Pesticide use and risk of systemic autoimmune diseases in the Agricultural Health Study.

BACKGROUND: Systemic lupus erythematosus (SLE) risk has been associated with pesticide use, but evidence on specific pesticides or other agricultural exposures is lacking. We investigated history of pesticide use and risk of SLE and a related disease, Sjögren's syndrome (SS), in the Agricultural Health Study. METHODS: The study sample (N = 54,419, 52% male, enrolled in 1993-1997) included licensed pesticide applicators from North Carolina and Iowa and spouses who completed any of the follow-up questionnaires (1999-2003, 2005-2010, 2013-2015). Self-reported cases were confirmed by medical records or medication use (total: 107 incident SLE or SS, 79% female). We examined ever use of 31 pesticides and farm tasks and exposures reported at enrollment in association with SLE/SS, using Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI), with age as the timescale and adjusting for gender, state, and correlated pesticides. RESULTS: In older participants (>62 years), SLE/SS was associated with ever use of the herbicide metribuzin (HR 5.33; 95%CI 2.19, 12.96) and applying pesticides 20+ days per year (2.97; 1.20, 7.33). Inverse associations were seen for petroleum oil/distillates (0.39; 0.18, 0.87) and the insecticide carbaryl (0.56; 0.36, 0.87). SLE/SS was inversely associated with having a childhood farm residence (0.59; 0.39, 0.91), but was not associated with other farm tasks/exposures (except welding, HR 2.65; 95%CI 0.96, 7.35). CONCLUSIONS: These findings suggest that some agricultural pesticides may be associated with higher or lower risk of SLE/SS. However, the overall risk associated with farming appears complex, involving other factors and childhood exposures.

Time to progression from discoid lupus erythematosus to systemic lupus erythematosus: a retrospective cohort study.

Determining the risk of progression to systemic lupus erythematosus (SLE) among patients diagnosed with discoid lupus erythematosus (DLE), and the time frame of this risk, are important clinical questions. Past reports have demonstrated a wide time frame of progression from DLE to SLE, with mean time to progression of approximately 8 years. Using data obtained from an academic lupus centre, we identified 32 patients who progressed from DLE to SLE. In our cohort, we found that the median time to progression from DLE to SLE was 453 days, much sooner than previously reported. We believe this information can help inform clinicians on monitoring visit intervals and how best to counsel patients on SLE progression.

Dietary patterns and risk of systemic lupus erythematosus in women.

OBJECTIVE: Dietary intake is a complex exposure and a potential risk factor for systemic lupus erythematosus (SLE) due to its impact on lipid and glucose metabolism, oxidative stress, and the intestinal microbiome. We aimed to test whether a prudent dietary pattern is associated with a lower risk of SLE, and whether a Western dietary pattern is associated with a higher risk of SLE. METHODS: We prospectively investigated two dietary patterns and SLE risk among women in the Nurses' Health Study (NHS, 1984-2014) and Nurses' Health Study II (NHSII, 1991-2015). Food frequency questionnaires were completed every four years. Congruent with prior work in NHS and NHSII, we derived two separate dietary patterns (prudent and Western) using principal component analysis within each cohort. Incident SLE was confirmed by the American College of Rheumatology's 1997 criteria. We estimated hazard ratios (HR) and 95% confidence intervals (CI) for SLE by dietary pattern quartiles using Cox models adjusted for time-varying covariates. Models were performed separately in each cohort and results were meta-analyzed. Stratified analyses tested the association of dietary patterns with anti-dsDNA positive SLE and anti-dsDNA negative SLE. RESULTS: We confirmed 82 NHS incident SLE cases and 98 NHSII SLE cases during 3,833,054 person-years of follow-up. A higher (healthier) prudent dietary pattern score was not associated with SLE risk (meta-analyzed HRQ4 versus Q1 0.84 [95% CI 0.51, 1.38]). Women with higher (less healthy) Western dietary pattern scores did not have a significantly increased risk for SLE (meta-analyzed HRQ4 versus Q1 1.35 [95% CI 0.77, 2.35]). Results were similar after further adjustment for body mass index. Incident anti-dsDNA positive SLE and anti-dsDNA negative SLE were not associated with either dietary pattern. CONCLUSION: We did not observe a relationship between prudent or Western dietary pattern score and risk of SLE.

