BACKGROUND:Disease-modifying antirheumatic drugs may confer greater benefits when combined with the antimetabolite methotrexate.OBJECTIVE:To evaluate the efficacy and safety of leflunomide versus placebo when added to ongoing, stable-dose methotrexate therapy in patients with persistently active rheumatoid arthritis.DESIGN:24-week, multicenter, randomized, double-blind, placebo-controlled trial.SETTING:20 centers in the United States and Canada.PATIENTS:Patients with persistent rheumatoid arthritis, as defined by American College of Rheumatology (ACR) criteria, despite receiving methotrexate for at least 6 months.INTERVENTION:Leflunomide or matching placebo added to existing methotrexate therapy.MEASUREMENTS:The primary efficacy variable was the rate of achievement of 20% improvement in ACR criteria (ACR20) at the end of the study. The Health Assessment Questionnaire Disability Index was assessed at each visit, and the Medical Outcomes Study 36-Item Short Form was completed as an end point analysis.RESULTS:In the leflunomide and placebo groups, 46.2% and 19.5% of patients, respectively, met ACR20 criteria at 24 weeks (P < 0.001). Clinical improvement was demonstrated by statistically significant mean changes in individual components of the ACR20 response criteria. Discontinuation rates were similar in both treatment groups (23.1% in the leflunomide group and 24.8% in the placebo group), as were the overall incidences of adverse events (89.2% vs. 89.5%, respectively). Adverse events were predominantly mild or moderate.CONCLUSIONS:Combination therapy with leflunomide and methotrexate provides statistically significant clinical benefit in patients with active rheumatoid arthritis who are receiving methotrexate therapy. Leflunomide plus methotrexate is generally well tolerated and can be used safely with appropriate liver enzyme and hematologic monitoring.

Background Combination therapy for the treatment of patients with RA may improve response rate in those who have responded inadequately to MTX alone. As LEF is increasingly being used in RA management, it is relevant to determine the impact of adding LEF to MTX. Objectives To investigate the benefits of adding LEF to an existing MTX regimen on efficacy, tolerability, physical function, and health-related quality of life (HRQOL) in patients with active RA in a 24-week multi-centre, randomised, double-blind placebo (PLC)-controlled trial. Methods Subjects with active RA receiving MTX (15?20 mg/week) for > = 6 months and at a stable dose for > = 8 weeks were randomised to receive LEF 100 mg QD x 2 days followed by 10 mg QD thereafter (n = 130) or matching PLC (n = 133). Mean doses of MTX were 16.7 mg/week and 16.2 mg/week for LEF+MTX and PLC+MTX, respectively. The primary efficacy endpoint was ACR 20 responder rate at 24 weeks, with a secondary endpoint of ACR 20 response using LOCF, with both analysed in the ITT population. ACR 20, 50 and 70 response rates, as well as safety monitoring, were assessed every 2 weeks up to week 8, and every 4 weeks thereafter. The Health Assessment Questionnaire (HAQ) and Medical Outcomes Survey Short Form (SF-36) questionnaire were administered and the mean improvements from baseline were compared at week 24 for the LEF+MTX group and the PLC+MTX group. Results Using the LOCF method, the ACR 20, 50 and 70 rates were LEF+MTX = 51.5%, 26.2% and 10.0% vs PLC+MTX = 23.3%, 6.0% and 2.3% (p < = 0.0001, p < = 0.0001, and p < = 0.02). At week 24, ACR 20 responder rates were LEF+MTX = 46.2% vs PLC+MTX = 19.5% (p < = 0.0001). Mean baseline values for the disability index (DI) derived from the HAQ were LEF+MTX = 1.6 vs PLC+MTX = 1.5 (NS). At 24 weeks, mean changes from baseline in HAQ DI were LEF+MTX = -0.42 vs PLC+MTX = -0.09 (p < = 0.0001); representing mean improvements of 29% and 5%, respectively, based on individual percent changes. Mean baseline values for the physical component summary scale (PCS) derived from the SF-36 were LEF+MTX = 28.4 vs PLC+MTX = 29 (NS). At 24 weeks, mean changes from baseline in the PC were LEF+MTX = 6.8 vs PLC+MTX = 0.3 (p < = 0.0001); representing mean improvements of 29% and 3%, respectively, based on individual percent changes. Reported AEs included diarrhoea (LEF+MTX = 25.4% vs PLC+MTX = 13.5%), upper respiratory infections (LEF+MTX = 22.3% vs PLC+MTX = 24.1%), nausea (LEF+MTX = 16.2% vs PLC+MTX = 11.3%) and dizziness (LEF = MTX = 7.7% vs PLC+MTX = 5.3%). Increases in LFTs of >3×ULN at any time during the 24-week treatment period for ALT and AST for LEF+MTX were 3.8% and 1.5%, respectively, compared to 0.8% on both for PLC+MTX. Conclusion LEF combined with an existing MTX regimen in patients with active RA is well tolerated and confers significant therapeutic advantages in terms of both efficacy and quality of life.

