Association of HLA-DRB1 locus with treatment response to abatacept or TNF inhibitors in patients with seropositive rheumatoid arthritis.

The strongest genetic risk factor for rheumatoid arthritis (RA) has been known as HLA-DRB1 based on amino acid positions 11, 71, and 74. This study analyzed the association between specific HLA-DRB1 locus and treatment response to abatacept or TNF inhibitors (TNFi) in patients with seropositive RA. A total of 374 Korean RA patients were treated with abatacept (n = 110) or TNFi (n = 264). Associations between HLA-DRB1 and treatment response after 6 months were analyzed using multivariable logistic regression. Seropositive RA patients with HLA-DRB1 shared epitope (SE) had a favorable response to abatacept (OR = 3.67, P = 0.067) and an inversely associated response to TNFi (OR 0.57, P = 0.058) based on EULAR response criteria, but the difference was not statistically significant in comparison to those without SE. In analyses using amino acid positions of HLA-DRB1, a significant association was found between valine at amino acid position 11 of SE and good response to abatacept (OR = 6.46, P = 5.4 × 10-3). The VRA haplotype also showed a good response to abatacept (OR = 4.56, P = 0.013), but not to TNFi. Our results suggest that treatment response to abatacept or TNFi may differ depending on HLA-DRB1 locus in seropositive RA, providing valuable insights for selecting optimal therapy.

MUC5B promoter variant rs35705950, rare but significant susceptibility locus in rheumatoid arthritis-interstitial lung disease with usual interstitial pneumonia in Asian populations.

BACKGROUND: MUC5B variant rs35705950 is the common and most significant risk variant for rheumatoid arthritis-interstitial lung disease (RA-ILD) in Western populations. However, little is known about its significant association with RA-ILD in Asian populations. We here investigate the association of rs35705950 with Korean patients with RA-ILD. METHODS: In this cross-sectional study, we genotyped rs35705950 in 2444 patients with RA. Among them, 683 patients with RA who have chest CT were divided into RA-ILD and RA-noILD. RA-ILD was classified as usual interstitial pneumonia (UIP) and other than UIP. The associations of rs35705950 with RA-ILD and its subtype were analysed using multivariable regression adjusted for age at RA diagnosis. Meta-analysis of a previously reported Japanese dataset and Korean dataset obtained for this study was conducted. RESULTS: The minor allele (T) frequency of rs35705950 was 0.37%, 1.43% and 2.38% in 2444 patients with RA, 105 patients with RA-ILD and 63 patients with UIP, respectively. Genotypic association of rs35705950 with RA-ILD was insignificant (OR 2.49, 95% CI 0.64 to 9.69, p=0.187), but showed significant association with UIP (OR 4.90, 95% CI 1.23 to 19.59, p=0.024) compared with RA-noILD. In meta-analysis (123 UIP and 878 RA-noILD) combining our data with previously reported Japanese data, this variant was found to be significantly associated with UIP (OR 3.51, 95% CI 1.19 to 10.37, p=0.023). CONCLUSION: MUC5B variant rs35705950 is a rare but significant risk factor for Asian patients with RA-ILD with UIP, suggesting a sharing of the genetic background between Asian and Western populations.

Use of Disease-modifying Antirheumatic Drugs After Cancer Diagnosis in Rheumatoid Arthritis Patients.