Arthritis and use of hydroxychloroquine associated with a decreased risk of macrophage activation syndrome among adult patients hospitalized with systemic lupus erythematosus.

Background Macrophage activation syndrome (MAS) is an uncommon but serious complication of systemic lupus erythematosus (SLE). We aimed to identify factors associated with MAS among adult hospitalized SLE patients. Methods Within the Brigham and Women's Hospital (BWH) Lupus Center Registry, we identified adult SLE patients > age 17 who had been hospitalized from 1970 to 2016, with either ferritin > 5000 ng/ml during admission or "macrophage activation syndrome" or "MAS" in discharge summary. We confirmed MAS by physician diagnosis in medical record review. We matched each hospitalized SLE patient with MAS to four SLE patients hospitalized without MAS (by SLE diagnosis date ±1 year). We employed conditional logistic regression models to identify clinical factors associated with MAS among hospitalized SLE patients. Results Among 2094 patients with confirmed SLE, we identified 23 who had a hospitalization with MAS and compared them to 92 hospitalized without MAS. Cases and controls had similar age at SLE diagnosis (29.0 vs. 30.5, p = 0.60), and hospital admission (43.0 vs. 38.3, p = 0.80), proportion female (78% vs. 84%, p = 0.55), and time between SLE diagnosis and hospitalization (1971 vs. 1732 days, p = 0.84). Arthritis (OR 0.04 (95% CI 0.004-0.35)) and hydroxychloroquine use (OR 0.18 (95% CI 0.04-0.72)) on admission were associated with decreased MAS risk. Admission Systemic Lupus Erythematosus Disease Activity Index scores (30 vs. 19, p = 0.002) and lengths of stay (16 days vs. 3 days, p < 0.0001) were much higher among cases. Death during hospitalization was 19% among cases and 3% among controls ( p = 0.03). Conclusions In this case-control study of hospitalized adult SLE patients, arthritis and hydroxychloroquine use at hospital admission were associated with decreased MAS risk. Further studies are needed to validate these factors associated with lowered MAS risk.

Disease activity and transition outcomes in a childhood-onset systemic lupus erythematosus cohort.

Objective The chronicity and severity of childhood-onset systemic lupus erythematosus (cSLE) necessitate effective transition from pediatric to adult providers. We studied transition outcomes in a cSLE cohort. Methods We identified patients at an adult lupus clinic diagnosed with SLE ≤ 18 years who had been followed by a pediatric rheumatologist. Data extracted from the first three years in adult care ("post-transition period") included: sociodemographics, depression, anxiety, SLE manifestations, SLE Disease Activity Index (SLEDAI) and Systemic Lupus International Collaborating Clinics/ACR Damage Index for SLE (SLICC) scores, non-adherence, and gaps in care (no appointments in the recommended time frame). Multivariable logistic regression analyses for predictors of: (1) time between pediatric and adult providers, (2) gaps in care, (3) unscheduled utilization (emergency department visits and admissions) (4) depression and/or anxiety were performed, as was a multivariable Poisson regression analysis for number of missed appointments. Results In 50 patients, SLEDAI scores were stable (mean 5.7 ± 5.0 at start vs. 4.7 ± 4.8 at year 3, p = 0.2), but SLICC scores increased (0.46 ± 0.84, vs. 0.78 ± 1.25, p = 0.01). Depression and anxiety increased significantly (10% vs. 26%, p = 0.02). Mean time from last pediatric to first adult provider visit was almost nine months (253 ± 392 days). Nearly 75% of patients had ≥ 1 gap in care. White race, low education level and non-adherence were significantly associated with missed appointments. Conclusion Despite moderate disease activity in this cSLE transition cohort, prolonged time between pediatric and adult providers and gaps in care in the post-transition period occurred. Anxiety and depression were frequently reported. Future work should identify methods to improve transition.

Specific systemic lupus erythematosus disease manifestations in the six months prior to conception are associated with similar disease manifestations during pregnancy.

