Systemic lupus erythematosus in a multiethnic US cohort: XXXIV. Deficient mannose‐binding lectin exon 1 polymorphisms are associated with cerebrovascular but not with other arterial thrombotic events

Objective

To study the association between deficient mannose‐binding lectin (MBL) genotypes and arterial thrombotic events in systemic lupus erythematosus (SLE).

Methods

Patients with SLE of Hispanic, African American, and Caucasian ethnicity from LUMINA (LUpus in MInorities, NAture versus nurture), a multiethnic, longitudinal study of outcome, were studied. Arterial thrombotic events (myocardial infarction, angina, coronary artery bypass graft surgery, stroke, claudication, gangrene, or tissue loss and/or peripheral arterial thrombosis) that occurred after diagnosis were recorded. Genotyping for MBL gene polymorphisms was performed and their distribution was compared between patients who did and did not have thrombotic events.

Results

There were 58 events (21 cardiovascular, 27 cerebrovascular, and 10 peripheral vascular) in 48 patients. Patients who had thrombotic events were older and were more likely to be smokers, to have more severe disease, and to have accrued more damage overall. Also, a larger proportion of these patients had C‐reactive protein values in the highest quintile of distribution. No significant difference in arterial thrombotic events was found in patients homozygous for MBL‐deficient alleles compared with others. Similar results were seen within ethnic groups. Caucasians who developed potential thrombotic events exhibited a higher frequency of MBL‐deficient alleles, but the difference was not statistically significant for all events together or for cardiovascular and cerebrovascular events combined. However, when only the cerebrovascular events were considered, the difference became statistically significant.

Conclusion

Age, smoking, and measures of activity and damage were associated with arterial thrombotic events in patients with SLE, but MBL‐deficient genotypes were not, with cerebrovascular events in Caucasians being the exception. The relationship between MBL‐variant alleles and arterial thrombotic events may exist only within select ethnic groups and event types.

     

Induction of endothelial cell apoptosis by heat‐shock protein 60–reactive antibodies from anti–endothelial cell autoantibody–positive systemic lupus erythematosus patients

Objective

To determine whether anti–endothelial cell autoantibodies (AECAs) from systemic lupus erythematosus (SLE) patients with the antiphospholipid syndrome are involved in the initial endothelial cell (EC) membrane perturbation effect that is postulated to provide a target for antiphospholipid antibody (aPL) binding and, hence, to trigger the thrombotic cascade. To identify the AECA antigenic target on ECs and to determine the mechanism whereby the EC membrane is disrupted.

Methods

AECAs from SLE patients were assayed for binding to ECs by flow cytometry. Positive AECAs were assayed by immunoblotting, and a consensus antigen was identified by mass spectrometry. This candidate antigen was tested in recombinant form for AECA recognition. AECAs were affinity‐purified on this antigen and incubated with ECs to determine their physiologic effects. Anti‐Hsp60 antibody titers were determined by enzyme‐linked immunosorbent assay. The relationship of anti‐Hsp60 status and lupus anticoagulant (LAC) status to thrombotic manifestations between disease onset and the last followup visit were analyzed.

Results

Most of the SLE sera (73%) possessed IgG that bound to the surface of ECs. These positive IgG shared reactivity against a 60‐kd EC surface polypeptide that was identified as human Hsp60. The presence of Hsp60 at the EC surface was established using anti‐Hsp60 antibodies from commercial sources or affinity‐purified from SLE sera that bound ECs. Incubation of ECs with these anti‐Hsp60 antibodies induced apoptosis in a time‐ and dose‐dependent manner, as determined by Hoechst 33342 dye staining of condensed nuclei and by annexin V binding to surface phosphatidylserine. Anti‐Hsp60 antibodies were not restricted to SLE patients, but were found in patients with other autoimmune diseases. However, anti‐Hsp60 antibodies were significantly associated with an increased frequency of thrombosis when present in combination with LAC in the SLE patients.

Conclusion

The presence of Hsp60 at the surface of ECs serves as a target for the anti‐Hsp60 antibodies in SLE sera. These anti‐Hsp60 antibodies bind to ECs and induce apoptosis, particularly phosphatidylserine exposure, thus providing a target for the binding of aPL and inducing the subsequent thrombotic cascade.

     

Association of autoantibodies to heat‐shock protein 60 with arterial vascular events in patients with antiphospholipid antibodies

Objective

Anti–heat shock protein 60 autoantibodies (anti‐Hsp60) are associated with cardiovascular disease and are known to affect endothelial cells in vitro, and we have recently shown that anti‐Hsp60 promote thrombosis in a murine model of arterial injury. Based on those findings, we undertook the present study to investigate the hypothesis that the presence of anti‐Hsp60, alone or in combination with other thrombogenic risk factors, is associated with an elevated risk of vascular events.

