Statins, which appear to have anti-inflammatory and immunomodulatory effects, may benefit patients with rheumatoid arthritis (RA). Our study sought to determine the association of statins use with disease activity and functional status in a group of patients with RA.
A cross-sectional study was performed in 209 Puerto Ricans with RA (per the 1987 classification criteria of the American College of Rheumatology). Demographic features, lifestyle-related behaviors, disease activity (per Disease Activity Score 28), comorbid conditions, functional status (per Health Assessment Questionnaire), pharmacologic therapy, and patients’ and physicians’ global assessments using visual analogue scales, were determined. Data were examined using univariate, bivariate, and multiple logistic regression analyses.
The mean (standard deviation [SD]) age of the study population at study visit was 56.8 (13.5) years (range: 24–86 years); 175 patients (83.7%) were women. The mean (SD) disease duration was 10.4 (9.5) years (range: 0.0–44.0 years). Thirty-two (15.3%) patients were using statins at study visit, and 36 (17.2%) had used statins in the past. In the multivariable analysis, the current use of statins was associated with higher functional status (odds ratio 0.42, 95% confidence interval 0.22–0.80) than was nonuse, after adjusting for age, disease duration, arterial hypertension, coronary artery disease, and dyslipidemia. No association between either current or past use of statins and disease activity was found.
In this group of RA patients, the current use of statins was associated with a higher functional status; conversely, no association was found between statins use and disease activity. However, larger and longitudinal studies are required to confirm these findings.
Rheumatoid arthritis; statins; disease activity; functional status; Puerto Ricans
The aim of this study was to determine the clinical outcome among
indigent patients with rheumatoid arthritis (RA) in Puerto Rico receiving their
healthcare in a managed care system, as compared to non-indigent patients
treated in fee-for-service settings. A cross-sectional study was conducted in
214 Puerto Ricans with RA (per American College of Rheumatology classification
criteria). Demographic features, health-related behaviors, cumulative clinical
manifestations, disease activity (per Disease Activity Score 28), comorbid
conditions, functional status (per Health Assessment Questionnaire, HAQ), and
pharmacologic profile were determined. Data were examined using univariable and
multivariable (logistic regression) analyses. The mean (standard deviation
[SD]) age of the study population was 56.6 (13.5) years; 180
(84.1%) were women. The mean (SD) disease duration was 10.8 (9.6) years.
Sixty-seven patients were treated in the managed care setting and 147 patients
received their healthcare in fee-for-service settings. In the multivariable
analyses RA patients treated in the managed care setting had more joint
deformities, extra-articular manifestations, arterial hypertension, type 2
diabetes mellitus, cardiovascular events, fibromyalgia syndrome, and poorer
functional status, while having a lower exposure to biologic agents than those
treated in fee-for-service settings. Efforts should be undertaken to curtail the
gap of health disparities among these Hispanic patients in order to improve
their long term outcomes.
Rheumatoid arthritis; medically-indigent patients; Hispanics; Puerto Ricans; healthcare; managed care system; fee-for-service system
Genome wide association studies have identified variants in PXK that confer risk for humoral autoimmune diseases, including systemic lupus erythematosus (SLE or lupus), rheumatoid arthritis and more recently systemic sclerosis. While PXK is involved in trafficking of epidermal growth factor Receptor (EGFR) in COS-7 cells, mechanisms linking PXK to lupus pathophysiology have remained undefined. In an effort to uncover the mechanism at this locus that increases lupus-risk, we undertook a fine-mapping analysis in a large multi-ancestral study of lupus patients and controls. We define a large (257kb) common haplotype marking a single causal variant that confers lupus risk detected only in European ancestral populations and spans the promoter through the 3′ UTR of PXK. The strongest association was found at rs6445972 with P < 4.62 × 10−10, OR 0.81 (0.75–0.86). Using stepwise logistic regression analysis, we demonstrate that one signal drives the genetic association in the region. Bayesian analysis confirms our results, identifying a 95% credible set consisting of 172 variants spanning 202 kb. Functionally, we found that PXK operates on the B-cell antigen receptor (BCR); we confirmed that PXK influenced the rate of BCR internalization. Furthermore, we demonstrate that individuals carrying the risk haplotype exhibited a decreased rate of BCR internalization, a process known to impact B cell survival and cell fate. Taken together, these data define a new candidate mechanism for the genetic association of variants around PXK with lupus risk and highlight the regulation of intracellular trafficking as a genetically regulated pathway mediating human autoimmunity.
lupus; PXK; fine-mapping; B cells; BCR
Thrombosis is a serious complication of systemic lupus erythematosus (SLE). Studies that have
investigated the genetics of thrombosis in SLE are limited. We undertook this study to assess the
association of previously implicated candidate genes, particularly Toll-like receptor (TLR) genes,
with pathogenesis of thrombosis.
