T cell expressions of aberrant gene signatures and Co-inhibitory receptors (Co-IRs) as predictors of renal damage and lupus disease activity.

BACKGROUND: Systemic lupus erythematosus (SLE) is distinguished by an extensive range of clinical heterogeneity with unpredictable disease flares and organ damage. This research investigates the potential of aberrant signatures on T cell genes, soluble Co-IRs/ligands, and Co-IRs expression on T cells as biomarkers for lupus disease parameters. METHODS: Comparative transcriptome profiling analysis of non-renal and end-stage renal disease (ESRD) phenotypes of SLE was performed using CD4 + and CD8 + cDNA microarrays of sorted T cells. Comparing the expression of Co-IRs on T cells and serum soluble mediators among healthy and SLE phenotypes. RESULTS: SLE patients with ESRD were downregulated CD38, PLEK, interferon-γ, CX3CR1, FGFBP2, and SLCO4C1 transcripts on CD4 + and CD8 + T cells simultaneously and NKG7, FCRL6, GZMB/H, FcγRIII, ITGAM, Fas ligand, TBX21, LYN, granulysin, CCL4L1, CMKLR1, HLA-DRß, KIR2DL3, and KLRD1 in CD8 T cells. Pathway enrichment and PPI network analyses revealed that the overwhelming majority of Differentially Expressed Genes (DEGs) have been affiliated with novel cytotoxic, antigen presentation, and chemokine-cell migration signature pathways. CD8 + GZMK + T cells that are varied in nature, including CD161 + Mucosal-associated invariant T (MAIT) cells and CD161- aged-associated T (Taa) cells and CD161-GZMK + GZMB + T cells might account for a higher level of GZMK in CD8 + T cells associated with ESRD. SLE patients have higher TIGIT + , PD1 + , and lower CD127 + cell percentages on CD4 + T cells, higher TIM3 + , TIGIT + , HLA-DR + cell frequency, and lower MFI expression of CD127, CD160 in CD8 T cells. Co-IRs expression in T cells was correlated with soluble PD-1, PDL-2, and TIM3 levels, as well as SLE disease activity, clinical phenotypes, and immune-therapy responses. CONCLUSION: The signature of dysfunctional pathways defines a distinct immunity pattern in LN ESRD patients. Expression levels of Co-IRs in peripheral blood T cells and serum levels of soluble PD1/PDL-2/TIM3 can serve as biomarkers for evaluating clinical parameters and therapeutic responses.

Genetic effects of B3GNT2 on ankylosing spondylitis susceptibility and clinical manifestations in Taiwanese.

BACKGROUND/PURPOSE: The intergenic SNP rs10865331 at 2p15 was identified as a major risk factor for ankylosing spondylitis (AS) susceptibility in genome-wide association studies (GWAS). B3GNT2 gene regulates polylactosamine synthesis is potentially functionally relevant to AS disease development. We investigated whether SNP rs10865331 and two B3GNT2 SNPs (rs11900673 and rs1136151) are associated with AS susceptibility and disease severity in Taiwanese. METHODS: Distributions of genotypes, alleles, and haplotypes of three SNPs were compared between 1,472 AS patients and 2,117 healthy blood donors and among AS patients stratified by clinical characteristics. RESULTS: The intergenic SNP rs10865331 was significantly associated with AS (PFDR = 1.02E-05) in Taiwanese. In AS patients stratified by positivity of HLA-B27 and syndesmophyte formation, all three B3GNT2 locus SNPs (rs11900673, rs1136151, and rs10865331) were significantly associated with syndesmophyte formation among HLA-B27 positive AS patients. Haplotype analyses revealed that the "CTA" (rs11900673C/rs1136151T/rs10865331A) haplotype was significantly associated with AS susceptibility (Padj = 0.0177) and syndesmophyte formation (Padj = 0.016) in HLA-B27 positive patients. In contrast, "TCG" (rs11900673T/rs1136151C/rs10865331G) haplotype showed protection against AS development (Padj = 0.0005 for HLA-B27 positive and Padj = 0.004 for HLA-B27 negative, respectively) and syndesmophyte formation (Padj = 0.0017) in HLA-B27 positive patients. Furthermore, B3GNT2 mRNA expressions were negatively associated with erythrocyte sedimentation rate (ESR, P = 0.0103), C-reactive protein (CRP, P = 0.0353), Bath ankylosing spondylitis functional index (BASFI, P = 0.0171), and syndesmophyte formation (P = 0.0148). CONCLUSION: Our data suggest that B3GNT2 gene may contribute to AS development and affect AS severity by interacting with HLA-B27 in Taiwanese.