Past studies have focused on aggregate lupus disease activity during pregnancy and have produced conflicting results. Our study evaluated lupus activity based on involvement of five specific organ systems during the six months prior to conception and during pregnancy. We assessed 147 pregnancies among 113 women followed at Brigham and Women's Lupus Center, 1990-2013. Organ-specific activity included hematologic disorder, nephritis, skin disease, arthritis, and serositis. We hypothesized that the presence of organ-specific activity six months prior to conception would increase the risk for that same type of activity during pregnancy. Our study population was 68% white; 100% had a positive ANA and 30% had a history of nephritis. Among women with organ-specific lupus activity during the six months before conception, the crude odds for the same type of activity during pregnancy was 7.7- to 32.5-fold higher compared to women without that type of activity immediately before conception. An adjusted logistic regression model also indicated significantly higher odds of organ-specific activity during pregnancy if that type of activity were present six months before conception. Approaching lupus based on specific organ systems may be a useful way for women and their physicians to consider the potential risk for disease activity during pregnancy.

Development of SLE among "potential SLE" patients seen in consultation: long-term follow-up.

OBJECTIVE: To identify factors associated with development of systemic lupus erythematosus (SLE) among patients evaluated at a tertiary care Lupus Center for potential SLE. METHODS: We identified patients first seen at the Brigham and Women's Hospital Lupus Center between 1 January 1992 and 31 December 2012 and thought to have potential SLE by a board-certified rheumatologist. All had 1-3 SLE ACR criteria at initial visit and > 2 follow-up visits ≥ 3 months apart. We reviewed medical records through 15 May 2013 for: SLE signs and symptoms, autoimmune serologies, prescriptions and diagnoses by board-certified rheumatologists. Bivariable analyses and multivariable logistic regression models were used to identify independent predictors of developing SLE. RESULTS: Two hundred and sixty four patients met inclusion criteria. At initial visit, mean age was 39.2 (SD 12.4) years, 94% were female and 67% white. Mean number of SLE ACR criteria was 2.7 (SD 1.0) and 88% were antinuclear antibody (ANA) positive at initial consultation. Mean follow-up time was 6.3 (SD 4.3) years and 67% were prescribed hydroxychloroquine in follow-up. At most recent visit, 56 (21%) had been diagnosed with SLE; 47 (18%) were thought not to have SLE and 161 (61%) were still considered to have potential SLE. In multivariable regression models, oral ulcers (OR 2.40, 95% CI 1.03-5.58), anti-dsDNA (OR 2.59, 95% CI 1.25-5.35) and baseline proteinuria or cellular casts (OR 16.20, 95% CI 1.63-161.02) were independent predictors of developing SLE. The most common other final diagnoses included fibromyalgia, Sjögren's syndrome, mixed connective tissue disease and cutaneous lupus. CONCLUSION: Among patients with potential SLE at initial consultation, 21% were diagnosed with definite SLE within 6.3 years. Oral ulcers, anti-dsDNA and proteinuria or cellular casts were independent predictors of developing definite SLE. A better means of accurately identifying those who will develop SLE among those presenting with potential disease is necessary.

Cigarette smoking, alcohol consumption and risk of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a complex multisystem autoimmune disease whose pathogenesis is thought to involve both genetic and environmental factors. It is possible that common environmental exposures, such as cigarette smoking and alcohol consumption, might modify risk of disease development in certain individuals. Here we aim to review the epidemiologic evidence related to the association of cigarette smoking, alcohol consumption and the risk of developing SLE. A growing body of evidence suggests that cigarette smoking confers a short-term increased risk of SLE in genetically susceptible individuals. On the other hand, alcohol consumption in moderate doses may have a protective effect against the development of SLE, although this is still debated. We also have reviewed proposed mechanistic explanations underlying the role of cigarette smoking and alcohol consumption in SLE pathogenesis.

Ultraviolet radiation and systemic lupus erythematosus.

Exposure to ultraviolet (UV) radiation is among the environmental factors that have been proposed and studied in association with systemic lupus erythematosus (SLE). While it is known that UV radiation exposure may exacerbate pre-existing lupus, it remains unclear whether UV exposure is a risk factor for the development of SLE. Experimental studies show a significant immunomodulatory role for UV radiation, but strong epidemiologic data regarding its role in triggering SLE onset are lacking. Further studies are needed to assess the role of UV radiation in relation to development of incident SLE, yet they are challenging to design due to difficulties in accurate exposure assessment, the heterogeneous nature of SLE, and the challenge of assessing photosensitivity, a feature of SLE, which often precedes its diagnosis.

