The goal of the present study was to estimate the risk ratio of herpes zoster among systemic lupus erythematosus patients after disease onset compared with a cohort of patients without systemic lupus erythematosus over a three-year period.
A nationwide population-based cohort study using the National Health Insurance Research Database identified 10,337 new cases of systemic lupus erythematosus as the study cohort. In addition, 62,022 patients without systemic lupus erythematosus, who were matched for age, gender, and date of systemic lupus erythematosus diagnosis, were used as the comparison cohort. These cohorts were followed-up for three years. A Cox proportional hazard regression was performed to estimate the risk ratio of herpes zoster, with adjustments for age, gender, level of insurance, urbanization level, geographic region, comorbid medical conditions, average daily dosage of corticosteroids, and the use of immune-modulation agents.
Compared to patients without systemic lupus erythematosus, the crude risk ratio and adjusted risk ratio of herpes zoster among systemic lupus erythematosus patients were 7.37 (95% confidence interval 6.75-8.04) and 2.45 (95% confidence interval 1.77-3.40), respectively. Stratified by gender, the adjusted risk ratio of herpes zoster was 2.10 (95% confidence interval 1.45-2.99) in women and 7.51 (95% confidence interval 2.89-19.52) in men. Stratified by age, the adjusted risk ratio peaked in systemic lupus erythematosus patients who were aged 18 to 24 years (risk ratio 8.78, 95% confidence interval 3.08-24.97).
Based on nationwide population-based data, there is an increased risk of herpes zoster in systemic lupus erythematosus patients compared with non-systemic lupus erythematosus patients, particularly among males and patients aged 18 to 24 years. Further research on the associated risk factors for herpes zoster in systemic lupus erythematosus patients is needed.
Herpes Zoster; Risk; Systemic Lupus Erythematosus; Population-Based Cohort Study; Database
The SLICC Damage Index (SDI) is a validated instrument for assessing organ damage in systemic lupus erythematosus (SLE). Trained physicians must complete it, limiting utility where this is impossible.
We developed and pilot-tested a self-assessed organ damage instrument, the Lupus Damage Index Questionnaire (LDIQ), in 37 SLE subjects and 7 physicians. After refinement, 569 English-speaking SLE subjects and 14 rheumatologists from 11 international SLE clinics participated in validation. Subjects and physicians completed instruments separately. We calculated sensitivity, specificity, Spearman correlations and agreement, using the SDI as gold standard. 605 SLE participants in the community-based National Data Bank for Rheumatic Diseases (NDB) study completed the LDIQ and we assessed correlations with outcome and disability measures.
Mean LDIQ score was 3.3 (0-16) and mean SDI score was 1.5 (0-9). LDIQ had a moderately high correlation with SDI (Spearman r=0.50, p<0.001). Specificities of individual LDIQ items were >80%, except for neuropathy. Sensitivities were variable and lowest for damage with <1% prevalence. Agreement between SDI and LDIQ was > 85% for all but neuropathy, reduced renal function, deforming arthritis and alopecia. In the NDB, LDIQ correlated well with comorbidity index (r=0.45), SF-36 physical component scale (0.43), Medical Research Council dyspnea scale (0.40), disability (0.37) and SLE Activity Questionnaire score (0.37).
The LDIQ’s metric properties are good compared to the SDI. It has construct validity and correlations with health assessments similar to the SDI. The LDIQ should allow expansion of SLE research. Its ultimate value will be determined in longitudinal studies.
systemic lupus erythematosus; questionnaire; damage; SLICC damage index; validation; self-assessed
To investigate if unemployment during an economic downturn is associated with mortality, even among men with markers of better health (higher cognitive function scores and qualifications), and to assess whether the associations vary by age at unemployment.
Longitudinal register-based cohort study.
Study entry was in 1990 and 2001 when Sweden was entering periods of significant economic contraction.
A representative sample of men from the general population (n=234 782) born between 1952 and 1956 who participated in military conscription examinations. Men in receipt of disability or sickness benefit at study entry were excluded.