Methods

The study population was derived from 3 ongoing cohort studies: 2 independent systemic lupus erythematosus (SLE) registries and 1 cohort comprising SLE patients and non‐SLE patients. Data from a total of 402 participants were captured; 199 of these participants had had confirmed vascular events (arterial vascular events in 102, venous vascular events in 76, and both arterial and venous vascular events in 21). Anti‐Hsp60 were detected by enzyme‐linked immunoassay, and association with vascular events was assessed by regression analysis.

Results

Multiple regression analysis revealed that arterial vascular events were associated with male sex, age, and hypertension. Analyses of the vascular events according to their origin showed an association of anti‐Hsp60 with arterial vascular events (odds ratio 2.26 [95% confidence interval 1.13–4.52]), but not with venous vascular events. Anti‐Hsp60 increased the risk of arterial vascular events (odds ratio 5.54 [95% confidence interval 1.89–16.25]) in antiphospholipid antibody (aPL)–positive, but not aPL‐negative, individuals.

Conclusion

We demonstrate that anti‐Hsp60 are associated with an increased risk of arterial vascular events, but not venous vascular events, in aPL‐positive individuals. These data suggest that anti‐Hsp60 may serve as a useful biomarker to distinguish risk of arterial and venous vascular events in patients with aPL.

     

Antiphospholipid syndrome nephropathy in patients with systemic lupus erythematosus and antiphospholipid antibodies: Prevalence,clinical associations,and long‐term outcome

Objective

To evaluate the prevalence, clinical associations, and outcome of antiphospholipid syndrome (APS) nephropathy in patients with systemic lupus erythematosus (SLE) and antiphospholipid antibodies (aPL) and in SLE patients without aPL.

Methods

Kidney biopsy specimens obtained from 81 patients with aPL (18 of whom had APS) and 70 patients without aPL were retrospectively examined for the presence of APS nephropathy. Clinical and serologic data obtained at the time of kidney biopsy and during a mean followup of 7 years were recorded. In cases for which serial kidney biopsy specimens were available, the evolution of APS nephropathy was examined.

Results

APS nephropathy existed in 39.5% of patients with aPL, compared with only 4.3% of patients without aPL. APS nephropathy was associated with both lupus anticoagulant and anticardiolipin antibodies. Among aPL‐positive SLE patients, APS nephropathy was found in two‐thirds of those with APS and in one‐third of those without APS. A strong association between APS nephropathy and the presence of arterial thrombosis and livedo reticularis was noted. Patients with APS nephropathy had a higher frequency of hypertension and elevated serum creatinine levels at the time of kidney biopsy but did not have a higher frequency of renal insufficiency, end‐stage renal disease, or death at the end of followup. Serial kidney biopsy specimens were available from 11 patients and showed progression of APS nephropathy lesions. During followup, manifestations of APS (especially arterial thromboses) developed more frequently in the SLE/non‐APS patients with APS nephropathy than in those without APS nephropathy.

Conclusion

Among patients with SLE, APS nephropathy occurs almost exclusively in those with aPL, suggesting an important role of aPL in the pathogenesis of APS nephropathy. Patients with APS nephropathy develop hypertension, raised serum creatinine levels, and progression of histologic lesions, all of which are associated with a poor renal outcome. Manifestations of APS also tend to develop in these patients. APS nephropathy should be included in the APS classification criteria, and the use of appropriate anticoagulant therapy should be tested.

     

Anti–β2‐glycoprotein I antibodies in pediatric systemic lupus erythematosus and antiphospholipid syndrome

Objective

To determine whether serum β₂‐glycoprotein I antibody (anti‐β₂GPI) detection improves identification of pediatric subjects at risk for antiphospholipid syndrome (APS).

Methods

Serum antiphospholipid antibodies (aPL) were identified by anticardiolipin enzyme‐linked immunosorbent assay (ELISA), lupus anticoagulant assays, and syphilis screening in children with primary APS, systemic lupus erythematosus (SLE), or SLE plus APS. Anti‐β₂GPI level and isotype were determined by β₂GPI ELISA and correlated with clinical manifestations and other aPL assays.