Objective: There is no recommendation for the use of disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA) who developed cancer. We examined changes in the DMARDs prescription patterns associated with cancer diagnosis in RA patients. Methods: We reviewed the medical records of 2,161 RA patients who visited rheumatology clinic between January 2008 and February 2017 and found 40 patients who developed cancer during RA treatment. In these patients, we examined DMARDs prescription patterns before and right after cancer diagnosis and at recent outpatient clinic visits. Results: Before cancer diagnosis, methotrexate (MTX)-combined conventional synthetic DMARDs (csDMARDs) were most commonly prescribed (22, 55.0%) and biological DMARDs (biologics) in nine patients (22.5%). For cancer treatment, 19 patients received chemotherapy (including adjuvant chemotherapy) and 21 patients had surgery only. Right after cancer diagnosis, changes in the DMARDs prescription patterns were similar in discontinuation (13, 32.5%), switching (14, 35.0%), and maintenance (13, 32.5%). DMARDs were discontinued more frequently in the chemotherapy group (9/19, 47.4%) than the surgery only group (4/2, 19.0%) (p<0.05). Among the 13 patients who discontinued DMARDs, nine (69.2%) resumed DMARDs after a median of 5.5 months (interquartile range [IQR] 2.9, 18.3) due to arthritis flare. At a median of 4.6 years (IQR 3.3, 6.7) after cancer diagnosis, 25 patients were evaluated at recent outpatient clinic visits. Four patients received no DMARD, three MTX monotherapies, 11 csDMARDs combination therapies, and seven biologics. Conclusion: A significant number of RA patients who developed cancer during RA treatment were still receiving DMARDs including biologics after cancer diagnosis.

Predictive Factors for Renal Response in Lupus Nephritis: A Single-center Prospective Cohort Study.

Objective: To identify the predictive factors for renal response in patients with lupus nephritis (LN). Methods: Patients and data were extracted from a prospective systemic lupus erythematosus cohort in Korea, in which clinical data were collected at 0, 3, 6, and 12 months after induction therapy. Treatment response of LN were evaluated as a complete response (CR), partial response (PR), or non-response (NR) at 3, 6, and 12 months, respectively. Predictive factors for CR at 6 months were evaluated using multivariable Poisson regression analysis. Results: A total of 75 patients with LN who underwent biopsy was enrolled. The mean age at diagnosis of LN was 28.9±9.7 years, and 68 (90.7%) were female. The frequencies of classes III, IV, III+V, IV+V, and V were 20.0%, 44.0%, 16.0%, 12.0%, and 8.0%, respectively. Compared to relapsed LN, new-onset LN showed a lower percentage of glomerulosclerosis (45.5% vs. 76.2%, p=0.013). The overall proportions of CR, PR, and NR at 6 and 12 months were 52.0%, 26.7%, 21.3% and 50.7%, 24.0%, 25.3%, respectively. In multivariate analysis, age at enrollment (odds ratio [OR]=1.02, p=0.022), relapsed LN (OR=0.71, p=0.037), anti-Ro antibody (OR=0.67, p=0.014), and class III LN (OR=1.48, p=0.001) were associated with CR at 6 months. Conclusion: In our prospective cohort, class III LN was a good predictive factor for CR at 6 months in patients with LN, whereas younger age, relapsed LN, and anti-Ro antibody were poor predictive factors.

Novel classification of axial spondyloarthritis to predict radiographic progression using machine learning.

OBJECTIVES: Prediction and determination of drug efficacy for radiographic progression is limited by the heterogeneity inherent in axial spondyloarthritis (axSpA). We investigated whether unbiased clustering analysis of phenotypic data can lead to coherent subgroups of axSpA patients with a distinct risk of radiographic progression. METHODS: A group of 412 patients with axSpA was clustered in an unbiased way using a agglomerative hierarchical clustering method, based on their phenotype mapping. We used a generalised linear model, naïve Bayes, Decision Trees, K-Nearest-Neighbors, and Support Vector Machines to construct a consensus classification method. Radiographic progression over 2 years was assessed using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). RESULTS: axSpA patients were classified into three distinct subgroups with distinct clinical characteristics. Sex, smoking, HLA-B27, baseline mSASSS, uveitis, and peripheral arthritis were the key features that were found to stratifying the phenogroups. The three phenogroups showed distinct differences in radiographic progression rate (p<0.05) and the proportion of progressors (p<0.001). Phenogroup 2, consisting of male smokers, had the worst radiographic progression, while phenogroup 3, exclusively suffering from uveitis, showed the least radiographic progression. The axSpA phenogroup classification, including its ability to stratify risk, was successfully replicated in an independent validation group. CONCLUSIONS: Phenotype mapping results in a clinically relevant classification of axSpA that is applicable for risk stratification. Novel coupling between phenotypic features and radiographic progression can provide a glimpse into the mechanisms underlying divergent and shared features of axSpA.

