Association of CD247 with systemic lupus erythematosus in Asian populations.

OBJECTIVE: Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with complex genetic inheritance. CD247 (CD3Z, TCRZ) plays a vital role in antigen recognition and signal transduction in antigen-specific immune responses, and is known to be involved in SLE pathogenesis. Weak disease association was reported for genetic variants in this gene in Caucasian studies for SLE, Crohn's disease and systemic sclerosis, but its role as a genetic risk factor was never firmly established. METHODS: In this study, using a collection of 612 SLE patients and 2193 controls of Chinese ethnicity living in Hong Kong in a genome-wide study, single nucleotide polymorphisms (SNPs) in and around CD247 were identified as being associated with SLE. The two most significant SNPs in this locus were selected for further replication using TaqMan genotyping assay in 3339 Asian patients from Hong Kong, Mainland China, and Thailand, as well as 4737 ethnically and geographically matched controls. RESULTS: The association of CD247 with SLE in Asian populations was confirmed (rs704853: odds ratio [OR] = 0. 81, p = 2.47 × 10(-7); rs858543: OR = 1.10, p = 0.0048). Patient-only analysis suggested that rs704853 is also linked to oral ulcers, hematologic disorders and anti-double-stranded DNA (dsDNA) antibody production. CONCLUSION: A significant association between variants in CD247 and SLE was demonstrated in Asian populations. Understanding the involvement of CD247 in SLE may shed new light on disease mechanisms and development of new treatment paradigms.

Two missense variants in UHRF1BP1 are independently associated with systemic lupus erythematosus in Hong Kong Chinese.

UHRF1BP1 encodes a highly conserved protein with unknown function. Previously, a coding variant in this gene was found to be associated with systemic lupus erythematosus (SLE) in populations of European ancestry (rs11755393, R454Q, P=2.22 x 10⁻8, odds ratio=1.17). In this study, by a combination of genome-wide study and replication involving a total of 1230 patients and 3144 controls, we confirmed the association of this coding variant to SLE in Hong Kong Chinese. We also identified another coding variant in this gene that independently contributes to SLE susceptibility (rs13205210, M1098T, P=4.44 x 10⁻9, odds ratio=1.49). Cross-population confirmation establishes the involvement of this locus in SLE and indicates that distinct alleles are contributing to disease susceptibility.

Prognostically distinct clinical patterns of systemic lupus erythematosus identified by cluster analysis.

The objective of this study was to evaluate the patterns of clinical manifestations and their mortality in a large cohort of Chinese patients with systemic lupus erythematosus. The cumulative clinical manifestations of a large group of Chinese systemic lupus erythematosus patients who fulfilled at least four American College of Rheumatology criteria for systemic lupus erythematosus were studied. Patients were divided into distinct groups by using the K-mean cluster analysis. Clinical features, prevalence of proliferative lupus nephritis (World Health Organization class III, IV), autoantibody profile, and treatment data were compared and the standardized mortality ratios were calculated for each cluster of patients. There were 1082 patients included in the study (mean age at systemic lupus erythematosus diagnosis 30.5 years; mean systemic lupus erythematosus duration 10.3 years). Three distinct groups of patients were identified. Cluster 1 (n = 347) was characterized predominantly by mucocutaneous manifestations (malar rash, discoid rash, photosensitivity, oral ulcer) and arthritis but having the lowest prevalence of serositis, hematologic manifestations (hemolytic anemia, leukopenia, and thrombocytopenia), and proliferative lupus nephritis. Patients in cluster 2 (n = 409) had mainly renal and hematological manifestations but having the lowest prevalence of mucocutaneous manifestations. Pulmonary and gastrointestinal manifestations were significantly more frequent in cluster 2 than the other clusters. Cluster 3 patients (n = 326) had the most heterogeneous features. Besides having a high prevalence of mucocutaneous manifestations, serositis and hematologic manifestations, renal involvement, and proliferative lupus nephritis was also most prevalent among the three clusters. Patients in cluster 2 had a much higher standardized mortality ratio [standardized mortality ratio 7.23 (6.7-7.7), p < 0.001] than those in cluster 3 [standardized mortality ratio 1.27 (1.1-1.5), p = 0.005] and cluster 1 [standardized mortality ratio 0.95 (0.5-1.7), p = 0.86]. In conclusion, patients with systemic lupus erythematosus could be clustered into prognostically distinct patterns of clinical manifestations.

