Christian A. Pineau

Recent corticosteroid use and recent disease activity: Independent determinants of coronary heart disease risk factors in systemic lupus erythematosus?

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.

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.

Biologic therapy and pregnancy outcomes in women with rheumatic diseases

Most of the autoimmune rheumatic diseases are more common in women than in men. Because many of these conditions (e.g., rheumatoid arthritis [RA]) affect women of childbearing potential, reproductive issues related to disease management often emerge. Although some autoimmune rheumatic diseases tend to improve during pregnancy, treatment is sometimes required throughout the pregnancy and/or during the postpartum period. Unfortunately, some important therapeutic agents (e.g., methotrexate [MTX] in RA and cyclophosphamide in vasculitis) are teratogenic; therefore, treatment options during pregnancy are limited, and newer treatment options would be welcome. However, none of the newer biologic therapies (anti–tumor necrosis factor [anti-TNF] agents, anakinra, rituximab, or abatacept) are classified by the US Food and Drug Administration (FDA) as safe to use during pregnancy (1). This lack of safety classification is mainly attributable to the lack of adequate and well-controlled studies. Still, in the last decade, numerous case series and case reports of pregnant patients exposed to biologic therapy have accumulated in the literature. Because biologic agents may constitute an important therapeutic alternative in pregnant women experiencing persistent or increased disease activity, we present a comprehensive review of the relevant data. Search strategy. We performed a systematic literature review to identify all studies with original human data on fetal and/or child outcomes following exposure to biologic agents during pregnancy and/or lactation. We searched the following electronic databases for primary studies: PubMed (1950 to October 2008), EMBase (1996 to October 2008), and Web of Science (1991 to October 2008). Our search strategy was restricted to articles published in English, French, or Spanish and included the following medical subject headings (MeSH)

Estimating the prevalence of polymyositis and dermatomyositis from administrative data: age, sex and regional differences

OBJECTIVE To estimate the prevalence of polymyositis and dermatomyositis using population-based administrative data, the sensitivity of case ascertainment approaches and patient demographics and these parameters. METHODS Cases were ascertained from Quebec physician billing and hospitalisation databases (approximately 7.5 million beneficiaries). Three different case definition algorithms were compared, and statistical methods were also used that account for imperfect case ascertainment, to generate estimates of disease prevalence and case ascertainment sensitivity. A hierarchical Bayesian latent class regression model was developed to assess patient characteristics with respect to these parameter estimates. RESULTS Using methods that account for the imperfect nature of both billing and hospitalisation databases, the 2003 prevalence of polymyositis and dermatomyositis was estimated to be 21.5/100,000 (95% credible interval (CrI) 19.4 to 23.9). Prevalence was higher for women and for older individuals, with a tendency for higher prevalence in urban areas. Prevalence estimates were lowest in young rural men (2.7/100,000, 95% CrI 1.6 to 4.1) and highest in older urban women (70/100,000, 95% CrI 61.3 to 79.3). Sensitivity of case ascertainment tended to be lower for older versus younger individuals, particularly for rheumatology billing data. Billing data appeared more sensitive in ascertaining cases in urban (vs rural) regions, whereas hospitalisation data seemed most useful in rural areas. CONCLUSIONS Marked variations were found in the prevalence of polymyositis and dermatomyositis according to age, sex and region. These methods allow adjustment for the imperfect nature of multiple data sources and estimation of the sensitivity of different case ascertainment approaches.

Osteoporosis in systemic lupus erythematosus: factors associated with referral for bone mineral density studies, prevalence of osteoporosis and factors associated with reduced bone density.

The purpose of this study was to evaluate the clinical characteristics of women with systemic lupus erythematosus (SLE) sent for a dual energy X-ray absorptiometry (DEXA) study, and to analyse the factors associated with a lower bone mineral density in these patients. Women with SLE who had a DEXA done between 1 January 1995 and 31 December 2000 were compared with those who did not have DEXA scans performed. SLE patients with osteoporosis (OP) were compared with those with a normal bone density. Of 516 women with SLE, 205 had a DEXA done. These patients had more traditional risk factors for osteoporosis, higher lupus disease activity, renal involvement, increased damage, higher mean steroid dose, increased use of immunosuppressants and occurrence of avascular necrosis. Of the 205 patients with DEXA, 18% had osteoporosis, 48.8% had osteopenia and 33.2% had normal bone mineral density. The two statistically significant predictors of a low bone density were a higher age at time of DEXA (P 1/4 0.0003) and a higher SDI score (P 1/4 0.0019). Osteoporosis is a significant comorbidity in SLE. Lupus patients referred for a DEXA have more traditional risk factors and use more corticosteroids. The main factors associated with a low bone density were however found to be age and increased damage. Interestingly, disease activity and corticosteroid use were not associated with osteoporosis in this study which may suggest other potential causes such as decreased physical activity associated with damage.