Genetic variants of PPAR-gamma coactivator 1B augment NLRP3-mediated inflammation in gouty arthritis.

Objective: Gout is characterized by recurrent attacks of arthritis with hyperuricaemia and urate crystal-induced inflammation. Although urate transporters are known as risk factors, the immunogenetics of gouty inflammation remains unclear. This study aimed to investigate the genetic association between immune/metabolism regulators and gout. Methods: We enrolled 448 gout patients and 943 population controls from Taiwan; all were Han Chinese. We screened association between gout and 22 variants of candidate genes, including NLRP3 , caspase 1, peroxisome proliferator-activated receptor-γ, proliferator-activated receptor-γ coactivator 1α ( PPARGC1A ) and 1ß ( PPARGC1B ). The association was validated by replication and combined-sample analyses. Functional assays were performed by quantitative PCR, ELISA, siRNA knockdown and transfection using THP-1 cells, peripheral blood mononuclear cells and synovial cells from patients. Results: Gouty arthritis exhibited significant association with variants of peroxisome PPARGC1B , which included a missense single nucleotide polymorphism, rs45520937 [P = 6.66 × 10 -9 ; odds ratio (95% CI): 1.85 (1.51, 2.28)]. Expression of PPARGC1B and NLRP3 was induced in urate crystal-activated THP-1, peripheral blood mononuclear cells and synovial cells from gout patients in acute stage. siRNA knockdown of PPARGC1B upregulated NLRP3 in urate crystal-activated macrophages. Compared with the wild-type carriers, patients with the risk A allele of rs45520937 showed statistically increased NLRP3 (P = 0.044) and plasma IL-1ß (P = 0.006). Transfection of PPARGC1B cDNA with rs45520937 A allele to macrophages significantly augmented the expression of NLRP3 and IL-1ß. Conclusion: Genetic variants of PPARGC1B are significantly associated with gout, and a missense single nucleotide polymorphism, rs45520937, augments NLRP3 and IL-1ß expression. These data suggest that variants of PPARGC1B , a regulator of metabolism and inflammation, contribute to the pathogenesis of gouty arthritis.

Human Leukocyte Antigen C*12:02:02 and Killer Immunoglobulin-Like Receptor 2DL5 are Distinctly Associated with Ankylosing Spondylitis in the Taiwanese.

Human leukocyte antigen (HLA) class I ligands and Killer immunoglobulin-like receptors (KIRs) regulate the cytolytic activity of natural killer (NK) cells and certain T cells. We examined their genetic predisposition to disease susceptibility and clinical phenotypes in Taiwanese ankylosing spondylitis (AS) patients. KIR genotyping and Human Leucocyte Antigen C (HLA-C) sequencing were performed in 653 Taiwanese AS patients and 952 healthy controls. KIR genotype distributions and HLA-C allele frequencies were compared in patients and controls and among patients with and without HLA-B27 positivity, early age onset and spinal syndesmophytes. HLA-C alleles were functionally characterized using 3D structural modelling with peptide simulation. This study discovered that the HLA-C*12:02:02 allele (43.42% vs. 3.31%; p < 0.00001 odds ratio (OR), 16.88; 95% confidence intervals (CI): 11.27-25.28) confers a strong risk for Taiwanese AS development. The 3D modelling results identified four unique amino acid polymorphisms, Ala73, Trp156, Arg219 and Met304, that may affect the function of the HLA-C*12:02:02 allele. KIR2DL5 (p = 0.0047; pFDR = 0.0423) and the KIR Bx haplotype (p = 0.0000275) were protective against Taiwanese AS, while KIR 2DS4/1D (22 base pair truncated deletion; p = 0.0044; pFDR = 0.1998) appeared to be a risk factor for it. KIR2DL5 combined with the HLA-C1/C2 heterozygous genotype showed a protective effect (AS 5.97% vs. normal 11.66%; p = 0.002; pFDR = 0.0127, OR, 0.48 95% CI: 0.33-0.70); in contrast, KIR 2DS4/1D combined with the HLA-C1C1 homozygous genotype (AS 45.33% vs. normal 35.92%; p = 0.002; pFDR = 0.0127, OR, 1.48 95% CI: 1.21-1.81) represented a risk factor for AS development. Our data suggested that interactions between KIRs and their cognate HLA-C ligands may contribute to the pathogenesis of AS.

