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Objective: The aim of this study is to determine whether the functional interferon regulatory factor 5 ( IRF5) polymorphism rs2004640 is associated with susceptibility to systemic lupus erythematosus (SLE) in multiple ethnic populations., Methods: A meta-analysis was conducted on the T allele of the IRF5 rs2004640 polymorphism in all study participants as well as each ethnic population., Results: Twenty research articles that included 28 comparative studies of 20,892 patients and 24,930 controls were included in the meta-analysis. The Asian population had a much lower prevalence of the T allele than any other study population at 28%, and the European population had the highest prevalence of the T allele at 52%. Meta-analysis showed an association between the IRF5 rs2004640 polymorphism and SLE in all participants (odds ratio = 1.472, 95% confidence interval = 1.370-1.582, p < 0.001). Analysis after stratification by ethnicity indicated that the IRF5 rs2004640 T allele is significantly associated with SLE in Europeans, Asians, Latin Americans and Arabs., Conclusions: This meta-analysis confirms that the IRF5 rs2004640 polymorphism is associated with SLE susceptibility in different ethnic groups, and that its prevalence is ethnicity dependent.

Objective: In cross-sectional studies, elevated osteopontin (OPN) levels have been proposed to reflect, and/or precede, progressive organ damage and disease severity in systemic lupus erythematosus (SLE). We aimed, in a cohort of patients with recent-onset SLE, to determine whether raised serum OPN levels precede damage and/or are associated with disease activity or certain disease phenotypes., Methods: We included 344 patients from the Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort who had 5 years of followup data available. All patients fulfilled the 1997 American College of Rheumatology (ACR) criteria. Baseline sera from patients and from age- and sex-matched population-based controls were analyzed for OPN using ELISA. Disease activity and damage were assessed at each annual followup visit using the SLE Disease Activity Index 2000 (SLEDAI-2K) and the SLICC/ACR damage index (SDI), respectively., Results: Compared to controls, baseline OPN was raised 4-fold in SLE cases (p < 0.0001). After relevant adjustments in a binary logistic regression model, OPN levels failed to significantly predict global damage accrual defined as SDI ≥ 1 at 5 years. However, baseline OPN correlated with SLEDAI-2K at enrollment into the cohort (r = 0.27, p < 0.0001), and patients with high disease activity (SLEDAI-2K ≥ 5) had raised serum OPN (p < 0.0001). In addition, higher OPN levels were found in patients with persistent disease activity (p = 0.0006), in cases with renal involvement (p < 0.0001) and impaired estimated glomerular filtration rate (p = 0.01)., Conclusion: The performance of OPN to predict development of organ damage was not impressive. However, OPN associated significantly with lupus nephritis and with raised disease activity at enrollment, as well as over time.

Objectives: To describe glucocorticoid (GC) use in the SLICC inception cohort and to explore factors associated with GC use. In particular we aimed to assess temporal trends in GC use and to what extent physician-related factors may influence use., Methods: Patients were recruited within 15 months of diagnosis of SLE from 33 centres between 1999 and 2011 and continue to be reviewed annually. Descriptive statistics were used to detail oral and parenteral GC use. Cross sectional and longitudinal analyses were performed to explore factors associated with GC use at enrolment and over time., Results: We studied 1700 patients with a mean (s.d.) follow-up duration of 7.26 (3.82) years. Over the entire study period, 1365 (81.3%) patients received oral GCs and 447 (26.3%) received parenteral GCs at some point. GC use was strongly associated with treatment centre, age, race/ethnicity, sex, disease duration and disease activity. There was no change in the proportion of patients on GCs or the average doses of GC used over time according to year of diagnosis., Conclusion: GCs remain a cornerstone in SLE management and there have been no significant changes in their use over the past 10-15 years. While patient and disease factors contribute to the variation in GC use, between-centre differences suggest that physician-related factors also contribute. Evidence-based treatment algorithms are needed to inform a more standardized approach to GC use in SLE.

