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1.
Rheumatol Int ; 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31784790

RESUMO

Systemic lupus erythematosus (SLE) severity, reflecting both disease intensity and duration, is heterogeneous making it challenging to study in administrative databases where severity may confound or mediate associations with outcomes. Garris et al. developed an administrative claims-based algorithm employing claims over a 1-year period to classify SLE severity as mild, moderate or severe. We sought to compare this administrative algorithm to a measure of SLE activity, the SLE Disease Activity Index-2000 (SLEDAI-2K) score at clinical visits. We identified 100 SLE patients followed in the Brigham and Women's Hospital (BWH) Lupus Center (in 2008-2010) with SLEDAI-2K scores at each visit over a 1-year period per person. We obtained data for the Garris algorithm for the same year per subject. We compared Garris SLE severity to the highest SLEDAI-2K in that year, with SLEDAI-2K categories of mild < 3, moderate 3-6, and severe > 6. We compared classification using weighted kappa statistics, and positive and negative predictive values (PPV, NPV). We also assessed the binary comparison of mild vs. moderate/severe. We calculated sensitivity, specificity, and McNemar's test. We analyzed 377 SLEDAI-2K assessments (mean 3.8 [SD 2.6] per subject/year). For classifying moderate/severe vs. mild SLE severity, the sensitivity was 85.7%, specificity 67.6%, PPV 81.8% and NPV 73.5%. The Garris algorithm for classifying SLE severity in administrative datasets had moderate agreement for classification of mild vs. moderate/severe SLE activity assessed by SLEDAI-2K assessments in an academic lupus center. It may be a useful tool for classifying SLE severity in administrative database studies.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31811708

RESUMO

OBJECTIVE: To elucidate how post-diagnosis multimorbidity and lifestyle changes contribute to the excess mortality of rheumatoid arthritis (RA). METHODS: We performed a matched cohort study among women in the Nurses' Health Study (1976-2018). We identified women with incident RA and matched each by age and year to 10 non-RA comparators at RA diagnosis index date. Specific causes of death were ascertained via death certificates and medical record review. Lifestyle and morbidity factors were reported biennially; 61 chronic conditions were combined into the Multimorbidity Weighted Index (MWI). After adjusting for baseline confounders, we used inverse probability weighting analysis to examine the mediating influence of post-index MWI and lifestyle factors on total, cardiovascular, and respiratory mortality, comparing women with RA to their matched comparators. RESULTS: We identified 1,007 incident RA patients and matched to 10,070 non-RA comparators. Adjusting for pre-index confounders, RA patients had elevated HRs and 95%CIs for total (1.46 [1.32,1.62]), cardiovascular (1.54 [1.22,1.94]), and respiratory (2.75 [2.05,3.71]) mortality, compared to non-RA comparators. Adjusting for post-index lifestyle factors (physical activity, BMI, diet, smoking) attenuated but did not substantially account for this excess RA mortality. After additional adjustment for post-index MWI, RA patients had HRs and 95%CIs of 1.18 [1.05,1.32] for total, 1.19 [0.94,1.51] for cardiovascular, and 1.93 [1.42,2.62] for respiratory mortality. CONCLUSION: We found that MWI substantially accounted for the excess total and cardiovascular mortality among women with RA. This finding underscores the importance of monitoring for the total disease burden as a whole in monitoring RA patients.

