Michel Zummer

The role of viscosupplementation with hylan G-F 20 (Synvisc®) in the treatment of osteoarthritis of the knee: a Canadian multicenter trial comparing hylan G-F 20 alone, hylan G-F 20 with non-steroidal anti-inflammatory drugs (NSAIDs) and NSAIDs alone*

To determine the safety and efficacy of viscosupplementation with hylan G-F 20, a cross-linked hyaluronan preparation, used either alone or in combination with continuous non-steroidal anti-inflammatory drug (NSAID) therapy, a randomized, controlled, multicenter clinical trial, assessed by a blinded assessor, was conducted in 102 patients with osteoarthritis (OA) of the knee. All patients were on continuous NSAID therapy for at least 30 days prior to entering the study. Patients were randomized into three parallel groups: (1) NSAID continuation plus three control arthrocenteses at weekly intervals; (2) NSAID discontinuation but with three weekly intra-articular injections of hylan G-F 20; and (3) NSAID continuation plus three injections, one every week, intra-articular injections of hylan G-F 20. Outcome measures of pain and joint function were evaluated by both the patients and an evaluator at baseline and weeks 1, 2, 3, 7 and 12, with a follow-up telephone evaluation at 26 weeks. At 12 weeks all groups showed statistically significant improvements from baseline, but did not differ from each other. A statistical test for the equivalence, the q-statistic, demonstrated that viscosupplementation with hylan G-F 20 was at least as good or better than continuous NSAID therapy for all outcome measurements except activity restriction. At 26 weeks both groups receiving hylan G-F 20 were significantly better than the group receiving NSAIDs alone. A transient local reaction was observed in three patients after hylan G-F 20 injection; only one patient withdrew from the study as a result and all recovered without any sequela. Hylan G-F 20 is a safe and effective treatment for OA of the knee and can be used either as a replacement for or an adjunct to NSAID therapy.

Canadian Rheumatology Association Recommendations for Pharmacological Management of Rheumatoid Arthritis with Traditional and Biologic Disease-modifying Antirheumatic Drugs

Objective. The Canadian Rheumatology Association (CRA) has developed recommendations for the pharmacological management of rheumatoid arthritis (RA) with traditional and biologic disease-modifying antirheumatic drugs (DMARD) in 2 parts. Part 1 is reported here. Methods. The CRA Therapeutics Committee assembled a national working group of RA clinical experts, researchers, patient consumers, and a general practitioner. Treatment questions were developed a priori based on results of a national needs assessment survey. A systematic review of all clinical practice guidelines and consensus statements regarding treatment with traditional and biologic DMARD in patients with RA published between January 2000 and June 2010 was performed in Medline, Embase, and CINAHL databases, and the grey literature. Guideline quality was assessed by 2 independent reviewers, and guideline characteristics, recommendations, and supporting evidence from observational studies and randomized controlled trials were synthesized into evidence tables. The full working group reviewed the evidence tables and developed recommendations using a modified Delphi technique. Results. Five overarching principles and 26 recommendations addressing general RA management strategies and treatment with glucocorticoids and traditional and biologic DMARD were developed for rheumatologists, other primary prescribers of RA drug therapies, and patients with RA. Conclusion. These recommendations were developed based on a synthesis of international guidelines, supporting evidence, and expert consensus considering the Canadian healthcare context with the intention of promoting best practices and improving healthcare delivery for persons with RA.

Cancer risk in systemic lupus: An updated international multi-centre cohort study

OBJECTIVE To update estimates of cancer risk in SLE relative to the general population. METHODS A multisite international SLE cohort was linked with regional tumor registries. Standardized incidence ratios (SIRs) were calculated as the ratio of observed to expected cancers. RESULTS Across 30 centres, 16,409 patients were observed for 121,283 (average 7.4) person-years. In total, 644 cancers occurred. Some cancers, notably hematologic malignancies, were substantially increased (SIR 3.02, 95% confidence interval, CI, 2.48, 3.63), particularly non-Hodgkins lymphoma, NHL (SIR 4.39, 95% CI 3.46, 5.49) and leukemia. In addition, increased risks of cancer of the vulva (SIR 3.78, 95% CI 1.52, 7.78), lung (SIR 1.30, 95% CI 1.04, 1.60), thyroid (SIR 1.76, 95% CI 1.13, 2.61) and possibly liver (SIR 1.87, 95% CI 0.97, 3.27) were suggested. However, a decreased risk was estimated for breast (SIR 0.73, 95% CI 0.61-0.88), endometrial (SIR 0.44, 95% CI 0.23-0.77), and possibly ovarian cancers (0.64, 95% CI 0.34-1.10). The variability of comparative rates across different cancers meant that only a small increased risk was estimated across all cancers (SIR 1.14, 95% CI 1.05, 1.23). CONCLUSION These data estimate only a small increased risk in SLE (versus the general population) for cancer over-all. However, there is clearly an increased risk of NHL, and cancers of the vulva, lung, thyroid, and possibly liver. It remains unclear to what extent the association with NHL is mediated by innate versus exogenous factors. Similarly, the etiology of the decreased breast, endometrial, and possibly ovarian cancer risk is uncertain, though investigations are ongoing.

