Rachel A. Mikolaitis

Network analysis of associations between serum interferon-α activity, autoantibodies, and clinical features in systemic lupus erythematosus.

OBJECTIVE Interferon-α (IFNα) is a primary pathogenic factor in systemic lupus erythematosus (SLE), and high IFNα levels may be associated with particular clinical manifestations. The prevalence of individual clinical and serologic features differs significantly by ancestry. This study was undertaken to detect associations between clinical and serologic disease manifestations and serum IFNα activity in a large diverse SLE cohort, using multivariate and network analyses. METHODS We studied 1,089 SLE patients (387 African American, 186 Hispanic American, and 516 European American patients). The presence or absence of individual American College of Rheumatology (ACR) clinical criteria for SLE, autoantibodies, and serum IFNα activity data were analyzed in univariate and multivariate models. Iterative multivariate logistic regression was performed in each ancestral background group separately to establish the network of associations between variables that were independently significant following Bonferroni correction. RESULTS In all ancestral backgrounds, high IFNα activity was associated with anti-Ro and anti-double-stranded DNA antibodies (P = 4.6 × 10(-18) and P = 2.9 × 10(-16) , respectively). Younger age, non-European ancestry, and anti-RNP were also independently associated with increased serum IFNα activity (P ≤ 6.7 × 10(-4) ). We found 14 unique associations between variables in network analysis, and only 7 of these associations were shared among >1 ancestral background. Associations between clinical criteria were different for different ancestral backgrounds, while autoantibody-IFNα relationships were similar across backgrounds. IFNα activity and autoantibodies were not associated with ACR clinical features in multivariate models. CONCLUSION Our findings indicate that serum IFNα activity is strongly and consistently associated with autoantibodies, and not independently associated with clinical features in SLE. IFNα may be more relevant to humoral tolerance and initial pathogenesis than later clinical disease manifestations.

Genetic Variation at the IRF7/PHRF1 Locus Is Associated With Autoantibody Profile and Serum Interferon-α Activity in Lupus Patients

OBJECTIVE Interferon-alpha (IFNalpha) is a heritable risk factor for systemic lupus erythematosus (SLE). Genetic variation near IRF7 is implicated in SLE susceptibility. SLE-associated autoantibodies can stimulate IFNalpha production through the Toll-like receptor/IRF7 pathway. This study was undertaken to determine whether variants of IRF7 act as risk factors for SLE by increasing IFNalpha production and whether autoantibodies are important to this phenomenon. METHODS We studied 492 patients with SLE (236 African American, 162 European American, and 94 Hispanic American subjects). Serum levels of IFNalpha were measured using a reporter cell assay, and single-nucleotide polymorphisms (SNPs) in the IRF7/PHRF1 locus were genotyped. RESULTS In a joint analysis of European American and Hispanic American subjects, the rs702966 C allele was associated with the presence of anti-double-stranded DNA (anti-dsDNA) antibodies (odds ratio [OR] 1.83, P = 0.0069). The rs702966 CC genotype was only associated with higher serum levels of IFNalpha in European American and Hispanic American patients with anti-dsDNA antibodies (joint analysis P = 4.1 x 10(-5) in anti-dsDNA-positive patients and P = 0.99 in anti-dsDNA-negative patients). In African American subjects, anti-Sm antibodies were associated with the rs4963128 SNP near IRF7 (OR 1.95, P = 0.0017). The rs4963128 CT and TT genotypes were associated with higher serum levels of IFNalpha only in African American patients with anti-Sm antibodies (P = 0.0012). In African American patients lacking anti-Sm antibodies, an effect of anti-dsDNA-rs702966 C allele interaction on serum levels of IFNalpha was observed, similar to the other patient groups (overall joint analysis P = 1.0 x 10(-6)). In European American and Hispanic American patients, the IRF5 SLE risk haplotype showed an additive effect with the rs702966 C allele on IFNalpha level in anti-dsDNA-positive patients. CONCLUSION Our findings indicate that IRF7/PHRF1 variants in combination with SLE-associated autoantibodies result in higher serum levels of IFNalpha, providing a biologic relevance for this locus at the protein level in human SLE in vivo.