6.
Clin Chem ; 65(12): 1508-1521, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31699704

RESUMO

BACKGROUND: Observational studies suggest vitamin D and marine ω-3 fatty acid (n-3 FA) supplements are associated with lower systemic inflammation. However, past trials have been inconsistent. METHODS: The randomized, double-blind, placebo-controlled VITamin D and OmegA-3 TriaL (VITAL) tested vitamin D (2000 IU/day) and/or n-3 FA (1 g/day) supplementation in a 2 × 2 factorial design among women ≥55 and men ≥50 years of age. We assessed changes in interleukin (IL)-6, tumor necrosis factor receptor 2 (TNFR2), and high-sensitivity C-reactive protein (hsCRP) concentrations from baseline to 1 year among participants randomized to vitamin D + n-3 FA (392), vitamin D (392), n-3 FA (392), or placebo only (385). Geometric means and percent changes were compared, adjusting for baseline factors. RESULTS: Baseline characteristics were well balanced. In the active arms, 25-OH vitamin D rose 39% and n-3 FA rose 55% vs minimal change in placebo arms. Neither supplement reduced biomarkers at 1 year. Vitamin D resulted in 8.2% higher IL-6 (95% CI, 1.5%-15.3%; adjusted P = 0.02), but TNFR2 and hsCRP did not. Among 784 receiving vitamin D, hsCRP increased 35.7% (7.8%-70.9%) in those with low (<20 ng/mL) but not with higher baseline serum 25(OH) vitamin D [0.45% (-8.9% to 10.8%); P interaction = 0.02]. Among 777 randomized to n-3 FA, hsCRP declined [-10.5% (-20.4% to 0.8%)] in those with baseline low (<1.5 servings/week), but not with higher fish intake [6.4% (95% CI, -7.11% to 21.8%); P interaction = 0.06]. CONCLUSIONS: In this large sample from a population-based randomized controlled trial, neither vitamin D nor n-3 FA supplementation over 1 year decreased these biomarkers of inflammation. CLINICALTRIALSGOV IDENTIFIER: NCT01169259; NCT01351805.

7.
Arthritis Res Ther ; 21(1): 246, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31753003

RESUMO

BACKGROUND: Anti-citrullinated protein antibodies (ACPA) are central to rheumatoid arthritis (RA) pathogenesis and may develop at inflamed mucosa. We investigated whether asthma, a disease of airway mucosal inflammation, was associated with elevated ACPA before RA diagnosis. METHODS: We performed a nested case-control study among women in two prospective cohorts, the Nurses' Health Study (NHS; 1976-2014) and NHSII (1989-2015). Blood was obtained on a subset (NHS: 1989-1990; NHSII: 1996-1999). Cases met 1987 ACR or 2010 ACR/EULAR RA criteria by medical record review and were classified as seropositive (ACPA+ or rheumatoid factor positivity) or seronegative by clinical laboratory testing at diagnosis. We identified RA cases with blood drawn before the date of RA diagnosis (index date), matching each to three controls by age, cohort, year, time from blood draw to index date, and menopause. Pre-RA ACPA elevation for cases was defined as >99th percentile of the control distribution on a research assay composed of autoantibodies targeting citrullinated protein epitopes or positivity on the second-generation commercial assay for cyclic citrullinated peptide. Asthma status and covariates were obtained through biennial questionnaires before blood draw. Conditional logistic regression estimated ORs and 95%CIs for RA by pre-RA ACPA and clinical serostatus, adjusted for matching factors, smoking pack-years, passive smoking, and body mass index (BMI). RESULTS: We identified 284 incident RA cases and 849 matched controls; mean age at the index date was 61.2 years (SD 10.1). Blood was drawn 9.7 years (mean; SD 5.8) before the index date. We identified 96 (33.8%) RA cases with elevated pre-RA ACPA. At blood draw, 17.7% of pre-RA ACPA+ cases and 6.3% of matched controls (p = 0.0008) reported clinician-diagnosed asthma. After adjusting for matching factors, smoking pack-years, passive smoking, and BMI, asthma was significantly associated with pre-RA ACPA+ RA (OR 3.57, 95%CI 1.58,8.04). Asthma was not associated with overall RA (OR 1.45, 95%CI 0.91,2.31), but was significantly associated with seropositive RA (OR 1.79, 95%CI 1.01,3.18). CONCLUSIONS: Asthma was strongly associated with ACPA elevation in blood drawn prior to RA diagnosis, independent of smoking. Chronic mucosal airway inflammation may contribute to ACPA development and RA pathogenesis.

8.
Arthritis Rheumatol ; 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31769217

RESUMO

In their letter (1), Dr. Rodrigues Fonseca and colleagues refer to their analysis of the new EULAR/ACR 2019 criteria in a group of 122 patients with childhood onset SLE and 89 patients with other diagnoses mimicking SLE (2). This analysis was published before the full contents of the EULAR/ACR 2019 manuscript (3;4) were available, which may have led to not taking important aspects into account.

