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Objective: To assess the potential benefits of methotrexate in patients with systemic lupus erythematosus (SLE)., Methods: A 12-month, double-blind, placebo-controlled trial of methotrexate with folic acid was conducted. Intent-to-treat analyses were performed with mixed linear models and alpha = 0.04 (96% confidence interval [96% CI]) to account for interim analysis of longitudinal data to assess the treatment effects on lupus disease activity and daily steroid dose across monthly measurements, and to test if the treatment effects depended on selected participant characteristics., Results: Of 215 participants screened, 94 were excluded, 35 declined, and 86 were randomized (methotrexate = 41, placebo = 45). The groups were balanced for demographic and disease characteristics. Antimalarial use was more frequent in the placebo group, which was adjusted for in multivariable analyses. Sixty participants (27 methotrexate, 33 placebo) completed the study and 26 terminated early. Among participants who had the same baseline prednisone dose, those taking methotrexate received, on average, 1.33 mg/day less prednisone during the trial period (96% CI 0.06, 2.72 mg/day; a 22% reduction of their average-during-trial daily dose) compared with those in the placebo group. For the primary measure of disease activity (revised Systemic Lupus Activity Measure), methotrexate use was also associated with a marginally significant reduction in the mean during-trial score of 0.86 units (96% CI 0.01, 1.71; P = 0.039). A significant interaction between treatment and baseline damage was found (P = 0.001)., Conclusion: Methotrexate conferred a significant advantage in participants with moderately active lupus by lowering daily prednisone dose and slightly decreasing lupus disease activity. As a therapeutic option in moderate SLE, methotrexate can be considered to be steroid sparing.

Objective: To identify in patients with Raynaud's phenomenon (RP) independent markers that predict progression to definite systemic sclerosis (SSc) and to determine in patients with progression to SSc the type and sequence of microvascular damage and its relationship to SSc-specific autoantibodies., Methods: Consecutive patients referred for evaluation of RP who had no definite connective tissue disease were evaluated for microvascular damage by nailfold capillary microscopy (NCM) and for anticentromere (anti-CENP-B), anti-Th/To, anti-topoisomerase I, and anti-RNA polymerase III (anti-RNAP III) autoantibodies by specific assays. Patients were studied prospectively., Results: Of the 586 patients who were followed up for 3,197 person-years, 74 (12.6%) developed definite SSc. A characteristic sequence of microvascular damage was identified, starting with enlarged capillaries, followed by capillary loss, and then by capillary telangiectases. Definite SSc was diagnosed in close temporal relationship to capillary loss. Enlarged capillaries, capillary loss, and SSc-specific autoantibodies independently predicted definite SSc. Anti-CENP-B and anti-Th/To antibodies predicted enlarged capillaries; these autoantibodies and anti-RNAP III predicted capillary loss. Each autoantibody was associated with a distinct time course of microvascular damage. At followup, 79.5% of patients with 1 of these autoantibodies and abnormal findings on NCM at baseline had developed definite SSc. Patients with both baseline predictors were 60 times more likely to develop definite SSc. The data validated the proposed criteria for early SSc., Conclusion: In RP evolving to definite SSc, microvascular damage is dynamic and sequential, while SSc-specific autoantibodies are associated with the course and type of capillary abnormalities. Abnormal findings on NCM at baseline together with an SSc-specific autoantibody indicate a very high probability of developing definite SSc, whereas their absence rules out this outcome.

Objective: Rheumatoid arthritis (RA) is associated with increased frequency of and mortality from infections, which may be related to host factors, RA itself, inflammation, or medication side effects. This study was undertaken to determine the effect of nonbiologic disease-modifying antirheumatic drugs (DMARDs) on infection risk in RA., Methods: We performed a retrospective, longitudinal study of a population-based RA cohort in British Columbia, Canada, followed from January 1996 to March 2003 using administrative data. We evaluated mild infections (requiring a physician visit or antibiotics) and serious infections (requiring or complicating hospitalization). Adjusted risk of mild and serious infections associated with DMARD exposure was estimated using generalized estimating equation extension of multivariate Poisson regression models, after adjusting for baseline covariates (age, sex, RA duration, socioeconomic status) and time-dependent covariates (corticosteroids, comorbidity, prior infections)., Results: A total of 27,710 individuals with RA provided 162,710 person-years of followup. Of these, 25,608 (92%) had at least 1 mild infection and 4,941 (18%) had at least 1 serious infection. Use of DMARDs without corticosteroids was associated with a small decrease in mild infection risk of statistical significance but unclear clinical significance (adjusted rate ratio [RR] 0.90, 95% confidence interval [95% CI] 0.88-0.93 relative to no corticosteroid or DMARD use). Use of DMARDs without corticosteroids was not associated with increased serious infection risk (adjusted RR 0.92, 95% CI 0.85-1.0). Use of corticosteroids increased the risk of mild and serious infections., Conclusion: Our results indicate that use of nonbiologic DMARDs, including methotrexate, does not increase the risk of infection in RA, whereas use of corticosteroids does. This has important implications for counseling individuals with RA concerning risks and benefits of DMARDs.