Results

One hundred‐ten subjects under 22 years of age and of mixed ethnicity were evaluated. Fifty‐seven had SLE (including 14 with APS), 25 had primary APS, 16 had SLE‐like APS, 6 were healthy children with aPL detected incidentally, 4 had other rheumatic diseases and 2 had other conditions. Anti‐β₂GPI were detected in 48% of SLE subjects and did not improve aPL detection over standard tests. Anti‐β₂GPI were associated with stroke (P = 0.014), but not with other APS manifestations, and were rarely detected in primary APS. Among subjects with APS manifesting as chronic thrombocytopenia, anti‐β₂GPI distinguished subjects with SLE from those with primary APS.

Conclusions

With the exception of stroke, anti‐β₂GPI detection does not improve identification of pediatric APS over that of traditional aPL assays. Anti‐β₂GPI are rare in pediatric primary APS, but may predict evolution of chronic thrombocytopenia to SLE.

     

Systemic lupus erythematosus in a multiethnic US cohort: Clinical features,course, and outcome in patients with late‐onset disease

Objective

To examine the clinical differences and the type and extent of organ damage in late‐ versus early‐onset systemic lupus erythematosus (SLE).

Methods

A nested case–control study was performed in the context of LUMINA (LUpus in MInorities, NAture versus nurture), a large, longitudinal, multiethnic cohort. Patients who developed SLE at or after the age of 50 years were considered cases. Two controls (patients who developed SLE at age ≤49 years) per case, matched for sex and disease duration, were randomly chosen. Selected baseline socioeconomic/demographic, behavioral, and psychological features, self‐reported quality of life, and cumulative clinical data (clinical manifestations, laboratory data, disease activity, damage, and mortality) were compared between cases and controls. Multivariable analyses with late‐onset lupus, damage accrual, and mortality as dependent variables were then performed.

Results

Two hundred seventeen patients were studied. Of them, 73 were cases. Cases were more likely to have neurologic involvement, arterial thrombotic events, osteoporosis, and hypertriglyceridemia, while renal involvement and anti‐Sm antibodies were less frequent. Disease activity at baseline was lower among cases. Cases also exhibited more cardiovascular and ocular damage. Late‐onset lupus was an independent predictor of damage accrual (t‐test = 2.23, P = 0.028), any damage at last visit (odds ratio [OR] 23.32, 95% confidence interval [95% CI] 3.98–141.56) (P < 0.001), and mortality (OR 10.74, 95% CI 3.07–37.56) (P < 0.001).

Conclusion

Patients with late‐onset lupus exhibit distinct clinical features. Although disease activity tends to be lower in these patients, they tend to accrue more damage and experience higher mortality than patients with early‐onset lupus. These findings probably reflect the contribution exerted by other comorbid conditions in the overall impact of lupus in these patients.

     

Systemic lupus erythematosus in a multiethnic US cohort (LUMINA): XXIII. Baseline predictors of vascular events

Objective

To determine the baseline (time 0) risk factors associated with the subsequent occurrence of vascular events in a multiethnic US cohort (LUMINA [LUpus in MInorities: NAture versus nurture]) of patients with systemic lupus erythematosus (SLE).

Methods

Five hundred forty‐six LUMINA patients were assessed at time 0 for traditional and nontraditional (disease‐related) risk factors for vascular events. These were defined as 1) cardiovascular (myocardial infarction and/or definite or classic angina and/or the undergoing of a vascular procedure for myocardial infarction [coronary artery bypass graft]), 2) cerebrovascular (stroke), and 3) peripheral vascular (arterial claudication and/or gangrene or significant tissue loss and/or arterial thrombosis in peripheral arteries). The observation time (followup time in the cohort) was the interval between time 0 and the last visit. The unit of analysis was the patient and not each vascular event. Variables at time 0 and vascular events were examined by univariable and multivariable (logistic and Cox proportional hazards regression) analyses. Age, sex, ethnicity, followup time, and all known risk factors for the occurrence of vascular events were included in the model.

Results

Thirty‐four patients (6.2%) developed one or more vascular event after time 0. The overall median duration of followup in the cohort was 73.8 months (range 10.8–111.3 months). Vascular events (13 cardiovascular, 18 cerebrovascular, 5 peripheral vascular) occurred in 7 Hispanics from Texas (6.5%), 1 Hispanic from Puerto Rico (1.2%), 15 African Americans (7.5%), and 11 Caucasians (7.1%). The mean total number of traditional risk factors was significantly higher in patients who developed vascular events than in those who did not (7.1 versus 5.6). Independent predictors of vascular events were older age, current smoking status, longer followup time, elevated serum levels of C‐reactive protein (CRP), and the presence of any antiphospholipid antibody. The same variables were identified when time‐dependent analyses were performed, although azathioprine use was also found to be a contributing factor.

