Racial differences in treatment preferences among lupus patients: a two-site study.

OBJECTIVES: To identify the demographic, clinical and psychosocial characteristics associated with racial differences in willingness to receive cyclophosphamide (CYC) or participate in a research clinical trial (RCT) among patients with systemic lupus erythematosus (SLE). METHODS: Data from 163 African-American (AA) and 180 white (WH) SLE patients were evaluated. Structured interviews and chart reviews were conducted to determine treatment preferences in hypothetical situations and identify variables that may affect preferences. Logistic regression models were performed to evaluate the relationship between patient preferences and race, adjusted for patient characteristics. RESULTS: Among patients who had never received CYC (n=293), 62.9% AAs compared to 87.6% WHs were willing to receive the medication (p<0.001). This difference persisted (OR 0.37 [95% CI, 0.16-0.87]) after adjusting for socio-demographics, clinical characteristics, and perceptions about CYC and physicians. Income and higher perception of CYC effectiveness were other determinants of willingness to receive CYC. Among patients who had never participated in an RCT (n=326), 64.9% AAs compared to 84.3% WHs were willing to do so (p<0.001). This difference persisted (OR 0.41 [95% CI, 0.20-0.83]) after adjusting for socio-demographics, clinical context and patients' perceptions of physicians. SLE damage score, number of immunosuppressive medications and higher trust in physicians were also independently associated with willingness to participate in an RCT. CONCLUSIONS: Race remains an independent determinant of treatment preferences after adjustment for income, medications, medication efficacy expectations and trust in physicians. While some factors related to racial differences in preferences are relatively fixed, others that may alleviate these differences also exist, including medication beliefs and provider trust.

In situ B cell-mediated immune responses and tubulointerstitial inflammation in human lupus nephritis.

The most prevalent severe manifestation of systemic lupus erythematosus is nephritis, which is characterized by immune complex deposition, inflammation, and scarring in glomeruli and the tubulointerstitium. Numerous studies indicated that glomerulonephritis results from a systemic break in B cell tolerance, resulting in the local deposition of immune complexes containing Abs reactive with ubiquitous self-Ags. However, the pathogenesis of systemic lupus erythematosus tubulointerstitial disease is not known. In this article, we demonstrate that in more than half of a cohort of 68 lupus nephritis biopsies, the tubulointerstitial infiltrate was organized into well-circumscribed T:B cell aggregates or germinal centers (GCs) containing follicular dendritic cells. Sampling of the in situ-expressed Ig repertoire revealed that both histological patterns were associated with intrarenal B cell clonal expansion and ongoing somatic hypermutation. However, in the GC histology, the proliferating cells were CD138(-)CD20(+) centroblasts, whereas they were CD138(+)CD20(low/-) plasmablasts in T:B aggregates. The presence of GCs or T:B aggregates was strongly associated with tubular basement membrane immune complexes. These data implicate tertiary lymphoid neogenesis in the pathogenesis of lupus tubulointerstitial inflammation.

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.

Correlates of sleep abnormalities in systemic lupus: a cross-sectional survey in an urban, academic center.

BACKGROUND: Systemic lupus erythematosus (SLE) is a complex autoimmune disease that is associated with poor health-related quality-of-life outcomes. OBJECTIVES: The objectives of this study were to identify correlates of the domains of the Medical Outcomes Study (MOS) Sleep Scale in SLE and to determine the factors most associated with overall sleep quality. METHODS: Sleep in 118 SLE patients was assessed using the self-administered MOS Sleep Scale. Bivariate correlations were determined between each of 6 MOS Sleep subscale scores and each sociodemographic, clinical, or psychological predictor variable. Serial hierarchical multiple regression analyses were computed to identify the variables associated with the individual sleep domains and the overall Sleep Problems Index. RESULTS: The MOS Sleep Scale scores of patients with SLE were poorer than the US general population. Depression moderately correlated with 5 (all P < 0.01) and anxiety with 4 subscale scores (all P < 0.05). The SLE Disease Activity Index did not significantly correlate with any of the subscale scores. Results of a multivariate regression model showed that sleep adequacy and sleep disturbance were independently associated with depression (ß = -0.84; 95% confidence interval [CI], -1.37 to -0.32; and ß = 0.80; 95% CI, 0.15-1.45; respectively). Daytime somnolence was significantly associated with daily prednisone dosage (ß = 0.54; 95% CI, 0.29-0.80) and anxiety trait (ß = 0.81; 95% CI, 0.41-1.21). Snoring independently correlated with anxiety (ß = 1.64; 95% CI, 0.80-2.29). When demographic, clinical, and psychological variables were simultaneously regressed on the Sleep Problems Index, pain trended toward association with overall sleep problems (ß = 0.17; 95% CI, -0.02 to 0.36). CONCLUSIONS: Patients with SLE have greater sleep problems relative to the general population. Psychosocial factors, particularly depression and anxiety, are important determinants that are significantly associated with sleep abnormalities in SLE.