Main outcome measure
Unemployment compared with employment in 1991 (ages 34–38 years) produced adjusted HRs (with 95% CIs) for all-cause mortality (3651 deaths) during follow-up to 2001 and after stratification by education of 2.35 (1.99 to 2.76) for compulsory education, 2.25 (1.97 to 2.58) for up to 3 years postcompulsory education and 1.90 (1.40 to 2.57) for more than 3 years postcompulsory education. When unemployment was compared with employment in 2001 (ages 45–49 years) with follow-up to 2010, the pattern of mortality risk (4271 deaths) stratified by education was reversed, producing adjusted HRs of 2.81 (2.47 to 3.21) for compulsory education, 2.87 (2.58 to 3.19) for up to 3 years postcompulsory education and 3.44 (2.78 to 4.25) for more than 3 years postcompulsory education. Interaction testing confirmed effect modification by age/period (p=0.003). The degree of gradient reversal was slightly less pronounced after stratification by cognitive function but produced a similar pattern of results (p=0.004).
Unemployment at older ages is associated with greater mortality risk than at younger ages, with the greatest relative increase in risk among men with markers of better health, suggesting the greater vulnerability of all older workers to unemployment-associated exposures.
Unemployment; Suicide; Mortality
Corticosteroids are the mainstay for treatment of systemic lupus erythematosus (SLE). The potential role of corticosteroid use on the pathogenesis of permanent organ damage requires appropriate adjustment for confounding by disease activity. We estimate the effect of corticosteroids (prednisone dose) on permanent organ damage among persons with SLE.
We identified 525 incident SLE patients in the Hopkins Lupus Cohort. At each visit, clinical activity indices, laboratory data, and treatment were recorded. The study population was followed from the month after the first visit until June 29 2006, irreversible organ damage, death, loss to follow-up, or receipt of pulse methylprednisolone therapy. We estimated the effect of cumulative average dose of prednisone on organ damage using a marginal structural model to adjust for time-dependent confounding by indication due to SLE disease activity.
Compared with non prednisone use, the hazard ratio (95% confidence interval) of organ damage for prednisone was 1.16 (0.59, 2.20) for cumulative average doses >0–180 mg/month, 1.50 (0.67, 3.39) for >180–360 mg/month, 1.64 (0.67, 4.06) for >360–540 mg/month, and 2.51 (1.02, 6.19) for >540 mg/month. In contrast, standard Cox regression models estimated higher hazard ratios at all dose levels.
Our results suggest that low doses of prednisone do not result in a substantially increased risk of irreversible organ damage.
causal modeling; marginal structural model; systemic lupus erythematosus; corticosteroid treatment; long-term prednisone therapy; permanent organ damage
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.
There have been a number of reviews on the association+ between unemployment and suicide, but none have investigated how this relationship is influenced by duration of unemployment.
A systematic review and meta-analysis was conducted of those studies that assessed duration of unemployment as a risk factor for suicide. Studies considered as eligible for inclusion were population-based cohort or case-control designs; population-based ecological designs, or hospital based clinical cohort or case-control designs published in the year 1980 or later.
The review identified 16 eligible studies, out of a possible 10,358 articles resulting from a search of four databases: PubMed, Web of Knowledge, Scopus and Proquest. While all 16 studies measured unemployment duration in different ways, a common finding was that longer duration of unemployment was related to greater risk of suicide and suicide attempt. A random effects meta-analysis on a subsample of six cohort studies indicated that the pooled relative risk of suicide in relation to average follow-up time after unemployment was 1.70 (95% CI 1.22 to 2.18). However, results also suggested a possible habituation effect to unemployment over time, with the greatest risk of suicide occurring within five years of unemployment compared to the employed population (RR = 2.50, 95% CI 1.83 to 3.17). Relative risk appeared to decline in studies of those unemployed between 12 and 16 years compared to those currently employed (RR = 1.21, 95% CI 1.10 to 1.33).
Findings suggest that long-term unemployment is associated with greater incidence of suicide. Results of the meta-analysis suggest that risk is greatest in the first five years, and persists at a lower but elevated level up to 16 years after unemployment. These findings are limited by the paucity of data on this topic.