OBJECTIVE:(1) To review the diagnoses after 10 years in patients who were identified within 12 months of the onset of well established and undifferentiated connective tissue diseases (CTD). (2) To examine the death rates and disease remissions in these patients.METHODS:This inception cohort of 410 patients had less than one year of signs and/or symptoms of CTD. Diagnoses of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and poly/dermatomyositis (PM/DM) were made in 197 patients using accepted diagnostic and classification criteria. Diagnoses of undifferentiated CTD were made in 213 patients. These latter patients were placed in 3 categories: isolated Raynaud's phenomenon (RP), unexplained polyarthritis (UPA), and undifferentiated CTD (UCTD), defined as meeting at least 3 of 11 specific manifestations of CTD. The diagnoses and remissions in all patients after 10 years were determined.RESULTS:Patients with well established CTD tended to remain with the original diagnosis. The 10 year survival was at least 87% in all diagnostic categories, with the exception of SSc, in which it was 56%. The progression of UPA to RA occurred infrequently. The presence of antinuclear antibodies suggested that UPA may develop additional symptoms and/or a specific diagnosis, and RP in these patients increased the likelihood of progressing to UCTD or a specific well established CTD. Ten percent of patients with RP progressed to SSc. In patients with UCTD, joint pain/tenderness and swelling counts were associated with progression to other diagnoses including RA, while either serositis, malar rash, or discoid lupus suggested the eventual diagnosis of SLE.CONCLUSION:The survival of patients with SSc was poor, with most dying early in the course of their disease. Remissions were seen in all groups of patients except SSc. The remissions were sometimes transient in SLE. Undifferentiated disease at initial examination within 12 months of onset usually remains undifferentiated.

OBJECTIVE To review the diagnoses after 5 years in patients who were identified within 12 months of the onset of well established and undifferentiated connective tissue diseases (CTD); to examine death rates and disease remissions in these patients. METHODS This inception cohort of 410 patients was identified in 10 academic rheumatology practices. They had less than one year of signs and/or symptoms of CTD. Diagnoses of specific well established CTD were made using accepted diagnostic and classification criteria. The diagnoses after 5 years were determined. RESULTS Patients with well established CTD tended to remain with the original diagnosis. The progression of unexplained polyarthritis to rheumatoid arthritis occurred infrequently. Ten percent of patients with isolated Raynaud's phenomenon progressed to systemic sclerosis (SSc). The 5 year survival was over 90% in all diagnostic categories, with the exception of SSc, in which it was 64%. CONCLUSION Patients with a well established CTD usually continued with the same diagnosis. Patients with undifferentiated CTD tended to remain undifferentiated or to remit.

