Alan W. Friedman

Systemic lupus erythematosus in three ethnic groups. VIII. Predictors of early mortality in the LUMINA cohort

Objective To determine the features associated with mortality in a multiethnic US cohort of patients with systemic lupus erythematosus (SLE) within 5 years of study onset. Methods Socioeconomic and demographic features (age, gender, ethnicity, marital status, education, occupation, poverty, and health-related behaviors [drinking, smoking, exercising]), clinical and immunologic features (disease duration, disease onset type, disease activity according to the Systemic Lupus Activity Measure [SLAM], disease damage according to the Systemic Lupus International Collaborating Clinics [SLICC] Damage Index [SDI], number of American College of Rheumatology criteria at diagnosis, organ system manifestations, fatigue and pain ratings, and medication usage and autoantibodies), immunogenetic features (HLA class II genotypes), and behavioral and psychosocial features (social support, illness-related behaviors, and helplessness), as obtained at enrollment into the study, were compared between survivors and deceased patients. Logistic regression analysis was used to determine significant independent risk factors for mortality. Results Within 5 years of study onset, 34 of 288 patients have died. Fourteen deaths could be directly attributed to SLE and 11 to infections. In 1 patient the cause of death could not be determined. In the remaining 8 patients the cause of death was neither infectious nor disease-related. There were 10 deaths among Hispanics, 18 among African Americans, and 6 among Caucasians (P< 0.05). Variables associated with mortality in the univariable analyses included poverty, less than full-time employment, difficulty in accessing health care, shorter disease duration, cardiovascular and renal involvement, higher serum creatinine levels and lower hematocrit values, higher SLAM and SDI scores, lower use of antimalarial drugs, and higher use of (some) immunosuppressants. Specific autoantibodies and class II HLA genotypes were not associated with mortality. Poverty and higher baseline SLAM and SDI scores were independently associated with mortality in the multivariable analyses. Conclusions Disease activity, disease damage, and poverty appear to be the most important determinants of mortality in this multiethnic US cohort of SLE patients. These results have applicability to the management of patients with SLE, a disease that more severely affects disadvantaged minority population groups.

Systemic lupus erythematosus in three ethnic groups: III A comparison of characteristics early in the natural history of the LUMINA cohort

Aim: To determine and contrast the socioeconomic-demographic and clinical features of patients with recent onset (5 y) systemic lupus erythematosus (SLE) from three ethnic groups, Hispanic, African-American and Caucasian (H, AA, C). Subjects and methods: SLE cases (American College of Rheumatology criteria) (incident (n ‘ 56), prevalent (n ‘ 173)), were enrolled in a longitudinal study at The University of Alabama at Birmingham, The University of Texas-Houston Health Science Center and The University of Texas Medical Branch at Galveston. Socioeconomic-demographic, clinical, immunological, behavioral and psychological data were obtained using validated instruments and standard laboratory techniques, and compared. Results: 70 H, 88 AA and 71 C SLE patients constitutethis cohort. H and AA patients were younger and of lower socioeconomic-demographic status. They also had evidence of more frequent organ system involvement (renal, cardiovascular), more auto-antibodies, more active disease (after adjusting for discrepant socioeconomic-demographic features), lower levels of social support and more abnormal illness-related behaviors (more in H than in AA). H also were more likely to have an abrupt disease onset; C were more likely to be on antimalarials but less likely to be on corticosteroids. H, AA, and C used health care resources comparably. They had similar levels of pain and physical and mental functioning after adjusting for age, disease duration, income, education, social support, illness-related behaviors, and Systemic Lupus Activity Measure or SLAM scores. Conclusions: H and AA patients have more active SLE, at an earlier age of onset, and a less favorable socioeconomic-demographic structure (worse among the H than AA) which predispose them to a less favorable natural history.

Systemic lupus erythematosus in three ethnic groups. IX. Differences in damage accrual.