Conclusion

Smoking, previously not reported in SLE, emerged as a predictor of vascular events and should be strongly discouraged. Antiphospholipid antibodies and CRP support the role of inflammation and autoimmunity in the development of accelerated atherosclerosis in SLE. Ethnicity was not associated with vascular events in our patients.

     

Interferon‐regulated chemokines as biomarkers of systemic lupus erythematosus disease activity: A validation study

Objective

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by unpredictable flares of disease activity and irreversible damage to multiple organ systems. An earlier study showed that SLE patients carrying an interferon (IFN) gene expression signature in blood have elevated serum levels of IFN‐regulated chemokines. These chemokines were associated with more‐severe and active disease and showed promise as SLE disease activity biomarkers. This study was designed to validate IFN‐regulated chemokines as biomarkers of SLE disease activity in 267 SLE patients followed up longitudinally.

Methods

To validate the potential utility of serum chemokine levels as biomarkers of disease activity, we measured serum levels of CXCL10 (IFNγ‐inducible 10‐kd protein), CCL2 (monocyte chemotactic protein 1), and CCL19 (macrophage inflammatory protein 3β) in an independent cohort of 267 SLE patients followed up longitudinally over 1 year (1,166 total clinic visits).

Results

Serum chemokine levels correlated with lupus activity at the current visit (P = 2 × 10⁻¹⁰), rising at the time of SLE flare (P = 2 × 10⁻³) and decreasing as disease remitted (P = 1 × 10⁻³); they also performed better than the currently available laboratory tests. Chemokine levels measured at a single baseline visit in patients with a Systemic Lupus Erythematosus Disease Activity Index of ≤4 were predictive of lupus flare over the ensuing year (P = 1 × 10⁻⁴).

Conclusion

Monitoring serum chemokine levels in SLE may improve the assessment of current disease activity, the prediction of future disease flares, and the overall clinical decision‐making.

     

Influence of coping skills on health‐related quality of life in patients with systemic lupus erythematosus

Objective

To identify coping strategies used by patients with systemic lupus erythematosus (SLE), and to assess the influence of main clinical and coping variables on health‐related quality of life (HRQOL).

Methods

We administered the Coping Orientation to Problems Experienced and the Short Form 36 questionnaire to a group of 144 patients with SLE and a group of 129 healthy controls. At the time of the psychological assessment, all patients underwent a complete clinical and laboratory evaluation.

Results

SLE patients had higher scores in acceptance (P < 0.001) and turning to religion (P = 0.05) and lower scores in planning (P = 0.001), suppression of competing activities (P = 0.010), restraint coping (P = 0.031), focusing on and venting of emotion (P = 0.009), and strategies focused on problem (P = 0.012) compared with controls. By means of linear regression analysis, HRQOL in SLE patients seemed to be influenced positively by restraint coping and positive reinterpretation and growth, and negatively by focusing on and venting of emotion, behavioral disengagement, and mental disengagement. When clinical variables were added to the multivariate analysis for coping strategies, more significant regression models that included joint pain were obtained.

Conclusion

In facing stressful situations, patients with SLE tend to use coping skills that are generally adopted for events perceived as nonmodifiable. Strategies that show a passive attitude and joint pain seem to impair these patients' HRQOL.

     

Systemic lupus erythematosus in a multiethnic US cohort (LUMINA): XXI. Disease activity,damage accrual,and vascular events in pre‐ and postmenopausal women

Objective

To determine the differences in clinical manifestations, disease activity, damage accrual, and medication use in systemic lupus erythematosus (SLE) patients as a function of menopausal status at disease onset.

Methods

Women with SLE as per the criteria of the American College of Rheumatology, with disease duration of ≤5 years and of Hispanic (Texas and Puerto Rico ancestries), African American, and Caucasian ethnicity, from LUMINA (LUpus in MInorities, NAture versus nurture), a multiethnic, longitudinal cohort, were studied. Menopause at the time of disease onset was defined as self‐report of climacteric symptoms, and/or amenorrhea lasting >6 months, and/or oophorectomy, and/or increased follicle‐stimulating hormone values for reproductive‐age women, and/or treatment with hormone replacement therapy. Patients were divided into premenopausal and postmenopausal categories. Socioeconomic status, cumulative clinical manifestations, disease activity (at study entry or time 0, last visit, and over time), as measured by the Systemic Lupus Activity Measure, and damage accrual, as measured by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index (at time 0 and at last visit) were compared between the 2 groups of women. Multivariable models were then examined making adjustments for all possible known confounders. Dependent variables in the models were renal involvement, damage accrual, arterial vascular events, and venous thrombosis.