Despite the progress in human leukocyte antigen (HLA) causal variant mapping, independent localization of major histocompatibility complex (MHC) risk from classical HLA genes is challenging. Here, we conducted a large-scale MHC fine-mapping analysis of rheumatoid arthritis (RA) in a Japanese population (6,244 RA cases and 23,731 controls) population by using HLA imputation, followed by a multi-ethnic validation study including east Asian and European populations (n = 7,097 and 23,149, respectively). Our study identified an independent risk of a synonymous mutation at HLA-DOA, a non-classical HLA gene, on anti-citrullinated protein autoantibody (ACPA)-positive RA risk (p = 1.4 × 10(-9)), which demonstrated a cis-expression quantitative trait loci (cis-eQTL) effect on HLA-DOA expression. Trans-ethnic comparison revealed different linkage disequilibrium (LD) patterns in HLA-DOA and HLA-DRB1, explaining the observed HLA-DOA variant risk heterogeneity among ethnicities, which was most evident in the Japanese population. Although previous HLA fine-mapping studies have identified amino acid polymorphisms of the classical HLA genes as driving genetic susceptibility to disease, our study additionally identifies the dosage contribution of a non-classical HLA gene to disease etiology. Our study contributes to the understanding of HLA immunology in human diseases and suggests the value of incorporating additional ancestry in MHC fine-mapping., (Copyright © 2016. Published by Elsevier Inc.)

Objective: The aim of this study was to determine whether the major histocompatibility complex class I chain-related gene A transmembrane (MICA-TM) polymorphism is associated with susceptibility to systemic lupus erythematous (SLE), rheumatoid arthritis (RA) and ankylosing spondylitis (AS)., Methods: A meta-analysis was conducted to establish the association between MICA-TM polymorphisms and SLE, RA and AS in the overall study population, as well as in each ethnic group., Results: A total of 13 comparison studies, including five SLE (1601 patients; 1846 controls), four RA (701 patients; 887 controls) and four AS (346 patients; 356 controls) studies were considered in the meta-analysis. An association between the MICA-TM A5.1 allele and SLE was demonstrated in Europeans but not in Asians: odds ratio (OR) = 1.699, 95 % confidence interval (CI) = 1.123-2.569, p = 0.012 and OR = 0.949, 95 % CI = 0.502-1.793, p = 0.871, respectively. However, no association was found in Europeans after Bonferroni correction (pcorrected = 0.060). An association was found between the MICA-TM A9 allele and RA in Asians (OR = 0.527, 95 % CI = 0.408-0.681, p = 8.9 × 10(-7)) but not in Europeans; the association in Asians remained significant after Bonferroni correction (pcorrected = 4.5 × 10(-6)). An association between the MICA-TM A4 phenotype and AS was observed in European and Asian populations (OR = 12.87, 95 % CI = 6.747-24.58, p < 1.0 × 10(-9) and OR = 9.461, 95 % CI = 5.754-15.55, p < 1.0 × 10(-9), respectively). Meta-analysis stratified by human leukocyte antigen (HLA)-B27 status revealed an association between the MICA-TM A4 phenotype and HLA-B27 positivity AS in Asians, but not in Europeans (OR = 0.318, 95 % CI = 0.102-0.995, p = 0.049 and OR = 2.080, 95 % CI = 0.422-10.25, p = 0.368, respectively). However, the association in Asians was not significant after Bonferroni correction (pcorrected = 0.245)., Conclusion: This meta-analysis demonstrated that there was no association between MICA-TM polymorphisms and SLE susceptibility, but that the MICA-TM A9 allele was associated with an RA risk in Asians. Moreover, the association between the MICA-TM A4 phenotype and AS was HLA-B27-dependent.

