapy  need close monitoring for toxicities . The Editors Rheumatoid arthritis has considerable societal costs ( 1 - 5 ) . Many patients with rheumatoid arthritis become disabled within a few years of disease onset ( 4 , 5 ) . Methotrexate is the st and ard treatment for rheumatoid arthritis . During the past several years , investigators have found that some disease-modifying antirheumatic drugs can increase the efficacy of methotrexate monotherapy ( 6 - 9 ) . Methotrexate is an antimetabolite and immunomodulator that affects many intracellular metabolic pathways of purine metabolism ( 10 ) . The precise intracellular biochemical pathway responsible for the observed clinical benefits of methotrexate in the treatment of rheumatoid arthritis is still the subject of some debate ( 11 ) , but methotrexate is thought to act primarily on purine pathways of cellular metabolism ( 10 ) . Leflunomide ( Arava , Aventis Pharmaceuticals , Bridgewater , New Jersey ) also has antimetabolic effects , inhibiting pyrimidine intracellular pathways ( 12 ) . Leflunomide has been shown to be effective for rheumatoid arthritis in double-blind , placebo-controlled trials ( 13 , 14 ) . Given the diverse intracellular pathways affected by both drugs , the combination of leflunomide and methotrexate has the potential for biochemical synergy . The possibility of increased benefits should be weighed against the possible toxicities of this combination . Abnormal aminotransferase levels have been seen with both methotrexate ( 15 ) and leflunomide ( 14 ) monotherapy in patients with rheumatoid arthritis . In a small open study , we previously observed that the combination of methotrexate and leflunomide led to considerable clinical improvements and reversible elevations in aminotransferase levels ( 16 ) . We therefore sought to determine whether similar results could be achieved in a large , double-blind investigation of the combination of these two antimetabolic agents . Methods Patients The study sample consisted of 263 patients who had rheumatoid arthritis as defined by American College of Rheumatology ( ACR ) criteria ( 17 ) . Patients were 18 to 75 years of age and were receiving stable dosages of methotrexate ( 15 to 20 mg/wk , or 10 to 15 mg/wk if this was the maximum tolerated dose ) . Patients were recruited from active outpatient practice centers , and study participants were approached without a particular schema . Eligible patients had active rheumatoid arthritis despite at least 6 months of methotrexate therapy , including stable dosage for at least 8 weeks . Patients with active rheumatoid arthritis were defined as meeting three of the following criteria on two different evaluations , 7 to 21 days apart : at least nine tender joints , at least six swollen joints , at least 45 minutes of morning stiffness , and an erythrocyte sedimentation rate of at least 28 mm/h . Previous disease-modifying antirheumatic drugs , not including ongoing methotrexate , had failed in 11 patients . Patients receiving corticosteroids  were required to have been taking a stable daily dose of 10 mg or less for at least 30 days before study drug administration , and the corticosteroid dose was required to remain constant throughout the study . Complete exclusion criteria are listed in Appendix Table 1 . Study Design The 24-week , r and omized , double-blind , placebo-controlled study , with evaluations occurring at 4-week intervals ( Figure 1 ) , was conducted in 20 centers in the United States and Canada between September 1998 and June 2000 . The primary objective was to evaluate the efficacy and safety of adding leflunomide or placebo to stable methotrexate therapy in patients with active rheumatoid arthritis . All participants provided written consent , and the institutional review board at each center approved the protocol . Figure 1 . Patient eligibility , r and omization , assignment , and discontinuation . Include no wish to continue in study , poor adherence to treatment , protocol violation , and moving away from the study area . A r and omization schedule , generated by and stored with Quintiles , Inc. , Kansas City , Missouri , was used to assign sequential numbers to r and omly allocated treatment codes . R and omization was done by using the Aventis st and ard r and om-code generator . Investigators allocated numbers to patients , beginning with the lowest available number . Quintiles , Inc. , packaged and