Results

Five hundred eighteen women from the LUMINA cohort were included; 436 (84.2%) were premenopausal and 82 (15.8%) were postmenopausal. Disease onset after menopause was more common among Caucasians. Renal involvement was more common in premenopausal women, whereas vascular arterial events were more frequent in postmenopausal women. All other disease manifestations, as well as disease activity, were comparable between both groups. The presence of damage accrual at time 0 and study end was more frequent in postmenopausal women. Age, rather than menopausal status, independently contributed to damage accrual, renal involvement, and vascular arterial events in these women.

Conclusion

A hypoestrogenemic state secondary to menopause appears not to be protective against disease activity and damage accrual. Age rather than menopausal status is a strong independent predictor of damage accrual and of vascular events in women with lupus.

     

Association of increased interferon‐inducible gene expression with disease activity and lupus nephritis in patients with systemic lupus erythematosus

Objective

To study 5 type I interferon (IFN)–inducible genes (LY6E, OAS1, OASL, MX1, and ISG15) in patients with systemic lupus erythematosus (SLE) and to correlate expression levels with disease activity and/or clinical manifestations.

Methods

Peripheral blood cells were obtained from 48 SLE patients, 48 normal controls, and 22 rheumatic disease controls, and total RNA was extracted and reverse transcribed into complementary DNA. Gene expression levels were measured by real‐time polymerase chain reaction, standardized to a housekeeping gene, and summed to an IFN score. Disease activity was determined by the Safety of Estrogens in Lupus Erythematosus: National Assessment–Systemic Lupus Erythematosus Disease Activity Index (SELENA‐SLEDAI) composite.

Results

Each gene was highly expressed in SLE patients compared with normal controls (P ≤ 0.0003) or disease controls (P ≤ 0.0008 except for MX1). IFN scores were positively associated with the SELENA‐SLEDAI instrument score (P = 0.001), the SELENA‐SLEDAI flare score (P = 0.03), and the physician's global assessment score (P = 0.005). Compared with patients without nephritis, lupus nephritis patients had higher IFN scores (overall P < 0.0001), especially during active renal disease. IFN scores were weakly associated with neurologic manifestations. Elevated IFN scores were positively associated with the current presence of anti–double‐stranded DNA (anti‐dsDNA) antibodies (P = 0.007) or hypocomplementemia (P = 0.007). LY6E expression levels distinguished active from inactive lupus nephritis (P = 0.02) and were positively associated with proteinuria (P = 0.009).

Conclusion

The 5 IFN‐inducible genes were highly expressed in SLE patients, and increased levels were correlated with disease activity defined by several methods. IFN scores, or LY6E levels, were elevated in lupus nephritis patients, especially during active renal disease, and in patients with anti‐dsDNA antibody positivity and hypocomplementemia. IFN scores, or LY6E levels, may be useful as a biomarker for lupus nephritis therapy.

     

Systemic lupus erythematosus in a multiethnic US cohort (LUMINA). XXV. Smoking, older age, disease activity, lupus anticoagulant, and glucocorticoid dose as risk factors for the occurrence of venous thrombosis in lupus patients

OBJECTIVE: Venous thrombosis is a relatively frequent and serious complication in systemic lupus erythematosus (SLE) that has been associated with the presence of antiphospholipid antibodies (aPL). However, venous thrombotic events can also be seen in patients without aPL, and only a few patients with aPL develop venous thrombosis. This study was carried out to ascertain other factors contributing to the development of venous thrombosis in SLE. METHODS: Patients with SLE, ages > or = 16 years with < or = 5 years disease duration and of Hispanic, African American, or Caucasian ethnicity, from LUMINA (LUpus in MInorities, NAture versus nurture), a multiethnic, longitudinal study of outcome, were studied. Selected socioeconomic/demographic, clinical, laboratory, and treatment-exposure variables were compared between patients who developed and those who did not develop venous thrombotic events. Significant and clinically relevant variables were then entered into different multivariable models (Cox proportional hazards and unconditional stepwise logistic regression) to identify independent risk factors associated with the primary outcome. In another model, only patients who developed an event after enrollment (time 0) in the cohort were included. RESULTS: Of 570 LUMINA patients, 51 developed at least 1 venous thrombotic event after SLE diagnosis. In univariable analyses, smoking (P = 0.020), shorter disease duration at time 0 (P = 0.017), serum levels of total cholesterol, low-density lipoprotein, and triglycerides (all P < 0.0001), and presence of lupus anticoagulant (LAC) (P = 0.045) were associated with venous thrombotic events. Survival analyses showed a time-dependent significant association of the primary outcome with smoking (P = 0.008) and a borderline significant association with the presence of LAC (P = 0.070). Multivariable models showed an independent association with smoking, age at time 0, disease activity over time, LAC, mean dose of glucocorticoids, and shorter disease duration at time 0. CONCLUSION: Venous thrombotic events occur early in the course of SLE. Our data confirm the association between LAC and venous thrombotic events. Smoking, shorter disease duration, older age, disease activity over time, and higher mean daily glucocorticoid dose were identified as additional risk factors for the development of this vascular complication. These findings may have implications for the management of patients with SLE.     

