Remission and low disease activity state (LDAS) are protective of intermediate and long-term outcomes in SLE patients. Results from LUMINA (LXXVIII), a multiethnic, multicenter US cohort.

OBJECTIVE: The objective of this report is to determine the impact of remission and low disease activity state (LDAS) on damage accrual and mortality in systemic lupus erythematosus (SLE) patients. PATIENTS AND METHODS: Visits from the Lupus in Minority populations: Nature vs. Nurture (LUMINA) cohort were categorized into remission (Systemic Lupus Activity Measure (SLAM) score = 0 and prednisone ≤ 5 mg/day and no immunosuppressants), LDAS ((not on remission), SLAM score ≤ 3, prednisone ≤ 7.5 mg/day, no immunosuppressants), or neither: active. Remission and LDAS visits were combined because of the relatively small number of remission visits. Their impact on damage accrual and mortality were examined by Poisson and logistic multivariable regressions adjusting for variables known to affect these outcomes. RESULTS: A total of 3879 visits for 558 patients (28% Caucasian, 37% African descent, 35% Hispanic) were studied. These visits corresponded to 71 in remission, 585 in LDAS, and 3223 active. The longer the percentage of time the patients were in remission/LDAS, the less damage accrual observed (rate ratio 0.1773 (95% confidence interval (CI) 0.1216 to 0.2584) p < 0.0001). A trend was observed in terms of mortality although statistical significance was not reached (odds ratio 0.303 (95% CI 0.063 to 1.456), p = 0.1360). CONCLUSIONS: The longer the patient's state on Remission/LDAS, the less damage accrual that occurs. The protective effect on mortality was not statistically significant.

Factors associated with disease expression patterns in systemic lupus erythematosus patients: results from LUMINA (LXXVII), a multiethnic US cohort.

Objective The objective of this study was to determine the association of disease expression patterns with demographic and clinical characteristics in SLE. Methods Patients from a multi-ethnic SLE cohort were included. Disease expression patterns were defined as acute SLE and insidious SLE; this group was divided into those who accrued three ACR criteria and then accrued the fourth (insidious pattern A) and those who have one or two and then accrued four criteria (insidious pattern B). Disease activity was ascertained with the SLAM-R and disease damage with SLICC/ACR damage index. Variables were compared using analysis of variance for numeric variables and χ2 for categorical variables. Multivariable analyses adjusting for possible confounders were performed. Results Six hundred and forty patients were included; the most frequent pattern was the insidious pattern B, with 415 (64.8%) patients, followed by the acute SLE group with 115 (18.0%) and the insidious pattern A with 110 (17.2%) patients. Patients from the insidious pattern A were older at diagnosis (pattern A: 39.8 vs pattern B: 36.7 vs acute: 32.4 years; p < 0.0001), more educated (13.6 vs 13.1 vs 12.1; p = 0.0008) and with a less active disease at baseline (8.8 vs 9.2 vs 10.7; p = 0.0227). Caucasian and Hispanic (Puerto Rico) ethnicities were overrepresented in this group (40.0% vs 27.7% vs 19.1% and 18.2% vs 17.1% vs 9.6%; p = 0.0003). Conclusions More insidious onset is associated with older age, Caucasian ethnicity, higher level of education, and lower disease activity than those with acute onset. However, after multivariable analyses, disease activity was not associated with any disease expression pattern.

A unique antiphospholipid assay recognizing phospholipid mixture compared with criteria antiphospholipid immunoassays in lupus patients.