labeled the study medication . The r and omization code used was concealed from investigators and patients throughout the study . R and omization was stratified by center . A set of 500 r and om numbers was generated , with treatment groups r and omly assigned in a balanced manner ( 1:1 ratio ) within each block of four consecutive r and om numbers ( block size , 4 ) . A set of these blocks was then sent to each investigative center . This method is identical to stratification by center because centers are balanced with respect to treatment assignment . Patients were r and omly assigned to receive leflunomide , 100 mg/d , for 2 days followed by 10 mg/d or matching placebo . If substantial adverse events occurred , this dose could be reduced to 10 mg every other day . If 10 mg/d was tolerated but active disease , as defined earlier , was still present at week 8 or thereafter , an increase to 20 mg of leflunomide or matching placebo per day was required . If substantial adverse events occurred while the patient was taking 20 mg of the study drug per day , a one-time dose reduction to 10 mg/d was allowed at the discretion of the investigator . At least 1 mg of folate supplementation per day was m and ated by the protocol . Adherence to study medication , assessed at each visit by tablet counts ( actual number of tablets returned compared with number expected to be returned ) , was similar in the two groups . The mean adherence for all patients in the intention-to-treat sample was 98.0 % ( 98.5 % for those receiving placebo and 97.4 % for those receiving leflunomide ) . In the placebo group and leflunomide group , respectively , 90.2 % ( 120 of 133 patients ) and 87.7 % ( 114 of 130 patients ) had adherence rates of 80 % to 120 % . Measurement of Efficacy The primary efficacy variable was the rate at which the intention-to-treat sample achieved 20 % improvement in ACR criteria ( ACR20 ) at the end of the study . To be classified as having achieved ACR20 , patients were required to complete 24 weeks of treatment and meet ACR20 response criteria at end of the study ( 13 ) . The ACR20 criteria were developed to define improvement in rheumatoid arthritis ( 18 ) . Clinical improvement is indicated by 20 % improvement in tender and swollen joint counts and 20 % improvement in three of the following five criteria : patient global assessment , physician global assessment , pain intensity , physical function or disability measure , and level of acute-phase reactant ( 19 ) . All ACR assessment s were performed by the investigators , and the same assessor performed all analyses throughout the study whenever possible to increase the reliability of the assessment . Patients who discontinued therapy before the end of week 24 or for whom data were insufficient to assess ACR20 response at week 24 were classified as nonresponders for the primary analysis . Count of tender joints was based on 68 joint assessment s , and count of swollen joints was based on 66 joint assessment s. Percentage changes in tender joint and swollen joint counts were based on the number of evaluable joints at a visit . Joints that had been replaced or had been injected with corticosteroids within 4 weeks before the assessment were considered nonevaluable . Secondary outcomes included ACR50 and ACR70 responder rates at week 24 ( analyses of responders at study end for the non primary efficacy measures ) . The ACR50 and ACR70 were defined as at least 50 % and 70 % improvement , respectively , in the same criteria used to calculate ACR20 response . Secondary efficacy variables also included change from baseline to end point in each of the individual components of the ACR response criteria and change from baseline to week 24 in levels of rheumatoid factor . Mean changes from baseline in individual efficacy measures are shown in Appendix Table 2 . Measurement of Safety Safety was evaluated by adverse event reports ; laboratory assays for changes in hematologic characteristics , blood chemistry , urinalysis , and liver function ; and physical examination . Potential adverse events were assessed by using open-ended questions at each study visit . The assessor was blinded to reported toxicities and to any additional information obtained at the visit . The study protocol provided recommendations for dosage change and discontinuation of drug therapy , without unblinding , when patients were found to have alanine aminotransferase ( ALT ) and aspartate aminotransferase ( AST ) values greater than two times the upper limit of normal . Investigators decreased the dose of the study medication if , on repeated analysis at 72 hours , test values remained greater than two times but less than or equal to five times the upper limit of normal ; only one dose adjustment was allowed before discontinuation of therapy with the study drug . Therapy with the study drug was also discontinued in patients with persistent elevations of aminotransferase enzyme levels to more than two times the upper limit of normal on repeated Background : Optimal use of disease-modifying antirheumatic drugs ( DMARDs ) in rheumatoid arthritis is vital if progression of disease is to be reduced . Methotrexate ( MTX ) and sulfasalazine ( SASP ) are widely used inexpensive DMARDs , recently often combined despite no firm evidence of benefit from previous studies . Aim : To establish whether a combination of SASP and MTX is superior to either drug alone in patients with rheumatoid arthritis with a suboptimal response to 6 months of SASP . Methods : A r and omised controlled study of step-up DMARD treatment in early rheumatoid arthritis . In phase I , 687 patients received SASP for 6 months . Those with a disease activity score ( DAS ) ⩾2.4 were offered additional treatment in phase II ( SASP alone , MTX alone or a combination of the two ) . The primary outcome measure was change in DAS . Results : At 6 months , 191 ( 28 % ) patients had a DAS < 2.4 , 123 ( 18 % ) were eligible but did not wish to enter phase II , 130 ( 19 % ) stopped SASP because of reversible adverse events and 165 ( 24 % ) entered phase II . DAS at 18 months was significantly lower in those who received combination treatment compared with those who received either SASP or MTX : monotherapy arms did not differ . Improvement in European League Against Rheumatism and American College of Rheumatology 20 , 50 and 70 scores favoured combination therapy . Conclusions : In this “ true-to-life ” study , an inexpensive combination of DMARDs proved more effective than monotherapy in patients with rheumatoid arthritis with a suboptimal response to SASP . There was no increase in toxicity . These results provide an evidence base for the use of this combination as a component of tight control strategies OBJECTIVE To evaluate the efficacy and safety of adding intramuscular ( IM ) gold to the treatment regimen of patients with rheumatoid arthritis ( RA ) who have a suboptimal response to methotrexate ( MTX ) .  METHODS A r and omized , double-blind , double-observer , placebo-controlled multicenter trial of 48 weeks was conducted . Sixty-five RA patients who had a suboptimal response to > /=12 weeks of MTX therapy were r and omly assigned to receive weekly IM gold or placebo in addition to MTX . Gold was administered according to a st and ard protocol developed for the study . The primary outcome measure was the percentage of patients who met the  American College of Rheumatology ( ACR ) 20 % improvement criteria ( achieved an ACR20 response ) at week 48 . Secondary outcomes included the percentages of patients achieving ACR50 and ACR70 responses , the individual criteria that make up the primary outcome , quality of life , direct and indirect health care costs , intraarticular steroid use , and adverse events , among other measures . Statistical analyses were based on an intent-to-treat strategy . RESULTS Sixty-one percent of patients receiving gold achieved an ACR20 response compared with 30 % of patients receiving placebo ( chi(2 ) = 6.04 , P = 0.014 ; logistic regression odds ratio 3.64 [ 95 % confidence interval 1.3 , 10.4 ] , P = 0.016 ) . Twenty-six percent of patients receiving gold achieved an ACR50 response compared with 4 % of patients receiving placebo ( P = 0.017 ) , and 21 % of patients receiving gold achieved an ACR70 response compared with 0 % of patients receiving placebo ( P = 0.011 ) . From both clinical and cost-effectiveness perspectives , gold was the preferred and dominant strategy . Study treatment was discontinued in 23 patients ( 14 in the placebo group compared with 9 in the gold group ; P = 0.022 ) due to loss to followup , adverse events , or lack of efficacy . CONCLUSION In RA patients with a suboptimal response to MTX , adding weekly IM gold causes significant clinical improvement . Adverse events were minor , and IM gold-related adverse events led to