Association of BANK1 and TNFSF4 with systemic lupus erythematosus in Hong Kong Chinese.

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with complex genetic inheritance. Recently, single nucleotide polymorphisms (SNPs) in BANK1 and TNFSF4 have been shown to be associated with SLE in Caucasian populations, but it is not known whether they are also involved in the disease in other ethnic groups. Recent data from our genome-wide association study (GWAS) for 314 SLE cases and 920 controls collected in Hong Kong identified SNPs in and around BANK1 and TNFSF4 to be associated with SLE risk. On the basis of the results of the reported studies and our GWAS, SNPs were selected for further genotyping in 949 SLE patients (overlapping with the 314 cases in our GWAS) and non-overlapping 1042 healthy controls. We confirmed the associations of BANK1 and TNFSF4 with SLE in Chinese (BANK1, rs3733197, odds ratio (OR)=0.84, P=0.021; BANK1, rs17266594, OR=0.61, P=4.67 x 10(-9); TNFSF4, rs844648, OR=1.22, P=2.47 x 10(-3); TNFSF4, rs2205960, OR=1.30, P=2.41 x 10(-4)). Another SNP located in intron 1 of BANK1, rs4522865, was separately replicated by Sequenom in 360 cases and 360 controls and was also confirmed to be associated with SLE (OR=0.725, P=2.93 x 10(-3)). Logistic regression analysis showed that rs3733197 (A383T in ankyrin domain) and rs17266594 (a branch point-site SNP) from BANK1 had independent contributions towards the disease association (P=0.037 and 6.63 x 10(-8), respectively). In TNFSF4, rs2205960 was associated with SLE independently from the effect of rs844648 (P=6.26 x 10(-3)), but not vice versa (P=0.55). These findings suggest that multiple independent genetic variants may be present within the gene locus, which exert their effects on SLE pathogenesis through different mechanisms.

Population differences in SLE susceptibility genes: STAT4 and BLK, but not PXK, are associated with systemic lupus erythematosus in Hong Kong Chinese.

In this study, we compared the association of several newly discovered susceptibility genes for systemic lupus erythematosus (SLE) between populations of European origin and two Asian populations. Using 910 SLE patients and 1440 healthy controls from Chinese living in Hong Kong, and 278 SLE patients and 383 controls in Thailand, we studied association of STAT4, BLK and PXK with the disease. Our data confirmed association of STAT4 (rs7574865, odds ratio (OR) =1.71, P=3.55 x 10(-23)) and BLK (rs13277113, OR=0.77, P=1.34 x 10(-5)) with SLE. It was showed that rs7574865 of STAT4 is also linked to hematologic disorders and potentially some other subphenotypes of the disease. More than one genetic variant in STAT4 were found to be associated with the disease independently in our populations (rs7601754, OR=0.59, P=1.39 x 10(-9), and P=0.00034 when controlling the effect of rs7574865). With the same set of samples, however, our study did not detect any significant disease association for PXK, a risk factor for populations of European origin (rs6445975, joint P=0.36, OR=1.06, 95% confidence interval: 0.93-1.21). Our study indicates that some of the susceptibility genes for this disease may be population specific.

Anti-cyclic citrullinated peptide: diagnostic and prognostic values in juvenile idiopathic arthritis and rheumatoid arthritis in a Chinese population.

OBJECTIVE: The incidence and clinical significance of anti-cyclic citrullinated peptide (CCP) antibodies in a cohort of Chinese patients with juvenile idiopathic arthritis (JIA) and adults with rheumatoid arthritis (RA) were studied. METHODS: Anti-CCP antibodies were determined by enzyme-linked immunosorbent assay (ELISA) in 59 patients with JIA, 129 adult RA patients, 48 children with diseases other than JIA, 68 adult patients with rheumatic diseases other than RA, and 60 normal adults. Associations between anti-CCP antibodies and clinical and laboratory parameters were determined by Fisher's exact test. RESULTS: Six of 59 (10.2%) patients with JIA and 71 of 129 (55%) patients with RA were positive for anti-CCP. Four of five RF-positive JIA patients and two of 54 RF-negative JIA patients were positive (p<0.001). One paediatric patient with allergy (0.9%) and two adult patients with rheumatic diseases other than RA (2.3%) were positive. All healthy controls were negative for anti-CCP. The specificity was 99.1% for JIA and 98.4% for RA. The sensitivity was 10.2% for JIA and 55% for RA. Positive predictive values were 85.7% for JIA and 97.3% for RA and negative predictive values were 66.9% for JIA and 68.5% for RA. CONCLUSION: The anti-CCP antibody assay is a valuable tool for the diagnosis of RA and a subset of JIA in Chinese patients. It could be a useful predictive test for joint erosion in JIA of the polyarticular RF-positive subset and may be influential in the choice of the best therapeutic strategy in patients with recent-onset arthritis.

