C. Douglas Smith

CONTROLLED TRIAL OF NIFEDIPINE IN THE TREATMENT OF RAYNAUD'S PHENOMENON

17 patients with moderate to severe Raynauds phenomenon were entered into a 6 week randomised double-blind crossover study to compare the efficacy of nifedipine with that of placebo. Nifedipine significantly reduced the frequency of attacks and also the severity of attacks, which was assessed by the patients on a linear analogue scale. Patients gave nifedipine a significantly higher drug-effectiveness score than placebo. Skin temperature recovery times were not affected by treatment with nifedipine. 12 of the patients regarded nifedipine as effective in reducing the frequency and severity of Raynauds phenomenon.

Steroid-sparing effects of methotrexate in systemic lupus erythematosus: A double-blind, randomized, placebo-controlled trial

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.

The 1000 Canadian Faces of Lupus: Determinants of Disease Outcome in a Large Multiethnic Cohort

Objective. To describe disease expression and damage accrual in systemic lupus erythematosus (SLE), and determine the influence of ethnicity and socioeconomic factors on damage accrual in a large multiethnic Canadian cohort. Methods. Adults with SLE were enrolled in a multicenter cohort. Data on sociodemographic factors, diagnostic criteria, disease activity, autoantibodies, treatment, and damage were collected using standardized tools, and results were compared across ethnic groups. We analyzed baseline data, testing for differences in sociodemographic and clinical factors, between the different ethnic groups, in univariate analyses; significant variables from univariate analyses were included in multivariate regression models examining for differences between ethnic groups, related to damage scores. Results. We studied 1416 patients, including 826 Caucasians, 249 Asians, 122 Afro-Caribbeans, and 73 Aboriginals. Although the overall number of American College of Rheumatology criteria in different ethnic groups was similar, there were differences in individual manifestations and autoantibody profiles. Asian and Afro-Caribbean patients had more frequent renal involvement and more exposure to immunosuppressives. Aboriginal patients had high frequencies of antiphospholipid antibodies and high rates of comorbidity, but disease manifestations similar to Caucasians. Asian patients had the youngest age at onset and the lowest damage scores. Aboriginals had the least education and lowest incomes. The final regression model (R2 = 0.27) for higher damage score included older age, longer disease duration, low income, prednisone treatment, higher disease activity, and cyclophosphamide treatment. Conclusion. There are differences in lupus phenotypes between ethnic populations. Although ethnicity was not found to be a significant independent predictor of damage accrual, low income was.

Neuropsychiatric Lupus: The Prevalence and Autoantibody Associations Depend on the Definition: Results from the 1000 Faces of Lupus Cohort