OBJECTIVE To determine the factors predictive of damage in a multiethnic (Hispanic, African American, and Caucasian) LUMINA (lupus in minority populations, nature versus nurture) cohort of patients with systemic lupus erythematosus (SLE) with disease duration of < or =5 years at enrollment (T0). METHODS Variables (socioeconomic/demographic, clinical, immunologic, immunogenetic, behavioral, and psychological) were measured at T0 and annually thereafter. Disease damage was measured with the Systemic Lupus International Collaborating Clinics Damage Index (SDI), and disease activity was measured with the Systemic Lupus Activity Measure. The relationship between the different variables and the SDI at the last visit (TL) was examined (mean followup from diagnosis to TL 61 months; adjusted for disease duration). Poisson regression was used to identify the independent association between the different variables and SDI scores at TL. RESULTS Seventy-two Hispanics, 104 African Americans, and 82 Caucasians were included. One-half of patients had not accrued any damage. Caucasians had the lowest SDI scores at T0, and Hispanics had the highest scores at TL. Renal damage occurred more frequently among Hispanics and African Americans, while integument damage was more frequent among African Americans. Neuropsychiatric (20%), renal (16%), and ocular (15%) damage occurred most frequently among all patients. Independent predictors of SDI at TL were age, corticosteroid use (maximum dose at T0), number of American College of Rheumatology (ACR) criteria met, disease activity, and abnormal illness-related behaviors. Other variables were less consistently associated with damage accrual (poverty in African Americans, lack of HLA-DRB1*0301 in Hispanics, presence of HLA-DQB1*0201 and acute onset of SLE in Caucasians). CONCLUSION Damage in SLE occurs from the outset in some, but not all, patients; Hispanics accrue damage more rapidly. Disease factors (corticosteroid use, number of ACR criteria met, disease activity, and acute-onset type) are important, but age and abnormal illness-related behaviors also contribute to overall damage in SLE.

Systemic lupus erythematosus in three ethnic groups: I. The effects of HLA class II, C4, and CR1 alleles, socioeconomic factors, and ethnicity at disease onset

Objective To study the relative impact of immunogenetic versus socioeconomic factors on systemic lupus erythematosus (SLE) at disease onset/presentation. Methods Medical records regarding SLE onset/presentation were abstracted on 229 SLE patients who were enrolled in a prospective lupus outcome study. Patients were grouped in equivalent proportions of Caucasians, African Americans, and Hispanics. HLA-DRB1, DQA1, and DQB1 oligotyping, as well as C4 and CR1 allotyping, were carried out by standard methods. In addition to these genetic factors, data on ethnicity, age at SLE onset, monthly income, level of education, and home ownership were entered into stepwise logistic or stepwise multiple linear regression models as independent variables, and each specific clinical feature (neurologic, renal, and cardiovascular disease due to SLE), as well as the total Systemic Lupus Activity Measure (SLAM) score and physicians global assessment of disease activity at disease onset, were entered as dependent variables. Results HLA-DRB1*0301 (DR3), DRB1*1503 (DR2), and DRB1*08 (DR8) alleles were more frequently found in Caucasians, African Americans, and Hispanics, respectively. Hispanics were more likely to have cardiac and renal disease, as well as a higher physicians global assessment of disease activity. African Americans were more likely to have neurologic disease, renal disease, and a higher SLAM score. Those with less education had a higher SLAM score. Patients with HLA-DRB1*01 had less renal disease and a lower SLAM score. Those with C4A*3 alleles had a higher SLAM score and a higher physicians global assessment of disease activity. Conclusion Both genetic and socioeconomic determinants, as well as other factors associated with Hispanic and African-American ethnicity, affect the presentation of SLE.

Systemic lupus erythematosus in three ethnic groups. II. Features predictive of disease activity early in its course