9.
J Rheumatol ; 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31676703

RESUMO

OBJECTIVE: Systemic lupus erythematosus (SLE) is a multi-system chronic inflammatory autoimmune disease with high prevalence of several risk factors for atrial fibrillation/flutter (AF). However, the incidence and risk of AF in SLE have not been well quantified. METHODS: We used U.S. Medicaid Analytic eXtract from 2007-2010 to identify beneficiaries ages 18-65, with prevalent SLE, each matched by age and sex to four non-SLE general Medicaid recipients. We estimated the incidence rates (IR) per 1,000 person-years (PY) for AF hospitalizations and used multivariable Cox regression to estimate the hazard ratio (HR) for AF hospitalization. RESULTS: We identified 46,876 U.S. Medicaid recipients with SLE, and 187,504 age- and sex-matched non-SLE controls (93% female; mean age 41.5+12.2). Known AF risk factors such as hypertension, cardiovascular disease (CVD) and kidney disease were more prevalent in SLE patients. During a mean follow-up of 1.9+1.1 years for SLE, and 1.8+1.1 years for controls, the IR per 1,000 PY for AF was 1.4 (95% CI 1.1-1.6) among SLE patients and 0.7 (95% 0.6-0.8) among non-SLE controls. In age- and sex- matched and race-adjusted Cox models, the HR for AF was 1.79 (95%CI 1.43-2.24); after adjustment for baseline hypertension and CVD, the adjusted HR was reduced to 1.17 (95%CI 0.92-1.48). CONCLUSION: SLE was associated with doubled rate of hospitalization for AF compared to age- and sexmatched general Medicaid patients. In a race-adjusted model, the risk was 80% higher. However, the AF risk factors hypertension and CVD were more prevalent among SLE patients and accounted for the excess risk.

11.
Lupus Sci Med ; 6(1): e000352, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31592329

RESUMO

Objective: Bone health in SLE is adversely affected by vitamin D deficiency, inflammatory cytokines and glucocorticoid use. We hypothesised that vitamin D supplementation would increase markers of bone formation and decrease markers of bone resorption in SLE subjects. Methods: We studied 43 vitamin D-deficient SLE subjects who participated in a 12-week randomised controlled trial of 2000-4000 IU/day vitamin D supplementation versus placebo. Subjects had inactive SLE (SLE Disease Activity Index ≤4) and were taking <20 mg prednisone daily at baseline. We assayed baseline and week 12 serum 25-hydroxyvitamin D, N-terminal propeptide of type 1 collagen (P1NP) and C-telopeptide (CTX). We tested the effect of vitamin D versus placebo on change (Δ) in P1NP and ΔCTX in an intention-to-treat analysis. Secondary analyses evaluated whether vitamin D affected bone turnover among subjects achieving vitamin D repletion (≥30 ng/mL) or currently taking glucocorticoids. Results: 28 subjects were randomised to vitamin D and 15 to placebo. Mean age was 39 years and 40% were using glucocorticoids at enrolment. Repletion was achieved by 46% in the vitamin D group versus none in the placebo group. Changes in bone turnover markers were not significantly different in the vitamin D group versus placebo group (median ΔP1NP -0.2 vitamin D group vs -1.1 placebo group (p=0.83); median ΔCTX +3.5 vitamin D group vs -37.0 placebo group (p=0.50)). The effect of vitamin D did not differ based on achieving vitamin D repletion or baseline glucocorticoid use. Conclusion: Vitamin D supplementation did not affect the 12-week change in bone turnover markers among SLE subjects in this trial.