OBJECTIVES The (ever) prevalence of neuropsychiatric systemic lupus erythematosus (NPSLE) can vary widely depending on the definition used. We determined the prevalence of NPSLE in 1000 Faces of Lupus, a large multicenter Canadian cohort. METHODS Adults enrolled at 10 sites who satisfied the American College of Rheumatology (ACR) classification for systemic lupus erythematosus (SLE) were included. NPSLE was defined as (i) NPSLE by ACR classification criteria (seizures or psychosis), (ii) ACR, SLEDAI (seizure, psychosis, organic brain syndrome, cranial nerve disorder, headache, and cerebrovascular accident (CVA)), SLAM (CVA, seizure, cortical dysfunction, and headache), and SLICC (cognitive impairment, psychosis, seizures, CVA, cranial or peripheral neuropathy, and transverse myelitis) with and (iii) without minor nonspecific NPSLE manifestations (including mild depression, mild cognitive impairment, and electromyogram-negative neuropathies), and (iv) by ACR and SLEDAI neuropsychiatric (NP) indexes alone. Factors associated with NPSLE were explored using regression models. RESULTS Cohort size was 1253, with mean disease 12 ± 10 years, mean age 41 ± 16 years, and 86% female. Subgroup size was dependent on the specific definition of NPSLE. Prevalence of NPSLE was 6.4% in group (i), n = 1253 (n = 80); 38.6% in group (ii), n = 681(n = 263); 28.7% in group (iii), n = 586 (n = 168); and 10.2% in group (iv), n = 1125 (n = 115). In univariate analysis, Aboriginals had a nearly 2-fold increase in frequency of NPSLE in all groups. Education level and income were not associated with NPSLE (P = 0.32 and 0.03, respectively). As well, number of ACR criteria, SLAM, age at diagnosis, disease duration, and gender were not associated with NPSLE. Anti-Ro was significantly associated in groups (i) and (iv) and antiphospholipid antibodies (aPL) were increased in groups (i), (ii), and (iii); however, this lost significance when thromboembolic events were excluded from SLICC, SLEDAI, and SLAM indexes. In group (iv), absence of anti-Sm was significant. In multivariate analysis, anti-Ro and aPL (i) and anti-Ro+ and lack of anti-Sm (iv) were significant. NPSLE was not increased in those with +anti-DNA, La, or ribonucleoprotein (RNP), lupus anticoagulant (LAC), or anticardiolipin (aCL) antibody. CONCLUSIONS The prevalence and factors associated with NPSLE varied depending on the definition used, was highest in Aboriginals, and may be higher if +anti-Ro or aPL are present. SLAM and SLICC include mild subjective disease manifestations, which contributed to a 10% higher prevalence of NPSLE compared to a more strict definition. NPSLE may be less in this database than other publications as its overall prevalence may be decreasing, or because of selection bias inherent to those who enter an observational cohort. NPSLE was associated with aPL and often anti-Ro and varied by ethnicity.

Reduced proportions of natural killer T cells are present in the relatives of lupus patients and are associated with autoimmunity

IntroductionSystemic lupus erythematosus is a genetically complex disease. Currently, the precise allelic polymorphisms associated with this condition remain largely unidentified. In part this reflects the fact that multiple genes, each having a relatively minor effect, act in concert to produce disease. Given this complexity, analysis of subclinical phenotypes may aid in the identification of susceptibility alleles. Here, we used flow cytometry to investigate whether some of the immune abnormalities that are seen in the peripheral blood lymphocyte population of lupus patients are seen in their first-degree relatives.MethodsPeripheral blood mononuclear cells were isolated from the subjects, stained with fluorochrome-conjugated monoclonal antibodies to identify various cellular subsets, and analyzed by flow cytometry.ResultsWe found reduced proportions of natural killer (NK)T cells among 367 first-degree relatives of lupus patients as compared with 102 control individuals. There were also slightly increased proportions of memory B and T cells, suggesting increased chronic low-grade activation of the immune system in first-degree relatives. However, only the deficiency of NKT cells was associated with a positive anti-nuclear antibody test and clinical autoimmune disease in family members. There was a significant association between mean parental, sibling, and proband values for the proportion of NKT cells, suggesting that this is a heritable trait.ConclusionsThe findings suggest that analysis of cellular phenotypes may enhance the ability to detect subclinical lupus and that genetically determined altered immunoregulation by NKT cells predisposes first-degree relatives of lupus patients to the development of autoimmunity.

Association of Smoking With Cutaneous Manifestations in Systemic Lupus Erythematosus

To examine the association between smoking and cutaneous involvement in systemic lupus erythematosus (SLE).

Treatment Algorithms in Systemic Lupus Erythematosus

To establish agreement on systemic lupus erythematosus (SLE) treatment.

Clinical and serologic factors associated with lupus pleuritis.