A study of racial/ethnic differences in treatment preferences among lupus patients.

OBJECTIVES: To determine whether there are racial/ethnic differences in the willingness of SLE patients to receive CYC or participate in clinical trials, and whether demographic, psychosocial and clinical characteristics contribute to these differences. METHODS: Data from 120 African-American and 62 white lupus patients were evaluated. Structured telephone interviews were conducted to determine treatment preferences, as well as to study characteristics and beliefs that may affect these preferences. Data were analysed using serial hierarchical multivariate logistic regression and deviances were calculated from a saturated model. RESULTS: Compared with their white counterparts, African-American SLE patients expressed less willingness to receive CYC (67.0% vs 84.9%, P = 0.02) if their lupus worsened. This racial/ethnic difference remained significant after adjusting for socioeconomic and psychosocial variables. Logistic regression analysis showed that African-American race [odds ratio (OR) 0.29, 95% CI 0.10, 0.80], physician trust (OR 1.05, 95% CI 1.00, 1.12) and perception of treatment effectiveness (OR 1.40, 95% CI 1.22, 1.61) were the most significant determinants of willingness to receive CYC. A trend in difference by race/ethnicity was also observed in willingness to participate in a clinical trial, but this difference was not significant. CONCLUSION: This study demonstrated reduced likelihood of accepting CYC in African-American lupus patients compared with white lupus patients. This racial/ethnic variation was associated with belief in medication effectiveness and trust in the medical provider, suggesting that education about therapy and improved trust can influence decision-making among SLE patients.

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.

Gene-expression-guided selection of candidate loci and molecular phenotype analyses enhance genetic discovery in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a highly heterogeneous autoimmune disorder characterized by differences in autoantibody profiles, serum cytokines, and clinical manifestations. We have previously conducted a case-case genome-wide association study (GWAS) of SLE patients to detect associations with autoantibody profile and serum interferon alpha (IFN-α). In this study, we used public gene expression data sets to rationally select additional single nucleotide polymorphisms (SNPs) for validation. The top 200 GWAS SNPs were searched in a database which compares genome-wide expression data to genome-wide SNP genotype data in HapMap cell lines. SNPs were chosen for validation if they were associated with differential expression of 15 or more genes at a significance of P < 9 × 10(-5). This resulted in 11 SNPs which were genotyped in 453 SLE patients and 418 matched controls. Three SNPs were associated with SLE-associated autoantibodies, and one of these SNPs was also associated with serum IFN-α (P < 4.5 × 10(-3) for all). One additional SNP was associated exclusively with serum IFN-α. Case-control analysis was insensitive to these molecular subphenotype associations. This study illustrates the use of gene expression data to rationally select candidate loci in autoimmune disease, and the utility of stratification by molecular phenotypes in the discovery of additional genetic associations in SLE.

The lupus family registry and repository.

The Lupus Family Registry and Repository (LFRR) was established with the goal of assembling and distributing materials and data from families with one or more living members diagnosed with SLE, in order to address SLE genetics. In the present article, we describe the problems and solutions of the registry design and biometric data gathering; the protocols implemented to guarantee data quality and protection of participant privacy and consent; and the establishment of a local and international network of collaborators. At the same time, we illustrate how the LFRR has enabled progress in lupus genetics research, answering old scientific questions while laying out new challenges in the elucidation of the biologic mechanisms that underlie disease pathogenesis. Trained staff ascertain SLE cases, unaffected family members and population-based controls, proceeding in compliance with the relevant laws and standards; participant consent and privacy are central to the LFRR's effort. Data, DNA, serum, plasma, peripheral blood and transformed B-cell lines are collected and stored, and subject to strict quality control and safety measures. Coded data and materials derived from the registry are available for approved scientific users. The LFRR has contributed to the discovery of most of the 37 genetic associations now known to contribute to lupus through 104 publications. The LFRR contains 2618 lupus cases from 1954 pedigrees that are being studied by 76 approved users and their collaborators. The registry includes difficult to obtain populations, such as multiplex pedigrees, minority patients and affected males, and constitutes the largest collection of lupus pedigrees in the world. The LFRR is a useful resource for the discovery and characterization of genetic associations in SLE.