discontinuation in only 11 % of the gold group over 48 weeks Background : Sulfasalazine and tetracyclines are effective against rheumatoid arthritis ( RA ) . Levofloxacin , the bacteriologically active isomer of ofloxacin , is used in the treatment of infections caused by periodontopathic bacteria and facultative anaerobic bacteria . The aim of this study is to evaluate the clinical efficacy , safety , and tolerability of levofloxacin in patients with rheumatoid arthritis . Methods : In a 6-month , double-blind trial , we r and omly assigned 76 patients with persistently active rheumatoid arthritis despite at least 6 months of methotrexate therapy at a stable dose of 15 to 25 mg per week to receive either levofloxacin ( 500 mg ) or placebo orally once daily while continuing to receive methotrexate . The change from baseline to six months in the swollen-joint count and tender-joint count was the primary measure of efficacy . Secondary endpoints included pain , quality of life , duration of morning stiffness , erythrocyte sedimentation rate , C-reactive protein level , and physician ’s and patient ’s global assessment s. The data were also analyzed to determine the number of patients meeting American College of Rheumatology criteria for 20 , 50 , and 70 % improvement . Results : The levofloxacin plus methotrexate was associated with the greatest reduction in the number of swollen or tender joints ( P < 0.001 ) . The levofloxacin plus methotrexate group also had significant improvement in many of the secondary outcome measures ( P < 0.001 ) . Levofloxacin was well tolerated . There were no dose-limiting toxic effects . Conclusion : In patients with active rheumatoid arthritis who received methotrexate , treatment with levofloxacin significantly improved the signs and symptoms of rheumatoid arthritis Context First-year results of the BeSt study showed that initial combination therapy for rheumatoid arthritis produced more rapid clinical improvement and less radiologic evidence of progression of joint damage than did initial monotherapy . Contribution The investigators assessed clinical and radiologic outcomes during year 2 while following a scheduled program of step-up and step-down medication adjustment based on disease activity score . All treatment groups achieved similar disease activity after 2 years , although initial monotherapy was often converted to combination therapy during follow-up . Implication s Although all regimens were equally effective in eventually controlling disease activity , the rapid control produced by initial combination therapy may translate into decreased joint damage . The Editors Over the past few years , the outcome for patients with rheumatoid arthritis has improved considerably ( 1 ) . Combinations of disease-modifying antirheumatic drugs ( DMARDs ) with corticosteroids and DMARDs with the new tumor necrosis factor antagonists seem to suppress the inflammatory process more effectively than single-drug therapy in patients with early ( 210 ) and established ( 1115 ) disease . This results in less progression of radiographic joint damage and better preservation of physical function compared with single-drug therapy . More recently , tight control of disease activity has been shown to improve outcome ( 16 ) , and there are indications that outcome is related to adherence to treatment guidelines ( 17 ) . Whether combination therapy with DMARDs , corticosteroids , or tumor necrosis factor antagonists should be considered for initial treatment in all patients with rheumatoid arthritis or whether such therapy should be reserved for patients who do not respond to monotherapy is unknown . Therefore , the BeSt study ( 9 ) evaluated the efficacy of 4 of the most frequently used treatment strategies in a head-to-head comparison : sequential monotherapy ( group 1 ) , step-up combination therapy ( group 2 ) , initial combination therapy with tapered high-dose prednisone ( group 3 ) , and initial combination therapy with infliximab ( group 4 ) . Treatment adjustments were made every 3 months in patients with an insufficient response or a continued good response . During the first year of treatment , initial combination therapy for groups 3 and 4 result ed in more rapid clinical improvement and less progression of joint damage compared with initial monotherapy for groups 1 and 2 . In the second year , response to therapy continued to be tightly monitored . Treatment