Somatosensation in OA: exploring the relationships of pain sensitization, vibratory perception and spontaneous pain.

BACKGROUND: Pain in osteoarthritis (OA) remains poorly understood. Different types of somatosensory alterations exist in OA including hyperesthesia and increased sensitivity to painful stimuli as well as those of decreased sensitivity to cutaneous stimuli including vibratory perception threshold. The relationship between these different somatosensory measures has not been previously evaluated in OA. In this observational study, we evaluated relationships between vibratory perception (VPT), pressure pain detection thresholds (PPT), allodynia and subjective pain in knee OA. METHODS: Forty-two persons with moderate to severe knee OA and 12 controls without OA were evaluated. VPT was measured using a biothesiometer. Allodynia was measured by application of a 60 g Von Frey monofilament repeatedly to predetermined sites. PPTs were measured using a pressure algometer. RESULTS: Increased vibratory acuity was associated with lower PPTs and presence of allodynia. Allodynia was more common in OA than controls (54.8% vs 16.6%, p = 0.024 in the ipsilateral knee, and 42.9% vs 0%, p = 0.005 in the contralateral knee). OA participants with allodynia had lower PPTs than those without allodynia. In those with OA, spontaneous knee pain was associated with lower PPTs and with allodynia. CONCLUSION: This study confirms the presence of somatosensory alterations in OA. Sensory alterations (vibratory perception) were shown to be related to nociceptive alterations (sensitization) in OA, showing a general increased sensitivity to cutaneous mechanical stimulation. Understanding these relationships is an important step in delineating the complicated pathophysiology of pain processing in OA.

Improvement in knee loading after use of specialized footwear for knee osteoarthritis: results of a six-month pilot investigation.

OBJECTIVE: Biomechanical interventions for knee osteoarthritis (OA) aim to improve pain and retard disease progression by decreasing knee loading. This study was undertaken to evaluate the effects of 6 months of use of flat, flexible footwear (the mobility shoe) on knee loading in OA. METHODS: Subjects with knee OA underwent baseline gait analyses under conditions of walking in their own shoes, walking in mobility shoes, and walking barefoot. Thereafter, subjects wore the mobility shoes at least 6 hours per day for 6 days per week. Gait evaluations were repeated at 6, 12, and 24 weeks. An intent-to-treat analysis was performed to assess the longitudinal effects on knee loading with the shoe intervention. RESULTS: Compared to knee loading at baseline with the participants' own shoes, there was an 18% reduction in the knee adduction moment (KAM) by 24 weeks with the mobility shoes (P < 0.001) and no significant differences in the KAM by 24 weeks between mobility shoe and barefoot walking (P = 0.192). Over the 6 months of followup, participants also experienced an 11% reduction in the KAM when walking in their own shoes (P = 0.002) and a 10% reduction in the KAM when walking barefoot (P = 0.002 for the whole followup), as compared to these values at baseline under the same conditions. CONCLUSION: This study suggests that use of flat, flexible footwear results in significant reductions in knee loading in subjects with OA. By 24 weeks, there is evidence of a gait adaptation with sustained load reduction even when the mobility shoes are removed, suggesting that footwear may serve as a biomechanical training device to achieve beneficial alterations in gait mechanics for knee OA.

Validation of the Cutaneous Lupus Disease Area and Severity Index (CLASI) using physician- and patient-assessed health outcome measures.

