Gerald McGwin

Derivation and validation of the systemic lupus international collaborating clinics classification criteria for systemic lupus erythematosus

OBJECTIVE The Systemic Lupus International Collaborating Clinics (SLICC) group revised and validated the American College of Rheumatology (ACR) systemic lupus erythematosus (SLE) classification criteria in order to improve clinical relevance, meet stringent methodology requirements, and incorporate new knowledge regarding the immunology of SLE. METHODS The classification criteria were derived from a set of 702 expert-rated patient scenarios. Recursive partitioning was used to derive an initial rule that was simplified and refined based on SLICC physician consensus. The SLICC group validated the classification criteria in a new validation sample of 690 new expert-rated patient scenarios. RESULTS Seventeen criteria were identified. In the derivation set, the SLICC classification criteria resulted in fewer misclassifications compared with the current ACR classification criteria (49 versus 70; P = 0.0082) and had greater sensitivity (94% versus 86%; P < 0.0001) and equal specificity (92% versus 93%; P = 0.39). In the validation set, the SLICC classification criteria resulted in fewer misclassifications compared with the current ACR classification criteria (62 versus 74; P = 0.24) and had greater sensitivity (97% versus 83%; P < 0.0001) but lower specificity (84% versus 96%; P < 0.0001). CONCLUSION The new SLICC classification criteria performed well in a large set of patient scenarios rated by experts. According to the SLICC rule for the classification of SLE, the patient must satisfy at least 4 criteria, including at least one clinical criterion and one immunologic criterion OR the patient must have biopsy-proven lupus nephritis in the presence of antinuclear antibodies or anti-double-stranded DNA antibodies.

Systemic lupus erythematosus in three ethnic groups. XII. Risk factors for lupus nephritis after diagnosis

The purpose of this study was to determine the cumulative incidence of lupus nephritis (LN) and the factors predictive of its occurrencein a multiethnic systemic lupus erythematosus (SLE) cohort. We studied 353 SLE patients as de” ned by the American College of Rheumatology (ACR) criteria (65 Hispanics, 93 African-Americans and 91 Caucasians). First, we determined the cumulative incidence of LN in all patients. Next, we determined the predictors for LN in those with nephritis occurring after diagnosis. The dependent variable, LN, was de” ned by: (1) A renal biopsy demonstrating World Health Organization (WHO), class II–V histopathology; and/or (2) proteinuria≥ 0.5 g=24 h or 3 + proteinuria attributable to SLE; and/or (3) one of the following features also attributable to SLE and present on two or more visits, which were performed at least 6 months apart— proteinuria≥ 2 +, serum creatinine≥ 1.4 mg/dl, creatinine clearance ≤ 79 ml/min, 10 RBCs or WBCs per high power ” eld (hpf), oŗ 3 granular or cellular casts per hpf. Independent variables assessed at diagnosis, and if absent, at baseline, were from four domains: sociodemographic, clinical, immunologic and immunogenetic (including the complete antibody pro” le and MHC class II alleles), and health habits. Variables with P < 0.05 by chi square analyses were entered into domain-speci”c stepwise logistic regression analyses controlling for disease duration, with LN as the dependent variable. Signi” cant domain-speci”c regression variables (P ≤ 0.1) were then entered into an overall model. The cumulative incidence of LN was 54.3% in all patients, and 35.3% for those developing LN after diagnosis. LN after diagnosis occurred in 43.1% of 65 Hispanics, 50.5% of 93 African-Americans, and 14.3% of 91 Caucasians, P < 0.0001. The duration of follow-up for those with LN after diagnosis was 5.5§ 2.4 vs 4.0§ 2.9 years for those without LN. Hispanic (odds ratio (OR) = 2.71, 95% con” dence limits (CL) = 1.07–6.87, P < 0.04) and African-American ethnicities (OR = 3.13, 95% CL = 1.21–8.09, P < 0.02), not married or living together (OR = 3.45, 95% CL = 1.69–7.69, P < 0.0003), higher SLAM score (OR = 1.11, 95% CL = 1.02–1.19, P < 0.007), anti-dsDNA (OR = 3.14, 95% CL = 1.50–6.57, P < 0.0001) and anti-RNP (OR = 4.24, CL = 1.98–9.07, P < 0.0001) antibodies were shown to be signi” cant predictors of the occurrence of LN. Repeated analyses excluding the patients with missing HLA data showed that absence of HLA-DQB1*0201 was also a signi” cant predictor for the occurrence of LN (OR = 2.34, CL = 1.13–5.26, P < 0.04). In conclusion, LN occurred signi” cantly more often in Hispanics and African-Americans with SLE. Sociodemographic,clinical and immunologic/immunogenetic factors seem to be predictive of LN occurring after the diagnosis of SLE has been made.