Clinical manifestations and survival among adults with (SLE) according to age at diagnosis.

OBJECTIVES: The objective of this paper is to determine the effect of clinical and laboratory manifestations, and medication prescribing, on survival according to patient age at diagnosis in a large academic systemic lupus erythematosus (SLE) cohort. METHODS: We identified SLE patients with a diagnosis at age ≥18, seen between 1970 through 2011, and with more than two visits to our lupus center. Data collection included SLE manifestations, serologies, other laboratory tests, medications, dates, and causes of death. We examined characteristics of those diagnosed before age 50 (adult onset) compared to those diagnosed at or after age 50 (late onset) using descriptive statistics. We used Kaplan-Meier curves with log rank tests to estimate five- and 10-year survival in age-stratified cohorts. Predictors of 10-year survival were assessed using Cox regression models, adjusted for calendar year, race/ethnicity, sex, lupus nephritis, and medication use. RESULTS: Of 928 SLE patients, the mean age at diagnosis was 35. Among the adult-onset group, there was significantly higher prevalence of malar rashes and lupus nephritis. Glucocorticoids, azathioprine, mycophenolate, and cyclophosphamide use were also more frequent in the adult-onset group compared to the late-onset group. Five-year survival rates were 99.5% and 94.9% and 10-year survival rates were 97.8% and 89.5%, among those diagnosed before and at or after age 50. In the entire cohort, increasing age at diagnosis, male sex, and black race were statistically significant predictors of reduced 10-year survival. Compared to those diagnosed before age 50, the late-onset group had a multivariable-adjusted hazard ratio for 10-year risk of death of 4.96 (95% CI 1.75-14.08). The most frequent cause of known death was a lupus manifestation, followed by cardiovascular disease and infection. CONCLUSIONS: In our cohort, several demographic features, SLE manifestations, and medication prescribing differed between those with adult-onset and late-onset SLE. Ten-year survival rates were high for both groups, but relatively lower among late-onset patients. A lupus manifestation as the cause of death was more common among adult-onset compared with late-onset patients.

Regional differences regarding risk of developing rheumatoid arthritis in Stockholm County, Sweden: results from the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) study.

OBJECTIVES: Rheumatoid arthritis (RA) is a complex disease that is associated with genetic and environmental factors. We have investigated geospatial variation in the risk of developing RA within Stockholm County, Sweden, with respect to established environmental risk factors for RA, as well as serologically defined subgroups of RA. METHOD: Information regarding geographical location for 1432 cases and 2529 controls from the Epidemiological Investigation of Rheumatoid Arthritis (EIRA) study, living in Stockholm County at RA symptom onset, or matched date for controls, was used to estimate geospatial variation in risk. We used generalized additive models (GAMs) to create a risk surface, calculate odds ratios (ORs), and adjust for potential confounding by smoking, education level, and RA within family. We performed a stratified analysis based on the presence/absence of anti-citrullinated peptide antibodies (ACPA). RESULTS: We found significant spatial variation in the odds of developing RA in Stockholm County. After adjustment for smoking, education level, and family history of RA, this geospatial variation remained. The stratified analysis showed areas with higher ORs for ACPA-positive RA and ACPA-negative RA, after adjusting for smoking, education level, and having a family history of RA. Living in the city of Stockholm was associated with decreased risk of RA. CONCLUSIONS: The risk of developing RA in Stockholm County is not distributed evenly and there are areas of increased risk that could not be explained by known factors. Further investigations of local exposures or social factors are warranted.

Designing an intervention for women with systemic lupus erythematosus from medically underserved areas to improve care: a qualitative study.