Background: Youth unemployment is an increasing problem for societies around the world. Research has revealed negative health effects of unemployment, and this longitudinal register-based cohort study examined the relationship between unemployment and later sickness absence, disability pension and death among youth in Sweden. Method: The study group of 199 623 individuals comprised all immigrants born between 1968 and 1972 who immigrated before 1990 (25 607) and a random sample of native Swedes in the same age-range (174 016). The baseline year was 1992, and the follow-up period was from 1993 to 2007. Subjects with unemployment benefit in 1990–91, disability pension in 1990–92, severe disorders leading to hospitalization in 1990–92 and subjects who emigrated during follow-up were excluded. Results: Those who were unemployed in 1992 had elevated risk of ≥60 days of sickness absence (OR 1.02–1.49), disability pension (HR 1.08–1.62) and all except native Swedish women had elevated risk of death (HR 1.01–1.65) during follow-up compared with non-unemployed individuals. The risk of future sickness absence increased with the length of unemployment in 1992 (OR 1.06–1.54), and the risk of sickness absence increased over time. A larger part of the immigrant cohort was unemployed at baseline than native Swedes. Selection to unemployment by less healthy subjects may explain part of the association between unemployment and the studied outcomes. Conclusion: Unemployment at an early age may influence the future health of the individual. To a society it may lead to increased burdens on the welfare system and productivity loss for many years.
Systemic lupus erythematosus (SLE) features are commonly observed in patients with rheumatoid arthritis (RA). However, their frequency and clinical significance are uncertain. We examined the frequency of SLE features in RA and their impact on overall mortality.
We assembled a population-based incidence cohort of subjects aged ≥18 years first diagnosed with RA (1987 American College of Rheumatology [ACR] criteria) between 1955–95. Information regarding disease characteristics, therapy, comorbidities and SLE features (1982 ACR criteria) were collected from the complete inpatient and outpatient medical records. Cox regression models were used to estimate the mortality risk associated with lupus features.
The study population comprised 603 incident RA subjects (mean age 58 years, 73% female) with a mean follow-up time of 15 years. By 25 years after RA incidence, ≥4 SLE features were observed in 15.5% of the RA subjects. After adjustment for age and sex, occurrence of ≥4 SLE features was associated with increased overall mortality (hazard ratio [HR] 5.54, 95% confidence interval [CI] 3.59–8.53). With further adjustment for RA characteristics, therapy and comorbidities, the association weakened but remained statistically significant (HR: 2.56, 95% CI 1.60–4.08). After adjustment for age, sex, RA characteristics, therapy and comorbidities, thrombocytopenia (2.0, 95% CI: 1.2, 3.1) and proteinuria (1.8, 95% CI: 1.3, 2.6) were significantly associated with mortality.
SLE features were common in RA, given sufficient observation time. Subjects with RA who developed ≥4 SLE features had an increased risk of death. Proteinuria and thrombocytopenia were individually associated with an increased mortality risk.
Rheumatoid arthritis; systemic lupus erythematosus; mortality
To examine the predictors of time-to-seizure occurrence and their impact on damage accrual and mortality in LUMINA, a multiethnic (Hispanic, African American and Caucasian) cohort of patients with systemic lupus erythematosus.
Seizures were defined as per the American College of Rheumatology (ARC) nomenclature and case definitions for neuropsychiatric lupus syndromes. Factors associated with time-to-seizure occurrence occurring at or after diagnosis (TD) of systemic lupus erythematosus were examined by univariable and multivariable Cox proportional hazard regression analyses. The impact of seizures on damage accrual and mortality was also examined by multivariable analyses after adjusting for variables known to affect these outcomes.
A total of 600 patients were included in these analyses. Of them, 40 (6.7%) developed seizures at or after TD; by multivariable analyses, disease activity and younger age were independent predictors of a shorter time-to-seizure occurrence (HR = 1.10 and 1.04; 95% CI 1.04 to 1.15 and 1.00 to 1.08, p = 0.0004 and 0.0304, respectively) whereas mucocutaneous involvement (HR = 0.34, 95% CI 0.16 to 0.41, p = 0.0039) and hydroxychloroquine use (HR = 0.35, 95% CI 0.15 to 0.80, p = 0.0131) were independent predictors of a longer time-to-seizure occurrence. Seizures were an independent contributor to damage accrual but not to mortality.
Seizures tend to occur early in the course of systemic lupus erythematosus, and contribute to damage accrual. Younger age and disease activity are independent predictors of a shorter time-to-seizure occurrence; antimalarials appear to have a protective role in seizure occurrence.
Background: The survival rate in patients with systemic lupus erythematosus (SLE) has improved dramatically during the past four decades to 96.6% (five year) in the Erlangen cohort, but it is nearly three times as high as in an age and sex matched control population. Reasons for death are mainly cardiovascular diseases (37%) and infections (29%).