We genotyped 3,587 SLE patients from 3 multiethnic populations for 77 single-nucleotide
polymorphisms (SNPs) in 10 genes, primarily in TLRs 2, 4, 7, and 9, and we also genotyped 64
ancestry-informative markers (AIMs). We first analyzed association with arterial and venous
thrombosis in the combined population via logistic regression, adjusting for top principal
components of the AIMs and other covariates. We also subjected an associated SNP, rs893629, to
meta-analysis (after stratification by ethnicity and study population) to confirm the association
and to test for study population or ethnicity effects.
In the combined analysis, the SNP rs893629 in the KIAA0922/TLR2 region was
significantly associated with arterial thrombosis (logistic P = 6.4 ×
10−5, false discovery rate P = 0.0044). Two additional SNPs in
TLR2 were also suggestive: rs1816702 (logistic P = 0.002) and
rs4235232 (logistic P = 0.009). In the meta-analysis by study population, the odds
ratio (OR) for arterial thrombosis with rs893629 was 2.44 (95% confidence interval
1.58–3.76), without evidence for heterogeneity (P = 0.78). By ethnicity, the
effect was most significant among African Americans (OR 2.42, P = 3.5 ×
10−4) and European Americans (OR 3.47, P = 0.024).
TLR2 gene variation is associated with thrombosis in SLE, particularly among
African Americans and European Americans. There was no evidence of association among Hispanics, and
results in Asian Americans were limited due to insufficient sample size. These results may help
elucidate the pathogenesis of this important clinical manifestation.
To examine the prevalence of isolated IgA anti-β2Glycoprotein I (anti-β2GPI) positivity and the association of these antibodies, and a subgroup that bind specifically to domain IV/V of β2GPI, with clinical manifestations of the Antiphospholipid Syndrome (APS) in three patients groups. The pathogenicity of IgA anti-β2GPI was also evaluated in a mouse model of thrombosis.
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-β2GPI titers and binding to domain IV/V of β2GPI were examined by enzyme-linked immunosorbent assay (ELISA). CD1 mice were inoculated with purified IgA anti- β2GPI antibodies, and surgical procedures and ELISAs were performed to evaluate thrombus development and tissue factor (TF) activity.
A total of 198 patients were found to be positive for IgA anti-β2GPI isotype, and 57 patients were positive exclusively for IgA anti-β2GPI 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-β2GPI positive serum samples reacted with domain IV/V of anti-β2GPI, and 77% of those had clinical features of APS. Isolated IgA anti-β2GPI positivity was associated with an increased risk for arterial thrombosis (p<0.001), venous thrombosis (p=0.015) and all thrombosis (p<0.001). The association between isolated IgA anti-β2GPI 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-β2GPI antibodies induced significantly larger thrombi and higher TF levels compared to controls.
Isolated IgA anti-β2GPI positive titers may identify additional patients with clinical features of APS. Testing for these antibodies when other antiphospholipid (aPL) tests are negative and APS is suspected is recommended. IgA anti-β2GPI antibodies directed to domain IV/V of β2GPI represent an important subgroup of clinically relevant antiphospholipids.
Although a higher prevalence of osteoarthritis (OA) has been reported among diabetes mellitus (DM) patients, inconsistencies and limitations of observational studies have precluded a conclusive association.
To evaluate the association of hand or knee OA with DM in a population of Hispanics from Puerto Rico.
A cross-sectional study was performed in 202 subjects (100 adult DM patients as per the National Diabetes Data Group Classification, and 102 non-diabetic subjects). OA of hand and knee was ascertained using the American College of Rheumatology classification criteria. Sociodemographic characteristics, health-related behaviors, comorbidities, pharmacotherapy and DM clinical manifestations were determined. Multivariable logistic regression was used to evaluate the association of DM with hand or knee OA, and to evaluate factors associated with hand or knee OA among DM patients.
The mean (standard deviation, SD) age for DM patients was 51.6 (13.1) years; 64.0% were females. The mean (SD) DM duration was 11.0 (10.4) years. The prevalence of OA in patients with DM and non-diabetics subjects was 49.0% and 26.5%, respectively (p<0.01). In the multivariable analysis, patients with DM had 2.18 the odds of having OA when compared to non-diabetic subjects (95% CI: 1.12–4.24). In a sub-analysis among DM patients, female patients were more likely to have hand or knee OA (OR [95% CI]: 5.06 [1.66–15.66]), whereas patients who did not use insulin alone for DM therapy were more likely to have OA (OR [95% CI]: 4.44 [1.22–16.12]).
In this population of Hispanics from Puerto Rico, DM patients were more likely to have OA of hands or knees than non-diabetic subjects. This association was retained in multivariable models accounting for established risk factors for OA. Among DM patients, females were at greater risk for OA, whereas the use of insulin was negatively associated.
diabetes mellitus; osteoarthritis; metabolic disorders; musculoskeletal disorders
To determine the clinical manifestations and disease damage associated with discoid rash in a large multiethnic systemic lupus erythematosus (SLE) cohort.
