A classic T-cell phenotype in Systemic lupus erythematosus (SLE) is the downregulation and replacement of the CD3ζ chain that alters TCR signaling. However, genetic associations with SLE in the human CD247 locus that encodes CD3ζ are not well established and require replication in independent cohorts. Our aim was therefore to examine, localize and validate CD247-SLE association in a large multi-ethnic population. We typed 44 contiguous CD247 SNPs in 8 922 SLE patients and 8 077 controls from four ethnically distinct populations. The strongest associations were found in the Asian population (11 SNPs in intron 1, 4.99×10−4
Ehlers-Danlos syndrome (EDS) comprises a group of hereditary connective tissue disorders in which collagen synthesis and fibrogenesis are impaired. Patients with EDS type III have a bleeding tendency manifested by ecchymoses and haematomas. However, thrombotic events are rare in this entity. Herein, we present a 48-year-old Hispanic man with EDS type III who had recurrent cephalic vein thrombophlebitis and thrombosis, and brachial vein thrombosis. Tests for hypercoagulable disorders including antithrombin III activity, protein C activity, protein S activity, anticardiolipin antibodies, homocysteine levels, factor V Leiden mutation and prothrombin gene mutation were negative. The patient required long-term anticoagulation with warfarin. After 3 years follow-up, he did not present further thrombotic events. Clinicians should be aware that patients with EDS might be at risk for hypercoagulable disorders.
Cryoglobulinaemic vasculitis is characterised by immunoglobulin deposition at low temperatures. The most common manifestations are cutaneous involvement, arthralgias, Raynaud's phenomenon, peripheral neuropathy and renal disease. Myopathy is unusual and only a few cases have been reported. Here, we present a 31-year-old woman who developed progressive muscle weakness involving upper and lower extremities, dysphagia, paraesthesias and palpable purpura. Diagnostic studies revealed elevated creatine kinase, diffuse myopathic and sensorimotor axonal neuropathy on electromyography and nerve conduction studies, and inflammatory myopathy on muscle biospsy. Cryoglobulin levels were elevated on two occasions. She responded favourably to cyclophosphamide and high-dose corticosteroids. Cyclophosphamide was continued for 1 year followed by methotrexate. Prednisone was gradually tapered and discontinued 1 year later. She remained in clinical remission after 4 years of follow-up. This case suggests that cryoglobulinaemia should be considered in the differential diagnosis of a patient presenting with inflammatory myopathy.
Osteonecrosis is a relatively common comorbidity in systemic lupus erythematosus (SLE), but avascular necrosis in multiple sites is unusual. Multifocal osteonecrosis is defined as osteonecrotic lesions affecting three or more separate anatomic sites. We report a case of a 24-year-old woman diagnosed with SLE when she presented with mucocutaneous, haematological and mild renal manifestations. Initially, she was treated with prednisone and hydroxychloroquine and her condition remained stable. Two years later, she developed severe bilateral pretibial ulcers intractable to immunosuppressive therapy and broad-spectrum antibiotics. MRI of both legs disclosed osteonecrosis of the distal tibia, proximal tibia, distal fibula and talus bilaterally. She had elevated anticardiolipin antibodies for which she was treated with chronic anticoagulation resulting in complete healing of the leg ulcers and no further episodes of osteonecrosis. In addition to this case, we review the demographic, clinical and pharmacological features of 14 cases reported in the literature.
Rituximab is an anti-CD20 monoclonal antibody that has been used to treat several complications of systemic lupus erythematosus (SLE) including nephritis, cerebritis, and hematological disorders. Neutropenia is among the adverse events associated with rituximab; this usually occurs several weeks after therapy. However, early-onset neutropenia has been reported only in a few cases. Herein, we describe a 36-year-old Hispanic SLE woman who developed severe early-onset neutropenia (0.3 × 109/L) after the second weekly rituximab infusion (375 mg/m2 weekly × 4) given for nephritis and hemolytic anemia. She also had early-onset thrombocytopenia after rituximab therapy. Both hematological disorders resolved 12 days after the fourth and final dose. This case, together with few others, suggests that early-onset neutropenia may occur during rituximab therapy. Even though rituximab-induced neutropenia seems to be transient, it may predispose SLE patients to severe complications such as infections.
Euforia, a supplement containing a variety of natural ingredients, is widely used as an antioxidant and anti-inflammatory formula. It is not approved by the US Food and Drug Administration and its side effects are unknown. We report a 45-year-old woman with limited systemic sclerosis who presented with jaundice and marked elevation of serum transaminases. One month before, she started taking Euforia juice. A liver biopsy disclosed submassive hepatocellular necrosis with histopathological changes consistent with toxic hepatitis. The patient's symptoms resolved with cessation of Euforia. Six months later, she persisted with abnormal liver function tests, but these resolved 18 months after discontinuation of Euforia. The mechanism by which Euforia causes liver injury is unknown. Some ingredients contained in this supplement (green tea, Aloe vera, noni and goji) are linked to hepatic injury. To our knowledge, this is the first report of hepatotoxicity associated with Euforia.