Insights into the poor prognosis of allopurinol-induced severe cutaneous adverse reactions: the impact of renal insufficiency, high plasma levels of oxypurinol and granulysin.

OBJECTIVE: Allopurinol, an antihyperuricaemic agent, is one of the common causes of life-threatening severe cutaneous adverse reactions (SCAR), including drug rash with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN). The prognostic factors for allopurinol-related SCAR remain unclear. This study aimed to investigate the relationship of dosing, renal function, plasma levels of oxypurinol and granulysin (a cytotoxic protein of SJS/TEN), the disease severity and mortality in allopurinol-SCAR. METHODS: We prospectively enrolled 48 patients with allopurinol-SCAR (26 SJS/TEN and 22 DRESS) and 138 allopurinol-tolerant controls from 2007 to 2012. The human leucocyte antigen (HLA)-B*58:01 status, plasma concentrations of oxypurinol and granulysin were determined. RESULTS: In this cohort, HLA-B*58:01 was strongly associated with allopurinol-SCAR (p<0.001, OR (95% CI) 109 (25 to 481)); however, the initial/maintenance dosages showed no relationship with the disease. Poor renal function was significantly associated with the delayed clearance of plasma oxypurinol, and increased the risk of allopurinol-SCAR (p<0.001, OR (95% CI) 8.0 (3.9 to 17)). Sustained high levels of oxypurinol after allopurinol withdrawal correlated with the poor prognosis of allopurinol-SCAR. In particular, the increased plasma levels of oxypurinol and granulysin linked to the high mortality of allopurinol-SJS/TEN (p<0.01), and strongly associated with prolonged cutaneous reactions in allopurinol-DRESS (p<0.05). CONCLUSIONS: Impaired renal function and increased plasma levels of oxypurinol and granulysin correlated with the poor prognosis of allopurinol-SCAR. Allopurinol prescription is suggested to be avoided in subjects with renal insufficiency and HLA-B*58:01 carriers. An early intervention to increase the clearance of plasma oxypurinol may improve the prognosis of allopurinol-SCAR.

Comprehensive Co-Inhibitory Receptor (Co-IR) Expression on T Cells and Soluble Proteins in Rheumatoid Arthritis.

Co-inhibitory receptors (Co-IRs) are essential in controlling the progression of immunopathology in rheumatoid arthritis (RA) by limiting T cell activation. The objective of this investigation was to determine the phenotypic expression of Co-IR T cells and to assess the levels of serum soluble PD-1, PDL-2, and TIM3 in Taiwanese RA patients. METHODS: Co-IRs T cells were immunophenotyped employing multicolor flow cytometry, and ELISA was utilized for measuring soluble PD-1, PDL-2, and TIM3. Correlations have been detected across the percentage of T cells expressing Co-IRs (MFI) and different indicators in the blood, including ESR, high-sensitivity CRP (hsCRP), 28 joint disease activity scores (DAS28), and soluble PD-1/PDL-2/TIM3. RESULTS: In RA patients, we recognized elevated levels of PD-1 (CD279), CTLA-4, and TIGIT in CD4+ T cells; TIGIT, HLA-DR, TIM3, and LAG3 in CD8+ T cells; and CD8+CD279+TIM3+, CD8+HLA-DR+CD38+ T cells. The following tests were revealed to be correlated with hsCRP: CD4/CD279 MFI, CD4/CD279%, CD4/TIM3%, CD8/TIM3%, CD8/TIM3 MFI, CD8/LAG3%, and CD8+HLA-DR+CD38+%. CD8/LAG3 and CD8/TIM3 MFIs are linked to ESR. DAS28-ESR and DAS28-CRP exhibited relationships with CD4/CD127 MFI, CD8/CD279%, and CD8/CD127 MFI, respectively. CD4+CD279+TIM3+% was correlated with DAS28-ESR (p = 0.0084, N = 46), DAS28-CRP (p = 0.007, N = 47), and hsCRP (p = 0.002, N = 56), respectively. In the serum of patients with RA, levels of soluble PD-1, PDL-2, and Tim3 were extremely elevated. CD4+ TIM3+% (p = 0.0089, N = 46) and CD8+ TIM3+% (p = 0.0305, N = 46) were correlated with sTIM3 levels; sPD1 levels were correlated with CD4+CD279+% (p < 0.0001, N = 31) and CD3+CD279+% (p = 0.0084, N = 30). CONCLUSIONS: Co-IR expressions on CD4+ and CD8+ T cells, as well as soluble PD-1, PDL-2, and TIM3 levels, could function as indicators of disease activity and potentially play crucial roles in the pathogenesis of RA.