Translation and validation of Arthritis Impact Measurement Scales 2 into Chinese: CAIMS2.

OBJECTIVE: To evaluate the validity, reliability, and cultural relevance of the Arthritis Impact Measurement Scales 2 (AIMS2) as a health assessment tool for Chinese-speaking patients with arthritis. METHODS: The cultural relevance, language equivalency, and content validity of the AIMS2, Chinese version (CAIMS2) were evaluated by an expert panel. Measurement performance was tested on 240 subjects (rheumatoid arthritis = 81, osteoarthritis = 77, healthy = 82). Subjects (n = 175) were retested within 2 weeks for testing of reliability. RESULTS: Three items were modified and 2 items were added, as suggested by the expert panel. Interitem reliability was satisfactory (intraclass correlation coefficient 0.8552-0.9594). Test-retest reliability of the CAIMS2 subscales ranged from 0.770 to 0.952 in subjects in whom the CAIMS2 was self administered. Significant score differences between patients with arthritis and healthy subjects were found in all 12 subscales, except for the support from family and friends and tension subscales. CAIMS2 subscale scores correlated with clinical and laboratory measures of disease activity and patients' perceived quality of life as measured using the Chinese version of the World Health Organization Quality of Life instrument. CONCLUSION: Empirical data support CAIMS2 is a valid and reliable health status measure for Chinese speaking patients with arthritis.

Interstitial lung disease in systemic sclerosis.

PURPOSE: To evaluate high-resolution CT (HRCT) parameters of inflammation and fibrosis in systemic sclerosis (SSc), for correlation with lung function, skin scores and exercise tolerance. MATERIAL AND METHODS: 45 SSc patients (40 women, 48.5+/-13.4 years), underwent thoracic HRCT, lung function assessment, and modified Rodnan skin scores. Exercise tolerance was also graded. HRCT were scored for extent of 4 HRCT patterns of interstitial lung disease (ILD): ground glass opacification (GGO), reticular, mixed and honeycomb pattern in each lobe. Total HRCT score, inflammation index (GGO and mixed score) and fibrosis index (reticular and honeycomb scores) were correlated with lung function and clinical parameters. RESULTS: ILD was present in 39/45 (86.7%) patients. Abnormal (<80% predicted) forced vital capacity (FVC), total lung capacity (TLC) and carbon monoxide diffusion factor (DLco) were detected in 30%, 22% and 46% of patients. Total HRCT score correlated with FVC (r=-0.43, p=0.008), FEV1 (forced expiratory volume) (r=-0.37, p=0.03), TLC (r=-0.47, p=0.003), and DLCO (r=-0.43, p=0.008); inflammatory index with DLCO (r=-0.43, p=0.008) and exercise tolerance (r=-0.39, p < 0.05); and fibrosis index with FVC (r=-0.31, p=0.05) and TLC (r=-0.38, p=0.02). Higher total HRCT score, and inflammation and fibrosis indices were found in patients with abnormal lung function. CONCLUSION: Qualitative HRCT is able to evaluate inflammation and fibrosis, showing important relationships with diffusion capacity and lung volume, respectively.

Lymphoepithelioma-like carcinoma of the parotid gland in a patient with rheumatoid arthritis.

Lymphoepithelioma-like carcinoma (LELC) is an Epstein-Barr virus (EBV) related malignancy. It is not a common condition and is usually found in the head and neck region. We describe the development of LELC involving the parotid gland in a patient with rheumatoid arthritis (RA) who had been receiving long-term azathioprine. A brief review is also made on the clinical presentation and histological features of LELC and the association of RA with EBV related diseases. The latter may be attributed to an increase in risk of malignancy associated with RA or as a result of the long-term immunosuppressive used.