OBJECTIVE: Systemic lupus erythematosus (lupus) disproportionately affects women, racial/ethnic minorities and low-income populations. We held focus groups for women from medically underserved communities to discuss interventions to improve care. METHODS: From our Lupus Registry, we invited 282 women, ≥18 years, residing in urban, medically underserved areas. Hospital-based clinics and support groups also recruited participants. Women were randomly assigned to three focus groups. Seventy-five-minute sessions were recorded, transcribed and coded thematically using interpretative phenomenologic analysis and single counting methods. We categorized interventions by benefits, limitations, target populations and implementation questions. RESULTS: Twenty-nine women with lupus participated in three focus groups, (n = 9, 9, 11). 80% were African American and 83% were from medically underserved zip codes. Themes included the desire for lupus education, isolation at the time of diagnosis, emotional and physical barriers to care, and the need for assistance navigating the healthcare system. Twenty of 29 participants (69%) favored a peer support intervention; 17 (59%) also supported a lupus health passport. Newly diagnosed women were optimal intervention targets. Improvements in quality of life and mental health were proposed outcome measures. CONCLUSION: Women with lupus from medically underserved areas have unique needs best addressed with an intervention designed through collaboration between community members and researchers.

Identification and validation of lupus nephritis cases using administrative data.

Large administrative databases such as Medicaid billing databases could be used to study care and outcomes of lupus nephritis if these patients could be correctly identified from claims data. We aimed to develop and validate an algorithm for the correct identification of cases of lupus nephritis using ICD-9 billing codes. We used the Research Patient Data Resource query tool at our institution to identify patients with potential lupus nephritis. We compared four ICD-9 code based strategies, identifying patients seen between 2000 and 2007 with Medicaid medical insurance with greater than two claims for a diagnosis of SLE (ICD-9 code 710.0) and a combination of greater than two nephrologist visits and/or renal ICD-9 codes. We assessed performance using the positive predictive value. Two hundred and thirty four subjects were identified and medical records reviewed. Our third strategy, based on a combination of lupus and renal ICD-9 codes and nephrologist encounter claims, had the highest positive predictive value (88%) for the identification of patients with lupus nephritis. This strategy may offer a sound method of identifying patients with lupus nephritis for health services research in addition to serving as a model for using claims data as a way to better understand rare diseases such as lupus.

Gene-environment interaction between HLA-DRB1 shared epitope and heavy cigarette smoking in predicting incident rheumatoid arthritis.

BACKGROUND: Previous studies have reported an interaction between ever cigarette smoking and the presence of the human leukocyte antigen (HLA)-DRB1 shared epitope (SE) genotype and rheumatoid arthritis (RA) risk. To address the effect of dosage, a case-control study nested within two prospective cohorts to determine the interaction between heavy smoking and the HLA-SE was conducted. METHODS: Blood was obtained from 32 826 women in the Nurses' Health Study and 29 611 women in the Nurses' Health Study II. Incident RA diagnoses were validated by chart review. Controls were matched for age, menopausal status and postmenopausal hormone use. High-resolution HLA-DRB1 genotyping was performed for SE alleles. HLA-SE, smoking, HLA-SE* smoking interactions and RA risk, were assessed using conditional logistic regression models, adjusted for age and reproductive factors. Additive and multiplicative interactions were tested. RESULTS: In all, 439 Caucasian matched pairs were included. Mean age at RA diagnosis was 55.2 years; 62% of cases were seropositive. A modest additive interaction was observed between ever smoking and HLA-SE in seropositive RA risk. A strong additive interaction (attributable proportion due to interaction (AP) = 0.50; p<0.001) and significant multiplicative interaction (p = 0.05) were found between heavy smoking (>10 pack-years) and any HLA-SE in seropositive RA risk. The highest risk was in heavy smokers with double copy HLA-SE (odds ratio (OR) 7.47, 95% CI 2.77 to 20.11). CONCLUSIONS: A strong gene-environment interaction was observed between HLA-SE and smoking when stratifying by pack-years of smoking rather than by ever smoking. Future studies should assess cumulative exposure to cigarette smoke when testing for gene-smoking interactions.

Validation of the Spanish, Portuguese and French versions of the Lupus Damage Index questionnaire: data from North and South America, Spain and Portugal.