SLE patients (per ACR criteria), age ≥ 16 years, disease duration ≤ 10 years at enrollment, and defined ethnicity (African American, Hispanic or Caucasian), from a longitudinal cohort were studied. Socioeconomic-demographic features, clinical manifestations and disease damage [as per the Systemic Lupus International Collaborating Clinics Damage Index (SDI)] were determined. The association of DLE with clinical manifestations and disease damage was examined using multivariable logistic regression.
A total of 2,228 SLE patients were studied. The mean (standard deviation, SD) age at diagnosis was 34.3 (12.8) years and the mean (SD) disease duration was 7.9 (6.0) years; 91.8% were women. Discoid lupus was observed in 393 (17.6%) of patients with SLE. In the multivariable analysis, patients with discoid lupus were more likely to be smokers and of African-American ethnicity, and to have malar rash, photosensitivity, oral ulcers, leukopenia and vasculitis. DLE patients were less likely to be of Hispanic (from Texas) ethnicity, and to have arthritis, end-stage renal disease (ESRD), and antinuclear, anti-dsDNA and anti-phospholipid antibodies. Patients with DLE had more damage accrual, particularly chronic seizures, scarring alopecia, scarring of the skin, and skin ulcers.
In this cohort of SLE patients, discoid lupus was associated with several clinical features including serious manifestations such as vasculitis and chronic seizures.
discoid rash; systemic lupus erythematosus; disease damage
To determine the prevalence of systemic lupus erythematosus (SLE) and its associated comorbidities in patients from Puerto Rico using a database from a health insurance company.
The insurance claims submitted by physicians in 2003 to a health insurance company of Puerto Rico were examined. Of 552,733 insured people, 877 had a diagnosis of SLE (code 710.0) per the International Classification of Diseases, Ninth Revision (ICD-9). Demographic parameters and selected comorbidities were determined. The diagnosis of comorbities was ascertained using the ICD-9 code, the Current Procedural Terminology-4 (CPT-4) code (for disease specific procedures) and/or the Medi-Span Therapeutic Classification System (for disease specific pharmacologic treatment). Fisher exact test and Chi-square were used to evaluate differences between SLE patients groups.
The mean age was 42.0 ± 13 and the female to male ratio was 12.5:1. The overall prevalence of SLE was 159 per 100,000 individuals. The prevalence for females was 277 per 100,000 women and for males it was 25 per 100,000 men. The most common comorbidities were high blood pressure (33.7%), osteopenia/osteoporosis (22.2%), hypothyroidism (19.0%), diabetes mellitus (11.6%) and hypercholesterolemia (11.6%). Overall, high blood pressure, diabetes mellitus, hypercholesterolemia, and coronary artery disease were more prevalent in SLE patients older than 54 years. Osteopenia/osteoporosis was more prevalent in women than in men.
The prevalence of SLE in Puerto Rico is very high. High blood pressure, diabetes mellitus, hypercholesterolemia, hypothyroidism and osteopenia/osteoporosis are common comorbidities in these patients. Identification and management of these comorbidities are critical for optimal medical care to this population.
Systemic lupus erythematosus; prevalence; comorbidities; Puerto Rico
The clinical outcome and therapeutic response to immunosuppressive agents vary among patients with lupus nephritis of different ethnic populations. Thus, we evaluated the efficacy of two established treatment protocols for lupus nephritis (low-dose versus standard-dose cyclophosphamide) in Puerto Ricans with systemic lupus erythematosus (SLE).
A retrospective cohort of 49 adult patients with SLE treated with intravenous low or standard-dose cyclophosphamide for clinical or biopsy confirmed lupus nephritis was studied. Demographic parameters, clinical manifestations, autoantibodies and pharmacological treatments were determined prior to cyclophosphamide treatment. Renal parameters, disease activity, damage accrual and corticosteroid use were determined before and after treatment. Cyclophosphamide-associated adverse events were also examined. Univariable and bivariable analyses were used to evaluate group differences.
Thirty-nine SLE patients received the standard-dose treatment and ten patients the low-dose therapy. Prior to cyclophosphamide infusion, demographic parameters, clinical manifestations, autoantibodies profile, disease damage and pharmacologic treatments were similar in both groups. Disease activity was higher in the low-dose group. After cyclophosphamide therapy, significant improvement of renal parameters (increase in the glomerular filtration rate and decrease in hematuria, pyuria, urinary cellular casts, proteinuria and hypertension) were observed only for patients that received the standard-dose therapy. Disease activity and corticosteroids requirement decreased in both groups after treatment. No differences were observed for adverse events associated with cyclophosphamide.
The standard-dose cyclophosphamide therapy appears to be more effective, and similar in terms of drug safety, than the low-dose regime for lupus nephritis in Puerto Ricans with SLE.
systemic lupus erythematosus; lupus nephritis; cyclophosphamide; Hispanics; Puerto Ricans
The aims of this study were to determine the outcome and predictors of renal disease progression in Puerto Ricans with systemic lupus erythematosus (SLE) initially presenting mild renal involvement.