Objective: To find risk factors existing at disease onset for a severe outcome in the Erlangen cohort.
Patients and methods: By using a database of 338 patients with SLE from a single centre, documented at least one to 15 years and including Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) damage score data and index (SDI) and an activity score (European Consensus Lupus Activity Measurement (ECLAM)), a retrospective search was made for risk factors for a severe outcome like death, end stage renal disease (ESRD), and thromboembolic events (TE) in SLE. For this purpose, multivariable Cox regression models were analysed using the statistical package SPSS 10.0 for Windows.
Results: The following were defined as risk factors for death at disease onset: male sex (p<0.001, relative risk (RR)=3.5), age >40 at disease onset (p<0.0001, RR=19.9), nephritis (p<0.05, RR=1.6), a reduction of creatinine clearance (p<0.001, RR=1.8), heart disease (p=0.05, RR=1.5), and central nervous system (CNS) disease (p=0.06, RR=1.6). An increase in the SDI of two or more points from the first to the third year of disease was the worst prognostic factor (p<0.0001, RR=7.7). The existence of Ro or nRNP antibodies, or both, was protective (p<0.05, RR =0.1). A low C3 (p<0.01 RR=3.0) and splenomegaly (p<0.01 RR=2.7) at disease onset turned out to be risk factors for ESRD besides a nephritis. In patients with hypertension (p<0.05) and/or high titres of dsDNA antibodies (>70 U/l) (p<0.01) and/or a mean ECLAM score of 4 (p<0.01) in the course of disease, a prevalence of ESRD was recorded in 9% (p<0.05) and 10% (p<0.01), and 8% (p<0.01) v 4% in the whole group. Analysis of risk factors at disease onset for TE identified positive lupus anticoagulant (p=0.17, RR=1.6), cryoglobulins (p<0.05, RR=1.8), and nephritis (p=0.05, RR=1.4), in addition to an age >40 at disease onset.
Conclusions: A subgroup of patients in the Erlangen cohort with a typical clinical and serological phenotype at disease onset that is at high risk for a worse outcome was identified. Identification of these white patients at risk at disease onset will enable treatment to be intensified and thereby possibly prevent or better control late stage manifestations.
C-reactive protein (CRP) may play an anti-inflammatory role during the acute phase of inflammation, and is also used as a marker of inflammation associated with cardiovascular disease. In the present study, we investigated the association between high-sensitivity CRP (hsCRP) and systemic lupus erythematosus (SLE) manifestations, autoantibodies, and organ damage.
In this cross-sectional study, 610 SLE patients from a prospective cohort had more than one hsCRP measurement. Organ damage was assessed using the Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology (ACR) Damage Index. Multiple linear regression models were used to adjust for age, gender, ethnicity, disease duration, body mass index, education, disease activity, current prednisone dose, statin use, and estrogen use.
After adjusting for confounders, hsCRP was associated with myocarditis, cardiac murmur, interstitial pulmonary fibrosis, pulmonary hypertension, gastrointestinal lupus manifestations, and anemia. Anti-dsDNA antibodies and lupus anticoagulant were associated with hsCRP in unadjusted models, and these associations remained significant after adjustment for confounders. hsCRP levels were significantly higher in patients with pulmonary, musculoskeletal, and endocrine damage, and a total SLICC Damage Index score ≥1. After adjustment, hsCRP was associated with pulmonary, musculoskeletal, and total damage, but no longer with endocrine damage.
hsCRP is associated with a broad range of clinical features and organ damage in SLE, particularly in the pulmonary and musculoskeletal systems. This association holds true independent of sociodemographic, disease activity, and treatment factors, and may be useful to identify high-risk SLE patients who would benefit from additional screening and surveillance studies.
Cardiovascular risk factors; C-reactive protein; systemic lupus erythematosus; inflammation
To examine the clinical and genetic correlates of hemolytic anemia and its impact on damage accrual and mortality in systemic lupus erythematosus (SLE) patients.