Association of systemic lupus erythematosus standard of care immunosuppressants with glucocorticoid use and disease outcomes: a multicentre cohort study.

BACKGROUND: This study examines the association of standard-of-care systemic lupus erythematosus (SLE) medications with key outcomes such as low disease activity attainment, flares, damage accrual, and steroid-sparing, for which there is current paucity of data. METHODS: The Asia Pacific Lupus Collaboration (APLC) prospectively collects data across numerous sites regarding demographic and disease characteristics, medication use, and lupus outcomes. Using propensity score methods and panel logistic regression models, we determined the association between lupus medications and outcomes. RESULTS: Among 1707 patients followed over 12,689 visits for a median of 2.19 years, 1332 (78.03%) patients achieved the Lupus Low Disease Activity State (LLDAS), 976 (57.18%) experienced flares, and on most visits patients were taking an anti-malarial (69.86%) or immunosuppressive drug (76.37%). Prednisolone, hydroxychloroquine and azathioprine were utilised with similar frequency across all organ domains; methotrexate for musculoskeletal activity. There were differences in medication utilisation between countries, with hydroxychloroquine less frequently, and calcineurin inhibitors more frequently, used in Japan. More patients taking leflunomide, methotrexate, chloroquine/hydroxychloroquine, azathioprine, and mycophenolate mofetil/mycophenolic acid were taking ≤ 7.5 mg/day of prednisolone (compared to > 7.5 mg/day) suggesting a steroid-sparing effect. Patients taking tacrolimus were more likely (Odds Ratio [95% Confidence Interval] 13.58 [2.23-82.78], p = 0.005) to attain LLDAS. Patients taking azathioprine (OR 0.67 [0.53-0.86], p = 0.001) and methotrexate (OR 0.68 [0.47-0.98], p = 0.038) were less likely to attain LLDAS. Patients taking mycophenolate mofetil were less likely to experience a flare (OR 0.79 [0.64-0.97], p = 0.025). None of the drugs was associated with a reduction in damage accrual. CONCLUSIONS: This study suggests a steroid-sparing benefit for most commonly used standard of care immunosuppressants used in SLE treatment, some of which were associated with an increased likelihood of attaining LLDAS, or reduced incidence of flares. It also highlights the unmet need for effective treatments in lupus.

Functional ERAP1 Variants Distinctively Associate with Ankylosing Spondylitis Susceptibility under the Influence of HLA-B27 in Taiwanese.

Epistasis of ERAP1 single nucleotide variations (SNVs) and HLA-B27 has been linked to ankylosing spondylitis susceptibility (AS). The current study examined how prevalent ERAP1 allelic variants (SNV haplotypes) in Taiwan affect ERAP1 functions and AS susceptibility in the presence or absence of HLA-B27. Sanger sequencing was used to discover all ERAP1 coding SNVs and common allelic variants in Taiwanese full-length cDNAs from 45 human patients. For the genetic association investigation, TaqMan genotyping assays were utilized to establish the genotypes of ERAP1 SNVs in 863 AS patients and 1438 healthy controls. Ex vivo biological analysis of peripheral blood mononuclear cells from homozygous donors of two common-risk ERAP1 allelic variants was performed. Two common-risk ERAP1 allelic variants were also cloned and functionally studied. In Taiwanese, eleven frequent ERAP1 SNVs and six major ERAP1 allelic variants were discovered. We discovered that in Taiwanese, the most prevalent ERAP1-001 variant with 56E, 127R, 276I, 349M, 528K, 575D, 725R, and 730Q interacting with HLA-B27 significantly contributed to the development of AS. In HLA-B27 negative group, however, the second most prevalent ERAP1-002 variant with 56E, 127P, 276M, 349M, 528R, 575D, 725R, and 730E was substantially related with an increased risk of AS. Ex vivo and in vitro research demonstrated that ERAP1 allelic variants have a significant impact on ERAP1 functions, suggesting that ERAP1 plays a role in the development of AS. In an HLA-B27-dependent manner, common ERAP1 allelic variants are related with AS susceptibility.