Objective: Systemic lupus erythematosus (SLE) is characterized by a markedly elevated risk for coronary heart disease (CHD), the exact pathogenesis of which is unknown. In particular, the causal roles of corticosteroid therapy and SLE disease activity, and whether their putative effects are mediated through conventional risk factors, remain unclear., Methods: Data abstracted retrospectively from the charts at 11,359 clinic visits for 310 patients with SLE to the Montreal General Hospital were used to investigate the associations of recent corticosteroid dose and recent Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score with 8 CHD risk factors (total serum cholesterol, high-density lipoprotein [HDL] cholesterol, low-density lipoprotein cholesterol, apolipoprotein B [Apo B], triglycerides, systolic blood pressure [BP], body mass index, and blood glucose) and the aggregate estimate of 2-year CHD risk. Separate multivariable linear regression models estimated the mutually-adjusted effects of average daily corticosteroid dose and average SLEDAI score within the past year on the current level of each risk factor while adjusting for age, sex, cumulative damage score, disease duration, and, where appropriate, use of relevant medications., Results: Higher past-year corticosteroid dose was independently associated with significantly higher overall 2-year CHD risk and with higher levels of all 8 individual risk factors. Higher past-year lupus disease activity was independently associated with higher overall 2-year CHD risk, lower HDL cholesterol, and higher values of systolic BP, Apo B, triglycerides, and blood glucose., Conclusion: In SLE, both recent use of corticosteroids and recent lupus activity are independently associated with higher values of several well-recognized CHD risk factors and overall 2-year CHD risk.

Objective: Care in rheumatoid arthritis (RA) is optimized by involvement of rheumatologists. We wished to determine whether patients suspected of having new-onset RA in Québec consulted with a rheumatologist, to document any delay in these consultations, and to determine factors associated with prompt consultation., Methods: Physician reimbursement administrative data were obtained for all adults in Québec. Suspected new-onset cases of RA in the year 2000 were defined operationally as a physician visit for RA (based on the International Classification of Diseases, Ninth Revision diagnostic codes), where there had been no prior visit code to any physician for RA in the preceding 3 years. For those patients who were first diagnosed by a nonrheumatologist, Cox regression modeling was used to identify patient and physician characteristics associated with time to consultation with a rheumatologist., Results: Of the 10,001 persons coded as incident RA by a nonrheumatologist, only 27.3% consulted a rheumatologist within the next 2.5-3.5 years. Of those who consulted, the median time from initial visit to a physician for RA to consultation with a rheumatologist was 79 days. The strongest predictors of shorter time to consultation were female sex, younger age, being in a higher socioeconomic class, and having greater comorbidity., Conclusion: Our data suggest that the vast majority of patients suspected of having new-onset RA do not receive rheumatology care. Further action should focus on this issue so that outcomes in RA may be optimized.

Objective: To identify predictors of maintenance of exercise for women with fibromyalgia (FM)., Methods: Women with FM who had been randomized to the exercise arm of a clinical trial were studied prospectively during and 3 months following treatment. Subjects completed exercise logs weekly and returned the data via postal mail. Outcome variables were duration of aerobic and stretching exercises. Two separate multivariate models for longitudinal data were built with adjustment for in-treatment adherence and time. Pretreatment characteristics (self efficacy, pain, disability, stress, exercise barriers and benefits, and age) and changes during treatment (pain, disability, stress, and exercise barriers and benefits) were considered potential predictors of exercise maintenance., Results: Stretching significantly decreased in the 3 months following treatment. High stress at baseline and increases in stress during treatment were associated with poor maintenance of stretching. Disability at baseline (measured with the Fibromyalgia Impact Questionnaire), an increase in barriers to exercise during treatment, and increases in upper-body pain during treatment were associated with worse maintenance of aerobic exercise in the 3 months following treatment., Conclusion: The maintenance of an exercise program in women with FM appears to be contingent on being able to deal with stress, pain, barriers to exercise, and disability.