BACKGROUND: The Cutaneous Lupus Disease Area and Severity Index (CLASI) has not been validated using rheumatologist-conducted disease activity and damage assessments, especially cutaneous assessments. Active skin disease and skin damage may have substantial effects on patient-reported outcomes and on body image. OBJECTIVE: We sought to validate the CLASI against: (1) physician-assessed disease activity and damage measures; and (2) patient-reported assessment of quality of life and body image. METHODS: Cross-sectional data were collected from 31 patients with cutaneous lupus erythematosus. Cutaneous disease activity and damage were measured by using the CLASI. Disease activity (using the Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus [SLE] Disease Activity Index [SLEDAI}), damage (Systemic Lupus International Collaboration Clinics-American College of Rheumatology Damage Index [SDI]), quality of life (LupusPRO), and body image (Body Image Quality of Life Inventory) were obtained. Descriptive statistics and Spearman correlations were ascertained. RESULTS: Mean (SD) age was 42.3 (12.8) years; 97% were women. The mean (SD) CLASI activity and damage scores were 10.5 (7.4) and 9.9 (9.5). Correlations noted were: total CLASI activity and SLEDAI-rash (r = 0.42, P = .02), CLASI-mucosal and SLEDAI-mucosal (r = 0.65, P = .001), CLASI-recent hair loss and SLEDAI-alopecia (r = 0.61, P = .001), and total CLASI activity and LupusPRO symptoms domain (r = -0.38, P = .04). Total CLASI-damage correlated with SDI-scarring/alopecia (r = 0.51, P = .004), SDI-extensive scarring/panniculum (r = 0.55, P = .003), and SDI-skin ulceration (r = 0.36, P = .05). CLASI scalp scarring correlated with SDI-skin scarring/alopecia (r = 0.94, P = .001). CLASI activity on the face and nose was associated with significant concerns on the Body Image Quality of Life Inventory. LIMITATIONS: Limitations include small sample size. CONCLUSION: CLASI activity and damage scores correlate with physician-assessed cutaneous activity and damage in cutaneous lupus erythematosus in patients with SLE. Cutaneous activity in visible areas may generate body image concerns.

The relationship of vibratory perception to dynamic joint loading, radiographic severity, and pain in knee osteoarthritis.

OBJECTIVE: Patients with knee osteoarthritis (OA) have been shown to have somatosensory deficits of the lower extremity. This study was designed to assess the association of these deficits with dynamic joint loading and their relationship to the structural and symptomatic severity of knee OA. METHODS: Subjects with symptomatic knee OA underwent evaluation of the vibratory perception threshold (VPT) using a biothesiometer at 5 sites at the lower extremity. Dynamic joint loading was assessed through gait analyses. Knee pain was evaluated using a visual analog scale score for pain based on the Western Ontario and McMaster Universities OA Index. Radiographic severity of knee OA was assessed using the Kellgren/Lawrence (K/L) grading scale on radiographs obtained with the knee in a standing position. RESULTS: Dynamic knee joint loading was directly associated with the VPT at the metatarsophalangeal (MTP) joint (Spearman's rho=0.384, P=0.033), indicating that the worse the vibratory sense, the higher the knee load during gait. The K/L severity grade was directly associated with the VPT at the MTP joint and lateral femoral condyle, after adjustment for age, sex, body mass index, and knee pain. After adjustment for confounders, there were no significant associations observed between the VPT and pain at any of the sites tested. CONCLUSION: These findings demonstrate an association between greater somatosensory deficits and higher dynamic loads in OA. They also demonstrate structural consequences associated with somatosensory deficits in OA, since the extent of sensory loss directly correlated with the radiographic severity of knee OA. However, there was no relationship observed between vibratory sense and symptomatic knee OA pain.

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.

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.

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.

Body image in patients with systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE), a multisystemic disease of young women may be disfiguring and affect physical and emotional health. Body image literature in SLE is scant and controversial. PURPOSE: We compared body image-related quality of life in subjects with (n = 87) and without (n = 78) SLE and determined its correlates using the body image quality of life inventory (BIQLI). METHOD: The tool was self-administered to consenting individuals. Demographic information along with disease activity and damage assessments for SLE patients were obtained. T test, chi square test, correlational, and regression analyses were used to make comparisons. RESULTS: Mean age (±SD) were 42.4 ± 13.1 and 38.7 ± 13.2 years for SLE and non-SLE subjects, respectively. Mean (±SD) BIQLI scores were significantly worse in SLE than non-SLE subjects: 19.9 ± 33.2 and 41.6 ± 24.8 (p = 0.001). In SLE, BIQLI scores correlated inversely with overall damage, irreversible cutaneous damage, alopecia, and self-reported depression, and directly with age and health status. CONCLUSION: Body image in SLE is poor, and effective interventions may be directed at cutaneous disease activity, damage, and depression.

