Early undifferentiated connective tissue disease. IV.Musculoskeletal manifestations in a large cohort of patients with undifferentiated connective tissue diseases compared with cohorts of patients with well-established connective tissue diseases: followup analyses in patients with unexplained polyarthritis and patients with rheumatoid arthritis at baseline.

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.

Comparison of hydroxychloroquine and placebo in the treatment of the arthropathy of mild systemic lupus erythematosus.

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.

Early undifferentiated connective tissue disease: III. Outcome and prognostic indicators in early scleroderma (systemic sclerosis).

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.

Comparison of auranofin, methotrexate, and the combination of both in the treatment of rheumatoid arthritis. A controlled clinical trial.

OBJECTIVE: To compare the relative safety and efficacy of auranofin (AUR), methotrexate (MTX), and the combination of both in the treatment of active rheumatoid arthritis (RA). METHODS: Three hundred thirty-five patients with active RA were entered into a 48-week, prospective, controlled, double-blind, multicenter trial and were randomly assigned to 1 of 3 treatment groups. RESULTS: Two hundred eleven patients completed the trial. No remissions were seen, and there were no statistically significant differences among the treatment groups in the clinical or laboratory variables measured. Patients taking AUR alone had a slower onset of response than did patients taking MTX alone or in combination. Withdrawals because of adverse drug reactions were slightly more common for those taking combination therapy, but the differences were not statistically significant. Withdrawals because of lack of response were more common for single-drug therapy, with the difference between AUR and the combination reaching statistical significance. No unexpected adverse drug effects were identified, and all reactions resolved without sequelae. CONCLUSION: Except for fewer withdrawals because of lack of response, combination therapy did not demonstrate any advantage in efficacy over single-drug treatment within the time frame of the study.

Early undifferentiated connective tissue disease. I. Early clinical manifestation in a large cohort of patients with undifferentiated connective tissue diseases compared with cohorts of well established connective tissue disease.

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.

Early undifferentiated connective tissue disease. II. The frequency of circulating antinuclear antibodies in patients with early rheumatic diseases.

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.

Renal function predicts colchicine toxicity: guidelines for the prophylactic use of colchicine in gout.

In order to establish the degree of renal malfunction necessary for colchicine toxicity in patients receiving it daily for the prevention of recurrent acute gout, we obtained serum creatinine levels and measured or estimated creatinine clearances in a consecutive series of 17 patients with demonstrated colchicine myotoxicity. An estimate of creatinine clearance, based on ideal body weight and age, was nearly always 50 ml/min or less, and was the most practical predictor of the risk of toxicity. By comparison, patients with gout from the same clinical data base, but without myotoxicity, had normal renal function. The data yield clear guidelines for safe use of colchicine chronically.

Treatment of scleroderma skin ulcers with a hydrocolloid membrane.

The purpose of this study was to determine the usefulness of hydrocolloid membrane dressings in the treatment of finger and hand ulcers of scleroderma (progressive systemic sclerosis). Ten pairs of ulcers occurring in seven patients were studied. The ulcers in each patient were treated in a paired comparison trial: one ulcer in each pair was treated with a hydrocolloid membrane; the other was a control. Treatment was continued until at least one ulcer of each pair was healed. The rate of healing of the hydrocolloid membrane-treated ulcers was significantly faster than that of the control ulcers. Pain was rapidly and dramatically reduced in all hydrocolloid membrane-treated ulcers. An infection caused by Pseudomonas aeruginosa occurred in a hydrocolloid membrane-treated ulcer but rapidly responded to topical therapy. Hydrocolloid membrane treatment of sclerodermatous hand ulcers appears to be an effective method of accelerating healing and reducing pain.

Therapy in gout.

The effective management of patients with gout is outlined. The treatment of the acute attack, the prevention of recurrent episodes, and the dissolution of tophi, when present, are generally straightforward and associated with relatively few complications. Patients with a resistant acute attack, with extensive tophaceous deposition, or with allergy or toxicity to any of the standard drugs, present more complex treatment decisions. All agents must be used in an individualized manner for each patient with appropriate concern for risks as well as for benefit.

Review: systemic toxicity associated with the intravenous administration of colchicine--guidelines for use.

Published experiences with severe toxicity with intravenous colchicine have been reviewed. All reported cases reflect inappropriate use of the drug. Therapeutic rules for colchicine have been derived from this information: (1) Single intravenous doses should not exceed 2-3 mg, and cumulative total doses for an attack should not be more than 4-5 mg. (2) Patients should receive no more colchicine by any route for 7 days. (3) Colchicine doses must be reduced in the presence of renal or hepatic disease, and in the older patient with apparently normal renal function. (4) Intravenous colchicine doses should be half the size of oral ones. (5) Absolute contraindications to intravenous colchicine therapy for acute gout include combined renal and hepatic disease, creatinine clearances below 10 cc/min, and extrahepatic biliary obstruction.

Correlation between systemic lupus erythematosus and T4 epitope phenotype.

Three groups of black subjects (systemic lupus erythematosus patients, patients with nonrheumatic disease, and normal subjects) were screened for the expression of the T4 epitope, as recognized by the monoclonal antibody OKT4. We found that the T cell subsets within each group were similar, regardless of the T4 epitope phenotype (intact, intermediate, or deficient). In the subgroup of Jamaican subjects, there was an association between systemic lupus erythematosus and the T4 epitope-intermediate and T4 epitope-deficient phenotypes; this association was not detected in the non-Jamaican population.

Lack of association between HLA-DR2 and clinical response to methotrexate in patients with rheumatoid arthritis.

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.

The allopurinol hypersensitivity syndrome. Unnecessary morbidity and mortality.

Patients receiving allopurinol are at risk of developing the allopurinol hypersensitivity syndrome, an immunologic reaction to the drug, characterized by multiple abnormalities such as fever, rash, decreased renal function, hepatocellular injury, leukocytosis, and eosinophilia. The records of 8 patients with the allopurinol hypersensitivity syndrome evaluated at the Downstate Medical Center hospitals and an additional 72 patients described in the literature were reviewed. All were seriously ill. Three of the 8 patients at the Downstate Medical Center hospitals died as a result of allopurinol hypersensitivity; 19 of the 72 previously described patients also died from consequences of taking the drug. Only 1 of our 8 patients with allopurinol hypersensitivity was given allopurinol for an appropriate reason. Eight of the 59 previously described patients on whom there was adequate information had legitimate indications for allopurinol therapy. Severe, often fatal iatrogenic disease occurred unnecessarily in the others.