Objective. Pleuritis is a common manifestation and independent predictor of mortality in systemic lupus erythematosus (SLE). We examined the prevalence of pleuritis and factors associated with pleuritis in a multicenter Canadian SLE cohort. Methods. We studied consecutive adults satisfying the American College of Rheumatology (ACR) classification criteria for SLE who had a completed Systemic Lupus International Collaborating Clinics/ACR Damage Index (SDI) score, at least 1 evaluable extractable nuclear antigen assay, and either a SLE Disease Activity Index (SLEDAI) or a SLE Activity Measure score. Pleuritis was defined as having pleuritis by satisfying the ACR criteria or the SLEDAI. Factors related to pleuritis were examined using univariate and multivariate logistic regression. Results. In our cohort of 876 patients, 91% were women, 65% Caucasian, mean age (± SD) was 46.8 ± 13.5 years, and disease duration at study entry was 12.1 ± 9.9 years; the prevalence of pleuritis was 34% (n = 296). Notably, greater disease duration (p = 0.002), higher SDI score (p ≤ 0.0001), age at SLE diagnosis (p = 0.009), and anti-Sm (p = 0.002) and anti-RNP (p = 0.002) seropositivity were significantly associated with pleuritis. In multivariate analysis with adjustment for disease duration, age at diagnosis, and SDI score, concomitant seropositivity for RNP and Sm were related to a nearly 2-fold greater prevalence of pleuritis (OR 1.98, 95% CI 1.31–2.82). Conclusion. Pleuritis occurred in one-third of this Canadian cohort. Concomitant Sm and RNP seropositivity, greater cumulative damage, longer disease duration, and younger age at SLE disease onset were related to a higher rate of SLE pleural disease.

Teaching the musculoskeletal examination: are patient educators as effective as rheumatology faculty?

Background: Effective education of clinical skills is essential if doctors are to meet the needs of patients with rheumatic disease, but shrinking faculty numbers has made clinical teaching difficult. A solution to this problem is to utilize patient educators. Purpose: This study evaluates the teaching effectiveness of patient educators compared to rheumatology faculty using the musculoskeletal (MSK) examination. Method: Sixty-two 2nd-year medical students were randomized to receive instruction from patient educators or faculty. Tutorial groups received instructions during three, 3-hr sessions. Clinical skills were evaluated by a 9 station objective structured clinical examination. Students completed a tutor evaluation form to assess their level of satisfaction with the process. Results: Faculty-taught students received a higher overall mark (66.5% vs. 62.1%,) and fewer failed than patient educator-taught students (5 vs. 0, p = 0.02). Students rated faculty educators higher than patient educators (4.13 vs. 3.58 on a 5-point Likert scale). Conclusion: Rheumatology faculty appear to be more effective teachers of the MSK physical exam than patient educators.

Medication use in systemic lupus erythematosus.

Objective. To evaluate factors affecting therapeutic approaches used in clinical practice for the management of systemic lupus erythematosus (SLE), in a multicenter cohort. Methods. We combined data from 10 clinical adult SLE cohort registries in Canada. We used multivariate generalized estimating equation methods to model dichotomized outcomes, running separate regressions where the outcome was current exposure of the patient to specific medications. Potential predictors of medication use included demographic (baseline age, sex, residence, race/ethnicity) and clinical factors (disease duration, time-dependent damage index scores, and adjusted mean SLE Disease Activity Index-2K scores). The models also adjusted for clustering by center. Results. Higher disease activity and damage scores were each independent predictors of exposure to nonsteroid immunosuppressive agents, and for exposure to prednisone. This was not definitely demonstrated for antimalarial agents. Older age at diagnosis was independently and inversely associated with exposure to any of the agents studied (immunosuppressive agents, prednisone, and antimalarial agents). An additional independent predictor of prednisone exposure was black race/ethnicity (adjusted RR 1.46, 95% CI 1.18, 1.81). For immunosuppressive exposure, an additional independent predictor was race/ethnicity, with greater exposure among Asians (RR 1.39, 95% CI 1.02, 1.89) and persons identifying themselves as First Nations/Inuit (2.09, 95% CI 1.43, 3.04) than among whites. All of these findings were reproduced when adjustment for disease activity was limited to renal involvement. Conclusion. Ours is the first portrayal of determinants of clinical practice patterns in SLE, and offers interesting real-world insights. Further work, including efforts to determine how differing clinical approaches may influence outcome, is in progress.