Objective: The frequency of coronary heart disease (CHD) and stroke are increased in systemic lupus erythematosus (SLE), but the extent of the increase is uncertain. We sought to determine to what extent the increase could not be explained by common risk factors., Methods: The participants at two SLE registries were assessed retrospectively for the baseline level of the Framingham study risk factors and for the presence of vascular outcomes: nonfatal myocardial infarction (MI), death due to CHD, overall CHD (nonfatal MI, death due to CHD, angina pectoris, and congestive heart failure due to CHD), and stroke. For each patient, the probability of the given outcome was estimated based on the individual's risk profile and the Framingham multiple logistic regression model, corrected for observed followup. Ninety-five percent confidence intervals (95% CIs) were estimated by bootstrap techniques., Results: Of 296 SLE patients, 33 with a vascular event prior to baseline were excluded. Of the 263 remaining patients, 34 had CHD events (17 nonfatal MIs, 12 CHD deaths) and 16 had strokes over a mean followup period of 8.6 years. After controlling for common risk factors at baseline, the increase in relative risk for these outcomes was 10.1 for nonfatal MI (95% CI 5.8-15.6), 17.0 for death due to CHD (95% CI 8.1-29.7), 7.5 for overall CHD (95% CI 5.1-10.4), and 7.9 for stroke (95% CI 4.0-13.6)., Conclusion: There is a substantial and statistically significant increase in CHD and stroke in SLE that cannot be fully explained by traditional Framingham risk factors alone.

Objective: To evaluate whether changes in laboratory test values are either simultaneous with or precede disease exacerbations in patients with systemic lupus erythematosus (SLE)., Methods: At 9, 6, and 3 months preceding a flare in disease activity (defined as a rise of > or = 6 points in the modified SLE Disease Activity Index), laboratory tests were performed to measure patients' hematocrit levels, white blood cell, lymphocyte, and platelet counts, erythrocyte sedimentation rate, C1q binding, DNA binding, and levels of C3 and C4. Flares were classified as either present or absent, and were divided into renal, vasculitic, central nervous system, skin, serosal, and musculoskeletal subgroups. The predictive patterns were 1) the simultaneous change in the test value from the mean of 9, 6, and 3 months preceding a flare to the time of the flare; 2) the gradual change, following a linear time trend, in test results for the same time points; and 3) the change from the mean of 9 and 6 months to 3 months preceding a flare, as a measure of predictive ability. These analyses used repeated-measures analysis of variance models. Multiple linear regression was used to study the cross-sectional association of average-over-time differences in test results with patients' flare subgroup., Results: Among 202 patients with SLE (median followup 86.5 months), 83 flares occurred in 53 patients. Of 189 statistical contrasts performed, only 14 were significant (versus 10 expected), and the differences were of minor importance. Nonetheless, evaluation of all test results over each patient's observed disease course revealed significant differences between selected test values in association with specific types of flare., Conclusion: Fluctuations in laboratory test values are poor predictors of disease exacerbations in SLE. Cross-sectional evaluation of some test results revealed differences at the time of flare for those patients who were destined to have different types of flares, because these values differed over the entire study period. This pattern explains the frequent cross-sectional association of disease activity with laboratory test results, and the inconsistent association of flares with recent changes in test values.

Objective: To assess the clinical, laboratory, and renal biopsy predictors of long-term outcome in lupus nephritis and to investigate the time-dependence of these predictors., Methods: Eighty-seven lupus nephritis patients were studied retrospectively for the outcomes renal failure and fatality due to renal involvement. In addition to a conventional Cox model analysis, a new generalized time-dependent analytic approach was developed and used to assess the time-dependence of a predictor variable's importance., Results: The mean followup time was 11.9 years. Renal failure (n = 19) was significantly predicted by measures of renal function (abnormal serum creatinine levels, proteinuria, duration of prior renal disease) and immunologic activity (elevated DNA binding, hypocomplementemia, and thrombocytopenia), by overall lupus disease activity measures (le Riche index, Lupus Activity Criteria Count), and by the activity index, the tubulointerstitial index, and the amount of subepithelial deposits on renal biopsy. In general, the laboratory predictors were significantly better prognostic markers in the early years after biopsy, the disease activity measures were best in the later years, and the biopsy variables were significant predictors over the entire observation period. In contrast to the renal failure outcome, the best predictors for death not directly related to lupus nephritis (n = 17) were the extent of comorbid diseases (principally vascular diseases), older age, and the chronicity index. All three predicted well over the extended observation period., Conclusion: The major predictor variables for renal outcomes and nonrenal outcomes are distinct. The time-dependence of the predictive ability of some variables may be important in managing individual patients. The new generalized time-dependent analytic technique may have widespread application in studies to identify prognostic factors for established disease or risk factors for the development of disease.