Objective To determine the factors associated with disease activity in patients with recent-onset (≤5 years) systemic lupus erythematosus (SLE) who were of Hispanic, African-American, or Caucasian ethnicity. Methods Incident and prevalent cases of SLE, as defined by the American College of Rheumatology criteria for SLE, among the 3 ethnic groups were identified in Alabama (The University of Alabama at Birmingham) and Texas (The University of Texas-Houston Health Science Center and The University of Texas Medical Branch at Galveston). Variables from the sociodemographic, clinical, immunologic, immunogenetic, behavioral, and psychological domains were obtained using validated instruments. Disease activity was ascertained with the Systemic Lupus Activity Measure (SLAM). Stepwise domain regressions with SLAM score as the dependent variable were performed. Final ethnic-specific and overall regression models were obtained by entering variables that were retained in the domain regressions. Results SLAM scores at study entry were higher in the African Americans (mean ± SD 12.6 ± 6.9) and Hispanics (11.0 ± 6.2) than in the Caucasians (8.5 ± 3.7) (P ≤ 0.001). The final overall regression model (R2 = 28%) for higher SLAM score included the following variables: African-American ethnicity, lack of private health insurance, abrupt disease onset, presence of anti-Ro antibodies, absence of HLA-DRB1*0301, higher levels of helplessness, and abnormal illness-related behaviors. Conclusion Socioeconomic, immunologic, immunogenetic, behavioral, and psychological variables were all predictive of disease activity early in the course of SLE, irrespective of ethnic group. However, there remain ethnic group differences in disease activity that were not explained by these factors.

Systemic lupus erythematosus in three ethnic groups. VI: Factors associated with fatigue within 5 years of criteria diagnosis

Objective: To determine the frequency, degree and associated features of fatigue among Hispanic (H), African American (AA) and Caucasian (C) patients with recent onset (5 yr) systemic lupus erythematosus (SLE) at their baseline evaluation. Methods: H(n = 69), AA (n = 83) and C (n = 71) patients from the LUMINA (LUpus in MInority populations: NAture vs Nurture) cohort were studied. Fatigue [Fatigue Severity Scale (FSS)] was defined as present if FSS score 3.0. Variables from functional, clinical, sociodemographic, health behaviors, behavioral and psychological and immunogenetics domains were ascertained at study entry. Associations were examined using regression models. Results: Eighty-six percent (85.7%) of patients reported having fatigue (82.6% H; 85.5% AA; 88.7% C); median FSS score, 5.3. Factors from the psychological and clinical domains were primarily associated with FSS; immunogenetic (HLA Class II phenotypes) features were not. Increased fatigue was strongly associated with decreasing function, both physical and mental. Variables associated with significantly greater degree of fatigue at baseline in the multivariable stepwise model in order of decreasing additional partial R2 explained included: abnormal illnessrelated behaviors, older age, higher self-reported pain, greater degree of helplessness, greater disease activity, Caucasian race, and lacking health insurance (model R2 = 37%). Conclusions: Fatigue is one of the most prevalent clinical manifestations of SLE across all ethnic groups. The perception of fatigue severity in SLE may be multifactorial in origin, including psychosocial factors and disease activity. If these prove causal, knowledge of their contribution may suggest therapeutic and/or behavioral interventions, which could ameliorate this pervasive and often incapacitating symptom of SLE.

Clinical, immunogenetic and outcome features of Hispanic systemic lupus erythematosus patients of different ethnic ancestry

The aim of this study was to compareand contrastthe clinical, immunogeneticand outcome featuresof two subgroups of Hispanic patients with systemic lupus erythematosus (SLE), one from Northern Spain (Spaniards) and one of from the USA (Hispano-Americans: Hispanics primarily of Mexican ancestry (Amerindian and Spaniard backgrounds). Patients with SLE as per the American College of Rheumatology classification criteria, from two University-affiliated Hospitals (Universidad de Cantabria) and disease of five or less years in duration (n 28) and with four years of follow up constituted the Spaniard subgroup. Fifty-two patients of Hispano-American ancestry from the LUMINA (Lupus in Minority populations: Nature versus Nurture) cohort constituted the Hispano-American subgroup. Patients were studied using a similar protocol. In short, sociodemographic, clinical, immunological, immunogenetic and psychosocial and behavioral features were obtained at enrollmentinto the study(baselinevisit) and yearly thereafter.The relationshipbetweenthesevariables and disease activity at baseline and over time, as measured by the systemic lupus activity measure (SLAM) and disease damage, as measured by the SLICC (Systemic Lupus InternationalCollaborating Clinics) Damage Index(SDI) were determined.Variablesfound to be significant at P 0.10 were then entered into multivariablelinear regression models with disease activity at baselineand over time, and damage as the outcome measures. Patients of Hispano-American and Spaniard ethnicity had comparablesociodemographicfeaturesexceptforhome density, which was higheramong theHispano-Americans.HLA-DRB1*08 was associatedwith SLE among the Hispano-Americansbutnotamong the Spaniards.Hispano-Americanpatientshad more severediseaseas manifestedby more frequentclinical manifestations(renal and neurological), higher SLAM scores at baselineand over time and higher SDI scoresat the year4 visit(thatdespitethefactthat Hispano-Americanpatientshad overallshorterdisease durationthan the Spaniard patients). Hispano-Americanethnicity, youngerage at disease onset and the number of ACR criteria at baseline and over time were consistently associated with disease activity, whereas increasedhome density and the absence of HLA-DRB1*0301 were significant predictors only over time. Disease damagewas associatedwith diseaseactivityover time, the number of ACR criteriaat baseline, increasedhomedensityandthe presenceof HLA-DRB1*08. This is thefirst longitudinalstudy of SLE in two different Hispanic subgroups. Hispanics with a strong Amerindian background have a more seriousdisease than that observedin Spaniards.Genetic and socio-economicdifferencesbetween these two Hispanic subgroups probably account for these findings