A retrospective cohort of 61 SLE patients (per American College of Rheumatology classification) with mild renal involvement was studied. Mild renal disease was defined as glomerular filtration rate (GFR) ≥ 90 ml/min in the presence of proteinuria (> 0.25g/day, but < 3.5 g/day), hematuria, and/or urinary cellular casts. Demographic parameters, clinical manifestations, serologic markers, comorbidities, pharmacologic treatments, disease activity and damage accrual were determined at onset of renal disease. Factors associated with renal disease progression were evaluated using recurrent event survival analysis.
Of 61 patients, 55(90.2%) were women. The mean [standard deviation (SD)] age at renal onset was 29(11.2) and the mean (SD) follow-up period was 5.1(3.4) years. Thirty-eight patients had a decline in GFR: Thirty-two had a mild decline (GFR = 60–89 ml/min), five developed moderate to severe renal insufficiency (GFR = 15–59 ml/min), and one evolved to end-stage renal disease (GFR< 15 ml/min). In the Cox model, low C4 levels and proteinuria > 0.5g/day were associated with an earlier decline in GFR.
The majority of SLE Puerto Rican patients initially presenting with mild renal involvement had a decrease in GFR after an average of five years of kidney disease, although most had a mild dysfunction. Low C4 levels and proteinuria were predictors of an earlier decline in GFR. The awareness of these factors may contribute to early identification of individuals at risk of renal deterioration.
systemic lupus erythematosus; lupus nephritis; proteinuria; hypocomplementemia; Puerto Ricans; Hispanics
Disease expression and outcomes in rheumatoid arthritis (RA) vary among different ethnic groups. There are limited data on the impact of age on disease severity and outcomes among Hispanics. Thus, we determined the demographic characteristics, clinical manifestations, comorbidities, pharmacologic profile, and functional status among Puerto Ricans with RA of different age groups.
A cross-sectional study was conducted in 214 Puerto Rican patients with RA (per American College of Rheumatology classification criteria). Demographic features, health-related behaviors, cumulative RA manifestations, treatment profiles, disease activity (Disease Activity Score 28), comorbid conditions, and functional status (Health Assessment Questionnaire) were determined at study visit. Three age groups were studied: <40, 40–59, and ≥ 60 years. Data were examined using univariable and multivariable (logistic regression) analyses.
The mean (SD) age of the study population was 56.5 (13.6) years with a mean disease duration (SD) of 10.8 (9.7) years; 180 patients (84.1%) were women. In the multivariable analyses, patients ≥ 60 years were more likely to have joint deformities, extra-articular manifestations, and comorbidities such as dyslipidemia, arterial hypertension, diabetes mellitus, vascular events, osteoarthritis, low back pain, and osteoporosis. In addition, older patients used corticosteroids more frequently. No differences were found for the use of disease-modifying anti-rheumatic drugs or biologic agents.
Puerto Rican RA patients ≥ 60 years present a severe type of disease having more joint damage, extra-articular manifestations, and comorbidities than younger patients. These disparities must be considered when establishing effective therapy for older RA patients.
Rheumatoid arthritis; outcome; Hispanics; Puerto Ricans
To characterize the clinical features of familial lupus, and determine its influence on damage accrual and survival using data from LUMINA, a longitudinal multiethnic US cohort.
Familial lupus was defined as patients with a first degree relative with SLE. Relative risks were estimated by logistic regression; odds ratios (OR) and their 95% confidence intervals (CI) were the measure of association for familial lupus. Hazard Ratios (HR) were calculated using Cox proportional hazard adjusted for potential confounders for damage and survival.
Thirty-two of 644 patients had familial and 612 had sporadic lupus; both groups were of comparable age (~ 36 years). Familial lupus patients were in decreasing order of frequency siblings, parents and children. In multivariable analyses, mucosal ulcers (OR=1.92, 95% CI 0.65–5.70), mitral valve prolapse (OR=1.74, 95% CI 0.50–6.10), cerebrovascular disease (OR=4.18, 95% CI 0.98–17.76) and oral contraceptive use (ever/never; OR=2.51, 95% CI 0.88–7.19) were more likely in familial lupus but a history of low platelet count (<150,000/mm3; OR=0.31, 95% CI 0.08–1.17) and pulmonary disease activity (OR=0.39, 95% CI 0.14–1.20) were less likely. However, none of these associations reached statistical significance. Familial lupus was not significantly associated with a shorter time to either damage accrual or death (HR=0.77, 95% CI 0.37–1.59, p = 0.4746 and HR=0.20, 95% CI 0.03–1.47, p = 0.2020, respectively).