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.

Baseline characteristics of a multiethnic lupus cohort: PROFILE

Purpose: To report the baseline characteristics of a US multi-ethnic, multi-regional, multi-institution cohort of patients with systemic lupus erythematosus (SLE) and how it was constituted. Methods: Patients with SLE per American college of Rheumatology (ACR) classification criteria, 16 years of age and older, with disease of 10 years or less, of Hispanic (H), African American (AA) or Caucasian (C) ethnicity and living in the geographic catchment areas of the participating institutions (the University of Alabama at Birmingham (UAB), Johns Hopkins University (JHU), The University of Texas-Houston Health Science Center (UTH) were eligible to enter the combined cohort (PROFILE, herein). Data from the individual SLE cohorts were pooled and the PROFILE cohort characteristics examined using descriptive statistics. Variables predictive of renal damage were then examined by logistic regression. Results: The PROFILE cohort constituted by 568 patients (H = 78, AA = 216, C = 260 (13 other ethnicities)) is predominantly female. Non-C had a greater number of ACR criteria, and of renal involvement. Among the two non-C groups, a higher proportion of H patients have developed overall renal damage, as well as decreased glomerular filtration rate. Other than Hispanic ethnicity (odds ratio, OR = 6.27, confidence limits, CL = 1.96–220.01), sustained hypertension (OR = 14.16, CL = 4.52–4.43) was a significant predictor of renal damage, whereas belonging to the JHU cohort was protective (OR = 0.18, CL = 0.05–0.63). Conclusions: We have constituted a large US multi-ethnic SLE cohort. Renal involvement was found to be more frequent among the non-C; within them, the H patients seem to be at higher risk for the occurrence of renal damage.

Effect of hydroxychloroquine treatment on pro-inflammatory cytokines and disease activity in SLE patients: data from LUMINA (LXXV), a multiethnic US cohort:

Objective: We sought to determine the effect of hydroxychloroquine therapy on the levels proinflammatory/prothrombotic markers and disease activity scores in patients with systemic lupus erythematosus (SLE) in a multiethnic, multi-center cohort (LUMINA). Methods: Plasma/serum samples from SLE patients (n = 35) were evaluated at baseline and after hydroxychloroquine treatment. Disease activity was assessed using SLAM-R scores. Interferon (IFN)-α2, interleukin (IL)-1β, IL-6, IL-8, inducible protein (IP)-10, monocyte chemotactic protein-1, tumor necrosis factor (TNF)-α and soluble CD40 ligand (sCD40L) levels were determined by a multiplex immunoassay. Anticardiolipin antibodies were evaluated using ELISA assays. Thirty-two frequency-matched plasma/serum samples from healthy donors were used as controls. Results: Levels of IL-6, IP-10, sCD40L, IFN-α and TNF-α were significantly elevated in SLE patients versus controls. There was a positive but moderate correlation between SLAM-R scores at baseline and levels of IFN-α (p = 0.0546). Hydroxychloroquine therapy resulted in a significant decrease in SLAM-R scores (p = 0.0157), and the decrease in SLAM-R after hydroxychloroquine therapy strongly correlated with decreases in IFN-α (p = 0.0087). Conclusions: Hydroxychloroquine therapy resulted in significant clinical improvement in SLE patients, which strongly correlated with reductions in IFN-α levels. This indicates an important role for the inhibition of endogenous TLR activation in the action of hydroxychloroquine in SLE and provides additional evidence for the importance of type I interferons in the pathogenesis of SLE. This study underscores the use of hydroxychloroquine in the treatment of SLE.