Background While essential for the classification of antiphospholipid syndrome (APS), anticardiolipin (aCL) assays lack specificity and anti-ß2glycoproteinI (anti-ß2GPI) assays lack sensitivity in this regard. Our aim was to perform a comparative analysis of the APhL ELISA assay (IgG/IgM) and criteria antiphospholipid (aPL) immunoassays in identifying APS-related clinical manifestations in a large group of patients with systemic lupus erythematosus (SLE). Methods Serum samples from 1178 patients from the Hopkins ( n = 543), LUMINA ( n = 588) and Jamaican SLE cohorts ( n = 47) were examined for IgG/IgM positivity in aCL (in-house), anti-ß2GPI (two commercial kits) and APhL (Louisville APL) ELISA assays. Correlation of assay positivity with clinical manifestations and sensitivity, specificity, positive and negative predictive values and likelihood ratios were evaluated. A case series analysis was also performed in patients for whom there was isolated positivity in the specific aPL assays. Results The prevalence of aCL positivity was 34.9%, anti-ß2GPI kit A was 22.6%, APhL was 11.5% and anti-ß2GPI kit B was 7.6% in the study population. Anti-ß2GPI kit B, aCL and APhL assays were correlated with venous thrombosis, while only APhL was significantly correlated with arterial thrombosis and consistently correlated with pregnancy-related morbidity. No significant correlations were noted for anti-ß2GPI kit A. Sensitivity was greatest for aCL assays followed by anti-ß2GPI kit A, APhL and anti-ß2GPI kit B, while specificity was greatest and equal for anti-ß2GPI kit B and APhL assays. Conclusions Overall, APhL antibodies, especially IgG, represent a promising biomarker for the classification of APS patients in the context of autoimmunity and in risk assessment with regards to pregnancy morbidity and thrombotic manifestations.

American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network 2015: recommendations for the treatment of ankylosing spondylitis and nonradiographic axial spondyloarthritis

OBJECTIVE: To provide evidence-based recommendations for the treatment of patients with ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (SpA). METHODS: A core group led the development of the recommendations, starting with the treatment questions. A literature review group conducted systematic literature reviews of studies that addressed 57 specific treatment questions, based on searches conducted in OVID Medline (1946-2014), PubMed (1966-2014), and the Cochrane Library. We assessed the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method. A separate voting group reviewed the evidence and voted on recommendations for each question using the GRADE framework. RESULTS: In patients with active AS, the strong recommendations included use of nonsteroidal antiinflammatory drugs (NSAIDs), use of tumor necrosis factor inhibitors (TNFi) when activity persists despite NSAID treatment, not to use systemic glucocorticoids, use of physical therapy, and use of hip arthroplasty for patients with advanced hip arthritis. Among the conditional recommendations was that no particular TNFi was preferred except in patients with concomitant inflammatory bowel disease or recurrent iritis, in whom TNFi monoclonal antibodies should be used. In patients with active nonradiographic axial SpA despite treatment with NSAIDs, we conditionally recommend treatment with TNFi. Other recommendations for patients with nonradiographic axial SpA were based on indirect evidence and were the same as for patients with AS. CONCLUSION: These recommendations provide guidance for the management of common clinical questions in AS and nonradiographic axial SpA. Additional research on optimal medication management over time, disease monitoring, and preventive care is needed to help establish best practices in these areas.(AU)

Association study of genes related to bone formation and resorption and the extent of radiographic change in ankylosing spondylitis.

OBJECTIVE: To identify genetic associations with severity of radiographic damage in ankylosing spondylitis (AS). METHOD: We studied 1537 AS cases of European descent; all fulfilled the modified New York Criteria. Radiographic severity was assessed from digitised lateral radiographs of the cervical and lumbar spine using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). A two-phase genotyping design was used. In phase 1, 498 single nucleotide polymorphisms (SNPs) were genotyped in 688 cases; these were selected to capture >90% of the common haplotypic variation in the exons, exon-intron boundaries, and 5 kb flanking DNA in the 5' and 3' UTR of 74 genes involved in anabolic or catabolic bone pathways. In phase 2, 15 SNPs exhibiting p<0.05 were genotyped in a further cohort of 830 AS cases; results were analysed both separately and in combination with the discovery phase data. Association was tested by contingency tables after separating the samples into 'mild' and 'severe' groups, defined as the bottom and top 40% by mSASSS, adjusted for gender and disease duration. RESULTS: Experiment-wise association was observed with the SNP rs8092336 (combined OR 0.32, p=1.2×10(-5)), which lies within RANK (receptor activator of NFκB), a gene involved in osteoclastogenesis, and in the interaction between T cells and dendritic cells. Association was also found with the SNP rs1236913 in PTGS1 (prostaglandin-endoperoxide synthase 1, cyclooxygenase 1), giving an OR of 0.53 (p=2.6×10(-3)). There was no observed association between radiographic severity and HLA-B*27. CONCLUSIONS: These findings support roles for bone resorption and prostaglandins pathways in the osteoproliferative changes in AS.

