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.

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 randomized 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.

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.

The present double-blind, placebo-controlled study was conducted to compare the safety and efficacy of tenidap in patients with rheumatoid arthritis (RA). Patients with flare of active RA following NSAID withdrawal were randomized to receive either placebo (n = 67) or tenidap (n = 131; 40-200 mg/day). The mean changes from baseline in efficacy and biochemical variables were compared between treatment groups at endpoint (4 weeks). The improvements in four of the five primary efficacy variables were significantly greater in the tenidap group compared with the placebo group (p < 0.01). Tenidap was also associated with an 18% reduction in erythrocyte sedimentation rate (ESR) and a marked, 51%, reduction in serum C-reactive protein (CRP) level, both of which were significantly greater than the changes in the placebo group (p < 0.05). The percentage of patients who discontinued because of side effects was the same in both groups (3%). In conclusion, tenidap 40-200 mg/day was effective and well tolerated in the treatment of patients with RA for 4 weeks.

To assess the relative efficacy of methotrexate (MTX), azathioprine (AZA), and their combination in the treatment of rheumatoid arthritis (RA), a double blind, prospective, 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, randomly 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.

The present double-blind, placebo-controlled study was conducted to Compare the safely and efficacy of tenidap in patients with rheumatoid arthritis (RA). Patients with dare of active RA following NSAID withdrawal were randomized to receive either placebo (n=67) or tenidap (n=131; 40-200 mg/day). The mean changes from baseline in efficacy and biochemical variables were compared between treatment groups at endpoint (4 weeks). The improvements in four of the five primary efficacy variables were significantly greater in the tenidap group compared with the placebo group (p<0.01). Tenidap was also associated with an 18% reduction in erythrocyte sedimentation rate (ESR) and a marked, 51%, reduction in serum C-reactive protein (CRP) lever, both of which were significantly greater than the changes in the placebo group (p<0.05). The percentage of patients who discontinued because of side effects was the same in both groups (3%). In conclusion, tenidap 40-200 mg/day was effective and well tolerated in the treatment of patients with RA for 4 weeks.

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, prospective, 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 (5mg 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, randomly 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.

In recent years there have been many significant developments in the ability to process radiographic pictures and transfer the images from one location to another, and we can now examine the application of computers in the radiographic evaluation of rheumatoid arthritis. Image management and communication systems can assist in providing better health care while lowering costs. Although this work is still in its infancy, the rapid growth in both hardware capability and software techniques will soon make these techniques available to physicians everywhere. The expanding capability in the commercial world is being embraced by the radiology department, and will soon allow rheumatologists to access images at greater distances, and do more with the images which become available.

OBJECTIVE:To compare the relative safety and efficacy of hydroxychloroquine (HCQ) and placebo (Pl) in the treatment of the articular complaints of systemic lupus erythematosus (SLE).METHODS:Seventy-one patients with mild SLE requiring < or = 10 mg of prednisone or equivalent daily and with arthritis or arthralgias were entered into a 48-week prospective, controlled, double blind multicenter trial and randomly assigned to either HCQ or Pl.RESULTS:Both HCQ and Pl were well tolerated in the 48-week trial. There were no remissions. With the exception of the patient assessment of joint pain, all other joint measures were similar between the groups. Twenty-nine patients withdrew before the end of the trial although only 2 patients withdrew for adverse drug effects.CONCLUSION:Our study found subjective pain relief as the only statistically significant difference in joint count variables from HCQ in the treatment of the articular manifestations of SLE.

The therapeutic efficacy and safety of ketoprofen extended-release (ER) and diclofenac were compared in a multicenter, randomized, double-blind, parallel-group study of 239 patients with active osteoarthritis of the hip and/or knee. Patients were treated for up to 4 months: 118 received ketoprofen ER, 200 mg once daily, and 121 patients received diclofenac, 75 mg twice daily. The demographic attributes of the two study groups were comparable. Clinical efficacy and safety assessments were made at weeks 1, 2, and 4, and at months 2, 3, and 4. The efficacy analysis included 230 patients: 114 in the ketoprofen ER group and 116 in the diclofenac group. Both treatments produced significant (P < 0.001) improvement from baseline in all efficacy variables at all time points. Except for nighttime pain/sleep disturbance at month 2 and patient's global assessment at week 2, there were no clinically significant differences between treatments. Ketoprofen ER and diclofenac produced rapid symptomatic relief (statistically significant at week 1), which was maintained over the 4-month treatment period. The rates of common treatment-emergent study events were similar in both groups; however, constipation and fever were more frequent with ketoprofen ER and liver test abnormalities were more frequent with diclofenac. Of the 29 patients who withdrew because of adverse study events, 10 were treated with ketoprofen ER (most had minor gastrointestinal events) and 19 were treated with diclofenac (many had increased transaminase activities). A duodenal ulcer was diagnosed in one diclofenac-treated patient at month 4. Fourteen diclofenac-treated patients had potentially clinically significant elevations in serum glutamic-oxaloacetic transaminase or serum glutamic-pyruvic transminase activities (>3 times the upper limit of the normal range). Ketoprofen ER and diclofenac were therapeutically equivalent in this study, but clinically significant signs of potential hepatotoxicity were seen only in the diclofenac-treated group.

Objective. To compare the relative safety and efficacy of naproxen and acetaminophen in the treatment of osteoarthritis (OA) of the knee. The major outcome measures were radiographic progression and withdrawal from the trial due to lack of efficacy.Methods. One hundred seventy-eight patients with OA of the knee were enrolled in a 2-year prospective, controlled, double-blind multicenter trial and were randomly assigned to receive acetaminophen (ACT) or naproxen (NPX) treatment.Results. After 6 weeks of treatment, modest improvement in pain on motion and in physician's global assessment was seen in both the ACT and the NPX groups, and the NPX group also had modest improvement in pain at rest and in 50-foot walk time. Sixty-two patients completed the 2-year study. Among these patients, radiographic progression was similar in the 2 treatment groups. Withdrawal from the trial due to lack of drug efficacy was slightly more frequent among patients in the ACT group (22% versus 16%), but withdrawal due to adverse drug effects was slightly more common in the NPX group (23% versus 18%).Conclusion. The efficacy of ACT treatment and NPX treatment was similar, although it was slightly better for NPX. The toxicity rate was slightly lower with ACT. However, the high rate of withdrawal in both treatment groups suggests that neither is satisfactory for the treatment of OA.

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.

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 prospective, controlled, double-blind, multicenter trial and were randomly 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.