Association of cumulative anti-cyclic citrullinated protein antibodies with radiographic progression in patients with rheumatoid arthritis.

INTRODUCTION: Antibody against cyclic citrullinated protein (ACPA) is counted as one of the most important biomarkers in diagnosis, classification, and prognosis of rheumatoid arthritis (RA). We examined the evolution of ACPA during disease course and assess predictive value of time-weighted cumulative ACPA titer on radiographic progression in RA patients. METHOD: A group of 734 patients with RA was followed longitudinally over 2 years, with annual measurements of ACPA. The cumulative titers of ACPA were calculated using the trapezoidal rule and were divided into three categories: negative, low-to-moderate, and high. Radiographs of the hands were scored with the modified Sharp score (SHS). Multivariable logistic regression models were performed to identify independent predictors over follow-up for individual patients with different combinations of risk factors. The effect size was computed by Cohen's d method. RESULTS: The patients with radiographic progression had a higher SHS at baseline; and smoking status, diabetes, RF positivity, and use of biologic DMARDs were independently associated with radiographic progression (all P < 0.05). As for ACPA, reversion happened more commonly in men and was associated with younger onset age and lower titer at baseline, but it had no direct relevance to radiographic outcome. In multivariable regression analysis, only high cumulative or baseline titer of ACPA had a predictive power for rapid radiographic progression (all P < 0.05), and cumulative ACPA titer was superior in terms of statistical significance (Cohen's d, 0.637 versus 0.583). CONCLUSIONS: High cumulative ACPA titer was independently associated with accelerated radiographic progression, especially with initiation of joint damage.

Identification of a Systemic Lupus Erythematosus Risk Locus Spanning ATG16L2, FCHSD2, and P2RY2 in Koreans.

OBJECTIVE: Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder whose etiology is incompletely understood, but likely involves environmental triggers in genetically susceptible individuals. Using an unbiased genome-wide association (GWA) scan and replication analysis, we sought to identify the genetic loci associated with SLE in a Korean population. METHODS: A total of 1,174 SLE cases and 4,246 population controls from Korea were genotyped and analyzed with a GWA scan to identify single-nucleotide polymorphisms (SNPs) significantly associated with SLE, after strict quality control measures were applied. For select variants, replication of SLE risk loci was tested in an independent data set of 1,416 SLE cases and 1,145 population controls from Korea and China. RESULTS: Eleven regions outside the HLA exceeded the genome-wide significance level (P = 5 × 10(-8) ). A novel SNP-SLE association was identified between FCHSD2 and P2RY2, peaking at rs11235667 (P = 1.03 × 10(-8) , odds ratio [OR] 0.59) on a 33-kb haplotype upstream of ATG16L2. In the independent replication data set, the SNP rs11235667 continued to show a significant association with SLE (replication meta-analysis P = 0.001, overall meta-analysis P = 6.67 × 10(-11) ; OR 0.63). Within the HLA region, the SNP-SLE association peaked in the class II region at rs116727542, with multiple independent effects observed in this region. Classic HLA allele imputation analysis identified HLA-DRB1*1501 and HLA-DQB1*0602, each highly correlated with one another, as most strongly associated with SLE. Ten previously established SLE risk loci were replicated: STAT1-STAT4, TNFSF4, TNFAIP3, IKZF1, HIP1, IRF5, BLK, WDFY4, ETS1, and IRAK1-MECP2. Of these loci, previously unreported, independent second risk effects of SNPs in TNFAIP3 and TNFSF4, as well as differences in the association with a putative causal variant in the WDFY4 region, were identified. CONCLUSION: Further studies are needed to identify true SLE risk effects in other loci suggestive of a significant association, and to identify the causal variants in the regions of ATG16L2, FCHSD2, and P2RY2.