adjustments were made according to the protocol . We evaluated whether the initial clinical and radiologic outcomes could be maintained and what treatment adjustments were needed in each group . Methods Patients Rheumatologists participating in the Foundation for Applied Rheumatology Research in 18 peripheral and 2 university hospitals in the western part of the Netherl and s design ed and conducted the BeSt study . Between April 2000 and August 2002 , we recruited patients with early rheumatoid arthritis who fulfilled the American College of Rheumatology ( ACR ) 1987 criteria for rheumatoid arthritis ( 18 ) . Patients were 18 years of age or older ; had a disease duration of 2 years or less ; had active disease with at least 6 of 66 swollen joints and at least 6 of 68 tender joints ; and had an erythrocyte sedimentation rate of 28 mm/h or greater or a global health score of 20 mm or more ( on a visual analogue scale of 0 mm [ best ] to 100 mm [ worst ] ) . Patient enrollment criteria have been described in detail previously ( 9 ) . The medical ethics committee at each participating center approved the study protocol , and all patients gave written informed consent before study inclusion . Treatment Protocol Patients were allocated to 1 of 4 treatment groups by variable block r and omization ( 913 ) , which was stratified per center . Treatment groups were sequential monotherapy ( group 1 ) , step-up combination therapy ( group 2 ) , initial combination therapy with tapered high-dose prednisone ( group 3 ) , and initial combination therapy with infliximab ( group 4 ) . For patients who did not respond to medication , the protocol prescribed many subsequent steps . The decision of whether to adjust medication was made every 3 months on the basis of disease activity score ( 19 ) , a continuous measure consisting of the Ritchie articular index and number of swollen joints in a 44-joint count , erythrocyte sedimentation rate , and global health as measured on a visual analogue scale . A disease activity score of 2.4 or less indicates low disease activity ( 20 ) . A research nurse who remained blinded to the allocated treatment group during the study period calculated the score . If the disease activity score was greater than 2.4 ( insufficient response ) , the treating physician immediately adjusted therapy by proceeding to the next step in the allocated treatment group . If the disease activity score was 2.4 or less for at least 6 months , medication was gradually withdrawn until 1 drug remained in a maintenance dosage . Patients in group 1 started with methotrexate , followed subsequently by sulfasalazine , leflunomide , methotrexate with infliximab , gold with methylprednisolone ( intramuscular ) , methotrexate with cyclosporine and prednisone , and azathioprine with prednisone . Patients in group 2 started with methotrexate , followed subsequently by methotrexate with sulfasalazine , methotrexate with sulfasalazine and hydroxychloroquine , methotrexate with sulfasalazine , hydroxychloroquine and prednisone , methotrexate with infliximab , methotrexate with cyclosporine and prednisone , leflunomide , and azathioprine with prednisone .  Patients in group 3 started with the combination of methotrexate , sulfasalazine , and tapered high-dose prednisone ( 2 ) , followed subsequently by methotrexate with cyclosporine and prednisone , methotrexate with infliximab , leflunomide , gold with methylprednisolone , and azathioprine with prednisone .  Patients in group 4 started with the combination of methotrexate and infliximab , followed subsequently by sulfasalazine , leflunomide , methotrexate with cyclosporine and prednisone , gold with methylprednisolone , and azathioprine with prednisone . In addition to the regular trimonthly assessment s , we calculated additional disease activity scores every 8 weeks in all patients who were treated with infliximab in the week before infusion . On the basis of these scores , we decided whether to increase or taper the dosage . The treatment protocol and dose regimen have been described in detail previously ( 9 ) . We permitted concomitant treatment with nonsteroidal anti-inflammatory drugs and intra-articular injections with corticosteroids and did not allow other parenteral corticosteroids . We allowed DMARDs or oral corticosteroids only as dictated by the treatment protocol . All patients received folic acid , 1 mg per day , during