Effects of statins on proinflammatory/prothrombotic biomarkers and on disease activity scores in SLE patients: data from LUMINA (LXXVI), a multi-ethnic US cohort.

OBJECTIVES: We sought to determine the effect of statin therapy on the levels of proinflammatory/prothrombotic markers and disease activity scores in patients with SLE in a multi-ethnic, multi-centre cohort (LUMINA). METHODS: Plasma/serum samples from SLE patients placed on statins (n=21) therapy taken before and after at least 6 months of treatment were tested. Disease activity was assessed using SLAM-R scores. Interleukin (IL)-1ß, IL-6, IL-8, tumour necrosis factor (TNF)-α, vascular endothelial growth factor (VEGF) and soluble CD40 ligand (sCD40L) levels were determined by a multiplex immunoassay. Soluble intercellular cell adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1 and anticardiolipin (aCL) antibodies were evaluated using ELISA assays while high sensitivity C-reactive protein (hsCRP) was assessed by nephelometry. Plasma/serum samples from frequency- matched healthy donors were used as controls. RESULTS: Levels of IL-6, VEGF, sCD40L and TNF-α were significantly elevated in SLE patients versus controls. Statin therapy resulted in a significant decrease in SLAM-R scores (p=0.0199) but no significant changes in biomarker levels were observed. There was no significant association of biomarkers with SLAM-R scores. CONCLUSIONS: Statin therapy resulted in significant clinical improvement in SLE patients, underscoring the use of statins in the treatment of SLE.

Efficacy of certolizumab pegol on signs and symptoms of axial spondyloarthritis including ankylosing spondylitis: 24-week results of a double-blind randomised placebo-controlled Phase 3 study.

OBJECTIVES: To evaluate the efficacy and safety of certolizumab pegol (CZP) after 24 weeks in RAPID-axSpA (NCT01087762), an ongoing Phase 3 trial in patients with axial spondyloarthritis (axSpA), including patients with ankylosing spondylitis (AS) and non-radiographic axSpA (nr-axSpA). METHODS: Patients with active axSpA were randomised 1:1:1 to placebo, CZP 200 mg every 2 weeks (Q2W) or CZP 400 mg every 4 weeks (Q4W). In total 325 patients were randomised. Primary endpoint was ASAS20 (Assessment of SpondyloArthritis international Society 20) response at week 12. Secondary outcomes included change from baseline in Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and Bath Ankylosing Spondylitis Metrology Index (BASMI) linear. RESULTS: Baseline disease activity was similar between AS and nr-axSpA. At week 12, ASAS20 response rates were significantly higher in CZP 200 mg Q2W and CZP 400 mg Q4W arms versus placebo (57.7 and 63.6 vs 38.3, p≤0.004). At week 24, combined CZP arms showed significant (p<0.001) differences in change from baseline versus placebo in BASFI (-2.28 vs -0.40), BASDAI (-3.05 vs -1.05), and BASMI (-0.52 vs -0.07). Improvements were observed as early as week 1. Similar improvements were reported with CZP versus placebo in both AS and nr-axSpA subpopulations. Adverse events were reported in 70.4% vs 62.6%, and serious adverse events in 4.7% vs 4.7% of All CZP versus placebo groups. No deaths or malignancies were reported. CONCLUSIONS: CZP rapidly reduced the signs and symptoms of axSpA, with no new safety signals observed compared to the safety profile of CZP in RA. Similar improvements were observed across CZP dosing regimens, and in AS and nr-axSpA patients.