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.

Clinical Efficacy and Safety of Baminercept, a Lymphotoxin ß Receptor Fusion Protein, in Primary Sjögren's Syndrome: Results From a Phase II Randomized, Double-Blind, Placebo-Controlled Trial.

OBJECTIVE: To evaluate the clinical efficacy and safety of baminercept, a lymphotoxin ß receptor IgG fusion protein (LTßR-Ig), for the treatment of primary Sjögren's syndrome (SS), and to explore the possible mechanisms of action of this treatment. METHODS: In this multicenter trial, 52 patients with primary SS were randomized in a 2:1 ratio to receive subcutaneous injections of 100 mg of baminercept every week for 24 weeks or matching placebo. The primary end point was the change between screening and week 24 in the stimulated whole salivary flow (SWSF) rate. Secondary end points included the European League Against Rheumatism Sjögren's Syndrome Disease Activity Index (ESSDAI), as well as measurements of select chemokines and cytokines and enumeration of peripheral blood B and T cell subsets. RESULTS: The change from baseline to week 24 in the SWSF rate was not significantly different between the baminercept and placebo treatment groups (baseline-adjusted mean change -0.01 versus 0.07 ml/minute; P = 0.332). The change in the ESSDAI during treatment was also not significantly different between the treatment groups (baseline-adjusted mean change -1.23 versus -0.15; P = 0.104). Although the incidence of adverse events was similar between the treatment groups, baminercept therapy was associated with a higher incidence of liver toxicity, including 2 serious adverse events. Baminercept also produced a significant decrease in plasma levels of CXCL13 and significant changes in the number of circulating B and T cells, consistent with its known inhibitory effects on LTßR signaling. CONCLUSION: In this trial, treatment with baminercept failed to significantly improve glandular and extraglandular disease in patients with primary SS, despite evidence from mechanistic studies showing that it blocks LTßR signaling.

Increased Whole Blood Viscosity Is Associated with the Presence of Digital Ulcers in Systemic Sclerosis: Results from a Cross-Sectional Pilot Study.

OBJECTIVE: To investigate the role of whole blood viscosity in digital ulcer (DU) development in patients with diffuse and limited Systemic sclerosis. METHODS: A convenience sample of patients with Systemic sclerosis (SSc) was selected from the adult Rheumatology clinic at the University of Chicago. The study group consisted of patients with SSc (with ulcers present, a history of ulcers, and no ulcers); the control group consisted of matched healthy Rheumatology clinic staff. WBV was measured using a scanning capillary viscometer at different shear rates (1-1000 1/s). RESULTS: Whole blood viscosity as measured by a scanning capillary viscometer was increased in patients with SSc compared to healthy controls (p < 0.0001). Additionally, patients with present DU had significantly higher whole blood viscosity when compared to patients with a history of DU and patients with no history of DU (p < 0.0001). These findings were most pronounced at lower shear rates between 1 and 10 1/s. CONCLUSION: Whole blood viscosity might be a contributing factor in DU development in patients with SSc. Further studies with larger patient cohorts are required to fully evaluate how increased WBV contributes to the development of DU and whether the currently available treatment options improve the microcirculation by influencing WBV.

Work disability, lost productivity and associated risk factors in patients diagnosed with systemic lupus erythematosus.

OBJECTIVE: To assess prevalence and correlates of work presenteeism, absenteeism and work disability (WD) in patients with systemic lupus erythematous (SLE) and matched controls. METHODS: Patients with SLE from six medical centres were recruited to complete a questionnaire consisting of several prevalidated survey instruments. The subject's rheumatologist completed medical history. Subjects recruited two non-SLE 'best friend' controls with matching demographics to complete a control survey. Analyses employed Student's t tests, χ(2) tests and logistic regression models. RESULTS: 344 subjects with SLE and 322 controls submitted completed questionnaires. Mean pain, fatigue, Brief Cognitive Symptoms Index (BCSI) scores and depressive symptoms were worse in patients with SLE with WD (all p<0.01). WD was associated with African-American race, older age (51-65 years) and less than 4-year college education (all p<0.01). High presenteeism was associated with low pain and fatigue levels, higher BCSI scores and negatively correlated with depressive symptoms (all p<0.05). Increased pain and fatigue were associated with elevated absenteeism (p<0.05). Subjects with physically and cognitively demanding work reported worse presenteeism compared with controls with similar jobs (77% vs 85%, p<0.05 and 75% vs 85%, p<0.001), respectively. Patients with most cognitively demanding jobs reported greater weekly absenteeism (mean, 5.9 h) compared with controls (mean, 6.9 overtime hours, p<0.05). CONCLUSIONS: The questionnaire demonstrated increased WD in SLE. Highly physical and highly cognitive jobs are challenging to patients with SLE and had increased absenteeism compared with controls. Depressive symptoms were correlated with better presenteeism without major socio-demographic determinants. Employability may be enhanced by improving treatment of depressive symptoms in patients with SLE.