SLE patients (American College of Rheumatology [ACR] criteria) of Hispanic (Texan or Puerto Rican), African American, and Caucasian ethnicity from the LUMINA (LUpus in MInorities, NAture versus nurture) cohort were studied. Hemolytic anemia was defined as anemia with reticulocytosis (ACR criterion). The association between degrees of hemolytic anemia and socioeconomic/demographic, clinical, pharmacologic, immunologic, psychological, and behavioral variables was examined by univariable and multivariable (proportional odds model) analyses. Genetic variables (FCGR and Fas/Fas ligand polymorphisms) were examined by 2 degrees of freedom test of association and Cochran-Armitage trend tests. The impact of hemolytic anemia on damage accrual and mortality was examined by multivariable linear and Cox regression analyses, respectively.
Of 628 patients studied, 90% were women, 19% were Texan Hispanic, 16% were Puerto Rican Hispanic, 37% were African American, and 28% were Caucasian. Sixty-five (10%) patients developed hemolytic anemia at some time during the disease course, 83% at or before diagnosis. Variables independently associated with degrees of hemolytic anemia were African American ethnicity, thrombocytopenia, and the use of azathioprine. Hemolytic anemia was associated with damage accrual after adjusting for variables known to affect this outcome; however, hemolytic anemia was not associated with mortality.
The association of hemolytic anemia with thrombocytopenia suggests a common mechanism in their pathophysiology. Hemolytic anemia is an early disease manifestation and is associated with African American ethnicity and the use of azathioprine; it appears to exert an impact on damage but not on mortality.
To determine the serum levels of interferon alpha in childhood-onset systemic lupus erythematosus patients, their first-degree relatives and healthy controls and to evaluate the associations between serum interferon alpha and disease activity, laboratory findings and treatment features.
We screened consecutive childhood-onset systemic lupus erythematosus patients in a longitudinal cohort at the pediatric rheumatology unit of the State University of Campinas between 2009 and 2010. All patients demonstrated disease onset before the age of 16. Disease status was assessed according to the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). Interferon alpha levels were measured using an enzyme-linked immunoabsorbent assay.
We included 57 childhood-onset systemic lupus erythematosus patients (mean age 17.33±4.50), 64 first-degree relatives (mean age 39.95±5.66), and 57 healthy (mean age 19.30±4.97) controls. Serum interferon alpha levels were significantly increased in childhood-onset systemic lupus erythematosus patients compared to their first-degree relatives and healthy controls. Interferon alpha levels were significantly increased in patients with positive dsDNA antibodies, patients with cutaneous vasculitis, patients with new malar rash and patients who were not receiving medication. Interferon alpha levels correlated with C3 levels and systemic lupus erythematosus Disease Activity Index scores. In addition, we observed an inverse correlation between patient age and interferon alpha levels.
Interferon alpha may play a role in the pathogenesis of childhood-onset systemic lupus erythematosus, especially in cutaneous manifestations and dsDNA antibody formation. The observation that interferon alpha levels are increased in patients who are not taking medication should be investigated in longitudinal studies to determine whether elevated interferon alpha levels may predict systemic lupus erythematosus flares.
Interferon alpha (IFN-α); SLEDAI; Childhood-onset; Systemic lupus erythematosus
To examine the risk factors for self‐reported work disability in patients from the LUpus in MInorities: NAture vs. Nurture cohort with systemic lupus erythematosus (SLE).
Patients with SLE of Hispanic (Texas and Puerto Rico), African American and Caucasian ethnicity were studied. Work disability was defined by patients' self‐report. Only patients known to be employed at the baseline visit were included. The probabilities of self‐reporting work disability over time were examined by the Kaplan–Meier method; differences between ethnic groups were examined by the log‐rank test. The relationship of baseline socioeconomic–demographic, clinical, behavioural and psychological features with work disability was examined by standard statistical tests. Variables with p⩽0.10 in these analyses were examined by logistic regression.
The rate of self‐reported work disability among the 273 patients studied was 19% at 5 years; it was numerically higher for the African Americans (25%) than for the Hispanics from Texas (19%) and the Caucasians (18%). The rate for the Hispanics from Puerto Rico was 7% at 2 years; 5‐year rates could not be estimated for this ethnic subgroup (shorter follow‐up in the cohort). In the regression analysis, age, male sex, poverty, total disease duration, disease activity and damage accrual were predictors of work disability.
The rate of work disability was 19% at 5 years. Patients with SLE with more severe disease and with lower socioeconomic status are at high risk of becoming disabled. The toll SLE imposes could possibly be reduced in patients at risk if, in addition to medical treatment, services needed to overcome their disadvantageous socioeconomic status are provided.