Implementation of NUDT15 Genotyping to Prevent Azathioprine-Induced Leukopenia for Patients With Autoimmune Disorders in Chinese Population.

Azathioprine (AZA) is commonly used for many autoimmune disorders; however, the limitation of its clinical use is due to potential toxicities, including severe leukopenia. Recent studies have identified genetic NUDT15 variants strongly associated with AZA-induced leukopenia in Asian patients. This study aimed to investigate the strength of above genetic association and evaluate the usefulness of prospective screening of the NUDT15 variants to prevent AZA-induced leukopenia in Chinese patients. AZA-induced leukopenia in patients with autoimmune disorders were enrolled from multiple medical centers in Taiwan/China between 2012 and 2017 to determine the strength of genetic association of NUDT15 or TPMT variants by whole exome sequencing (WES). Furthermore, a prospective study was conducted between 2018 and 2021 to investigate the incidence of AZA-induced leukopenia with and without genetic screening. The WES result showed the genetic variants of NUDT15 R139C (rs116855232) (P = 3.7 × 10-25 , odds ratio (OR) = 21.7, 95% confidence interval (95% CI) = 12.1-38.8) and NUDT15 rs746071566 (P = 4.2 × 10-9 , OR = 7.1, 95% CI = 3.7-13.7), but not TPMT, were associated with AZA-induced leukopenia and NUDT15 R139C variant shows the highest sensitivity with 92.5%. Furthermore, the targeted screening of 1,013 participants for NUDT15 R139C enabled those identified as carriers to use alternative immunosuppressants. This strategy resulted in a significant decrease in the incidence of AZA-induced leukopenia compared with historical incidence (incidence rate = from 7.6% decreased to 0.4%; P = 9.3 × 10-20 ). In conclusion, the NUDT15 R139C variant was strongly associated with AZA-induced leukopenia in Chinese patients. The genetic screening of NUDT15 R139C followed by use of alternative immunosuppressants in identified carriers effectively decreased the incidence of AZA leukopenia for patients with autoimmune disorders.

MICA*019 Allele and Soluble MICA as Biomarkers for Ankylosing Spondylitis in Taiwanese.

MICA (major histocompatibility complex class I chain-related gene A) interacts with NKG2D on immune cells to regulate host immune responses. We aimed to determine whether MICA alleles are associated with AS susceptibility in Taiwanese. MICA alleles were determined through haplotype analyses of major MICA coding SNP (cSNP) data from 895 AS patients and 896 normal healthy controls in Taiwan. The distributions of MICA alleles were compared between AS patients and normal healthy controls and among AS patients, stratified by clinical characteristics. ELISA was used to determine soluble MICA (sMICA) levels in serum of AS patients and healthy controls. Stable cell lines expressing four major MICA alleles (MICA*002, MICA*008, MICA*010 and MICA*019) in Taiwanese were used for biological analyses. We found that MICA*019 is the only major MICA allele significantly associated with AS susceptibility (PFDR = 2.25 × 10-115; OR, 14.90; 95% CI, 11.83-18.77) in Taiwanese. In addition, the MICA*019 allele is associated with syndesmophyte formation (PFDR = 0.0017; OR, 1.69; 95% CI, 1.29-2.22) and HLA-B27 positivity (PFDR = 1.45 × 10-33; OR, 28.79; 95% CI, 16.83-49.26) in AS patients. Serum sMICA levels were significantly increased in AS patients as compared to healthy controls. Additionally, MICA*019 homozygous subjects produced the highest levels of sMICA, compared to donors with other genotypes. Furthermore, in vitro experiments revealed that cells expressing MICA*019 produced the highest level of sMICA, as compared to other major MICA alleles. In summary, the MICA*019 allele, producing the highest levels of sMICA, is a significant risk factor for AS and syndesmophyte formation in Taiwanese. Our data indicate that a high level of sMICA is a biomarker for AS.

Herbal Formula SS-1 Increases Tear Secretion for Sjögren's Syndrome.