The sense of smell in systemic lupus erythematosus

Objective

To assess the olfactory functions in systemic lupus erythematosus (SLE) patients compared with age‐ and sex‐matched healthy controls, and to examine the association between the sense of smell and disease activity and central nervous system (CNS) involvement.

Methods

Olfactory functions in 50 SLE patients and 50 age‐ and sex‐matched controls were evaluated using the Sniffin' Sticks test, the 3 stages of which are threshold, discrimination, and identification (TDI) of different odors. TDI scores were analyzed according to SLE disease activity and CNS involvement.

Results

In both the SLE and control groups, smell deficit correlated with male sex and older age. A decrease in the sense of smell was observed in SLE patients (46%) and controls (25%) (P ≤ 0.02), while loss of smell (anosmia) was documented only in SLE patients (10%). Total TDI scores and individual stages of smell correlated with SLE Disease Activity Index (P < 0.001) and CNS manifestations (P < 0.03).

Conclusion

Our findings suggest that there is a decrease in the sense of smell in SLE patients compared with healthy subjects and that the decrease in the sense of smell among SLE patients correlates with disease activity and CNS involvement.

     

The −169C/T polymorphism in FCRL3 is not associated with susceptibility to rheumatoid arthritis or systemic lupus erythematosus in a case–control study of Koreans

Objective

In Japanese individuals, the −169C/T single‐nucleotide polymorphism (SNP) in FCRL3 has been reported to be associated with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and autoimmune thyroid diseases. The objective of this study was to test the association of this SNP with RA and SLE, in a case–control study of Korean individuals.

Methods

The −169C/T SNP in FCRL3 was genotyped in 1,060 patients with RA, 457 patients with SLE, and 697 unaffected control subjects, using the MassARRAY SNP genotyping system. Associations were tested by multivariate logistic regression, with adjustments for age and sex.

Results

No association was detected between the −169C/T SNP and RA (odds ratio [OR] 1.11, 95% confidence interval [95% CI] 0.83–1.48, P = 0.50) or SLE (OR 1.00, 95% CI 0.73–1.37, P = 0.99). This SNP was not associated with rheumatoid factor status, shared epitope status, radiographic severity in patients with RA, or disease manifestations in patients with SLE.

Conclusion

The association of the −169C/T SNP in FCRL3 with RA and SLE that was observed in Japanese patients was not replicated in a Korean population.

     

Assessment of cognitive function in systemic lupus erythematosus,rheumatoid arthritis,and multiple sclerosis by computerized neuropsychological tests

Objective

Computerized neuropsychological testing may facilitate screening for cognitive impairment in systemic lupus erythematosus (SLE). This study was undertaken to compare patients with SLE, patients with rheumatoid arthritis (RA), and patients with multiple sclerosis (MS) with healthy controls using the Automated Neuropsychological Assessment Metrics (ANAM).

Methods

Patients with SLE (n = 68), RA (n = 33), and MS (n = 20) were compared with healthy controls (n = 29). Efficiency of cognitive performance on 8 ANAM subtests was examined using throughput (TP), inverse efficiency (IE), and adjusted IE scores. The latter is more sensitive to higher cognitive functions because it adjusts for the impact of simple reaction time on performance. The results were analyzed using O'Brien's generalized least squares test.

Results

Control subjects were the most efficient in cognitive performance. MS patients were least efficient overall (as assessed by TP and IE scores) and were less efficient than both SLE patients (P = 0.01) and RA patients (P < 0.01), who did not differ. Adjusted IE scores were similar between SLE patients, RA patients, and controls, reflecting the impact of simple reaction time on cognitive performance. Thus, 50% of SLE patients, 61% of RA patients, and 75% of MS patients had impaired performance on ≥1 ANAM subtest. Only 9% of RA patients and 11% of SLE patients had impaired performance on ≥4 subtests, whereas this was true for 20% of MS patients.