Perceptions of racism in healthcare among patients with systemic lupus erythematosus: a cross-sectional study.

BACKGROUND: Racial disparities in the clinical outcomes of systemic lupus erythematosus (SLE) exist. Perceived racial discrimination may contribute to disparities in health. OBJECTIVES: To determine if perceived racism in healthcare differs by race among patients with SLE and to evaluate its contribution to racial disparities in SLE-related outcomes. METHODS: 163 African-American (AA) and 180 white (WH) patients with SLE were enrolled. Structured interviews and chart reviews were done to determine perceptions of racism, SLE-related outcomes (Systemic Lupus International Collaborating Clinics (SLICC) Damage Index, SLE Disease Activity, Center for Epidemiologic Studies-Depression (CES-D)), and other variables that may affect perceptions of racism. Serial hierarchical multivariable logistic regression models were conducted. Race-stratified analyses were also performed. RESULTS: 56.0% of AA patients compared with 32.8% of WH patients had high perceptions of discrimination in healthcare (p<0.001). This difference remained (OR 4.75 (95% CI 2.41 to 8.68)) after adjustment for background, identity and healthcare experiences. Female gender (p=0.012) and lower trust in physicians (p<0.001) were also associated with high perceived racism. The odds of having greater disease damage (SLICC damage index ≥2) were higher in AA patients than in WH patients (crude OR 1.55 (95% CI 1.01 to 2.38)). The odds of having moderate to severe depression (CES-D ≥17) were also higher in AA patients than in WH patients (crude OR 1.94 (95% CI 1.26 to 2.98)). When adjusted for sociodemographic and clinical characteristics, racial disparities in disease damage and depression were no longer significant. Among AA patients, higher perceived racism was associated with having moderate to severe depression (adjusted OR 1.23 (95% CI 1.05 to 1.43)) even after adjusting for sociodemographic and clinical variables. CONCLUSIONS: Perceptions of racism in healthcare were more common in AA patients than in WH patients with SLE and were associated with depression. Interventions aimed at modifiable factors (eg, trust in providers) may reduce higher perceptions of race-based discrimination in SLE.

Cell distance mapping identifies functional T follicular helper cells in inflamed human renal tissue.

T follicular helper (TFH) cells are critical for B cell activation in germinal centers and are often observed in human inflamed tissue. However, it is difficult to know if they contribute in situ to inflammation. Expressed markers define TFH subsets associated with distinct functions in vitro. However, such markers may not reflect in situ function. The delivery of T cell help to B cells requires direct cognate recognition. We hypothesized that by visualizing and quantifying such interactions, we could directly assess TFH cell competency in situ. Therefore, we developed computational tools to quantify spatial relationships between different cell subtypes in tissue [cell distance mapping (CDM)]. Analysis of inflamed human tissues indicated that measurement of internuclear distances between TFH and B cells could be used to discriminate between apparent cognate and noncognate interactions. Furthermore, only cognate-competent TFH cell populations expressed high levels of Bcl-6 and interleukin-21. These data suggest that CDM can be used to identify adaptive immune cell networks driving in situ inflammation. Such knowledge should help identify diseases, and disease subsets, that may benefit from therapeutic targeting of specific T cell-antigen-presenting cell interactions.

Significance of chronic tachycardia in systemic lupus erythematosus.