Although some clinical differences were observed in patients with familial and sporadic lupus, familial lupus was not associated with a significantly greater disease burden (damage, survival) than sporadic lupus.
familial lupus; lupus; sporadic lupus; LUMINA; multiethnic cohort
To determine the factors associated with peripheral vascular damage in systemic lupus erythematosus (SLE) patients and its impact on survival from LUMINA, a longitudinal multiethnic cohort. Peripheral vascular damage was defined by the Systemic Lupus International Collaborating Clinics (SLICC) Damage Index (SDI). Factors associated with peripheral vascular damage were examined by univariable and multivariable logistic regression models and its impact on survival by a Cox multivariable regression. Thirty-four (5.3%) of 637 patients (90% women, mean [SD] age 36.5 [12.6] (16-87) years developed peripheral vascular damage. Age and the SDI (without peripheral vascular damage) were statistically significant (odds ratio [OR] =1.05, 95% confidence interval [CI] 1.01-1.08; p=0.0107 and OR=1.30, 95% CI 0.09-1.56; p=0.0043, respectively) in multivariable analyses. Azathioprine, warfarin and statins were also statistically significant, glucocorticoid use was borderline statistically significant (OR=1.03, 95% CI 0.10-1.06; p=0.0975). In the survival analysis, peripheral vascular damage was independenly associated with a diminished survival (Hazard Ratio =2.36; 95% CI 1.07-5.19; p=0.0334). In short, age was independently associated with peripheral vascular damage, but so was the presence of damage in others organs (ocular, neuropsychiatric, renal, cardiovascular, pulmonary, musculoskeletal and integument) and some medications (probably reflecting more severe disease). Peripheral vascular damage also negatively affected survival.
The objectives of the present study were (1) to clarify and quantify the relationship between age and disease duration with the rate of change in disease activity over time in patients with systemic lupus erythematosus (SLE) and (2) to explore other possible factors associated with this rate of change. To this end, SLE patients from LUMINA were studied if they had ≥3 visits in which disease activity (Systemic Lupus Activity Measure-Revised or SLAM-R) had been ascertained. Variables associated with the rate (slope) of change in disease activity (obtained by regressing the SLAM-R scores against the length of time from diagnosis to last visit) were examined by univariable and multivariable analyses. Five-hundred forty-two of the 632 patients had ≥3 SLAM-R scores. In multivariable analyses Caucasians exhibited the fastest decline in disease activity; Texan Hispanics exhibited the slowest, trailed by the African Americans. Longer disease duration and HLA-DRB1*1503 positivity were associated with a slower decline whereas a greater number of ACR criteria and abnormal laboratory parameters (white blood cell and platelet counts, hematocrit and serum creatinine) were associated with a faster decline. These findings complement existing knowledge on SLE disease activity and are potentially useful to clinicians managing these patients.
Lupus; disease activity; rate of change; ethnicity; cohort
In patients with systemic lupus erythematosus (SLE), hydroxychloroquine prevents disease flares and damage accrual and facilitates the response to mycophenolate mofetil in those with renal involvement. A study was undertaken to determine whether hydroxychloroquine also exerts a protective effect on survival.
Patients with SLE from the multiethnic LUMINA (LUpus in MInorities: NAture vs nurture) cohort were studied. A case‐control study was performed within the context of this cohort in which deceased patients (cases) were matched for disease duration (within 6 months) with alive patients (controls) in a proportion of 3:1. Survival was the outcome of interest. Propensity scores were derived by logistic regression to adjust for confounding by indication as patients with SLE with milder disease manifestations are more likely to be prescribed hydroxychloroquine. A conditional logistic regression model was used to estimate the risk of death and hydroxychloroquine use with and without the propensity score as the adjustment variable.
There were 608 patients, of whom 61 had died (cases). Hydroxychloroquine had a protective effect on survival (OR 0.128 (95% CI 0.054 to 0.301 for hydroxychloroquine alone and OR 0.319 (95% CI 0.118 to 0.864) after adding the propensity score). As expected, the propensity score itself was also protective.
Hydroxychloroquine, which overall is well tolerated by patients with SLE, has a protective effect on survival which is evident even after taking into consideration the factors associated with treatment decisions. This information is of importance to all clinicians involved in the care of patients with SLE.
To examine the predictors of the occurrence of hypertension in a large multiethnic US cohort.
Patients and methods
There were 614 patients with systemic lupus erythematoses (SLE; ⩾4 American College of Rheumatology revised criteria) with ⩽5 years of disease duration at entry into the cohort (T0) and of Hispanic (Texan or Puerto Rican), African–American or Caucasian ethnicity. T0 variables were compared between patients who did and did not develop hypertension (blood pressure ⩾140/90 mm Hg on at least two occasions and/or the use of antihypertensive drugs) after T0. Significant and clinically relevant variables were then examined by a stepwise logistic regression model.
A total of 379 patients without hypertension at T0 were included (patients who developed hypertension prior to SLE diagnosis (n = 126) or before T0 (n = 109) were excluded). Predictors of hypertension were African–American and Texan–Hispanic ethnicities, renal involvement and a higher body mass index.
Traditional cardiovascular risk factors, disease‐related factors and ethnicity play a role in the occurrence of hypertension in patients with SLE. Controlling renal involvement and optimising body weight may prevent the occurrence of hypertension.