OBJECTIVES To examine the musculoskeletal manifestations in a large cohort of patients (n = 410) diagnosed with either a well-established connective tissue disease (CTD) (n = 197) or an early undifferentiated CTD (n = 213) with a symptom duration of <1 year. This study was aimed at determining the predictive value of demographic, clinical, and laboratory features on outcome in patients with unexplained polyarthritis (UPA) (from the early undifferentiated CTD cohort; n = 67) or rheumatoid arthritis (RA) (from the well-established CTD cohort; n = 57), over a 5-year followup period. METHODS Patients from both cohorts were assessed at years 1, 3, and 5. At the study visits, clinical data were collected in a standardized manner, and sera were obtained and stored. A priori criteria were established for patient ascertainment and diagnosis over the duration of the study. Standard statistics were used for comparisons of baseline characteristics in patients diagnosed as having systemic lupus erythematosus, RA, undifferentiated CTD, and UPA at entry into the cohorts. Baseline features in patients with UPA were examined according to the different subsequent outcomes (RA, CTD, or undifferentiated CTD, remission [nonpersistent], or persistent or active UPA). Baseline features in patients with RA whose disease remained active versus those in whom remission was attained were also examined. Two multivariable analyses, classification trees and polychotomous logistic regression, were performed to predict disease outcomes over time. RESULTS The overall rate of ascertainment for the 410 patients ranged from 90 % at year 1 to 71 % at year 5. Patients with established CTDs showed a tendency for more stable diagnoses than those with early undifferentiated CTDs (90-100% versus 45-70%). Consistent baseline predictors of persistent active disease among patients with RA, in both univariate and multivariable analyses, were higher joint counts for pain and tenderness and higher erythrocyte sedimentation rate (ESR). In approximately 20% of patients who were classified as having RA when they originally entered the cohort, the disease was in remission at 5 years. Twenty percent of the patients originally classified as having UPA developed RA over the duration of the study. These patients tended to be older and to have swelling of small joints at baseline. However, a consistent pattern of predictive variables could not be identified in the multivariable analyses, other than at year 1 (higher small joint counts for swelling and higher ESR). CONCLUSION Baseline features (joint counts, and ESR) among RA patients were variously predictive of persistently active disease at years 1-5. Consistent baseline predictors of outcome among patients with UPA only emerged at year 1. Remission occurred in approximately 20% of RA patients, whereas a similar percentage of patients with UPA developed RA. These findings have implications with regard to treatment decisions in patients with early RA and/or UPA.

Objective: To characterize the course of early scleroderma and to delineate prognostic factors present within 1 year of disease onset that might identify patients at high risk.Design: Inception cohort study.Setting: Ten university-based rheumatology clinics participating in the Cooperative Systematic Studies of Rheumatic Diseases Program.Patients: Forty-eight patients who had had scleroderma for less than 1 year.Measurements: Fifteen patients with early scleroderma who died were compared with those still living during the initial study period (1982 to 1992). Kaplan-Meier survival estimation and Cox proportional hazards analysis were used to analyze baseline variables for their ability to predict survival duration.Results: Eight of 15 deaths were due to cardiac or pulmonary system failure. The estimated 5-year survival rate was 68%. Baseline factors that were the most predictive of a poor outcome included the presence of abnormal cardiopulmonary signs and abnormal urine sediment (pyuria, hematuria).Conclusion: Evidence of early cardiopulmonary disease, renal disease, inflammation, or immune activation may identify a subset of patients with scleroderma who will experience rapidly progressive disease and early death.

The presence of antinuclear antibodies (ANA) in the serum is a common finding in various connective tissue disorders, but usefulness of these antibodies in making diagnoses or prognoses is not known. We report the results of a panel of ANA determinations including ANA, anti-dsDNA, Sm, RNP, SSA, SSB, Jo-1, Scl-70 and PM-1 in 410 patients in a 5-year descriptive study of 410 patients with rheumatic disease symptoms of less than one year's duration. While some patients met diagnostic criteria for a specific rheumatologic diagnosis, others were classified as undifferentiated connective tissue disease (UCTD) and were subclassified by a constellation of symptoms. Our results show that ANA is sensitive in systemic lupus erythematosus (SLE) and progressive systemic sclerosis even in early disease but is not specific. Other "specific" autoantibodies were seen most frequently in SLE but were relatively insensitive and were seen in low frequency in UCTD. ANA have limited diagnostic value in patients with early disease. The prognostic value of these tests will be assessed as the prospective study of these cohorts progresses.