OBJECTIVE: A significant subset of systemic lupus erythematosus (SLE) patients exhibit chronic tachycardia (CT) of unknown significance. We postulated that CT is a marker of lupus activity and severity. METHODS: A cross-sectional database at the University of Chicago recorded disease activity, damage, disease manifestations, pain, anxiety, and physical function (PF). CT was defined as a heart rate of ≥95 beats per minute in at least 3 out of 4 sequential visits. Demographic, disease-specific, and self-reported symptoms were compared between groups with and without tachycardia. RESULTS: Of the 243 subjects analyzed, 14.8% had CT. On univariate analysis, CT was associated with younger age at the time of enrollment (P = 0.004), number of hospitalizations adjusted for years of SLE (P = 0.001), current prednisone dose (P < 0.0001), history of serositis (P = 0.03), anxiety score (P = 0.004), and poor PF (P = 0.0017). All domains of the Short Form 36 (SF-36) health survey correlated strongly with CT, but on multivariate regression this correlation appeared to be driven by poor PF. On multivariate regression, the Systemic Lupus Erythematosus Disease Activity Index score (P = 0.03), younger age (P = 0.04), and poor PF by the SF-36 domain (P = 0.006) were independently correlated with CT, and anxiety trait and hemoglobin both trended closely to significant association (P = 0.08 for both). CONCLUSION: CT is prevalent in SLE and is a clinically relevant physical finding. It implies greater lupus activity and physical frailty. Univariate association with serositis raises the possibility of subclinical serositis or pancarditis. Further study to elucidate the cardiopulmonary status of SLE patients with unexplained CT is planned.

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.

Effect of belimumab on vaccine antigen antibodies to influenza, pneumococcal, and tetanus vaccines in patients with systemic lupus erythematosus in the BLISS-76 trial.

OBJECTIVE: In patients with systemic lupus erythematosus (SLE), evidence suggests that most vaccines (except live-virus vaccines) are safe, although antibody response may be reduced. This substudy from the phase III, randomized, double-blind, placebo-controlled BLISS-76 trial evaluated the effects of belimumab on preexisting antibody levels against pneumococcal, tetanus, and influenza antigens in patients with SLE. METHODS: In BLISS-76, patients with autoantibody-positive, active SLE were treated with placebo or belimumab 1 or 10 mg/kg every 2 weeks for 28 days and every 28 days thereafter, plus standard SLE therapy, for 76 weeks. This analysis included a subset of patients who had received pneumococcal or tetanus vaccine within 5 years or influenza vaccine within 1 year of study participation. Antibodies to vaccine antigens were tested at baseline and Week 52, and percentage changes in antibody levels from baseline and proportions of patients maintaining levels at Week 52 were assessed. Antibody titers were also assessed in a small number of patients vaccinated during the study. RESULTS: Consistent with preservation of the memory B cell compartment with belimumab treatment, the proportions of patients maintaining antibody responses to pneumococcal, tetanus, and influenza antigens were not reduced. In a small group receiving influenza vaccine on study, antibody responses were frequently lower with belimumab, although titer levels were > 1:10 in all patients treated with 10 mg/kg and in the majority treated with 1 mg/kg. CONCLUSION: Treatment with belimumab did not affect the ability of patients with SLE to maintain antibody titers to previous pneumococcal, tetanus, and influenza immunizations. [ClinicalTrials.gov registration number NCT 00410384].

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.

Predicting outcomes of lupus nephritis with tubulointerstitial inflammation and scarring.

OBJECTIVE: In lupus nephritis, glomerular injury correlates poorly with progression to renal failure. While the tubulointerstitium is also commonly involved, the importance of such involvement is not well defined. Therefore, we developed a simple method to assess the prognostic utility of measuring tubulointerstitial inflammation (TI). METHODS: Sixty-eight systemic lupus erythematosus patients with lupus nephritis were enrolled. Tubulointerstitial lymphocytic infiltrates were quantitated both by anti-CD45 antibody staining and standard histochemical staining. Followup data were obtained and survival analysis was carried out to determine which histologic features were predictive of subsequent renal failure. RESULTS: By CD45 staining, TI was a common pathologic finding, with 72% of biopsies having moderate or severe involvement. The extent of TI correlated with serum creatinine, but not with double-stranded DNA antibodies, serum C3, or glomerular inflammation. TI severity, but not glomerular injury, identified patients at greater risk for renal failure (P = 0.02). A high National Institutes of Health (NIH) chronicity index also identified patients at risk for renal failure. However, when the glomerular and tubulointerstitial subcomponents of the NIH chronicity index were separated in a bivariate model, only tubulointerstitial chronicity provided prognostic information (hazard ratio [HR] 2.2, 95% confidence interval [95% CI] 1.3-3.6; P = 0.002 versus HR 1.0, 95% CI 0.7-1.5; P = 0.97 for glomerular chronicity). CONCLUSION: TI identifies lupus nephritis patients at greatest risk for progression to renal failure. The immunologic mechanisms underlying TI may provide novel targets for therapeutic intervention.