Association between copy number variations of HLA-DQA1 and ankylosing spondylitis in the Chinese Han population.

Ankylosing spondylitis (AS) is a chronic inflammatory disease with complex genetic traits. Multiple sequence variations have been associated with AS, but explained only a proportion of heritability. The studies herein aimed to explore potential associations between genomic copy number (CN) variation (CNV) and AS in Han Chinese. Five AS patients were examined with the high-density comparative genomic hybridization microarrays in the first screen test for AS-associated CNVs. A total of 533 AS patients and 792 unrelated controls were examined in confirmation studies with the AccuCopy assays. A significant association was observed between the CNV of HLA-DQA1 and that of AS. Compared with controls, AS patients showed an aberrant CN, and a significantly increased number of patients had more than two copies of HLA-DQA1. Therefore, the CNV of HLA-DQA1 may have an important role in susceptibility to AS in the Han Chinese population.

Measuring therapeutic adherence in systemic lupus erythematosus with electronic monitoring.

OBJECTIVE: We used an electronic monitoring system to quantify adherence to prescribed oral therapies by patients with systemic lupus erythematosus (SLE). METHODS: Participants were included from a larger longitudinal study cohort of 110 patients recruited from publicly-funded rheumatology clinics, 78 of whom agreed to have their SLE drug therapy electronically monitored for two years with the Medication Events Monitoring System (MEMS®, AARDEX Group). Adherence was determined as the percentage of days (weeks for methotrexate) the patient took the medication as prescribed by the physician. Collected data included SLEDAI; SLICC damage index for SLE (SDI); medical outcome study social support survey (MOS-SSS); Center for Epidemiologic Studies depression scale (CESD); and quality of life (SF-12). RESULTS: Ninety percent of the cohort was female, 45% were Hispanic, and 49% were African-American. Mean age was 36.3 years, disease duration was 5.9 years, SLEDAI score was 3.2, and SDI score was 0.9. Adherence was 62% for all drugs combined and did not differ significantly for individual medications. Patients with more depression (p < 0.02), and higher number of pills taken daily (p < 0.02) were more likely to be non-adherent. Only one-fourth of the patients had an average adherence of ≥80%; these patients had a better mental component score (SF-12) at 24 months than non-adherent patients (p < 0.01). CONCLUSIONS: Electronic monitoring demonstrated that only one-fourth of the patients had an adherence rate ≥80%. Polypharmacy and depression were associated with non-adherence.

A functional haplotype of UBE2L3 confers risk for systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease with diverse clinical manifestations characterized by the development of pathogenic autoantibodies manifesting in inflammation of target organs such as the kidneys, skin and joints. Genome-wide association studies have identified genetic variants in the UBE2L3 region that are associated with SLE in subjects of European and Asian ancestry. UBE2L3 encodes an ubiquitin-conjugating enzyme, UBCH7, involved in cell proliferation and immune function. In this study, we sought to further characterize the genetic association in the region of UBE2L3 and use molecular methods to determine the functional effect of the risk haplotype. We identified significant associations between variants in the region of UBE2L3 and SLE in individuals of European and Asian ancestry that exceeded a Bonferroni-corrected threshold (P<1 × 10(-4)). A single risk haplotype was observed in all associated populations. Individuals harboring the risk haplotype display a significant increase in both UBE2L3 mRNA expression (P=0.0004) and UBCH7 protein expression (P=0.0068). The results suggest that variants carried on the SLE-associated UBE2L3 risk haplotype influence autoimmunity by modulating UBCH7 expression.

Effect of hydroxychloroquine treatment on pro-inflammatory cytokines and disease activity in SLE patients: data from LUMINA (LXXV), a multiethnic US cohort.