The gene coding for C-reactive protein (CRP) is located on chromosome 1q23.2, which falls within a linkage region thought to harbor a systemic lupus erythematosus (SLE) susceptibility gene. Recently, two SNPs in the CRP gene (+838, +2043) have been shown to be associated with CRP levels and/or SLE risk in a British family-based cohort. The current study was done to confirm the reported association in an independent population-based case-control cohort, and also to investigate the impact of three additional CRP tagSNPs (-861, -390, +90) on SLE risk and serum CRP levels.
DNA from 337 white women who met the ACR criteria for definite (n = 324) or probable (n = 13) SLE and 448 white female healthy controls was genotyped for five CRP tagSNPs (-861, -390, +90, +838, +2043). Genotyping was performed using PCR-RFLP, pyrosequencing or TaqMan assays. Serum CRP levels were measured using ELISA. Association studies were performed using the χ2 distribution, Z-test, Fisher's exact test and ANOVA. Haplotype analysis was performed using EH software and haplo.stats package in R 2.1.2.
While none of the SNPs were found to be associated with SLE risk individually, there was an association with the five-SNP haplotypes (p<0.000001). Three SNPs (-861, -390, +90) were found to significantly influence serum CRP level in SLE cases, both independently and as haplotypes.
Our data suggests that unique haplotype combinations in the CRP gene may modify the risk of developing SLE and influence circulating CRP levels.
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that has a significantly higher prevalence, morbidity and mortality in African Americans compared with Americans of European descent. The pathogenesis of lupus is unclear but appears to be a result of environmental factors interacting with a genetically susceptible host. Despite the high disease load of SLE in African Americans, there is the perception that lupus is relatively rare in Africa. This prevalence gradient suggests that comparative studies of related cohorts from the two continents may provide insight into the genetic/environmental interactions that result in the development of lupus. To define if a lupus gradient exists, we began a study of autoimmunity prevalence utilizing two unique cohorts. The first is the Gullah population of the Sea Islands of South Carolina, who are unique in their low genetic admixture and their known ancestral heritage. The second is the population of young women served by the West Africa Fistula Foundation in Bo, Sierra Leone. Anthropologic studies indicate a direct ancestral link between the Gullah population and Sierra Leoneans. Since it is impossible to perform an epidemiologic study of lupus in Sierra Leone at this time, we assessed the prevalence of lupus serum autoantibodies, serologic evidence of specific infections and levels of serum 25-OH vitamin D in young women in the two cohorts who have no known relatives with lupus. Our results indicate similar prevalence of serum antinuclear antibodies in the two cohorts, though there was a significantly increased prevalence of antiphospholipid and anti-Sm antibodies in the Sierra Leone cohort. Seropositivity to common viral infections was significantly higher in women from Sierra Leone, while serum 25-OH vitamin D levels were markedly lower in the Gullah population. These data suggest that the prevalence of autoimmunity is similar in the two populations, but that there are significant environmental differences that may impact progression to autoimmune disease. Further studies comparing these two cohorts is likely to provide important insight into the impact of environmental factors on development of lupus.
African American; lupus; prevalence gradient; vitamin D
To identify the prevalence of disability in a wide range of valued life activities (VLAs) among individuals with systemic lupus erythematosus (SLE), 1-year changes in such disability, and predictors of and changes in VLA disability.
Data were from 2 waves of a cohort of 829 individuals with SLE interviewed annually by telephone. VLA disability was assessed using a scale rating the difficulty of performing 21 activities. Scores were also calculated for subscales corresponding to obligatory, committed, and discretionary activities. Changes in VLA disability from baseline to 1-year followup were assessed. Sociodemographic and disease status measures were examined as predictors of and changes in VLA disability using multiple regression analyses.
Almost half of the subjects were unable to perform ≥1 VLA at baseline. Almost all (91%) reported ≥1 VLA affected by SLE. One-quarter of the subjects experienced a significant increase in the number of activities they were unable to perform; approximately half experienced significant increases in the number of activities affected and in difficulty scores. Proportions of individuals whose disability increased and whose disability decreased were roughly equivalent. Disease status measures accounted for 62–72% of the variation in VLA difficulty. More severe disease status was predictive of increases in VLA difficulty; few predictors of improvements were identified.