Osteopontin alleles are associated with clinical characteristics in systemic lupus erythematosus.

Variants of the osteopontin (OPN) gene have been associated with systemic lupus erythematosus (SLE) susceptibility and cytokine profiles in SLE patients. It is not known whether these alleles are associated with specific clinical phenotypes in SLE. We studied 252 well-characterized SLE patients from a multiethnic cohort, genotyping the rs11730582, rs28357094, rs6532040, and rs9138 SNPs in the OPN gene. Ancestry informative markers were used to control for genetic ancestry. The SLE-risk allele rs9138C in the 3' UTR region was associated with photosensitivity in lupus patients across all ancestral backgrounds (meta-analysis OR = 3.2, 95% CI = 1.6-6.5, P = 1.0 × 10⁻³). Additionally, the promoter variant rs11730582C demonstrated suggestive evidence for association with two hematologic traits: thrombocytopenia (OR = 2.1, P = 0.023) and hemolytic anemia (OR = 2.6, P = 0.036). These clinical associations with SNPs in the promoter and 3' UTR regions align with previously reported SLE-susceptibility SNPs in OPN and suggest potential roles for these variants in antibody-mediated cytopenias and skin inflammation in SLE.

Promoter variant of PIK3C3 is associated with autoimmunity against Ro and Sm epitopes in African-American lupus patients.

The PIK3C3 locus was implicated in case-case genome-wide association study of systemic lupus erythematosus (SLE) which we had performed to detect genes associated with autoantibodies and serum interferon-alpha (IFN-alpha). Herein, we examine a PIK3C3 promoter variant (rs3813065/-442 C/T) in an independent multiancestral cohort of 478 SLE cases and 522 controls. rs3813065 C was strongly associated with the simultaneous presence of both anti-Ro and anti-Sm antibodies in African-American patients [OR = 2.24 (1.34-3.73), P = 2.0 x 10(-3)]. This autoantibody profile was associated with higher serum IFN-alpha (P = 7.6 x 10(-6)). In the HapMap Yoruba population, rs3813065 was associated with differential expression of ERAP2 (P = 2.0 x 10(-5)), which encodes an enzyme involved in MHC class I peptide processing. Thus, rs3813065 C is associated with a particular autoantibody profile and altered expression of an MHC peptide processing enzyme, suggesting that this variant modulates serologic autoimmunity in African-American SLE patients.

Development and validation of the Lupus Impact Tracker: a patient-completed tool for clinical practice to assess and monitor the impact of systemic lupus erythematosus.

OBJECTIVE: To derive and validate a brief patient-completed instrument, the Lupus Impact Tracker (LIT), to assess and monitor the impact of systemic lupus erythematosus (SLE). METHODS: Items for the LIT were selected from the LupusPRO, a validated patient-reported outcomes measure, using 3 approaches: confirmatory factor analysis (CFA), stepwise regression, and patient focus groups. CFA was conducted to find items from the LupusPRO that fit a unidimensional structure to allow scoring as a single index. Stepwise regression methods identified items with the strongest relationship (convergent validity) with disease activity measures and patient health rating. Focus groups (n = 26 patients) identified the most important items describing SLE impact. Selected items were evaluated for reliability and validity. RESULTS: CFA found 21 items that fit a unidimensional structure. Stepwise regressions identified 15 of 21 items having good convergent validity with clinical measures. Patient focus groups identified 9 of 15 items as best capturing the impact of SLE. Overall, 7 items were selected across all 3 approaches (CFA, stepwise regression, and focus groups). Another 15 items were selected across 2 approaches. Through consensus with rheumatology clinician experts, a final set of 10 items was selected for the LIT. The LIT items showed good internal consistency (0.89) and test-retest reliabilities (0.87). Mean LIT scores differed significantly (P < 0.05) across criterion groups in the hypothesized direction, providing evidence of discriminant validity and responsiveness. CONCLUSION: The LIT is reliable and valid in SLE patients and offers a practical way for physicians and patients to assess and monitor the impact of SLE.