We identified a cohort of 410 patients with connective tissue disorders (CTD) of less than or equal to 1 year duration among the participating clinics of the Cooperative Systematic Studies of the Rheumatic Diseases Program. Fifty-seven had rheumatic arthritis (RA), 57 systemic lupus erythematosus, 37 poly/dermatomyositis, 46 scleroderma, and 213 early undifferentiated CTD, including patients with Raynaud's phenomenon, unexplained polyarthritis or at least 3 CTD manifestations such as rashes, myalgias, etc. Baseline clinical data are now being reported. The followup of these patients may prove to be valuable in understanding these diseases. To our knowledge no similar cohort of patients is available for further investigation.

In a double-blind, randomized trial of methotrexate vs placebo in rheumatoid arthritis, the effect of treatment on physical, social, and emotional function was measured in two different ways: the same, standard measurements in all patients, and individualized measurements selected by the patients at the start of the trial as representing the functions they most wanted to have improved by treatment. On the standard measurements, methotrexate-treated patients fared better than placebo-treated patients in their physical, social, and emotional function by 11%, 5%, and 6%, respectively, results that, although statistically significant, were small. However, methotrexate-treated patients were 29% better in the individualized measures, a result that was both highly statistically significant and greater than the differences in the standard measurements or in joint counts, grip strength, proximal interphalangeal joint circumference, morning stiffness, or walking time. Because the individualized measurements were as efficient as the best direct joint examination measures, yet reflected functional outcomes of greatest importance to individual patients, they constitute useful measures for such trials.

One hundred eight-six patients with active rheumatoid arthritis were evaluated in a double-blind, randomized study that compared treatment with sulfasalazine (SSZ) (2 mg/day), gold sodium thiomalate (GST) (50 mg/week), and placebo (PBO). The 37-week course of therapy was completed by 109 patients. While marked improvement was seen in all 3 treatment groups, the only statistically significant differences between SSZ or GST and PBO were in a decreased erythrocyte sedimentation rate and increased grip strength in the right hand. GST is known to be superior to PBO, and the response of the GST-treated group was similar to that seen in other trials. The response of the PBO group, however, was much greater than in other placebo groups we have studied. SSZ was similar in efficacy to injectable gold, but was better tolerated. Because of adverse drug reactions (most commonly, rash, stomatitis, and proteinuria), 41% of patients were withdrawn from the GST treatment. Untoward drug effects (most frequently, rash and gastrointestinal distress) caused 16% of patients to be withdrawn from SSZ therapy.

Recent studies have indicated an association between the HLA-DR2 phenotype and substantial response to methrotrexate in patients with rheumatoid arthritis (RA). To further resolve this issue, we analyzed this relationship. Our data, obtained from a multicenter, double-blind study of rigorously assessed patients with RA, demonstrated that neither HLA-DR2 nor any other HLA-DR specificity is significantly associated with a substantial clinical response to methotrexate in patients with RA.

One hundred eighty-nine patients with rheumatoid arthritis were entered into a prospective, controlled, double-blind multicenter trial comparing placebo and methotrexate (MTX). One hundred ten patients completed 18 weeks of therapy. No remissions were seen, but patients able to tolerate low-dose pulse MTX therapy were significantly improved, compared with patients receiving placebo therapy, for all clinical variables measured, including joint pain/tenderness and swelling counts, rheumatoid nodules, and patient and physician assessment of disease activity. MTX treatment demonstrated statistically significant improvement over placebo in patients with anemia, elevated erythrocyte sedimentation rate, and rheumatoid factor. However, nearly one-third of the patients receiving MTX were withdrawn for adverse drug reactions, of which elevated levels of liver enzymes was the most common. Pancytopenia occurred in 2 patients taking MTX. All adverse drug effects resolved without sequelae. MTX appears to be effective in the treatment of active rheumatoid arthritis but requires close monitoring for toxicity.