VLA disability was common, with more disability noted in committed and discretionary activities than in obligatory activities. Because VLA disability has been linked to psychological well-being in previous studies, identification of factors that may protect against such disability is important.
Tumid lupus erythematosus is a rare variant of chronic cutaneous lupus erythematosus that is characterized clinically by smooth, nonscarring, pink to violaceous papules or plaques without evidence of surface change. Histopathologic features include superficial and deep lymphocytic infiltration in a perivascular and periadnexal distribution, with dermal interstitial mucin deposition and focal or absent dermoepidermal junction involvement. These clinical and histopathologic features can be challenging to differentiate from other cutaneous diseases. This is particularly true because patients with tumid lupus erythematosus usually do not have other manifestations of systemic lupus erythematosus or cutaneous lupus erythematosus. We present two cases of tumid lupus erythematosus, one associated with concomitant systemic lupus erythematosus and the other occurring concurrently with discoid lupus erythematosus. Furthermore, we demonstrate the rare occurrence of a patient with tumid LE occurring below the waist at a photoprotected site.
tumid lupus erythematosus; systemic lupus erythematosus; discoid lupus erythematosus; chronic cutaneous lupus erythematosus
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
Systemic lupus erythematosus (SLE) is an autoimmune disease with heterogeneous manifestations including severe organ damage and vascular dysfunction leading to premature atherosclerosis. Interferon-alpha (IFN-α) has been proposed to have an important role in the development of lupus and lupus-related cardiovascular disease, partly by repression of IL-1 pathways leading to impairments in vascular repair induced by endothelial progenitor cells (EPCs) and circulating angiogenic cells (CACs). Counterintuitively, SLE patients also display transcriptional upregulation of the IL-1β/IL-18 processing machinery, the inflammasome. To understand this dichotomy and its impact on SLE-related cardiovascular disease, we examined cultures of human and murine control or lupus EPC/CACs to determine the role of the inflammasome in endothelial differentiation. We show that caspase-1 inhibition improves dysfunctional SLE EPC/CAC differentiation into mature endothelial cells and blocks IFN-α-mediated repression of this differentiation, implicating inflammasome activation as a crucial downstream pathway leading to aberrant vasculogenesis. Furthermore, serum IL-18 levels are elevatedin SLE and correlate with EPC/CAC dysfunction. Exogenous IL-18 inhibits endothelial differentiation in control EPC/CACs and neutralization of IL-18 in SLE EPC/CAC cultures restores their capacity to differentiate into mature endothelial cells, supporting a deleterious effect of IL-18 on vascular repair in vivo. Upregulation of the inflammasome machinery was operational in vivo, as evidenced by gene array analysis of lupus nephritis biopsies. Thus, the effects of IFN-α are complex and contribute to an elevated risk of cardiovascular disease by suppression of IL-1β pathways and by upregulation of the inflammasome machinery and potentiation of IL-18 activation.
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 other autoimmune diseases (AID) in black, Caucasian and South Asian patients with systemic lupus erythematosus (SLE) compared with the prevalence of these AID in the UK population, and to assess the impact of these additional AID on damage scores and mortality.
The prevalence and chronology of development of additional AID in SLE patients was determined by case note review. Comparisons were made with prevalence data for AID in the general UK population. The impact of additional AID on mortality and damage scores at up to 10 years was determined in the index cases (patients who developed another AID either in the same year or within 5 years of onset of SLE) compared with controls matched for sex, age, ethnicity and year of onset of SLE.
There was no significant difference in the total number of AID that developed in patients from each ethnic group but differences in the frequency of some AID were noted. Mortality and damage scores were worse at 5 years in the study cases than the controls, particularly in the peripheral vascular category.
Patients with SLE might develop other AID that could complicate management of SLE by having an adverse impact on damage scores and mortality.