The autoimmune disease risk allele of UBE2L3 in African American patients with systemic lupus erythematosus: a recessive effect upon subphenotypes.

OBJECTIVE: UBE2L3 is associated with susceptibility to systemic lupus erythematosus (SLE) and rheumatoid arthritis in European ancestry populations, and this locus has not been investigated fully in non-European populations. We studied the UBE2L3 risk allele for association with SLE, interferon-α (IFN-α), and autoantibodies in a predominantly African American SLE cohort. METHODS: We studied 395 patients with SLE and 344 controls. The UBE2L3 rs5754217 polymorphism was genotyped using Taqman primer-probe sets, and IFN-α was measured using a reporter cell assay. RESULTS: The UBE2L3 rs5754217 T allele was strongly enriched in African American patients with anti-La antibodies as compared to controls, and a recessive model was the best fit for this association (OR 2.55, p = 0.0061). Serum IFN-α also demonstrated a recessive association with the rs5754217 genotype in African American patients, and the TT/anti-La-positive patients formed a significantly high IFN-α subgroup (p = 0.0040). Similar nonstatistically significant patterns of association were observed in the European American patients with SLE. Case-control analysis did not show large allele frequency differences, supporting the idea that this allele is most strongly associated with anti-La-positive patients. CONCLUSION: This pattern of recessive influence within a subgroup of patients may explain why this allele does not produce a strong signal in standard case-control studies, and subphenotypes should be included in future studies of UBE2L3. The interaction we observed between UBE2L3 genotype and autoantibodies upon serum IFN-α suggests a biological role for this locus in patients with SLE in vivo.

Rheumatologists' quality of care for lupus: comparison study between a university and county hospital.

OBJECTIVE: Quality of care received from physicians may impact health outcomes in systemic lupus erythematosus (SLE). We compared physician quality of care (P-QOC), health-related quality of life (HRQOL), and disease activity and damage between SLE patients receiving outpatient care at a university and a county rheumatology clinic. METHODS: Forty-two university and 41 county clinic SLE patients provided data on 5 P-QOC parameters and HRQOL health outcomes (Short Form 36 [SF-36] health survey and EuroQol 5-domain instrument [EQ-5D]). Disease activity and damage were measured. Chi-square analysis and Student's t-tests were used for comparisons. RESULTS: Overall satisfaction with medical care was similar; however, university patients had higher P-QOC scores than county patients in "perception of doctor's understanding of impact of SLE on patient's life" (P = 0.02) and "providing education/educational information to understand their disease" (P = 0.05). HRQOL, disease activity, and damage were similar in the 2 groups. Overall satisfaction with medical care was directly related SF-36 general health (r = 0.34, P = 0.03) and EQ-5D visual analog scale on state of health (r = 0.39, P = 0.01), and inversely related EQ-5D pain (r = -0.37, P = 0.02). CONCLUSION: Patient perceptions of P-QOC differed across the 2 centers despite similar demographics, clinical and HRQOL outcomes, and significant overlap in the physicians serving each clinic. Patients' overall satisfaction with medical care is associated with better HRQOL.