The objective of this study was to determine the factors associated with the occurrence of arterial vascular events in a multiethnic systemic lupus erythematosus (SLE) cohort. The PROFILE cohort, comprised of SLE patients (n=1,333) of defined ethnicity from five different U.S. institutions, was studied to determine demographic, clinical and biological variables associated with vascular events. An arterial vascular event (first episode) was either a myocardial infarction, angina pectoris and/or a vascular procedure for myocardial infarction, stroke, claudication and/or evidence of gangrene. Patient characteristics were analyzed by univariable and multivariable Cox proportional hazards regression analyses. One-hundred twenty-three (9.8%) patients had at least one incident arterial event. Age at cohort enrollment (HR= 1.04, 95% CI 1.03-1.06), smoking (HR= 2.20, 95% CI 1.40-3.46), and the CRP2* C alleles (HR= 1.91, 95%CI 1.04-3.49) were associated with a shorter time-to-the occurrence of arterial vascular events. Some clinical manifestations of disease activity were associated with a shorter time-to-occurrence [psychosis (HR= 2.21, 95% CI 1.10-4.44), seizures (HR= 1.85, 95% CI 1.00-3.24) and anemia (HR= 1.83, 95% CI 1.02-3.31)], but others were not [arthritis (HR= 0.32, 95% CI 0.18-0.58)]. In conclusion, older patients, especially in the context of a predisposing environmental factor (smoking) and severe clinical manifestations, are at higher risk of having arterial vascular events. The genetic contribution of the variation at the CRP locus was not obscured by demographic or clinical variables. Awareness of these factors should lead to more effective management strategies of patients at risk for arterial vascular events.
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production and altered type I interferon expression. Genetic surveys and genome-wide association studies have identified more than 30 SLE susceptibility genes. One of these genes, TNIP1, encodes the ABIN1 protein. ABIN1 functions in the immune system by restricting the NF-κB signaling. In order to better understand the genetic factors that influence association with SLE in genes that regulate the NF-κB pathway, we analyzed a dense set of genetic markers spanning TNIP1 and TAX1BP1, as well as the TNIP1 homolog, TNIP2, in case-control sets of diverse ethnic origins.
We fine-mapped TNIP1, TNIP2, and TAX1BP1 in a total of 8372 SLE cases and 7492 healthy controls from European-ancestry, African-American, Hispanic, East Asian, and African-American Gullah populations. Levels of TNIP1 mRNA and ABIN1 protein were analyzed using quantitative RT-PCR and Western blotting, respectively, in EBV-transformed human B cell lines.
We found significant associations between genetic variants within TNIP1 and SLE but not in TNIP2 or TAX1BP1. After resequencing and imputation, we identified two independent risk haplotypes within TNIP1 in individuals of European-ancestry that were also present in African-American and Hispanic populations. These risk haplotypes produced lower levels of TNIP1 mRNA and ABIN1 protein suggesting they harbor hypomorphic functional variants that influence susceptibility to SLE by restricting ABIN1 expression.
Our results confirmed the association signals between SLE and TNIP1 variants in multiple populations and provide new insight into the mechanism by which TNIP1 variants may contribute to SLE pathogenesis.
To examine the utilization of health services and prescription patterns among patients with systemic lupus erythematosus (SLE) followed by primary care physicians and rheumatologists in Puerto Rico.
The insurance claims submitted by physicians to a health insurance company of Puerto Rico in 2003 were examined. The diagnosis of lupus was determined by using the International Classification of Diseases, Ninth Revision, code for SLE (710.0). Of 552,733 insured people, 665 SLE patients were seen by rheumatologists, and 92 were followed by primary care physicians. Demographic features, selected co-morbidities, healthcare utilization parameters, and prescription patterns were examined. Fisher exact test, χ2 test, and analysis of variances were used to evaluate differences between the study groups.
SLE patients followed by rheumatologists had osteopenia/osteoporosis diagnosed more frequently than did patients followed by primary care physicians. The frequency of high blood pressure, diabetes mellitus, hypercholesterolemia, coronary artery disease, and renal disease was similar for both groups. Rheumatologists were more likely to order erythrocyte sedimentation rate, anti-dsDNA antibodies, and serum complements. No differences were observed for office or emergency room visits, hospitalizations, and utilization of routine laboratory tests. Rheumatologists prescribed hydroxychloroquine more frequently than did primary care physicians. The use of nonsteroidal antiinflammatory drugs, cyclooxygenase-2 inhibitors, glucocorticoids, azathioprine, cyclophosphamide, and methotrexate was similar for both groups.
Overall, the utilization of health services and prescription patterns among SLE patients followed by primary care physicians and rheumatologists in Puerto Rico are similar. However, rheumatologists ordered SLE biomarkers of disease activity and prescribed hydroxychloroquine more frequently than did primary care physicians.