Systemic lupus erythematosus (SLE; OMIM 152700) is characterised by the production of antibodies to nuclear antigens. We previously identified variants in complement receptor 2 (CR2/CD21) that were associated with decreased risk of SLE. This study aimed to identify the causal variant for this association.
Genotyped and imputed genetic variants spanning CR2 were assessed for association with SLE in 15 750 case-control subjects from four ancestral groups. Allele-specific functional effects of associated variants were determined using quantitative real-time PCR, quantitative flow cytometry, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP)-PCR.
The strongest association signal was detected at rs1876453 in intron 1 of CR2 (pmeta=4.2×10−4, OR 0.85), specifically when subjects were stratified based on the presence of dsDNA autoantibodies (case-control pmeta=7.6×10−7, OR 0.71; case-only pmeta=1.9×10−4, OR 0.75). Although allele-specific effects on B cell CR2 mRNA or protein levels were not identified, levels of complement receptor 1 (CR1/CD35) mRNA and protein were significantly higher on B cells of subjects harbouring the minor allele (p=0.0248 and p=0.0006, respectively). The minor allele altered the formation of several DNA protein complexes by EMSA, including one containing CCCTC-binding factor (CTCF), an effect that was confirmed by ChIP-PCR.
These data suggest that rs1876453 in CR2 has long-range effects on gene regulation that decrease susceptibility to lupus. Since the minor allele at rs1876453 is preferentially associated with reduced risk of the highly specific dsDNA autoantibodies that are present in preclinical, active and severe lupus, understanding its mechanisms will have important therapeutic implications.
Systemic Lupus Erythematosus; Autoantibodies; Gene Polymorphism; B cells
Exploiting genotyping, DNA sequencing, imputation and trans-ancestral mapping, we used Bayesian and frequentist approaches to model the IRF5–TNPO3 locus association, now implicated in two immunotherapies and seven autoimmune diseases. Specifically, in systemic lupus erythematosus (SLE), we resolved separate associations in the IRF5 promoter (all ancestries) and with an extended European haplotype. We captured 3230 IRF5–TNPO3 high-quality, common variants across 5 ethnicities in 8395 SLE cases and 7367 controls. The genetic effect from the IRF5 promoter can be explained by any one of four variants in 5.7 kb (P-valuemeta = 6 × 10−49; OR = 1.38–1.97). The second genetic effect spanned an 85.5-kb, 24-variant haplotype that included the genes IRF5 and TNPO3 (P-valuesEU = 10−27–10−32, OR = 1.7–1.81). Many variants at the IRF5 locus with previously assigned biological function are not members of either final credible set of potential causal variants identified herein. In addition to the known biologically functional variants, we demonstrated that the risk allele of rs4728142, a variant in the promoter among the lowest frequentist probability and highest Bayesian posterior probability, was correlated with IRF5 expression and differentially binds the transcription factor ZBTB3. Our analytical strategy provides a novel framework for future studies aimed at dissecting etiological genetic effects. Finally, both SLE elements of the statistical model appear to operate in Sjögren's syndrome and systemic sclerosis whereas only the IRF5–TNPO3 gene-spanning haplotype is associated with primary biliary cirrhosis, demonstrating the nuance of similarity and difference in autoimmune disease risk mechanisms at IRF5–TNPO3.
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
Patients with systemic lupus erythematosus (SLE) may develop thrombotic thrombocytopaenic purpura (TTP) or TTP-like illness manifested by microangiopathic haemolytic anaemia (MAHA) and thrombocytopaenia. The distinction between active SLE and TTP is difficult because these entities share similar clinical features. Drug-induced TTP caused by an immune-mediated reaction have been documented for several drugs. Herein, we report a middle-aged Hispanic woman with long-standing SLE, who developed a TTP-like illness characterised by MAHA and thrombocytopaenia after exposure to nitrofurantoin. The patient responded well to plasmapheresis and immunosuppressive therapy and has remained clinically stable after 18 months of follow-up. To our knowledge, this is the first case that reports the association between nitrofurantoin and a TTP-like presentation.
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
To determine the extent of mitochondrial DNA (mtDNA) damage in systemic lupus erythematosus (SLE) patients compared to healthy subjects and to determine the factors associated with mtDNA damage among SLE patients.
A cross-sectional study was performed in 86 SLE patients (per American College of Rheumatology classification criteria) and 86 healthy individuals matched for age and gender. Peripheral blood mononuclear cells (PBMCs) were collected from subjects to assess the relative amounts of mtDNA damage. Quantitative polymerase chain reaction assay was used to measure the frequency of mtDNA lesions and mtDNA abundance. Socioeconomic-demographic features, clinical manifestations, pharmacologic treatment, disease activity, and damage accrual were determined. Statistical analyses were performed using t test, pairwise correlation, and Pearson’s chi-square test (or Fisher’s exact test) as appropriate.
Among SLE patients, 93.0% were women. The mean (SD) age was 38.0 (10.4) years and the mean (SD) disease duration was 8.7 (7.5) years. SLE patients exhibited increased levels of mtDNA damage as shown by higher levels of mtDNA lesions and decreased mtDNA abundance as compared to healthy individuals. There was a negative correlation between disease damage and mtDNA abundance and a positive correlation between mtDNA lesions and disease duration. No association was found between disease activity and mtDNA damage.