We have previously developed and validated a self-administered questionnaire, modelled after the Systemic Lupus International Collaborating Clinics Damage Index (SDI), the Lupus Damage Index Questionnaire (LDIQ), which may allow the ascertainment of this construct in systemic lupus erythematosus (SLE) patients followed in the community and thus expand observations made about damage. We have now translated, back-translated and adapted the LDIQ to Spanish, Portuguese and French and applied it to patients followed at academic and non-academic centres in North and South America, Portugal and Spain while their physicians scored the SDI. A total of 887 patients (659 Spanish-speaking, 140 Portuguese-speaking and 80 French-speaking patients) and 40 physicians participated. Overall, patients scored all LDIQ versions higher than their physicians (total score and all domains). Infrequent manifestations had less optimal clinimetric properties but overall agreement was more than 95% for the majority of items. Higher correlations were observed among the Spanish-speaking patients than the Portuguese-speaking and French-speaking patients; further adjustments may be needed before the Portuguese and French versions of the LDIQ are applied in community-based studies. The relationship between the LDIQ and other outcome parameters is currently being investigated in a different patient sample.

Dyspnoea in a young woman with active systemic lupus erythematosus.

Diffuse alveolar haemorrhage (DAH) is a rare but life-threatening complication of systemic lupus erythematosus (SLE). We present the case of a 24-year-old Cambodian woman with SLE followed in the Brigham and Women's Hospital Lupus Center in Boston, Massachusetts. She presented with dyspnoea and chest pain and was found to have DAH that required a prolonged hospitalization that was complicated by recurrent DAH episodes and multiple infections. We discuss the diagnostic approach and management of patients with SLE-associated DAH as well as treatment options for refractory disease. Emerging therapies include plasmapheresis, the anti-CD20 monoclonal antibody rituximab and recombinant activated Factor VII therapy. In addition, we review the literature to date and compile what is known about the epidemiology, presenting features, diagnostic findings, management and outcomes in this condition. We found that DAH has been reported in 1.9% of patients with SLE. These patients were mostly female (88%) and young (mean age 30.2 years). Common presenting features included dyspnoea (94%), anaemia (97%) and new radiographic chest infiltrate (99%). Bronchoscopy, when performed, identified DAH in 90% of cases. Corticosteroids were the mainstay of care, and usage of cyclophosphamide varied by report. Despite recent advances in therapy, mortality has not improved substantially (48% overall survival versus 53% survival in reports published since 1993).

Exposure to maternal smoking and incident SLE in a prospective cohort study.

Current cigarette smoking is a risk factor for SLE, and recent work has demonstrated that early-life smoke exposure was related to the risk of related rheumatic conditions in female children. Therefore, we sought to investigate whether early-life cigarette smoke exposure might be associated with incidence of SLE in adult women. We studied 93,054 Nurses' Health Study (NHS) and 95,554 NHSII participants free of SLE at baseline who provided information on perinatal exposures. By medical record review, 236 incident SLE cases were confirmed (142 NHS and 94 NHSII) among these women using American College of Rheumatology criteria. We used stratified Cox models to estimate the association of smoke exposure with SLE adjusting for race, birth weight, preterm birth and parents' occupation. Combined estimates were computed using random effects meta-analytic techniques. Maternal cigarette smoking did not increase the risk of SLE (relative risk (RR) = 0.9, 95%CI: 0.6 to 1.4) nor did paternal smoking during the participant's childhood (RR = 1.0, 95% CI: 0.8 to 1.3) in combined analyses. Early-life exposure to cigarette smoke due to mothers' or fathers' smoking was not associated with increased risk of adult-onset SLE in women.

Co-existing sarcoidosis, systemic lupus erythematosus and the antiphospholipid antibody syndrome: case reports and discussion from the Brigham and Women's Hospital Lupus Center.

Sarcoidosis, systemic lupus erythematosus (SLE) and antiphospholipid antibody syndrome (APS) are chronic conditions of immune dysregulation whose aetiologies remain mysterious. Expression of sarcoidosis and SLE within individuals has been reported in a handful of cases in the last 60 years. In this study, we report two cases of sarcoidosis and SLE occurring together, and each case demonstrated complications associated with the presence of anticardiolipin antibodies. Clinical, serological and pathological findings confirmed the diagnoses in each case and both patients improved with therapy. The association of sarcoidosis, SLE and APS is unique and may present difficult therapeutic options, as well as to shed light on their immunopathogenesis.