treatment with methotrexate . Study End Points and Assessment s The primary efficacy end point was functional ability , as measured by the Dutch Health Assessment Question naire . Higher scores indicated more severe loss of physical function ( 21 ) . Secondary efficacy end points were 20 % and 70 % improvement according to the ACR ( ACR20 and ACR70 , respectively ) response criteria ( 22 ) and clinical remission , defined as a disease activity score less than 1.6 ( 23 ) . Assessment s were done every 3 months by blinded research nurses , who were trained at study onset and every 6 months thereafter to maintain consistency . Two study physicians ensured adherence to the protocol every 3 months . All protocol deviations were recorded . Patients were not informed about study outcomes until the end of the second year of follow-up . The primary radiographic end point was the change in the total Sharpvan der Heijde score for joint damage , which ranged from 0 to 448 , over 2 years ( 24 ) . Two trained readers independently scored the radiographs of h and s , wrists , and feet at baseline and at the 2-year follow-up . The patient 's identity , treatment group , and sequence of the films in sets were masked to the readers . We used the mean score of the 2 readers for the analysis . The intraobserver coefficients were 0.90 and 0.91 , and the interobserver coefficient was 0.94 . Erosive disease was defined as a mean erosion score greater than 0.5 . Toxicity We performed physical examination and laboratory tests and recorded all adverse events at all visits . If necessary , the treating physician adjusted the patient 's medication as outlined previously . Serious adverse events were defined as an adverse reaction result ing in any of the following outcomes : a life-threatening condition or death , substantial or permanent disability , malignant disease , hospitalization or prolongation of hospitalization , or a congenital abnormality or birth defect . Before beginning infliximab therapy , all patients were evaluated for  tuberculosis  with a purified protein derivative skin test and chest radiography . In the beginning of 2002 , congestive heart failure was added as a contraindication for treatment with infliximab . Treatment was discontinued for previously enrolled patients with functional classes I , II , III , and IV concomitant congestive heart failure , as defined by the New York Heart Association ( 25 ) . These patients ' conditions seemed to be worsening with infliximab therapy . Worsening was defined as every transition to a higher functional class . Statistical Analysis We needed a sample size of 468 patients ( 117 per group ) to ascertain 80 % power to detect a difference of at least 0.2 in the Health Assessment Question naire score . This was set as a clinical ly relevant difference with a 5 % significance level and adjustment for multiple comparisons between groups , assuming an SD of 0.45 . The sample size also ensured greater than 80 % power to detect a difference of 20 % or greater in the change in score for radiologic joint damage . We performed intention-to-treat analyses . When appropriate , we Objective : To evaluate whether early combined therapy with methotrexate ( MTX ) and sulfasalazine ( SSZ ) during the first year in early rheumatoid arthritis ( RA ) induces long term beneficial effects , compared with monotherapy , when the further treatment strategy is a free choice . Methods : Study design : five year multicentre prospect i ve longitudinal trial . Participants : 146/205 patients with RA previously included in a one year prospect i ve r and omised trial comparing the effects of treatment with MTX , SSZ , or a combination of both . Criteria for inclusion : patients with early RA ( ⩽1 year duration ) . Follow up : between the end of years 1 and 5 , patients were followed up and treated by their own rheumatologist , who was allowed to indicate any treatment . Outcome measures : disease activity score ( DAS ) , health assessment question naire ( HAQ ) , and Sharp/van der Heijde radiological score at baseline and after five years of follow up . Analysis : comparison of the five year follow up DAS , HAQ , and radiological scores in patients given combined and single treatment during the first year . Results : At the end of the five years of follow up , the patients primarily receiving single or combined treatment had similar mean DAS , HAQ , and radiographic scores . Conclusion : Treatment of patients with early RA using combined therapy with MTX and SSZ during the first year did not influence the long term inflammatory status , or disability , or structural changes , compared with single disease modifying antirheumatic drug treatment BACKGROUND Patients with severe rheumatoid arthritis who are treated with methotrexate  frequently have only partial improvement . METHODS In a six-month r and omized , double-blind trial , we compared combination therapy with cyclosporine ( 2.5 to 5 mg per kilogram of body weight per day in two divided doses at 12-hour intervals ) and methotrexate ( at the maximal tolerated dose ) with methotrexate and placebo in 148 patients with rheumatoid arthritis who had residual inflammation and disability despite partial but substantial responses to prior methotrexate treatment . The primary outcome measure was the change in the number of tender joints . RESULTS The mean ( + /- SD ) dose of cyclosporine at the final treatment was 2.97 + /- 1.02 mg per kilogram per day . As compared with the placebo group , the patients in the treatment group had a net 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 3.8 joints ( 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 in the degree of disability ( 26 percent , P < 0.001 ) . The mean erythrocyte sedimentation rate increased by 4.2 mm per hour in the cyclosporine group and decreased by 4.8 mm per hour in the placebo group ( P = 0.006 ) . Thirty-six patients ( 48 percent ) in the cyclosporine group and 12 patients ( 16 percent ) in the placebo group ( P < 0.001 ) met the 1993 criteria for improvement of the American College of Rheumatology ( more than 20 percent improvement in the numbers of both swollen and tender joints and improvement in three of five other variables ) . Seventeen patients in the cyclosporine group and 12 patients in the placebo group were withdrawn from the study ; 2 patients in the cyclosporine group died , 1 from viral pneumonia and the other in a motor vehicle accident . Serum creatinine concentrations increased by a mean of 0.14 + /- 0.27 mg per deciliter ( 12 + /- 24 mmol per liter ) in the cyclosporine group and by 0.05 + /- 0.19 mg per deciliter ( 4 + /- 17 mmol per liter ) in the placebo group ( P = 0.02 ) . CONCLUSIONS In a six-month study , patients with severe rheumatoid arthritis and only partial responses to methotrexate  had clinical ly important improvement after combination therapy with cyclosporine and methotrexate .  Side effects were not substantially increased . Long-term follow-up of patients treated with this combination is needed To compare the efficacy of sulphasalazine , methotrexate , and the combination of both in patients with early rheumatoid arthritis ( RA ) , not treated with disease-modifying anti-rheumatic drugs previously , we conducted a double-blind , double-dummy , controlled , clinical trial . One hundred and five patients with active , early RA , rheumatoid factor and /or HLA DR1/4 positive were r and omized between sulphasalazine ( SSZ ) 2000 ( maximum 3000 ) mg daily , or methotrexate ( MTX ) 7.5 ( maximum 15 ) mg weekly , or the combination ( COMBI ) of both , and were followed up by a single observer for 52 weeks . The mean change over time per patient , including all visits , in Disease Activity Score ( DAS ) was : SSZ : -1.6 ( 95 % CI -2.0 to -1.2 ) ; MTX : -1.7 ( -2.0 to -1.4 ) ; COMBI : -1.9 ( -2.2 to -1.6 ) ; the difference week 0-week 52 ( SSZ , MTX , COMBI respectively ) ; DAS : -1.8 , -2.0 , -2.3 , Ritchie articular index : -9.2 , -9.5 , -10.6 , swollen joints : -9.2 , -12.4 , -14.3 , erythrocyte sedimentation rate : -17 , -21 , -28 . Nausea occurred significantly more in the COMBI group . The numbers of drop-outs due to toxicity were SSZ 9 , MTX 2 , COMBI 5 . In conclusion , there were no significant differences in efficacy between combination and single therapy , only a modest trend favouring COMBI . The results of MTX and SSZ were very comparable . Nausea occurred more often in the COMBI group : the number of withdrawals due to adverse events did not differ significantly
BACKGROUND Methotrexate ( MTX ) is among the most effective disease modifying anti-rheumatic drugs ( DMARDs ) in rheumatoid arthritis ( RA ) with less toxicity and better tolerability .
OBJECTIVES To evaluate the efficacy and toxicity of MTX monotherapy compared to MTX combination with non-biologic DMARDs in adult with RA .