Lupus Risk Variant Increases pSTAT1 Binding and Decreases ETS1 Expression.

Genetic variants at chromosomal region 11q23.3, near the gene ETS1, have been associated with systemic lupus erythematosus (SLE), or lupus, in independent cohorts of Asian ancestry. Several recent studies have implicated ETS1 as a critical driver of immune cell function and differentiation, and mice deficient in ETS1 develop an SLE-like autoimmunity. We performed a fine-mapping study of 14,551 subjects from multi-ancestral cohorts by starting with genotyped variants and imputing to all common variants spanning ETS1. By constructing genetic models via frequentist and Bayesian association methods, we identified 16 variants that are statistically likely to be causal. We functionally assessed each of these variants on the basis of their likelihood of affecting transcription factor binding, miRNA binding, or chromatin state. Of the four variants that we experimentally examined, only rs6590330 differentially binds lysate from B cells. Using mass spectrometry, we found more binding of the transcription factor signal transducer and activator of transcription 1 (STAT1) to DNA near the risk allele of rs6590330 than near the non-risk allele. Immunoblot analysis and chromatin immunoprecipitation of pSTAT1 in B cells heterozygous for rs6590330 confirmed that the risk allele increased binding to the active form of STAT1. Analysis with expression quantitative trait loci indicated that the risk allele of rs6590330 is associated with decreased ETS1 expression in Han Chinese, but not other ancestral cohorts. We propose a model in which the risk allele of rs6590330 is associated with decreased ETS1 expression and increases SLE risk by enhancing the binding of pSTAT1.

Bone morphogenetic protein 6 polymorphisms are associated with radiographic progression in ankylosing spondylitis.

BACKGROUND AND OBJECT: Nearly 25 genetic loci associated with susceptibility to ankylosing spondylitis (AS) have been identified by several large studies. However, there have been limited studies to identify the genes associated with radiographic severity of the disease. Thus we investigated which genes involved in bone formation pathways might be associated with radiographic severity in AS. METHODS: A total of 417 Korean AS patients were classified into two groups based on the radiographic severity as defined by the modified Stoke' Ankylosing Spondylitis Spinal Score (mSASSS) system. Severe AS was defined by the presence of syndesmophytes and/or fusion in the lumbar or cervical spine (n = 195). Mild AS was defined by the absence of any syndesmophyte or fusion (n = 170). A total of 251 single nucleotide polymorphisms (SNPs) within 52 genes related to bone formation were selected and genotyped. Odds ratios (OR) and 95% confidence interval (95% CI) were analysed by multivariate logistic regression controlling for age at onset of symptoms, sex, disease duration, and smoking status as covariates. RESULTS: We identified new loci of bone morphogenetic protein 6 (BMP6) associated with radiographic severity in patients with AS that passed false discovery rate threshold. Two SNPs in BMP6 were significantly associated with radiologic severity [rs270378 (OR 1.97, p = 6.74 × 10(-4)) and rs1235192 [OR 1.92, p = 1.17 × 10(-3)]) adjusted by covariates. CONCLUSION: This is the first study to demonstrate that BMP6 is associated with radiographic severity in AS, supporting the role wingless-type like/BMP pathway on radiographic progression in AS.

Prevalence and incidence of systemic lupus erythematosus in South Korea.