13.
Artigo em Inglês | MEDLINE | ID: mdl-31628721

RESUMO

OBJECTIVE: Individuals with systemic lupus erythematosus (SLE) are at high risk for infections, SLE- and medication-related complications. We defined a set of SLE-specific adverse outcomes that could be prevented, or their complications minimized, if timely, effective ambulatory care had been received. METHODS: We used a modified Delphi process beginning with a literature review and key informant interviews to select initial SLE-specific potentially preventable conditions. We assembled a panel of sixteen nationally-recognized U.S.-based experts from eight subspecialties. Guided by the RAND-UCLA Appropriateness Method, we held two survey rounds with controlled feedback and an interactive webinar to reach consensus regarding preventability and importance on a population level for a set of SLE-specific adverse conditions. In a final round, the panelists endorsed the potentially preventable conditions. RESULTS: Thirty-five potential conditions were initially proposed; 62 conditions were ultimately considered during the Delphi process. The response rate was 100% for both survey rounds, 88% for the webinar, and 94% for final approval. The 25 SLE-specific conditions meeting consensus as potentially preventable and important on a population level fell into four categories: vaccine-preventable illnesses (6 conditions), medication-related complications (8), reproductive health-related complications (6) and SLE-related complications (5). CONCLUSIONS: We reached consensus on a diverse set of adverse outcomes relevant to SLE patients that may be preventable if patients received high quality ambulatory care. This set of outcomes may be studied at the health system level to determine how to best allocate resources and improve quality to reduce avoidable outcomes and disparities among those at highest risk.

14.
Artigo em Inglês | MEDLINE | ID: mdl-31560454

RESUMO

A project towards new SLE classification criteria supported by both EULAR and the ACR is based on weighted criteria that include both laboratory and clinical items. Combinations of certain symptoms may occur commonly in SLE, which would argue against independently counting these items. However, these interrelationships have not been formally investigated. OBJECTIVES: To evaluate the interrelationship between candidate criteria items in an international early SLE cohort and in the Euro-Lupus cohort. METHODS: The international early SLE cohort included 389 patients, who were diagnosed within the last 3 years. Data on ACR 1997, SLICC 2012 and 30 additional items were collected. To evaluate the inter-relationship of criteria, a tetrachoric correlation was used to assess the degree of association between different manifestations of the same organ-system. The correlations identified in the international early SLE cohort were validated in the Euro-Lupus cohort. RESULTS: A few relevant correlations were observed among specific clinical cutaneous manifestations (in particular, malar rash correlated with photosensitivity, alopecia, and oral ulcers) and serologic manifestations (anti-Sm and anti-dsDNA and anti-RNP, anti-Ro with anti-La, and between anti-phospholipid antibodies), and these results were validated in the Euro-Lupus cohort. The associations within the mucocutaneous domain, hematologic and the specific autoantibodies suggest that within a single domain only the highest ranking item should be counted to avoid overrepresentation. CONCLUSIONS: Some of the candidate SLE criteria do cluster within domains. Given these interrelationships, multiple criteria within a domain should not be independently counted. These results are important for the structure of new SLE classification criteria.

17.
JCI Insight ; 4(20)2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31536480

RESUMO

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by pathologic T cell-B cell interactions and autoantibody production. Defining the T cell populations that drive B cell responses in SLE may enable design of therapies that specifically target pathologic cell subsets. Here, we evaluated the phenotypes of CD4+ T cells in the circulation of 52 SLE patients drawn from multiple cohorts and identified a highly expanded PD-1hiCXCR5-CD4+ T cell population. Cytometric, transcriptomic, and functional assays demonstrated that PD-1hiCXCR5-CD4+ T cells from SLE patients are T peripheral helper (Tph) cells, a CXCR5- T cell population that stimulates B cell responses via IL-21. The frequency of Tph cells, but not T follicular helper (Tfh) cells, correlated with both clinical disease activity and the frequency of CD11c+ B cells in SLE patients. PD-1hiCD4+ T cells were found within lupus nephritis kidneys and correlated with B cell numbers in the kidney. Both IL-21 neutralization and CRISPR-mediated deletion of MAF abrogated the ability of Tph cells to induce memory B cell differentiation into plasmablasts in vitro. These findings identify Tph cells as a highly expanded T cell population in SLE and suggest a key role for Tph cells in stimulating pathologic B cell responses.