Systemic Lupus Erythematosus; Healthcare Utilization; Prescription Pattern; Puerto Rico
Immunoregulatory cytokine interleukin-10 (IL-10) is elevated in sera from patients with systemic lupus erythematosus (SLE) correlating with disease activity. The established association of IL10 with SLE and other autoimmune diseases led us to fine map causal variant(s) and to explore underlying mechanisms. We assessed 19 tag SNPs, covering the IL10 gene cluster including IL19, IL20 and IL24, for association with SLE in 15,533 case and control subjects from four ancestries. The previously reported IL10 variant, rs3024505 located at 1 kb downstream of IL10, exhibited the strongest association signal and was confirmed for association with SLE in European American (EA) (P = 2.7×10−8, OR = 1.30), but not in non-EA ancestries. SNP imputation conducted in EA dataset identified three additional SLE-associated SNPs tagged by rs3024505 (rs3122605, rs3024493 and rs3024495 located at 9.2 kb upstream, intron 3 and 4 of IL10, respectively), and SLE-risk alleles of these SNPs were dose-dependently associated with elevated levels of IL10 mRNA in PBMCs and circulating IL-10 protein in SLE patients and controls. Using nuclear extracts of peripheral blood cells from SLE patients for electrophoretic mobility shift assays, we identified specific binding of transcription factor Elk-1 to oligodeoxynucleotides containing the risk (G) allele of rs3122605, suggesting rs3122605 as the most likely causal variant regulating IL10 expression. Elk-1 is known to be activated by phosphorylation and nuclear localization to induce transcription. Of interest, phosphorylated Elk-1 (p-Elk-1) detected only in nuclear extracts of SLE PBMCs appeared to increase with disease activity. Co-expression levels of p-Elk-1 and IL-10 were elevated in SLE T, B cells and monocytes, associated with increased disease activity in SLE B cells, and were best downregulated by ERK inhibitor. Taken together, our data suggest that preferential binding of activated Elk-1 to the IL10 rs3122605-G allele upregulates IL10 expression and confers increased risk for SLE in European Americans.
Systemic lupus erythematosus (SLE), a debilitating autoimmune disease characterized by the production of pathogenic autoantibodies, has a strong genetic basis. Variants of the IL10 gene, which encodes cytokine interleukin-10 (IL-10) with known function of promoting B cell hyperactivity and autoantibody production, are associated with SLE and other autoimmune diseases, and serum IL-10 levels are elevated in SLE patients correlating with increased disease activity. In this study, to discover SLE-predisposing causal variant(s), we assessed variants within the genomic region containing IL10 and its gene family member IL19, IL20 and IL24 for association with SLE in case and control subjects from diverse ancestries. We identified SLE-associated SNP rs3122605 located at 9.2 kb upstream of IL10 as the most likely causal variant in subjects of European ancestry. The SLE-risk allele of rs3122605 was dose-dependently associated with elevated IL10 expression at both mRNA and protein levels in peripheral blood samples from SLE patients and controls, which could be explained, at least in part, by its preferential binding to Elk-1, a transcription factor activated in B cells during active disease of SLE patients. Elk-1-mediated IL-10 overexpression could be downregulated by inhibiting activation of mitogen-activated protein kinases, suggesting a potential therapeutic target for SLE.
The aims of this study were to examine the predictors of time-to-neuropsychiatric (NP) damage and its impact on mortality in 632 systemic lupus erythematosus (SLE) African American, Hispanic and Caucasian LUMINA patients, age ≥ 16 years and disease duration ≤ 5 years at baseline (T0). Time-to-NP damage and its impact on mortality were examined by Cox proportional hazards regressions. One-hundred eighty-five (29.3%) patients developed NP-damage over a mean (SD) disease duration of 5.6 (3.7) years. After adjusting for neuropsychiatric manifestations present, older age [Hazard ratio (HR)=1.02; 95% [Confidence interval (CI) 1.00–1.04)], Caucasian ethnicity (HR=1.87; 95% CI 1.22-2.87), disease activity over the disease course (HR=1.16; 95% CI 1.12–1.21), diabetes (HR=3.47; 95% CI 1.44–8.38) and abnormal illness-related behaviors (HR=1.05; 95% CI 1.02–1.08) were associated with a shorter time to NP-damage. Photosensitivity (HR=0.65; 95% CI 0.44–0.95), anemia (HR=0.56; 95% CI 0.31–0.98), Raynaud’s phenomenon (HR=0.49; 95% CI 0.34–0.72), a medium dose of prednisone (HR=0.56; 95% CI 0.35–0.92) and hydroxychloroquine use (HR=0.58; 95% CI 0.36–0.93) were associated with a longer time. NP-damage did not contribute to mortality. Older age, Caucasian ethnicity, disease activity and abnormal illness-related behaviors are associated with a shorter time-to-NP damage; hydroxychloroquine and a medium dose of prednisone with a longer time.