OBJECTIVE: We sought to determine the effect of hydroxychloroquine therapy on the levels proinflammatory/prothrombotic markers and disease activity scores in patients with systemic lupus erythematosus (SLE) in a multiethnic, multi-center cohort (LUMINA). METHODS: Plasma/serum samples from SLE patients (n = 35) were evaluated at baseline and after hydroxychloroquine treatment. Disease activity was assessed using SLAM-R scores. Interferon (IFN)-α2, interleukin (IL)-1ß, IL-6, IL-8, inducible protein (IP)-10, monocyte chemotactic protein-1, tumor necrosis factor (TNF)-α and soluble CD40 ligand (sCD40L) levels were determined by a multiplex immunoassay. Anticardiolipin antibodies were evaluated using ELISA assays. Thirty-two frequency-matched plasma/serum samples from healthy donors were used as controls. RESULTS: Levels of IL-6, IP-10, sCD40L, IFN-α and TNF-α were significantly elevated in SLE patients versus controls. There was a positive but moderate correlation between SLAM-R scores at baseline and levels of IFN-α (p = 0.0546). Hydroxychloroquine therapy resulted in a significant decrease in SLAM-R scores (p = 0.0157), and the decrease in SLAM-R after hydroxychloroquine therapy strongly correlated with decreases in IFN-α (p = 0.0087). CONCLUSIONS: Hydroxychloroquine therapy resulted in significant clinical improvement in SLE patients, which strongly correlated with reductions in IFN-α levels. This indicates an important role for the inhibition of endogenous TLR activation in the action of hydroxychloroquine in SLE and provides additional evidence for the importance of type I interferons in the pathogenesis of SLE. This study underscores the use of hydroxychloroquine in the treatment of SLE.

Role of MYH9 and APOL1 in African and non-African populations with lupus nephritis.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by autoantibody production and organ damage. Lupus nephritis (LN) is one of the most severe manifestations of SLE. Multiple studies reported associations between renal diseases and variants in the non-muscle myosin heavy chain 9 (MYH9) and the neighboring apolipoprotein L 1 (APOL1) genes. We evaluated 167 variants spanning MYH9 for association with LN in a multiethnic sample. The two previously identified risk variants in APOL1 were also tested for association with LN in European-Americans (EAs) (N = 579) and African-Americans (AAs) (N = 407). Multiple peaks of association exceeding a Bonferroni corrected P-value of P < 2.03 × 10(-3) were observed between LN and MYH9 in EAs (N = 4620), with the most pronounced association at rs2157257 (P = 4.7 × 10(-4), odds ratio (OR) = 1.205). A modest effect with MYH9 was also detected in Gullah (rs8136069, P = 0.0019, OR = 2.304). No association between LN and MYH9 was found in AAs, Asians, Amerindians or Hispanics. This study provides the first investigation of MYH9 in LN in non-Africans and of APOL1 in LN in any population, and presents novel insight into the potential role of MYH9 in LN in EAs.

Analysis of the influence of PTPN22 gene polymorphisms in systemic sclerosis.

OBJECTIVE: Two functional single nucleotide polymorphisms (SNP) in the PTPN22 gene (rs24746601 and rs33996649) have been associated with autoimmunity. The aim of this study was to investigate the role of the R263Q SNP for the first time and to re-evaluate the role of the R620W SNP in the genetic predisposition to systemic sclerosis (SSc) susceptibility and clinical phenotypes. METHODS: 3422 SSc patients (2020 with limited cutaneous SSc and 1208 with diffuse cutaneous SSc) and 3638 healthy controls of Caucasian ancestry from an initial case--control set of Spain and seven additional independent replication cohorts were included in our study. Both rs33996649 and rs2476601 PTPN22 polymorphisms were genotyped by TaqMan allelic discrimination assay. A meta-analysis was performed to test the overall effect of these PTPN22 polymorphisms in SSc. RESULTS: The meta-analysis revealed evidence of association of the rs2476601 T allele with SSc susceptibility (p(FDRcorrected)=0.03 pooled, OR 1.15, 95% CI 1.03 to 1.28). In addition, the rs2476601 T allele was significantly associated with anticentromere-positive status (p(FDRcorrected)=0.02 pooled, OR 1.22, 95% CI 1.05 to 1.42). Although the rs33996649 A allele was significantly associated with SSc in the Spanish population (p(FDRcorrected)=0.04, OR 0.58, 95% CI 0.36 to 0.92), this association was not confirmed in the meta-analysis (p=0.36 pooled, OR 0.89, 95% CI 0.72 to 1.1). CONCLUSION: The study suggests that the PTPN22 R620W polymorphism influences SSc genetic susceptibility but the novel R263Q genetic variant does not. These data strengthen evidence that the R620W mutation is a common risk factor in autoimmune diseases.