Autoimmune Disease Risk Variant of IFIH1 Is Associated with Increased Sensitivity to IFN-α and Serologic Autoimmunity in Lupus Patients

Increased IFN-α signaling is a heritable risk factor for systemic lupus erythematosus (SLE). IFN induced with helicase C domain 1 (IFIH1) is a cytoplasmic dsRNA sensor that activates IFN-α pathway signaling. We studied the impact of the autoimmune-disease–associated IFIH1 rs1990760 (A946T) single nucleotide polymorphism upon IFN-α signaling in SLE patients in vivo. We studied 563 SLE patients (278 African-American, 179 European-American, and 106 Hispanic-American). Logistic regression models were used to detect genetic associations with autoantibody traits, and multiple linear regression was used to analyze IFN-α–induced gene expression in PBMCs in the context of serum IFN-α in the same blood sample. We found that the rs1990760 T allele was associated with anti-dsDNA Abs across all of the studied ancestral backgrounds (meta-analysis odds ratio = 1.34, p = 0.026). This allele also was associated with lower serum IFN-α levels in subjects who had anti-dsDNA Abs (p = 0.0026). When we studied simultaneous serum and PBMC samples from SLE patients, we found that the IFIH1 rs1990760 T allele was associated with increased IFN-induced gene expression in PBMCs in response to a given amount of serum IFN-α in anti-dsDNA–positive patients. This effect was independent of the STAT4 genotype, which modulates sensitivity to IFN-α in a similar way. Thus, the IFIH1 rs1990760 T allele was associated with dsDNA Abs, and in patients with anti-dsDNA Abs this risk allele increased sensitivity to IFN-α signaling. These studies suggest a role for the IFIH1 risk allele in SLE in vivo.

Trait-stratified genome-wide association study identifies novel and diverse genetic associations with serologic and cytokine phenotypes in systemic lupus erythematosus

IntroductionSystemic lupus erythematosus (SLE) is a highly heterogeneous disorder, characterized by differences in autoantibody profile, serum cytokines, and clinical manifestations. SLE-associated autoantibodies and high serum interferon alpha (IFN-α) are important heritable phenotypes in SLE which are correlated with each other, and play a role in disease pathogenesis. These two heritable risk factors are shared between ancestral backgrounds. The aim of the study was to detect genetic factors associated with autoantibody profiles and serum IFN-α in SLE.MethodsWe undertook a case-case genome-wide association study of SLE patients stratified by ancestry and extremes of phenotype in serology and serum IFN-α. Single nucleotide polymorphisms (SNPs) in seven loci were selected for follow-up in a large independent cohort of 538 SLE patients and 522 controls using a multi-step screening approach based on novel metrics and expert database review. The seven loci were: leucine-rich repeat containing 20 (LRRC20); protein phosphatase 1 H (PPM1H); lysophosphatidic acid receptor 1 (LPAR1); ankyrin repeat and sterile alpha motif domain 1A (ANKS1A); protein tyrosine phosphatase, receptor type M (PTPRM); ephrin A5 (EFNA5); and V-set and immunoglobulin domain containing 2 (VSIG2).ResultsSNPs in the LRRC20, PPM1H, LPAR1, ANKS1A, and VSIG2 loci each demonstrated strong association with a particular serologic profile (all odds ratios > 2.2 and P < 3.5 × 10-4). Each of these serologic profiles was associated with increased serum IFN-α. SNPs in both PTPRM and LRRC20 were associated with increased serum IFN-α independent of serologic profile (P = 2.2 × 10-6 and P = 2.6 × 10-3 respectively). None of the SNPs were strongly associated with SLE in case-control analysis, suggesting that the major impact of these variants will be upon subphenotypes in SLE.ConclusionsThis study demonstrates the power of using serologic and cytokine subphenotypes to elucidate genetic factors involved in complex autoimmune disease. The distinct associations observed emphasize the heterogeneity of molecular pathogenesis in SLE, and the need for stratification by subphenotypes in genetic studies. We hypothesize that these genetic variants play a role in disease manifestations and severity in SLE.