Conclusion

ANAM is sensitive to cognitive impairment. While such computerized testing may be a valuable screening tool, our results emphasize the lack of specificity of slowed performance as a reliable indicator of impairment of higher cognitive function in SLE patients.

     

A phase III,randomized, placebo‐controlled study of belimumab,a monoclonal antibody that inhibits B lymphocyte stimulator,in patients with systemic lupus erythematosus

Objective

To assess the efficacy/safety of the B lymphocyte stimulator inhibitor belimumab plus standard therapy compared with placebo plus standard therapy in active systemic lupus erythematosus (SLE).

Methods

In a phase III, multicenter, randomized, placebo‐controlled trial, 819 antinuclear antibody–positive or anti–double‐stranded DNA–positive SLE patients with scores ≥6 on the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) version of the SLE Disease Activity Index (SLEDAI) were randomized in a 1:1:1 ratio to receive 1 mg/kg belimumab, 10 mg/kg belimumab, or placebo intravenously on days 0, 14, and 28 and then every 28 days for 72 weeks. The primary efficacy end point was the SLE Responder Index (SRI) response rate at week 52 (an SRI response was defined as a ≥4‐point reduction in SELENA–SLEDAI score, no new British Isles Lupus Assessment Group [BILAG] A organ domain score and no more than 1 new BILAG B score, and no worsening in physician's global assessment score versus baseline).

Results

Belimumab at 10 mg/kg plus standard therapy met the primary efficacy end point, generating a significantly greater SRI response at week 52 compared with placebo (43.2% versus 33.5%; P = 0.017). The rate with 1 mg/kg belimumab was 40.6% (P = 0.089). Response rates at week 76 were 32.4%, 39.1%, and 38.5% with placebo, 1 mg/kg belimumab, and 10 mg/kg belimumab, respectively. In post hoc sensitivity analyses evaluating higher SELENA–SLEDAI score thresholds, 10 mg/kg belimumab achieved better discrimination at weeks 52 and 76. Risk of severe flares over 76 weeks (based on the modified SLE Flare Index) was reduced with 1 mg/kg belimumab (34%) (P = 0.023) and 10 mg/kg belimumab (23%) (P = 0.13). Serious and severe adverse events, including infections, laboratory abnormalities, malignancies, and deaths, were comparable across groups.

Conclusion

Belimumab plus standard therapy significantly improved SRI response rate, reduced SLE disease activity and severe flares, and was generally well tolerated in SLE.

     

Macrophage activation syndrome in children with systemic lupus erythematosus and children with juvenile idiopathic arthritis

Objective

To describe patient demographics, interventions, and outcomes in hospitalized children with macrophage activation syndrome (MAS) complicating systemic lupus erythematosus (SLE) or juvenile idiopathic arthritis (JIA).

Methods

We performed a retrospective cohort study using data recorded in the Pediatric Health Information System (PHIS) database from October 1, 2006 to September 30, 2010. Participants had International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes for MAS and either SLE or JIA. The primary outcome was hospital mortality (for the index admission). Secondary outcomes included intensive care unit (ICU) admission, critical care interventions, and medication use.

Results

A total of 121 children at 28 children's hospitals met the inclusion criteria, including 19 children with SLE and 102 children with JIA. The index admission mortality rate was 7% (8 of 121 patients). ICU admission (33%), mechanical ventilation (26%), and inotrope/vasopressor therapy (26%) were common. Compared to children with JIA, those with SLE had a similar mortality rate (6% versus 11%, respectively; exact P = 0.6). More patients with SLE than those with JIA received ICU care (63% versus 27%; P = 0.002), received mechanical ventilation (53% versus 21%; P = 0.003), and had cardiovascular dysfunction (47% versus 23% received inotrope/vasopressor therapy; P = 0.02). Children with SLE and those with JIA received cyclosporine at similar rates, but more children with SLE received cyclophosphamide and mycophenolate mofetil, and more children with JIA received interleukin‐1 antagonists.

Conclusion

Organ system dysfunction is common in children with rheumatic diseases complicated by MAS, and more organ system support is required in children with underlying SLE than in children with JIA. Current treatment of pediatric MAS varies based on the underlying rheumatic disease.

     

Association between physician volume and in‐hospital mortality in patients with systemic lupus erythematosus

Objective

Systemic lupus erythematosus (SLE) is an uncommon, clinically complex disease for which prior experience treating similar patients may be particularly important. This study was undertaken to determine if physician volume is associated with the outcome of hospitalization of patients with SLE.