Objective: To update estimates of cancer risk in SLE relative to the general population., Methods: A multisite international SLE cohort was linked with regional tumor registries. Standardized incidence ratios (SIRs) were calculated as the ratio of observed to expected cancers., Results: Across 30 centres, 16,409 patients were observed for 121,283 (average 7.4) person-years. In total, 644 cancers occurred. Some cancers, notably hematologic malignancies, were substantially increased (SIR 3.02, 95% confidence interval, CI, 2.48, 3.63), particularly non-Hodgkin's lymphoma, NHL (SIR 4.39, 95% CI 3.46, 5.49) and leukemia. In addition, increased risks of cancer of the vulva (SIR 3.78, 95% CI 1.52, 7.78), lung (SIR 1.30, 95% CI 1.04, 1.60), thyroid (SIR 1.76, 95% CI 1.13, 2.61) and possibly liver (SIR 1.87, 95% CI 0.97, 3.27) were suggested. However, a decreased risk was estimated for breast (SIR 0.73, 95% CI 0.61-0.88), endometrial (SIR 0.44, 95% CI 0.23-0.77), and possibly ovarian cancers (0.64, 95% CI 0.34-1.10). The variability of comparative rates across different cancers meant that only a small increased risk was estimated across all cancers (SIR 1.14, 95% CI 1.05, 1.23)., Conclusion: These data estimate only a small increased risk in SLE (versus the general population) for cancer over-all. However, there is clearly an increased risk of NHL, and cancers of the vulva, lung, thyroid, and possibly liver. It remains unclear to what extent the association with NHL is mediated by innate versus exogenous factors. Similarly, the etiology of the decreased breast, endometrial, and possibly ovarian cancer risk is uncertain, though investigations are ongoing., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objective: We describe disease activity, damage, and the accrual of key autoantibodies in an inception systemic lupus erythematosus (SLE) cohort., Methods: The Systemic Lupus International Collaborating Clinics (SLICC) International Research Network, comprising 27 centers from 11 countries, has followed an inception cohort of SLE patients yearly according to a standardized protocol. Of these patients, 298 were followed for a minimum of 5 years and constitute the study population. Disease activity was assessed using the SLE Disease Activity Index 2000 (SLEDAI-2K) and damage was assessed using the SLICC/American College of Rheumatology Damage Index (SDI). Antinuclear antibody (ANA), anti-DNA, and anticardiolipin antibody (aCL) levels and lupus anticoagulant were assessed yearly. Descriptive statistics were generated and repeated-measures general linear models were used to evaluate SLEDAI-2K and SDI over time between whites and nonwhites., Results: Of the 298 patients, 87% were women, 55% were white, 12% were African American, 14% were Asian, 16% were Hispanic, and 2% were categorized as "other." At enrollment, the mean age was 35.3 years, the mean SLEDAI-2K score was 5.9, and the mean disease duration was 5.5 months. Mean SLEDAI-2K scores decreased in the first year and then remained low. SLEDAI-2K scores were significantly lower at each year in whites compared to nonwhites. Mean SDI scores increased progressively over 5 years; there was no significant difference between whites and nonwhites. As expected, ANA positivity was high and anti-DNA positivity was relatively low at enrollment, and both increased over 5 years. Although lupus anticoagulant increased slightly over 5 years, aCL positivity did not., Conclusion: Disease activity in newly diagnosed patients decreases over their first 5 years, while damage increases. Antibody positivity ran variable courses over this period., (Copyright © 2012 by the American College of Rheumatology.)

Objective: To perform a genome-wide association study (GWAS) in Koreans in order to identify susceptibility loci for rheumatoid arthritis (RA)., Methods: We generated high-quality genotypes for 441,398 single-nucleotide polymorphisms (SNPs) in 801 RA cases and 757 controls. We then tested 79 markers from 46 loci for replication in an independent sample of 718 RA cases and 719 controls., Results: Genome-wide significance (P < 5 × 10(-08) ) was attained by markers from the major histocompatibility complex region and from the PADI4 gene. The replication data showed nominal association signals (P < 5 × 10(-02) ) for markers from 11 of the 46 replicated loci, greatly exceeding random expectation. Genes that were most significant in the replication stage and in the combined analysis include the known European RA loci BLK, AFF3, and CCL21. Thus, in addition to the previously associated STAT4 alleles, variants at these three loci may contribute to RA not only among Europeans, but also among Asians. In addition, we observed replication signals near the genes PTPN2, FLI1, ARHGEF3, LCP2, GPR137B, TRHDE, and CGA1. Based on the excess of small P values in the replication stage study, we estimate that more than half of these loci are genuine RA susceptibility genes. Finally, we systematically analyzed the presence of association signals in Koreans at established European RA loci, which showed a significant enrichment of European RA loci among the Korean RA loci., Conclusion: Genetic risk for RA involves both population-specific loci as well as many shared genetic susceptibility loci in comparisons of Asian and European populations., (Copyright © 2011 by the American College of Rheumatology.)