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.

Scleroderma prevalence: Demographic variations in a population‐based sample

OBJECTIVE To estimate the prevalence of systemic sclerosis (SSc) using population-based administrative data, and to assess the sensitivity of case ascertainment approaches. METHODS We ascertained SSc cases from Quebec physician billing and hospitalization databases (covering approximately 7.5 million individuals). Three case definition algorithms were compared, and statistical methods accounting for imperfect case ascertainment were used to estimate SSc prevalence and case ascertainment sensitivity. A hierarchical Bayesian latent class regression model that accounted for possible between-test dependence conditional on disease status estimated the effect of patient characteristics on SSc prevalence and the sensitivity of the 3 ascertainment algorithms. RESULTS Accounting for error inherent in both the billing and the hospitalization data, we estimated SSc prevalence in 2003 at 74.4 cases per 100,000 women (95% credible interval [95% CrI] 69.3-79.7) and 13.3 cases per 100,000 men (95% CrI 11.1-16.1). Prevalence was higher for older individuals, particularly in urban women (161.2 cases per 100,000, 95% CrI 148.6-175.0). Prevalence was lowest in young men (in rural areas, as low as 2.8 cases per 100,000, 95% CrI 1.4-4.8). In general, no single algorithm was very sensitive, with point estimates for sensitivity ranging from 20-73%. CONCLUSION We found marked differences in SSc prevalence according to age, sex, and region. In general, no single case ascertainment approach was very sensitive for SSc. Therefore, using data from multiple sources, with adjustment for the imperfect nature of each, is an important strategy in population-based studies of SSc and similar conditions.

Associations between Ambient Fine Particulate Levels and Disease Activity in Patients with Systemic Lupus Erythematosus (SLE)

Background Systemic lupus erythematosus (SLE) is a chronic disease of unclear etiology, characterized by an overactive immune system and the production of antibodies that may target normal tissues of many organ systems, including the kidneys. It can arise at any age and occurs mainly in women. Objective Our aim was to evaluate the potential influence of particulate matter (PM) air pollution on clinical aspects of SLE. Methods We studied a clinic cohort of SLE patients living on the island of Montreal, followed annually with a structured clinical assessment. We assessed the association between ambient levels of fine PM [median aerodynamic diameter ≤ 2.5 μm (PM2.5)] measured at fixed-site monitoring stations and SLE disease activity measured with the SLE Disease Activity Index, version 2000 (SLEDAI-2K), which includes anti–double-stranded DNA (anti-dsDNA) serum-specific autoantibodies and renal tubule cellular casts in urine, which reflects serious renal inflammation. We used mixed effects regression models that we adjusted for daily ambient temperatures and ozone levels. Results We assessed 237 patients (223 women) who together had 1,083 clinic visits from 2000 through 2007 (mean age at time of first visit, 41.2 years). PM2.5 levels were associated with anti-dsDNA and cellular casts. The crude and adjusted odds ratios (reflecting a 10-μg/m3 increase in PM2.5 averaged over the 48 hr prior to clinical assessment) were 1.26 [95% confidence interval (CI), 0.96–1.65] and 1.34 (95% CI, 1.02–1.77) for anti-dsDNA antibodies and 1.43 (95% CI, 1.05–1.95) and 1.28 (0.92–1.80) for cellular casts. The total SLEDAI-2K scores were not associated with PM2.5 levels. Conclusions We provide novel data that suggest that short-term variations in air pollution may influence disease activity in established autoimmune rheumatic disease in humans. Our results add weight to concerns that pollution may be an important trigger of inflammation and autoimmunity.

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).