Is familial lupus different from sporadic lupus? Data from LUMINA (LXXIII), a multiethnic US cohort.

The aim of this study was 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 systemic lupus erythematosus. Relative risks were estimated by logistic regression; odds ratios (ORs) and their 95% confidence intervals (CIs) were the measure of association for familial lupus. Hazard ratios were calculated using Cox proportional hazards adjusted for potential confounders for damage and survival. Of 644 patients, 32 had familial and 612 had sporadic lupus; both groups were of comparable age (~36 years). Patients with familial lupus 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/mm(3); 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). We conclude that although some clinical differences were observed between patients with familial and sporadic lupus, familial lupus was not associated with a significantly greater disease burden (damage, survival) than sporadic lupus.

Plasma endogenous enkephalin levels in early systemic sclerosis: clinical and laboratory associations.

OBJECTIVE: Met- and leu-enkephalins are endogenous opioid neuropeptides with potent analgesic, vasoactive, immunomodulatory and anti-apoptotic properties. We hypothesised that clinical or immunological variables of early systemic sclerosis (SSc) might be correlated to plasma enkephalin levels. METHODS: Plasma samples were collected at study entry of the Genetics versus Environment in Scleroderma Outcomes Study (GENISOS) cohort (early SSc, n=116). Plasma met-enkephalin and leu-enkephalin levels (microg/ml) were measured by high performance liquid chromatography (HPLC) and correlated to clinical and laboratory parameters in the GENISOS database. Statistical analyses were performed by nonparametric Wilcoxon rank sum tests and Pearson correlation coefficients. RESULTS: Significantly lower plasma met-enkephalin levels were associated with anti-topoisomerase-I seropositivity (6+8.3 vs. 14.9+22.8 microg/ml, p=0.02). Plasma leu-enkephalin levels were significantly higher in SSc patients with digital pulp loss (95.6+130 vs. 64.9+101 microg/ml, p=0.02). Lower mean plasma met-enkephalin levels and inversely higher leu-enkephalin levels were noted in SSc patients with Raynaud's phenomena (p=NS). CONCLUSION: The associations of plasma enkephalin levels to immunologic or clinical pathologies may underscore their vasogenic or fibrogenic significance and potential as therapeutic targets in early SSc.

Predictors of the rate of change in disease activity over time in LUMINA, a multiethnic US cohort of patients with systemic lupus erythematosus: LUMINA LXX.

The objectives of the present study were (1) to clarify and quantify the relationship between age and disease duration with the rate of change in disease activity over time in patients with systemic lupus erythematosus (SLE) and (2) to explore other possible factors associated with this rate of change. To this end, SLE patients from LUMINA were studied if they had at least three visits in which disease activity (Systemic Lupus Activity Measure-Revised [SLAM-R]) had been ascertained. Variables associated with the rate (slope) of change in disease activity (obtained by regressing the SLAM-R score against the length of time from diagnosis to visit date) were examined by univariable and multivariable analyses. Five hundred and forty two of the 632 patients had at least three SLAM-R score. In multivariable analyses, Whites exhibited the fastest decline in disease activity, Texan Hispanics exhibited the slowest, trailed by the African Americans. Longer disease duration and HLA-DRB1*1503 positivity were associated with a slower decline whereas a greater number of American College of Rheumatology criteria and abnormal laboratory parameters (white blood cell counts, hematocrit and serum creatinine) were associated with a faster decline. These findings complement existing knowledge on SLE disease activity and are potentially useful to clinicians managing these patients.