Disease-Specific Patient Reported Outcome Tools for Systemic Lupus Erythematosus

PURPOSE Systemic lupus erythematosus (SLE) can significantly affect both health and non-health-related quality of life (HRQOL and non-HRQOL). However, of the existent published patient-reported outcome (PRO) tools, none were developed from US patients, an ethnically diverse population. Furthermore, these tools do not address men with SLE or assess non-HRQOL issues. Herein, we present the development and validation of the Lupus Patient-Reported Outcome tool (LupusPRO) and discuss its clinical utility and research value compared with other PRO tools currently available for SLE. METHODS Beginning with a conceptual framework, items for LupusPRO were generated using feedback from women and men with SLE. The tool underwent iterations based on patient feedback and clinimetric and psychometric analyses. Validity (content, construct, and criterion) and reliability (internal consistency and test-retest) for the 44-item LupusPRO tool are presented. RESULTS Consistent with the conceptual framework, items were identified that were related to HRQOL and non-HRQOL constructs. HRQOL domains included (1) lupus symptoms; (2) physical health (physical function, role physical); (3) pain-vitality; (4) emotional health (emotional function and role emotional); (5) body image; (6) cognition; (7) procreation; and (8) lupus medications. Non-HRQOL domains were (1) available social support and coping; (2) desires-goals; and (3) satisfaction with medical care. Internal consistency reliability (0.68-0.94), test-retest reliability (0.55-0.92), content, construct (r > 0.50 with SF-36), and criterion (r > -0.35 with disease activity) validity were fair to good. CONCLUSIONS LupusPRO is a valid and reliable disease-targeted patient-reported health outcome tool that is generalizable to SLE patients in the United States of varied ethnic backgrounds and either gender.

Lupus-specific health outcome measure for US patients: the LupusQoL-US version

Background: Patient-reported outcomes are valuable for the management of chronic diseases like systematic lupus erythematosus (SLE), but no measures have been validated for use in US-based patients with SLE. Objectives: To adapt and assess the validity and reliability of an SLE-specific quality of life (QoL) measure developed in the United Kingdom, the LupusQoL, for use in US-based patients with SLE. Methods: Debriefing interviews of subjects with SLE guided the language modifications of the tool. The LupusQoL-US, SF-36 and EQ5D were administered. Internal consistency (ICR) and test–retest (TRT) reliability, convergent and discriminative validity were examined. Factor analyses were performed. Results: The mean (SD) age of the 185 subjects with SLE was 42.5 (12.9) years. ICR and TRT of the eight domains ranged from 0.85 to 0.94 and 0.68 to 0.92, respectively. Related domains on the SF-36 correlated with the LupusQoL domains (physical health and physical function r = 0.73, physical health and role physical r = 0.57, emotional health and mental health r = 0.72, emotional health and role emotional r = 0.48, pain and bodily pain r = 0.66, fatigue and vitality r = 0.70, planning and social functioning r = 0.58). Most LupusQoL-US domains could discriminate between subjects with varied disease activity and damage. Principal component analysis disclosed five factors in the US version, with physical function, pain and planning items loading on one factor. Conclusions: These data provide evidence to support the psychometric properties of the LupusQoL-US, suggesting its utility as an assessment tool for patients with SLE in the USA.

Psychometric Properties of the EuroQol-5D and Short Form-6D in Patients with Systemic Lupus Erythematosus