18.
Ann Rheum Dis ; 78(9): 1151-1159, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31383717

RESUMO

OBJECTIVE: To develop new classification criteria for systemic lupus erythematosus (SLE) jointly supported by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). METHODS: This international initiative had four phases. (1) Evaluation of antinuclear antibody (ANA) as an entry criterion through systematic review and meta-regression of the literature and criteria generation through an international Delphi exercise, an early patient cohort and a patient survey. (2) Criteria reduction by Delphi and nominal group technique exercises. (3) Criteria definition and weighting based on criterion performance and on results of a multi-criteria decision analysis. (4) Refinement of weights and threshold scores in a new derivation cohort of 1001 subjects and validation compared with previous criteria in a new validation cohort of 1270 subjects. RESULTS: The 2019 EULAR/ACR classification criteria for SLE include positive ANA at least once as obligatory entry criterion; followed by additive weighted criteria grouped in seven clinical (constitutional, haematological, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, renal) and three immunological (antiphospholipid antibodies, complement proteins, SLE-specific antibodies) domains, and weighted from 2 to 10. Patients accumulating ≥10 points are classified. In the validation cohort, the new criteria had a sensitivity of 96.1% and specificity of 93.4%, compared with 82.8% sensitivity and 93.4% specificity of the ACR 1997 and 96.7% sensitivity and 83.7% specificity of the Systemic Lupus International Collaborating Clinics 2012 criteria. CONCLUSION: These new classification criteria were developed using rigorous methodology with multidisciplinary and international input, and have excellent sensitivity and specificity. Use of ANA entry criterion, hierarchically clustered and weighted criteria reflect current thinking about SLE and provide an improved foundation for SLE research.

19.
Arthritis Rheumatol ; 71(9): 1400-1412, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31385462

RESUMO

OBJECTIVE: To develop new classification criteria for systemic lupus erythematosus (SLE) jointly supported by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). METHODS: This international initiative had four phases. 1) Evaluation of antinuclear antibody (ANA) as an entry criterion through systematic review and meta-regression of the literature and criteria generation through an international Delphi exercise, an early patient cohort, and a patient survey. 2) Criteria reduction by Delphi and nominal group technique exercises. 3) Criteria definition and weighting based on criterion performance and on results of a multi-criteria decision analysis. 4) Refinement of weights and threshold scores in a new derivation cohort of 1,001 subjects and validation compared with previous criteria in a new validation cohort of 1,270 subjects. RESULTS: The 2019 EULAR/ACR classification criteria for SLE include positive ANA at least once as obligatory entry criterion; followed by additive weighted criteria grouped in 7 clinical (constitutional, hematologic, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, renal) and 3 immunologic (antiphospholipid antibodies, complement proteins, SLE-specific antibodies) domains, and weighted from 2 to 10. Patients accumulating ≥10 points are classified. In the validation cohort, the new criteria had a sensitivity of 96.1% and specificity of 93.4%, compared with 82.8% sensitivity and 93.4% specificity of the ACR 1997 and 96.7% sensitivity and 83.7% specificity of the Systemic Lupus International Collaborating Clinics 2012 criteria. CONCLUSION: These new classification criteria were developed using rigorous methodology with multidisciplinary and international input, and have excellent sensitivity and specificity. Use of ANA entry criterion, hierarchically clustered, and weighted criteria reflects current thinking about SLE and provides an improved foundation for SLE research.

20.
Genet Epidemiol ; 43(7): 844-863, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31407831

RESUMO

Epidemiologic studies show an increased risk of non-Hodgkin lymphoma (NHL) in patients with autoimmune disease (AD), due to a combination of shared environmental factors and/or genetic factors, or a causative cascade: chronic inflammation/antigen-stimulation in one disease leads to another. Here we assess shared genetic risk in genome-wide-association-studies (GWAS). Secondary analysis of GWAS of NHL subtypes (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, and marginal zone lymphoma) and ADs (rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis). Shared genetic risk was assessed by (a) description of regional genetic of overlap, (b) polygenic risk score (PRS), (c)"diseasome", (d)meta-analysis. Descriptive analysis revealed few shared genetic factors between each AD and each NHL subtype. The PRS of ADs were not increased in NHL patients (nor vice versa). In the diseasome, NHLs shared more genetic etiology with ADs than solid cancers (p = .0041). A meta-analysis (combing AD with NHL) implicated genes of apoptosis and telomere length. This GWAS-based analysis four NHL subtypes and three ADs revealed few weakly-associated shared loci, explaining little total risk. This suggests common genetic variation, as assessed by GWAS in these sample sizes, may not be the primary explanation for the link between these ADs and NHLs.


Assuntos
Doenças Autoimunes/genética , Predisposição Genética para Doença , Linfoma não Hodgkin/genética , Alelos , Feminino , Antígenos HLA/genética , Humanos , Masculino , Pessoa de Meia-Idade , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
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