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.
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
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
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 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
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.
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.
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
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.
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