Objective. Health related quality of life (HRQOL) is an important patient-reported outcome in systemic lupus erythematosus (SLE). We evaluated the psychometric properties of 2 widely used preference-based generic HRQOL measures, EuroQol-5D (EQ-5D) and Short Form-6D (SF-6D), among United States patients with SLE. Methods. Patients with SLE enrolled at an academic institution were assessed for self-reported generic HRQOL (EQ-5D, Medical Outcomes Study SF-36), disease activity, and disease damage SF-6D. Physical Component Score (PCS) and Mental Component Score (MCS) were calculated from SF-36. Criterion validity, convergent validity, and known-groups comparisons were evaluated for EQ-5D and SF-6D. Sensitivity to change (t tests, effect size) was evaluated in a subset of the cohort followed longitudinally. Results. One hundred sixty-seven patients with SLE were enrolled. Related domains on the EQ-5D and SF-36 correlated strongly, e.g., mobility and physical functioning (r = 0.60), whereas unrelated domains showed weak to moderate correlation. EQ-5D index, EQ-5D visual analog scale, and SF-6D score correlated strongly among each other as well as with most domains of SF-36. Both EQ-5D and SF-6D indices differentiated among patients of varied disease severity. EQ-5D and SF-6D were found to be sensitive to self-reported change in health but insensitive to change in disease activity longitudinally. Disease activity and damage showed weak correlation with HRQOL measures. Conclusion. The SF-6D and EQ-5D exhibited satisfactory psychometric properties for use among US patients with SLE. Measures of disease activity and damage were weakly correlated with HRQOL, suggesting that HRQOL is an important complementary source of information about patients with SLE.

Serum free light chains as biomarkers for systemic lupus erythematosus disease activity

To evaluate serum free light chains (FLC) as a putative biomarker of systemic lupus erythematosus (SLE) activity.

Education, zip code based annualized household income and health outcomes in patients with systemic lupus erythematosus

Objective. To determine the association of socioeconomic status [SES; education and zip code-based annual household income (Z-AHI)] and ethnicity with health-related quality of life (HRQOL) among patients with systemic lupus erythematosus (SLE). Methods. Data on 211 subjects from a cross-sectional study (LupusPRO©) using the Medical Outcomes Study Short Form-36 questionnaire to evaluate physical health scores (PCS) and mental health scores were used to obtain education and zip code. The 2000 US Census was used to obtain each zip code’s median annual household income. Results. Education and Z-AHI correlated with PCS (education standardized β = 0.17, 95% CI 0.47, 3.65, p = 0.01, r2 = 0.03; Z-AHI standardized β = 0.15, 95% CI 0.57, 8.30, p = 0.02, r2 = 0.02) on regression analysis. Z-AHI was linked to PCS, independent of education. Ethnicity was associated with PCS through disease activity and SES. Conclusion. SES is associated with HRQOL in SLE. Z-AHI and education are equally predictive surrogates of SES; however, Z-AHI, independent of education, was predictive of HRQOL. Z-AHI has less subject bias and is easily obtainable, therefore its use for future HRQOL studies is suggested.

Asymmetric loading and bone mineral density at the asymptomatic knees of patients with unilateral hip osteoarthritis

OBJECTIVE In patients with unilateral end-stage hip osteoarthritis (OA), the contralateral knee is known to be at greater risk for end-stage knee OA compared to the ipsilateral (i.e., same-side) knee. The contralateral knee is known to have increased dynamic joint loads compared to the ipsilateral knee. The present study was undertaken to examine patients who had unilateral hip OA but who did not have symptoms of knee OA, in order to detect early asymmetries in knee loading. METHODS Data on 62 patients with unilateral hip OA were evaluated. Patients underwent gait analyses of dynamic knee loads as well as dual x-ray absorptiometry for determination of bone mineral density (BMD) in both knees. Differences between knees were compared. RESULTS Peak dynamic knee loads were significantly higher at the contralateral knee compared to the ipsilateral knee (mean ± SD 2.46 ± 0.71 percent of body weight × height versus 2.23 ± 0.81 percent of body weight × height; P = 0.029). Similarly, medial compartment tibial BMD was significantly higher in the contralateral knee compared to the ipsilateral knee (mean ± SD 0.897 ± 0.208 gm/cm(2) versus 0.854 ± 0.206 gm/cm(2); P = 0.033). Interestingly, there was a direct correlation between the contralateral:ipsilateral dynamic knee load and contralateral:ipsilateral medial compartment tibial BMD (ρ = 0.287, P = 0.036). CONCLUSION The risk of developing progressive symptomatic OA in contralateral knees is higher compared to the risk in ipsilateral knees in patients with unilateral hip OA. The present study demonstrates that loading and structural asymmetries appear early in the disease course, while the knees are still asymptomatic. These early biomechanical asymmetries may have corresponding long-term consequences, providing further evidence for the potential role of loading in OA onset and progression.