The aim of this study was to estimate the nationwide prevalence and incidence of systemic lupus erythematosus (SLE) in South Korea. National Health Insurance claims data covering almost all Koreans (~50 million) during 2006-2010 were analyzed. Individuals with SLE were identified if (1) they had experienced at least one hospitalization for SLE (International Classification of Diseases, 10th revision code M32), (2) they had taken at least one concomitant prescription of immunosuppressant and hydroxychloroquine, or (3) they had taken anti-dsDNA antibody (≥2) or complement tests (≥2) during each calendar year. Incident cases were defined only if they had not been SLE prevalent for the preceding 2 years and had been SLE prevalent for 2 years consecutively thereafter. The annual prevalence (per 100,000) increased slightly from 20.6 [95% confidence interval (95% CI) 20.2-21.0] in 2006 to 26.5 (95% CI 26.0-27.0) in 2010, and the incidence (per 100,000) ranged between 2.5 (95% CI 2.4-2.6) in 2008 and 2.8 (95% CI 2.7-2.9) in 2009. The number of SLE-prevalent female patients outnumbered SLE-prevalent male patients by approximately sixfold, with a female-to-male incidence ratio of ~9:1. The prevalence and incidence of SLE increased significantly with age, regardless of sex, to a peak the age of 30-39 years. However, while both of them significantly decreased thereafter in females, this tendency was not observed in males.

Association of genetic polymorphisms in CD40 with susceptibility to SLE in the Korean population.

OBJECTIVE: The aim of this study was to examine the association of CD40 polymorphisms with the risk of SLE in the Korean population. METHODS: A total of 601 Korean SLE patients and 984 healthy controls were enrolled. We selected seven CD40 gene SNPs based on previous results of CD40 gene sequencing in the Korean population. Statistical analysis was carried out by logistic regression, controlling for age and sex as covariates. Odds ratios (ORs) and P-values in co-dominant, dominant and recessive models were also calculated. RESULTS: SNP rs3765456 showed significant association with risk of SLE (OR = 1.34, P = 0.007, Pcorr = 0.03) in the dominant model. SNPs rs1883832 and rs4810485, and haplotype 2 (GTTCTAA) were also associated with the risk of SLE in the dominant model, but statistical significance disappeared after correction for multiple testing. Haplotype 2 had a protective effect on LN (OR = 0.47, P = 0.01, Pcorr = 0.05) in the recessive model while rs73115010, rs6074028 and haplotype 3 (ACGTCGG) resulted in increased risk of arthritis in the recessive model (OR = 2.87, 2.76 and 2.46, P = 0.002, 0.004 and 0.01, Pcorr = 0.009, 0.02 and 0.05, respectively). CONCLUSION: CD40 gene polymorphisms are possible risk factors for SLE development, especially rs3765456 in the dominant model. CD40 polymorphisms are also associated with SLE clinical manifestation, mainly nephritis and arthritis. Further replication with larger numbers, and populations of different ethnicities, are needed to confirm our findings.

Association of two independent functional risk haplotypes in TNIP1 with systemic lupus erythematosus.

OBJECTIVE: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production and altered type I interferon expression. Genetic surveys and genome-wide association studies have identified >30 SLE susceptibility genes. One of these genes, TNIP1, encodes the ABIN1 protein. ABIN1 functions in the immune system by restricting NF-κB signaling. The present study was undertaken to investigate the genetic factors that influence association with SLE in genes that regulate the NF-κB pathway. METHODS: We analyzed a dense set of genetic markers spanning TNIP1 and TAX1BP1, as well as the TNIP1 homolog TNIP2, in case-control populations of diverse ethnic origins. TNIP1, TNIP2, and TAX1BP1 were fine-mapped in a total of 8,372 SLE cases and 7,492 healthy controls from European-ancestry, African American, Hispanic, East Asian, and African American Gullah populations. Levels of TNIP1 messenger RNA (mRNA) and ABIN1 protein in Epstein-Barr virus-transformed human B cell lines were analyzed by quantitative reverse transcription-polymerase chain reaction and Western blotting, respectively. RESULTS: We found significant associations between SLE and genetic variants within TNIP1, but not in TNIP2 or TAX1BP1. After resequencing and imputation, we identified 2 independent risk haplotypes within TNIP1 in individuals of European ancestry that were also present in African American and Hispanic populations. Levels of TNIP1 mRNA and ABIN1 protein were reduced among subjects with these haplotypes, suggesting that they harbor hypomorphic functional variants that influence susceptibility to SLE by restricting ABIN1 expression. CONCLUSION: Our results confirm the association signals between SLE and TNIP1 variants in multiple populations and provide new insight into the mechanism by which TNIP1 variants may contribute to SLE pathogenesis.