BANK1 functional variants are associated with susceptibility to diffuse systemic sclerosis in Caucasians.

OBJECTIVE: To investigate the possible association of the BANK1 gene with genetic susceptibility to systemic sclerosis (SSc) and its subphenotypes. METHODS: A large multicentre case-control association study including 2380 patients with SSc and 3270 healthy controls from six independent case-control sets of Caucasian ancestry (American, Spanish, Dutch, German, Swedish and Italian) was conducted. Three putative functional BANK1 polymorphisms (rs17266594 T/C, rs10516487 G/A, rs3733197 G/A) were selected as genetic markers and genotyped by Taqman 5 allelic discrimination assay. RESULTS: A significant association of the rs10516487 G and rs17266594 T alleles with SSc susceptibility was observed (pooled OR=1.12, 95% CI 1.03 to 1.22; p=0.01 and pooled OR=1.14, 95% CI 1.05 to 1.25; p=0.003, respectively), whereas the rs3733197 genetic variant showed no statistically significant deviation. Stratification for cutaneous SSc phenotype showed that the BANK1 rs10516487 G, rs17266594 T and rs3733197 G alleles were strongly associated with susceptibility to diffuse SSc (dcSSc) (pooled OR=1.20, 95% CI 1.05 to 1.37, p=0.005; pooled OR=1.23, 95% CI 1.08 to 1.41, p=0.001; pooled OR=1.15, 95% CI 1.02 to 1.31, p=0.02, respectively). Similarly, stratification for specific SSc autoantibodies showed that the association of BANK1 rs10516487, rs17266594 and rs3733197 polymorphisms was restricted to the subgroup of patients carrying anti-topoisomerase I antibodies (pooled OR=1.20, 95% CI 1.02 to 1.41, p=0.03; pooled OR=1.24, 95% CI 1.05 to 1.46, p=0.01; pooled OR=1.26, 95% CI 1.07 to 1.47, p=0.004, respectively). CONCLUSION: The results suggest that the BANK1 gene confers susceptibility to SSc in general, and specifically to the dcSSc and anti-topoisomerase I antibody subsets.

Challenges comparing functional limitations in rheumatoid arthritis and ankylosing spondylitis.

Whether physical functioning in patients with rheumatoid arthritis (RA) differs from that in patients with ankylosing spondylitis (AS) is presently uncertain. Such a comparison poses challenges, not only because the two diseases differ in the domains of functioning affected, but also because of the different instruments used to measure functional limitations. Limiting our analysis to studies using similar self-report questionnaires, we examined published observational studies of unselected cohorts of patients with RA and patients with AS to compare and contrast the severity of functional limitations. Available studies from a few direct comparisons, and mostly indirect comparisons, suggested that patients with RA are generally more severely limited in physical functioning throughout the disease course than patients with AS. Since most studies did not adjust adequately for potentially important confounders, such as age, gender, comorbidity, and disease duration, reported differences in functional disability between patients with RA and patients with AS must be interpreted cautiously.

Peripheral vascular damage in systemic lupus erythematosus: data from LUMINA, a large multi-ethnic U.S. cohort (LXIX).

To determine the factors associated with peripheral vascular damage in systemic lupus erythematosus patients and its impact on survival from Lupus in Minorities, Nature versus Nurture, a longitudinal US multi-ethnic cohort. Peripheral vascular damage was defined by the Systemic Lupus International Collaborating Clinics Damage Index (SDI). Factors associated with peripheral vascular damage were examined by univariable and multi-variable logistic regression models and its impact on survival by a Cox multi-variable 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 multi-variable analyses. Azathioprine, warfarin and statins were also statistically significant, and 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 independently 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 other organs (ocular, neuropsychiatric, renal, cardiovascular, pulmonary, musculoskeletal and integument) and some medications (probably reflecting more severe disease). Peripheral vascular damage also negatively affected survival.

Factors associated with arterial vascular events in PROFILE: a Multiethnic Lupus Cohort.

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 SLE patients (n = 1333) of defined ethnicity from five different US 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 anaemia (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.