Protein tyrosine phosphatase non-receptor type 22 (PTPN22) is a negative regulator of T-cell activation associated with several autoimmune diseases, including systemic lupus erythematosus (SLE). Missense rs2476601 is associated with SLE in individuals with European ancestry. Since the rs2476601 risk allele frequency differs dramatically across ethnicities, we assessed robustness of PTPN22 association with SLE and its clinical sub-phenotypes across four ethnically diverse populations. Ten SNPs were genotyped in 8220 SLE cases and 7369 controls from in European-Americans (EA), African-Americans (AA), Asians (AS), and Hispanics (HS). We performed imputation-based association followed by conditional analysis to identify independent associations. Significantly associated SNPs were tested for association with SLE clinical sub-phenotypes, including autoantibody profiles. Multiple testing was accounted for by using false discovery rate. We successfully imputed and tested allelic association for 107 SNPs within the PTPN22 region and detected evidence of ethnic-specific associations from EA and HS. In EA, the strongest association was at rs2476601 (P = 4.7×10−9, OR = 1.40 (95% CI = 1.25–1.56)). Independent association with rs1217414 was also observed in EA, and both SNPs are correlated with increased European ancestry. For HS imputed intronic SNP, rs3765598, predicted to be a cis-eQTL, was associated (P = 0.007, OR = 0.79 and 95% CI = 0.67–0.94). No significant associations were observed in AA or AS. Case-only analysis using lupus-related clinical criteria revealed differences between EA SLE patients positive for moderate to high titers of IgG anti-cardiolipin (aCL IgG >20) versus negative aCL IgG at rs2476601 (P = 0.012, OR = 1.65). Association was reinforced when these cases were compared to controls (P = 2.7×10−5, OR = 2.11). Our results validate that rs2476601 is the most significantly associated SNP in individuals with European ancestry. Additionally, rs1217414 and rs3765598 may be associated with SLE. Further studies are required to confirm the involvement of rs2476601 with aCL IgG.
Little is known about the genetic etiology of systemic lupus erythematosus (SLE) in individuals of African ancestry, despite its higher prevalence and greater disease severity. Overproduction of nitric oxide (NO) and reactive oxygen species are implicated in the pathogenesis and severity of SLE, making NO synthases and other reactive intermediate related genes biological candidates for disease susceptibility. This study analyzed variation in reactive intermediate genes for association with SLE in two populations with African ancestry.
A total of 244 SNPs from 53 regions were analyzed in non-Gullah African Americans (AA; 1432 cases and 1687 controls) and the genetically more homogeneous Gullah of the Sea Islands of South Carolina (133 cases and 112 controls) and. Single-marker, haplotype, and two-locus interaction tests were computed for these populations.
The glutathione reductase gene GSR (rs2253409, P=0.0014, OR [95% CI]=1.26 [1.09–1.44]) was the most significant single-SNP association in AA. In the Gullah, the NADH dehydrogenase NDUFS4 (rs381575, P=0.0065, OR [95%CI]=2.10 [1.23–3.59]) and nitric oxide synthase gene NOS1 (rs561712, P=0.0072, OR [95%CI]=0.62 [0.44–0.88]) were most strongly associated with SLE. When both populations were analyzed together, GSR remained the most significant effect (rs2253409, P=0.00072, OR [95%CI]=1.26 [1.10–1.44]). Haplotype and two-locus interaction analyses also uncovered different loci in each population.
These results suggest distinct patterns of association with SLE in African-derived populations; specific loci may be more strongly associated within select population groups.
systemic lupus erythematosus; African Americans; genetic association studies; oxygen compounds; single nucleotide polymorphism
Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with significant immune system aberrations resulting from complex heritable genetics as well as environmental factors. TRAF6 is a candidate gene for SLE, which has a major role in several signaling pathways that are important for immunity and organ development.
Fifteen single-nucleotide polymorphisms (SNPs), across TRAF6 were evaluated in 7,490 SLE and 6,780 control subjects from different ancestries. Population-based case-control association analyses and meta-analyses were performed. P values, false discovery rate q values, and odds ratios with 95% confidence intervals were calculated.
Evidence of associations in multiple SNPs was detected. The best overall p values were obtained for SNPs rs5030437 and rs4755453 (p=7.85×10−5 and p=4.73×10−5, respectively) without significant heterogeneity among populations (p=0.67 and p=0.50 in Q-statistic). In addition, rs540386 previously reported to be associated with RA was found to be in LD with these two SNPs (r2= 0.95) and demonstrated evidence of association with SLE in the same direction (meta-analysis p=9.15×10−4, OR=0.89, 95%CI=0.83–0.95). Thrombocytopenia improved the overall results in different populations (meta-analysis p=1.99×10−6, OR=0.57, 95%CI=0.45–0.72, for rs5030470). Finally evidence of family based association in 34 African-American pedigrees with the presence of thrombocytopenia were detected in one available SNP rs5030437 with Z score magnitude of 2.28 (p=0.02) under a dominant model.
Our data indicate the presence of association of TRAF6 with SLE in agreement with the previous report of association with RA. These data provide further support for the involvement of TRAF6 in the pathogenesis of autoimmunity.
TRAF6; polymorphism; systemic lupus erythematosus