Measurement of interleukin-33 (IL-33) and IL-33 receptors (sST2 and ST2L) in patients with rheumatoid arthritis.

The interleukin-33 (IL-33)/ST2 pathway has emerged as an intercellular signaling system that participates in antigen-allergen response, autoimmunity and fibrosis. It has been suggested that IL-33/ST2 signaling has been involved in the pathogenesis of rheumatoid arthritis (RA), because IL-33 and its receptor have been specifically mapped to RA synovium. The aim of this study was to determine the levels of IL-33 and sST2 in sera and synovial fluids in patients with RA. The serum level of IL-33 was significantly higher in patients with RA (294.9 ± 464.0 pg/mL) than in healthy controls (96.0 ± 236.9 pg/mL, P = 0.002). The synovial fluid level of IL-33 was significantly higher in RA patients than in osteoarthritis patients. The level of serum sST2 was higher in RA patients than in healthy controls (P = 0.042). A significant relationship was found between the levels of IL-33 and IL-1ß (r = 0.311, P = 0.005), and IL-33 and IL-6 (r = 0.264, P = 0.017) in 81 RA patients. The levels of IL-33, sST2 and C-reactive protein decreased after conventional disease-modifying antirheumatic drugs treatment in 10 patients with treatment-naïve RA. Conclusively, IL-33 is involved in the pathogenesis of RA and may reflect the degree of inflammation in patients with RA.

Synchronous development of KIT positive acute myeloid leukemia in a patient with gastrointestinal stromal tumor.

We report a case of synchronous occurrence of KIT-positive acute myeloid leukemia (AML) and gastrointestinal stromal tumor (GIST). A 63-year-old woman was hospitalized for dizziness, and abdominal computed tomography revealed an exophytic gastric mass and hepatic metastasis. The patient was diagnosed with GIST and was administered imatinib (400 mg/day) for the metastatic unresectable tumor. After 2 weeks of imatinib treatment, the patient developed pancytopenia, which persisted even after the drug was discontinued, thereby necessitating bone marrow biopsy. Biopsy examination indicated AML, and karyotyping revealed a complex karyotype. We did not observe point mutations at residues D816 and N822 of KIT. Therefore, the patient received standard induction chemotherapy, but on the 18(th) day after completion of chemotherapy, she died of septic shock and multi-organ failure. Since KIT plays an important role in both GIST and AML, we consider that both these malignancies may have been associated with each other.

A case of hypertrophic cranial pachymeningitis presenting with scleritis in a patient with undifferentiated connective tissue disease.

Hypertrophic cranial pachymeningitis (HCP) is an uncommon disorder that causes a localized or diffuse thickening of the dura mater and has been reported to be infrequently associated with systemic autoimmune disorders such as Wegener's granulomatosis, rheumatoid arthritis, sarcoidosis, Behçet's disease, Sjögren syndrome, and temporal arteritis. Here, we report a case of HCP initially presented with scleritis and headache in a patient with undifferentiated connective tissue disease (UCTD). HCP was initially suspected on brain magnetic resonance imaging and defined pathologically on meningial biopsy. Immunologic studies showed the presence of anti-RNP antibody. After high dose corticosteroid therapy, the patient's symptoms and radiologic abnormalities of brain were improved. Our case suggested that HCP should be considered in the differential diagnosis of headache in a patient with UCTD presenting with scleritis.