PBMCs from SLE patients exhibited more mtDNA damage compared to healthy subjects. Higher levels of mtDNA damage were observed among SLE patients with major organ involvement and damage accrual. These results suggest that mtDNA damage have a potential role in the pathogenesis of SLE.
Systemic lupus erythematosus; disease activity; disease damage; mitochondrial DNA; mitochondrial dysfunction; oxidative stress
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
The aim of the study was to determine the prevalence and factors associated with bursitis/tendonitis disorders in Puerto Ricans with diabetes mellitus (DM). A cross-sectional study was performed in 202 adult Puerto Ricans (100 DM patients and 102 non-diabetic subjects). For each participant, a complete medical history and a musculoskeletal exam were systematically performed. Socio-demographic parameters, health-related behaviors, comorbidities, and pharmacotherapy were determined for all subjects. For DM patients, disease duration, glycemic control, and DM long-term complications were also examined. Multivariate logistic regression analyses were used to determine the factors associated with bursitis/tendonitis disorders. The mean (SD) age for DM patients and non-diabetic controls were 53.3 (12.9) and 50.0 (13.1) years; 64.0 and 64.7 % of DM patients and controls were females, respectively. Overall, the prevalence of bursitis/tendonitis was higher in DM patients than among non-diabetics (59.0 % vs. 29.4 %, p<0.01). In multivariate analyses, DM patients had 2.47 (95 % CI 1.05, 5.84) the odds of having bursitis/tendonitis as compared to non-diabetics. Specifically, DM patients had a higher frequency of flexor tenosynovitis, De Quervain’s tenosynovitis, lateral epicondylitis, medial epicondylitis, trochanteric bursitis, and anserine bursitis than non-diabetic subjects (p<0.05). Among DM patients, multivariate analyses showed that those with bursitis/tendonitis were more likely to be female [OR (95 % CI) 4.55 (1.42, 14.55)] and have peripheral vascular disease [OR (95 % CI) 8.48 (1.71, 41.93)]. In conclusion, bursitis/tendonitis disorders were common in this population of Hispanics with DM. Among DM patients, bursitis/tendonitis disorders were more frequent in women and those with long-term complications such as peripheral vascular disease.
Bursitis; Diabetes mellitus; Hispanics; Puerto Rico; Regional rheumatic pain disorders; Tendonitis
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 investigate whether the FcγRIIIa-66R/H/L polymorphism influences net effective receptor function and to assess if the FCGR3A combined genotypes formed by FcγRIIIa-66R/H/L and FcγRIIIa-176F/V as well as copy number variation (CNV) confer risk for development of SLE and lupus nephritis.
FcγRIIIa variants, expressed on A20 IIA1.6 cells, were used in flow cytometry-based human IgG binding assays. FCGR3A SNP and CNV genotypes were determined by Pyrosequencing methodology in a cohort of 1728 SLE patients and 2404 healthy controls.
The FcγRIIIa-66L/H/R (rs10127939) polymorphism influences ligand binding capacity in the context of the FcγRIIIa-176V (rs396991) allele. The low binding FcγRIIIa-176F allele was associated with SLE nephritis (p = 0.0609) in African Americans but not in European Americans (p > 0.10). Nephritis among African American SLE subjects was associated with FcγRIIIa low binding haplotypes containing the 66R/H/L and 176F variants (p = 0.03) and with low binding genotype combinations (p = 0.002). No association was observed in European American SLE patients. The distribution of FCGR3A CNV was not significantly different between controls and SLE patients with or without nephritis.
FcγRIIIa-66R/H/L influences ligand binding. The low binding haplotypes formed by 66R/H/L and 176F confer enhanced risk for lupus nephritis in African Americans. FCGR3A CNVs are not associated with SLE or SLE nephritis in either African Americans or European Americans.
To examine the factors associated with fibromyalgia syndrome (FMS) tender point count (TPC) in a group of Hispanic patients from Puerto Rico.
A cross-sectional study was performed in 144 FMS patients as determined using American College of Rheumatology [ACR] classification). Socio-demographic features, clinical manifestations, comorbidities, and pharmacologic agents were determined during the study visit. Tender points were assessed as described in the ACR classification for FMS. A t-test and one-way ANOVA test were used to examine the relationships between continuous, dichotomous, and nominal variables.
The mean (standard deviation, [SD]) age of the FMS patients in this study was 50.2 (9.9) years; 95.1% were females. The mean (SD) TPC was 15.0 (4.7). Dysmenorrhea, the sicca syndrome, subjective swelling, increased urinary frequency, shortness of breath, headache, constipation, paresthesia, cognitive dysfunction, arthralgia, tiredness, morning stiffness, depression, and anxiety were associated with higher TPC. No associations were seen between socio-demographic features and FMS pharmacologic therapies.
In this group of Puerto Ricans with FMS, TPC was associated with several FMS symptoms and comorbidities. This study suggests that TPC may be a simple and effective tool for assessing disease severity in FMS patients.
Fibromyalgia; tender point count; comorbidities; Hispanics
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