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.

Mortality related to cerebrovascular disease in systemic lupus erythematosus

The objective of this study was to examine mortality rates related to cerebrovascular disease in systemic lupus erythematosus (SLE) compared to the general population. Our sample was a multisite Canadian SLE cohort (10 centres, n = 2688 patients). Deaths due to cerebrovascular disease were ascertained by vital statistics registry linkage using ICD diagnostic codes. Standardized mortality ratio (SMR, ratio of deaths observed to expected) estimates were calculated. The total SMR for death due to cerebrovascular disease was 2.0 (95% confidence interval [CI] 1.0, 3.7). When considering specific types of events, the category with the greatest increased risk was that of ill-defined cerebrovascular events (SMR 44.9, 95% CI 9.3, 131.3) and other cerebrovascular disease (SMR 8.4, 95% CI 2.3, 21.6). Deaths due to cerebral infarctions appeared to be less common than hemorrhages and other types of cerebrovascular events. Our data suggest an increase in mortality related to cerebrovascular disease in SLE patients compared to the general population. The large increase in illdefined cerebrovascular events may represent cases of cerebral vasculitis or other rare forms of nervous system disease; alternately, it may reflect diagnostic uncertainty regarding the etiology of some clinical presentations in SLE patients. The suggestion that more deaths are attributed to cerebral hemorrhage, as opposed to infarction, indicates that inherent or iatrogenic factors (eg, thrombocytopenia or anticoagulation) may be important. In view of the paucity of large-scale studies of mortality attributed to neuropsychiatric outcomes in SLE, our findings highlight the need for additional research in large SLE cohorts.

The clinimetric properties of the World Health Organization Disability Assessment Schedule II in early inflammatory arthritis.

OBJECTIVE To assess the clinimetric properties of a new health-related quality of life (HRQOL) instrument, the World Health Organization Disability Assessment Schedule II (WHODAS II), in patients with early inflammatory arthritis. METHODS Internal consistency as well as criterion, construct, and discriminative validity of the WHODAS II were assessed in 172 patients with early inflammatory arthritis who completed the WHODAS II, the Medical Outcomes Study Short Form 36 (SF-36), and other measures of disease severity, functioning, pain, depression, and resource use. Test-retest reliability of the WHODAS II was assessed by having a subset of 20 patients complete the WHODAS II a second time, 1 week after the first assessment. RESULTS The WHODAS II had high internal consistency (Cronbachs alpha = 0.96 for patients working or in school and 0.93 for patients not working or in school). Test-retest intraclass correlation coefficients of the WHODAS II total score and subscales ranged from 0.82-0.96. The WHODAS II total score was strongly correlated with the SF-36 physical component score (Kendalls tau-b 0.51, P < 0.001) and moderately correlated with the SF-36 mental component score (tau-b 0.43, P < 0.001). WHODAS II correlations with disease outcomes ranged from Kendalls tau-b 0.15-0.55. The WHODAS II significantly differentiated between every aspect of disease severity assessed with the exception of measures of health resource use. CONCLUSION The WHODAS II is a valid and reliable measure of HRQOL in cross-sectional studies of patients with early inflammatory arthritis. Research is still required to investigate potential item redundancy and determine its usefulness in longitudinal studies.

Counterbalancing Patient Demands With Evidence: Results From a Pan-Canadian Randomized Clinical Trial of Brief Supportive-Expressive Group Psychotherapy for Women With Systemic Lupus Erythematosus

Objective: To evaluate the effect of Brief Supportive-Expressive Group Psychotherapy as an adjunct to standard medical care in reducing psychological distress, medical symptoms, and health care costs and improving quality of life in women with systemic lupus erythematosus (SLE). Methods: A randomized clinical trial was conducted with 133 SLE female patients from 9 clinics across Canada. Clinical and psychosocial measures were taken at baseline, posttreatment, and 6 and 12 months posttreatment. Outcomes assessed were psychological distress, quality of life, disease activity, health service utilization, and diminished productivity. Results: Intention-to-treat analyses revealed that there were no clinically important group differences on any of the outcome measures. Conclusion: Although both groups improved over time on several measures (e.g., decreases in psychological distress, stress, and emotion-oriented coping), these changes could not be attributed to the psychotherapeutic intervention. Thus, evidence does not support the referral of these patients to this type of intervention.

Association of Smoking With Cutaneous Manifestations in Systemic Lupus Erythematosus

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