Systemic lupus erythematosus is a complement-mediated autoimmune disease. While genetic deficiencies of classical pathway components lead to an increased risk of developing systemic lupus erythematosus, end organ damage is associated with complement activation and immune complex deposition. The role of classical pathway regulators in systemic lupus erythematosus is unknown. C4 binding protein (C4bp) is a major negative regulator of the classical pathway. In order to study the role of C4bp deficiency in an established murine model of lupus nephritis, mice with a targeted deletion in the gene encoding C4bp were backcrossed into the MRL/lpr genetic background. Compared with control MRL/lpr mice, C4bp knockout MLR/lpr mice had similar mortality and similar degrees of lymphoproliferation. There were no differences in the extent of proteinuria or renal inflammation. Staining for complement proteins and immunoglobulins in the kidneys of diseased mice revealed no significant strain differences. Moreover, there was no difference in autoantibody production or in levels of circulating immune complexes. In comparison with C57BL/6 mice, MRL/lpr mice had depressed C4 levels as early as 3 weeks of age. The absence of C4bp did not impact serum C4 levels or alter classical pathway hemolytic activity. Given that immune complex renal injury in the MRL/lpr mouse is independent of Fc receptors as well as the major negative regulator of the classical pathway, new mechanisms for immune-complex-mediated renal injury need to be considered.
Systemic lupus erythematosus (SLE) is a chronic multisystem genetically complex autoimmune disease characterised by the production of autoantibodies to nuclear and cellular antigens, tissue inflammation and organ damage. Genome-wide association studies have shown that variants within the major histocompatibility complex (MHC) region on chromosome 6 confer the greatest genetic risk for SLE in European and Chinese populations. However, the causal variants remain elusive due to tight linkage disequilibrium across disease-associated MHC haplotypes, the highly polymorphic nature of many MHC genes and the heterogeneity of the SLE phenotype.
A high-density case-control single nucleotide polymorphism (SNP) study of the MHC region was undertaken in SLE cohorts of Spanish and Filipino ancestry using a custom Illumina chip in order to fine-map association signals in these haplotypically diverse populations. In addition, comparative analyses were performed between these two datasets and a northern European UK SLE cohort. A total of 1433 cases and 1458 matched controls were examined.
Using this transancestral SNP mapping approach, novel independent loci were identified within the MHC region in UK, Spanish and Filipino patients with SLE with some evidence of interaction. These loci include HLA-DPB1, HLA-G and MSH5 which are independent of each other and HLA-DRB1 alleles. Furthermore, the established SLE-associated HLA-DRB1*15 signal was refined to an interval encompassing HLA-DRB1 and HLA-DQA1. Increased frequencies of MHC region risk alleles and haplotypes were found in the Filipino population compared with Europeans, suggesting that the greater disease burden in non-European SLE may be due in part to this phenomenon.
These data highlight the usefulness of mapping disease susceptibility loci using a transancestral approach, particularly in a region as complex as the MHC, and offer a springboard for further fine-mapping, resequencing and transcriptomic analysis.
The objective of this study is to examine the clinical features and outcomes of patients with systemic lupus erythematosus (SLE) whose disease began in adolescence [juvenile-onset SLE (jSLE)] compared with adult-onset patients [adult-onset SLE (aSLE)] from a large multiethnic cohort. Systemic lupus erythematosus patients of African-American, Caucasian, or Hispanic ethnicity and ≥1 year follow-up were studied in two groups: jSLE (diagnosed at ≤18 years); aSLE (diagnosed at 19–50 years; matched for gender and disease duration at enrolment). Sociodemographic data, SLE manifestations, disease activity, damage accrual, SLE-related hospitalizations or emergency room visits, drug utilization, mortality and psychosocial characteristics and quality of life were compared. Data were analysed by univariable and multivariable analyses. Seventy-nine patients were studied (31 jSLE, 48 aSLE); 90% were women. Mean (SD) total disease duration was 6.8 (2.7) years in jSLE and 5.6 (3.3) years in aSLE (p = 0.077). Mean age at cohort entry was 18.4 (1.8) and 33.9 (9.2) years in jSLE and aSLE respectively. By univariable analysis, jSLE patients were more commonly of African-American descent, were more likely to have renal and neurological involvements, and to accrue renal damage; jSLE patients had lower levels of helplessness and scored higher in the physical component measure of the SF-36 than aSLE patients. Renal involvement [OR = 1.549, 95% CI (1.397–15.856)] and neurological involvement [OR = 1.642, 95% CI (1.689–15.786)] were independently associated with jSLE by multivariable analysis. There was a larger proportion of African-Americans within the jSLE group. After adjusting for ethnicity and follow-up time, jSLE patients experienced more renal and neurological manifestations, with more renal damage. There was a two-fold higher mortality rate in the jSLE group.
juvenile-onset SLE; outcome