Background: Sjögren's syndrome (SS) is an autoimmune inflammatory disease that primarily affects the exocrine glands, leading to glandular dysfunction. The hallmark symptoms of SS are dry eyes and mouth, compromising the quality of life of patients and decreasing their capacity to perform their daily activities. Objective: This study aims to evaluate the efficacy of the herbal formula SS-1 for its potential therapeutic benefits for patients with Sjögren's syndrome. Materials and Methods: The bioactivity profile of SS-1 was determined using four different SS-1 concentrations across 12 human primary cell systems of the BioMAP profile. After that, a randomized, double-blind, crossover, placebo-controlled trial was performed including 57 patients treated with SS-1 for 28 weeks. Results: Biologically multiplexed activity profiling in cell-based models indicated that SS-1 exerted anti-proliferative activity in B cells and promoted anti-inflammatory and immunomodulatory activity. In the clinical trial, Schirmer's test results revealed significant improvements in both eyes, with increases of 3.42 mm (95% CI, 2.44-4.41 mm) and 3.45 mm (95% CI, 2.32-4.59 mm), respectively, and a significant reduction in artificial tear use, which was -1.38 times/day, 95% CI, -1.95 to -0.81 times/day. Moreover, the increases in B-cell activating factor (BAFF) and B-cell maturation antigen (BCMA) levels were dampened by 53.20% (295.29 versus 555.02 pg/ml) and 58.33% (99.16 versus 169.99 pg/ml), respectively. Conclusion: SS-1 treatment significantly inhibited B-cell maturation antigen. No serious drug-related adverse effects were observed. Oral SS-1 administration may be a complementary treatment for Sjögren's syndrome.

Development of the Asia Pacific Lupus Collaboration cohort.

AIM: The aim of this manuscript is to describe the development of the Asia Pacific Lupus Collaboration (APLC) cohort. METHOD: The APLC cohort is an ongoing, prospective longitudinal cohort. Adult patients who meet either the American College of Rheumatology (ACR) Modified Classification Criteria for systemic lupus erythematosus (SLE), or the Systemic Lupus International Collaborating Clinics (SLICC) Classification Criteria, and provide informed consent are recruited into the cohort. Patients are routinely followed up at 3- to 6-monthly intervals. Information on demographics, clinical manifestations, treatment, pathology results, outcomes, and patient-reported quality of life (Short-form 36 version 2) are collected using a standardized case report form. Each site is responsible for obtaining local ethics and governance approval, patient recruitment, data collection, and data transfer into a centralized APLC database. RESULTS: The latest APLC cohort comprises 2160 patients with >12 000 visits from Australia, China, Hong Kong, Indonesia, Japan, Malaysia, Philippines, Singapore, Taiwan and Thailand. The APLC has proposed the Lupus Low Disease Activity State (LLDAS) as a treat-to-target (T2T) endpoint, and reported several retrospective and cross-sectional analyses consistent with the validity of LLDAS. Longitudinal validation of LLDAS as a T2T endpoint is currently underway. CONCLUSION: The APLC cohort is one of the largest contemporary SLE patient cohorts in the world. It is the only cohort with substantial representation of Asian patients. This cohort represents a unique resource for future clinical research including evaluation of other endpoints and quality of care.

Interferon-λ3/4 genetic variants and interferon-λ3 serum levels are biomarkers of lupus nephritis and disease activity in Taiwanese.

BACKGROUND: Type III interferons (IFNs) or IFN-λs are the newly discovered cytokines that primarily target the cells of epithelial and myeloid lineages, which are major components of kidneys. The current study aimed to investigate whether IFN-λs are involved in the pathogenesis of systemic lupus erythematosus (SLE) and lupus nephritis. METHODS: TaqMan allele discrimination assays were used to determine IFNL3/4 SNP genotypes of 1620 healthy controls and 1013 SLE patients (two independent cohorts consisting of 831 and 182 subjects, respectively) from Taiwan. The distributions of IFNL3/4 SNP genotypes and allele frequencies were compared between SLE patients and healthy controls and among SLE patients stratified by clinical phenotypes. ELISA was used to determine the serum IFN-λ3 concentrations of SLE patients. RESULTS: All major IFN3/4 SNP alleles were significantly associated with the risk for lupus nephritis (rs8099917T, PFDR = 0.0021, OR 1.75, 95% CI 1.24-2.47; rs12979860C, PFDR = 0.0034, OR 1.65, 95% CI 1.18-2.30; rs4803217C, PFDR = 0.0021, OR 1.76, 95% CI 1.25-2.48; and ss469415590TT, PFDR = 0.0021, OR 1.73, 95% CI 1.23-2.42) among SLE patients. Similarly, the major IFNL3/4 SNP haplotype rs8099917T-ss469415590TT-rs12979860C-rs4803217C (or T-TT-C-C) was a significant risk factor for lupus nephritis (P = 0.0015, OR 1.68, 95% CI 1.22-2.32). Additionally, all minor IFN3/4 SNP alleles were significantly associated with SLE susceptibility in nephritis-negative SLE patients as compared to normal healthy controls (rs8099917G, PFDR = 0.00177, OR 1.68, 95% CI 1.24-2.28; rs12979860T, PFDR = 0.00299, OR 1.58, 95% CI 1.18-2.32; rs4803217A, PFDR = 0.00176, OR 1.65, 95% CI 1.22-2.23; and ss469415590ΔG, PFDR = 0.00176, OR 1.70, 95% CI 1.26-2.29). Furthermore, the elevated serum levels of IFN-λ3 were significantly correlated with the complement depression and the high SLE disease activities in SLE patients. CONCLUSIONS: IFN-λ3/4 genetic variants play a unique role in the development of lupus nephritis and SLE.