Reduction of vancomycin-resistant enterococcal infections by limitation of broad-spectrum cephalosporin use in a trauma and burn intensive care unit

Both vancomycin and third-generation cephalosporin use are believed to contribute to a rise in vancomycin-resistant enterococci (VRE) infections. In 1998, the largest number of VRE infections in our hospital occurred in the trauma/burn intensive care unit (TBICU), accounting for nearly 20% of hospital infections. In an attempt to control the VRE infection rate, antibiotic protocols for prophylaxis, empiric, and definitive therapy were initiated during the final quarter of 1998 to minimize cephalosporin use by the introduction of piperacillin/tazobactam. Therefore, we undertook a study of the VRE infection rate for the TBICU in relation to vancomycin, piperacillin/tazobactam, piperacillin, third-generation cephalosporin, and total cephalosporin use before and after efforts to limit cephalosporins. These data were compared to those in the medical and surgical intensive care units. During 1998, seven VRE infections occurred in the TBICU. Following initiation of antibiotic protocols, one case of VRE infection occurred in the subsequent month and no cases in the 17 months since. The decrease in the VRE infection rate corresponded with a significant increase in the use of piperacillin/tazobactam and a reduction in third-generation and total cephalosporin use. In contrast, cephalosporin use in the medical and surgical intensive care units remains significantly higher than in the TBICU, and neither unit has had a reduction in their VRE infection rates.

Long-term trends in mortality according to age among adult burn patients.

The purpose of this study was to evaluate differences in mortality among adult burn patients over a 25-year period according to age. All patients admitted to a regional burn center between 1973 and 1997 were divided into three age groups (18-34, 35-54, and 55 and older), and mortality rates were compared over time. Between 1973 and 1997, the proportion of patients in each age group remained consistent, as did the type of burns. The average total body surface area burned declined steadily from 31.6% in the 1970s to 18.2% in the late 1990s. The absolute change in mortality was small (7.7%), moderate (16.3%), and large (30.2%) in the young, middle-aged, and old, respectively. However, the relative change demonstrated the opposite pattern. The results of this study suggest that declines in mortality among adult burn patients have occurred across the age spectrum over the past 25 years.

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.

Value of isolated IgA anti-β2 -glycoprotein I positivity in the diagnosis of the antiphospholipid syndrome.

OBJECTIVE To examine the prevalence of isolated IgA anti-β2 -glycoprotein I (anti-β2 GPI) positivity and the association of these antibodies, and a subgroup that bind specifically to domain IV/V of β2 GPI, with clinical manifestations of the antiphospholipid syndrome (APS) in 3 patient groups and to evaluate the pathogenicity of IgA anti-β2 GPI in a mouse model of thrombosis. METHODS Patients with systemic lupus erythematosus (SLE) from a multiethnic, multicenter cohort (LUpus in MInorities, NAture versus nurture [LUMINA]) (n = 558), patients with SLE from the Hopkins Lupus Cohort (n = 215), and serum samples referred to the Antiphospholipid Standardization Laboratory (APLS) (n = 5,098) were evaluated. IgA anti-β2 GPI titers and binding to domain IV/V of β2 GPI were examined by enzyme-linked immunosorbent assay (ELISA). CD1 mice were inoculated with purified IgA anti-β2 GPI antibodies, and surgical procedures and ELISAs were performed to evaluate thrombus development and tissue factor (TF) activity. RESULTS A total of 198 patients were found to be positive for IgA anti-β2 GPI isotype, and 57 patients were positive exclusively for IgA anti-β2 GPI antibodies. Of these, 13 of 23 patients (56.5%) in the LUMINA cohort, 17 of 17 patients (100%) in the Hopkins cohort, and 10 of 17 patients (58.9%) referred to APLS had at least one APS-related clinical manifestation. Fifty-four percent of all the IgA anti-β2 GPI-positive serum samples reacted with domain IV/V of anti-β2 GPI, and 77% of those had clinical features of APS. Isolated IgA anti-β2 GPI positivity was associated with an increased risk of arterial thrombosis (P < 0.001), venous thrombosis (P = 0.015), and all thrombosis (P < 0.001). The association between isolated IgA anti-β2 GPI and arterial thrombosis (P = 0.0003) and all thrombosis (P = 0.0003) remained significant after adjusting for other risk factors for thrombosis. In vivo mouse studies demonstrated that IgA anti-β2 GPI antibodies induced significantly larger thrombi and higher TF levels compared to controls. CONCLUSION Isolated IgA anti-β2 GPI-positive titers may identify additional patients with clinical features of APS. Testing for these antibodies when other antiphospholipid tests are negative and APS is suspected is recommended. IgA anti-β2 GPI antibodies directed to domain IV/V of β2 GPI represent an important subgroup of clinically relevant antiphospholipids.