Systemic lupus erythematosus in three ethnic groups: XV prevalence and correlates of fibromyalgia

The purpose of this study was to determine the prevalence and correlates of fibromyalgia (FM) in a prospective, multiethnic systemic lupus (SLE) cohort. A total of 266 SLE patients with disease duration of ≤5 years at study entry were evaluated longitudinallyfor the presence of FM (per ACR criteria). Sociodemographicfactors, behavioral=psychologicalvariables, clinical features, serologic factors (autoantibodies), and self-reportedfunctioning(MOS SF-36) were ascertainedin all patients. Subjects were evaluated at study entry and annually thereafter. The prevalence of FM was then calculated, as was the prevalence of FM-like manifestations (widespread pain with at least 6, but fewer than 11=18 tender points). Variables were evaluated for association with FM or FM-like manifestationsby univariate and stepwise logistic regressionanalyses.FM was present in 14 patients (5%; 9=92 Caucasians (C), 4=109 African Americans (AA), 1=65 Hispanics (H)) and FM=FM-like manifestationsin 35 (13%; 16 C, 9 AA, 10 H). There was no difference noted between those with and without FM with respect to gender, education level, income below poverty level, disease activity or damage. By stepwise logistic regression analyses, the strongest association with both FM and FM=FM-like manifestationswas a self-reported history of anxiety or affective disorder (P = 0.0237, OR = 4.6 and P = 0.0068, OR = 3.4, respectively). Caucasian ethnicity was strongly associated with FM (P = 0.0066, OR = 7.5) and African American ethnicity was negatively associated with FM=FM-like (P = 0.0204, OR = 0.3). Poorer self-reported physical functioning was associated with FM=FM-like (P = 0.0443, OR = 0.96). FM and FM-like manifestations correlate best with the presence of Caucasian ethnicity, concomitant anxiety or affective disorder, and to a lesser extent with poorer self-reported physical functioning. African American ethnicity is negatively associated with the combination of FM and FM-like manifestations. Clinical measures of disease activity, disease damage, specific organ dysfunction, sociodemographicfactors and serologic features are not correlated with FM in this early SLE cohort.

A Phase IIb Study of ABT‐494, a Selective JAK‐1 Inhibitor, in Patients With Rheumatoid Arthritis and an Inadequate Response to Anti–Tumor Necrosis Factor Therapy

To compare the efficacy and safety of ABT‐494, a novel selective JAK‐1 inhibitor, with placebo in patients with moderate‐to‐severe rheumatoid arthritis (RA) and an inadequate response or intolerance to at least 1 anti–tumor necrosis factor (anti‐TNF) agent.

A Phase 2b Study of ABT-494, a Selective JAK1 Inhibitor, in Patients With Rheumatoid Arthritis and an Inadequate Response to Anti-TNF Therapy.

To compare the efficacy and safety of ABT‐494, a novel selective JAK‐1 inhibitor, with placebo in patients with moderate‐to‐severe rheumatoid arthritis (RA) and an inadequate response or intolerance to at least 1 anti–tumor necrosis factor (anti‐TNF) agent.