A brief assessment tool for body image in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) may adversely affect body image in multitude ways. Development and validation of a brief and valid SLE specific body image tool were undertaken. Eleven items were identified on interview of 21 SLE patients for the Body Image Lupus Scale (BILS v1.0). The tool was administered to 70 SLE patients. Based on analysis, feedback, and refinement of items, the final iteration BILS v1.2 with five items was administered to 233 SLE patients along with validated body image measures (Situational Inventory of Body Image Dysphoria and Body Image Quality of Life Inventory) and health-related quality of life measures for a subsample. The BILS scores' had an internal consistency reliability of .94. It correlated with both the referent body image measures, and with health-related quality of life. It differentiated participants by health status and disease activity. Test-retest reliability estimates exceeded .90. These results support the psychometric properties of BILS.

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.

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

OBJECTIVE: To evaluate serum free light chains (FLC) as a putative biomarker of systemic lupus erythematosus (SLE) activity. METHODS: Seventy-five SLE patients and 41 age- and sex-matched rheumatoid arthritis (RA) controls were enrolled. Disease activity was assessed using the Safety of Estrogens in Lupus Erythematosus: National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) definition and physician global assessments for SLE and the Disease Activity Score in 28 joints for RA. Serum FLC levels were compared against other biomarkers (IgG, C3, C4, double-stranded DNA [dsDNA] antibody). Nonparametric tests were used to compare 1) FLC and IgG in SLE versus RA and healthy controls, 2) FLC and IgG among different levels of activity in SLE, and 3) FLC in active versus nonactive RA. Correlation of FLC, C3, C4, dsDNA antibody, and IgG with the SLEDAI and modified SLEDAI (M-SLEDAI) were obtained. RESULTS: FLC was higher in SLE than in RA; both were higher than referent healthy controls. Total FLC was significantly higher in subjects with greater SLE disease activity than lower/no activity. There were no significant differences in IgG, C4, or dsDNA antibody stratified by disease activity. Total FLC and C3 showed moderate to strong correlation with the SLEDAI and M-SLEDAI. In RA, no differences were seen in FLC levels for different levels of disease activity. Similar results were seen after controlling for renal function, age, and sex. In multiple linear regression, FLC significantly explained 50% variance of the SLEDAI after adjusting for renal function, age, and sex. CONCLUSION: Serum FLC levels correlate strongly with disease activity in SLE, but not in RA. Serum FLC may be used as a biomarker of SLE disease activity.

LupusQoL-US benchmarks for US patients with systemic lupus erythematosus.

OBJECTIVE: The LupusQoL-US instrument was recently validated in the US. We studied the benchmarks for a US patient cohort with systemic lupus erythematosus (SLE) and relevant demographic and disease correlates. METHODS: LupusQoL-US was administered to 185 patients with SLE. Demographic data (age, sex, ethnicity, marital status) and disease features (duration, disease activity and damage) were assessed simultaneously. Descriptive statistics were obtained. LupusQoL-US domain scores were calculated, and compared by sex, ethnicity, and marital status using nonparametric tests. Correlation between LupusQoL-US domains and age, disease duration, disease activity, and disease damage were obtained. RESULTS: Mean age of patients was 42.2 +/- 14.5 years; 94% of subjects were women. African American patients comprised 60% of the study cohort. The most affected domains were Fatigue and Physical Health. The least affected was Intimate Relationships. Age correlated with Physical Health, Pain, and Body Image (r = 0.15-0.18). Differences were observed based on sex and marital status, but not by ethnicity; there the LupusQoL-US correlated inversely with disease activity (r = -0.001 to -0.36) and damage (r = -0.003 to -0.40). CONCLUSION: All domains of the LupusQoL-US based health related quality of life (HRQOL) were affected adversely. HRQOL varied by age, sex, and marital status in our SLE cohort.

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 beta = 0.17, 95% CI 0.47, 3.65, p = 0.01, r(2) = 0.03; Z-AHI standardized beta = 0.15, 95% CI 0.57, 8.30, p = 0.02, r(2) = 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.

Genetic variation at the IRF7/PHRF1 locus is associated with autoantibody profile and serum interferon-alpha 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.

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

INTRODUCTION: Systemic 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. METHODS: We 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). RESULTS: SNPs 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. CONCLUSIONS: This 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.