High levels of soluble GPR56/ADGRG1 are associated with positive rheumatoid factor and elevated tumor necrosis factor in patients with rheumatoid arthritis.

BACKGROUND: GPR56/ADGRG1 is a member of the adhesion-class G protein-coupled receptor (aGPCR) family important in brain development, oncogenesis and tumor metastasis. Like other aGPCRs, GPR56 is cleaved at the GPCR proteolysis site (GPS) motif into an N-terminal fragment (NTF) and a C-terminal fragment (CTF). Existence of soluble GPR56 (sGPR56) has been shown in vitro, however the underlying mechanism and its pathophysiologic role remains undetermined. OBJECTIVE: To assess the presence of sGPR56 in human serum using ELISA assay and compare the serum sGPR56 levels among patients of various chronic inflammatory diseases and healthy subjects. PATIENTS AND METHODS: In this study, serum samples from patients with systemic lupus erythematosus (SLE) (n = 57), rheumatoid arthritis (RA) (n = 95), Sjögren's syndrome (SS) (n = 29), ankylosing spondylitis (AS) (n = 51), and normal controls (n = 81) were analyzed using sGPR56-specific ELISA. RESULT: We show that serum sGPR56 levels are increased in patients of RA, but not in those with SLE, SS and AS. Intriguingly, serum sGPR56 levels in RA patients correlated with positive rheumatoid factor, a marker of bone erosion and poor outcome. In addition, an elevated sGPR56 level is also noted in RA patients with higher tumor necrosis factor level. CONCLUSION: we conclude that sGPR56 is present in vivo and sGPR56 level is elevated in certain chronic inflammatory diseases such as RA. Hence, sGPR56 might be considered a potential biomarker for RA disease progression.

Interstitial lung disease in polymyositis and dermatomyositis.

The aim of the study was to estimate the prevalence, characteristics, and prognostic factors of interstitial lung disease (ILD) in patients with polymyositis (PM) and dermatomyositis (DM). The medical records of 151 PM/DM patients treated at Chang Gung Memorial Hospital between January, 2000 and June, 2007 were retrospectively reviewed. Thirty of 151 (19.9%) PM/DM patients had developed ILD. Older age at PM/DM onset, anti-Jo-1 antibody, and arthritis/arthralgia were associated with the presence of ILD (p = 0.004, p = 0.008, and p = 0.026, respectively). Anti-Jo-1 was initially excluded from the multivariate analysis because only 80 patients underwent the test. An older age at onset above 45 years (odds ratio 3.28, 95% confidence interval (CI) 1.15-9.34, p = 0.026) and arthritis/arthralgia at onset (odds ratio (OR) 2.57, 95% CI 1.09-6.08, p = 0.032) were the two independent risk factors for developing ILD. If anti-Jo-1 was included in the multivariate analysis (n = 80), then an older age at onset above 45 years (OR 7.30, 95% CI 1.70-31.40, p = 0.008) and anti-Jo-1 positive (OR 7.89, 95% CI 1.18-52.87, p = 0.033) were associated with ILD, while arthritis/arthralgia was no longer significant (OR 2.64, 95% CI 0.70-10.01, p = 0.153). Of the 30 ILD patients, 16 (53.3%) died. The survival time was significantly shorter in ILD patients than in patients without ILD (p < 0.001). Poor survival in ILD patients was associated with male gender (p = 0.039), a Hamman-Rich-like presentation (p = 0.039), and a clinical diagnosis of acute interstitial pneumonia (p = 0.007).