Methods

Data on in‐hospital mortality in a population‐based sample of 15,509 patients with SLE ages 18 years or older who were hospitalized in 2000, 2001, or 2002 in New York or Pennsylvania were obtained from state health planning agencies. Risks of in‐hospital mortality were examined in relation to the average annual number of patients with SLE hospitalized by the admitting physician.

Results

Physician volume was inversely associated with mortality. Mortality was 4.1% among patients of physicians who treated <1 hospitalized patient with SLE per year, 3.5% among patients of physicians who treated 1–3 patients per year, and 2.5% among patients of physicians who treated >3 patients per year. After adjustment for demographic characteristics, severity of illness, and hospital characteristics, the mortality risk was 20% lower among patients in the middle category of physician volume (odds ratio 0.80, 95% confidence interval 0.66–0.96, P =0.02), and 42% lower among patients in the highest category of physician volume (odds ratio 0.58, 95% confidence interval 0.42–0.82, P = 0.002), compared with patients in the lowest category. The association was stronger among patients with nephritis (n = 2,673), for whom the adjusted odds of mortality were ∼60% lower among those in the highest category of physician volume.

Conclusion

Our findings indicate that higher disease‐specific physician volume is associated with lower risks of in‐hospital mortality in patients with SLE.

     

Brief Report: Single‐nucleotide polymorphisms in VKORC1 are risk factors for systemic lupus erythematosus in Asians

Objective

The increased risk of thrombosis in systemic lupus erythematosus (SLE) may be partially explained by interrelated genetic pathways for thrombosis and SLE. The present study was undertaken to investigate whether 33 established and novel single‐nucleotide polymorphisms (SNPs) in 20 genes involved in hemostasis pathways that have been associated with deep venous thrombosis (DVT) in the general population are risk factors for SLE among Asian subjects.

Methods

Patients in the discovery cohort were enrolled in 1 of 2 North American SLE cohorts. Patients in the replication cohort were enrolled in 1 of 4 Asian or 2 North American cohorts. We first genotyped 263 Asian patients with SLE and 357 healthy Asian control subjects for 33 SNPs in the discovery phase, and then genotyped 5 SNPs in up to an additional 1,496 patients and 993 controls in the replication phase. Patients were compared to controls for bivariate association with minor alleles. Principal components analysis was used to control for intra‐Asian ancestry in the replication cohort.

Results

Two genetic variants in the gene VKORC1 were highly significant in both the discovery and replication cohorts: rs9934438 (in the discovery cohort, odds ratio [OR] 2.45, P = 2 × 10⁻⁹; in the replication cohort, OR 1.54, P = 4 × 10⁻⁶) and rs9923231 (in the discovery cohort, OR 2.40, P = 6 × 10⁻⁹; in the replication cohort, OR 1.53, P = 5 × 10⁻⁶). These associations were significant in the replication cohort after adjustment for intra‐Asian ancestry: for rs9934438, OR 1.34, P = 0.0029; for rs9923231, OR 1.34, P = 0.0032.

Conclusion

Genetic variants in VKORC1, which are involved in vitamin K reduction and associated with DVT, correlate with SLE development in Asian subjects. These results suggest that there may be intersecting genetic pathways for the development of SLE and thrombosis.

     

Linkage analysis of human systemic lupus erythematosus–related traits: A principal component approach

Objective

To identify chromosomal regions containing genes involved in the susceptibility to human systemic lupus erythematosus (SLE)–related traits.

Methods

In the context of a genome scan, we analyzed 101 SLE‐affected sibpairs with respect to dermatologic, renal, immunologic, hematologic, neurologic, cardiopulmonary, and arthritic characteristics. Phenotypes were redefined in terms of principal components, which are synthetic variables composed of linear combinations of the original traits. Using 9 principal components obtained from these 7 traits plus age at SLE onset and race, we analyzed genome scan data with the multivariate version of the new Haseman‐Elston regression model.

Results

The largest linkage for an individual trait was on chromosome 2 at 228 cM (immunologic; P = 0.00048). The most significant linkage to an individual principal component was on chromosome 4 at 208 cM (P = 0.00007). The largest multivariate linkage was on chromosome 7 at 69 cM (P = 0.0001). Of the individual organ systems, dermatologic involvement had the largest effect (P = 0.0083) at this peak at 7p13 on chromosome 7. Further analyses revealed that malar rash, a subtype of dermatologic involvement, was linked significantly (P = 0.00458) to this location.

Conclusion

These results provide evidence of the presence and locations of genes that are involved in the genetic susceptibility to SLE‐related traits in humans.