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Background: Exact comprehension of the prevalence of SARS-CoV-2 infection is essential for the preventive measures. In the clinical settings, however, patients infected with SARS-CoV-2 may not be fully detected by PCR. In the long-term prevalence study, cut-off of IgG assay may not be appropriate due to waning IgG titer., Methods: 24 PCR-negative subjects suspected of COVID-19 were categorized into cohorts termed "presumed COVID-19 positive" and "presumed COVID-19 negative" by chest CT images. IgG against nucleocapsid protein of SARS-CoV-2 (IgG (N)) and IgG against receptor biding domain of SARS-CoV-2 (IgG (RBD)) were measured in sera of the subjects and the concordance with the cohort categorization was assessed by receiver operating characteristics (ROC) analyses., Results: Area under the curves (AUC's) by the ROC analyses with the 24 subjects were 0.982 with IgG (N) and 0.854 with IgG (RBD). Even when we excluded the subjects whose initial PCR was performed after five days from symptom onset, the AUC's were 0.967 with IgG (N) and 0.800 with IgG (RBD). The ROC analysis indicated 0.2 S/C as the optimum cut-off forIgG (N)., Conclusion: Both IgG (N) and IgG (RBD) titers were significantly elevated in subjects whose PCR never showed positive but suggestive of SARS-CoV-2 infection, which indicated the necessity of serological tests in complementing the shortcomings of PCR. For a long-term prevalence study, a cut-off lower than the one used in the ongoing infection phase (e.g. 0.2 S/C vs. 1.4 S/C) was indicated to be more appropriate for IgG (N)., (Copyright © 2021. Published by Elsevier B.V.)

Mixed connective tissue disease (MCTD) is a rare systemic autoimmune disease characterized by the production of anti-U1 ribonucleoprotein antibodies and systemic symptoms similar to those of some other autoimmune diseases. HLA-DRB1 polymorphisms are important genetic risk factors for MCTD, but precise associations of DRB1 genotypes with MCTD have not been reported in Japanese people. Genotyping of HLA-DRB1 and -DQB1 was performed in Japanese MCTD patients (n = 116) and controls (n = 413). Associations of specific allele carriers and genotype frequencies with MCTD were analyzed.The following alleles were found to be associated with predisposition to MCTD: HLA-DRB1*04:01 (P = 8.66 × 10 -6 , Pc = 0.0003, odds ratio [OR] 7.96, 95% confidence interval [CI] 3.13‒20.24) and DRB1*09:01 (P = 0.0189, Pc = 0.5468, OR 1.73, 95% CI 1.12‒2.67). In contrast, the carrier frequency of the DRB1*13:02 allele (P = 0.0032, Pc = 0.0929, OR 0.28, 95% CI 0.11‒0.72) was lower in MCTD patients than in controls. The frequencies of heterozygosity for HLA-DRB1*04:01/*15 (P = 1.88 × 10 -7 , OR 81.54, 95% CI 4.74‒1402.63) and DRB1*09:01/*15 (P = 0.0061, OR 2.94, 95% CI 1.38‒6.25) were also higher in MCTD patients. Haplotype and logistic regression analyses suggested a predisposing role for HLA-DRB1*04:01, DQB1*03:03, and a protective role for DRB1*13:02. Increased frequencies of HLA-DRB1*04:01/*15 and DRB1*09:01/*15 heterozygous genotypes were found in Japanese MCTD patients., (© 2022. The Author(s).)

Background: To control COVID-19 pandemic is of critical importance to the global public health. To capture the prevalence in an accurate and timely manner and to understand the mode of nosocomial infection are essential for its preventive measure., Methods: We recruited 685 healthcare workers (HCW's) at Tokyo Shinagawa Hospital prior to the vaccination with COVID-19 vaccine. Sera of the subjects were tested by assays for the titer of IgG against S protein's receptor binding domain (IgG (RBD)) or IgG against nucleocapsid protein (IgG (N)) of SARS-CoV-2. Together with PCR data, the positive rates by these methods were evaluated., Results: Overall positive rates among HCW's by PCR, IgG (RBD), IgG (N) with a cut-off of 1.4 S/C (IgG (N)1.4), and IgG (N) with a cut-off of 0.2 S/C (IgG (N)0.2) were 3.5%, 9.5%, 6.1%, and 27.7%, respectively. Positive rates of HCW's working in COVID-19 ward were significantly higher than those of HCW's working in non-COVID-19 ward by all the four methods. Concordances of IgG (RBD), IgG (N)1.4, and IgG (N)0.2 against PCR were 97.1%, 71.4%, and 88.6%, respectively. By subtracting the positive rates of PCR from that of IgG (RBD), the rate of overall silent infection and that of HCW's in COVID-19 ward were estimated to be 6.0% and 21.1%, respectively., Conclusions: For the prevention of nosocomial infection of SARS-CoV-2, identification of silent infection is essential. For the detection of ongoing infection, periodical screening with IgG (RBD) in addition to PCR would be an effective measure. For the surveillance of morbidity in the population, on the other hand, IgG (N)0.2 could be the most reliable indicator among the three serological tests., Competing Interests: S.S. is an employee of Abbott Japan’s. None of the other authors have competing interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Intestinal mucosal injury that develops as a complication of tocilizumab (TCZ) is usually associated with diverticulosis. We herein report a rare case of TCZ-induced intestinal mucosal injury in the absence of diverticulosis. A 74-year-old woman suffering from rheumatoid arthritis started taking TCZ. Six months later, she complained of hematochezia and abdominal pain. Colonoscopy revealed multiple ulcers spreading from the cecum to the transverse colon but no diverticulosis. These lesions were cured at three months after the discontinuation of TCZ. We should consider TCZ as a risk factor for intestinal mucosal injury, even if patients have no history of intestinal disease associated with diverticulosis.

Background: To further improve rheumatoid arthritis (RA) treatment, it is necessary to understand each RA patient's satisfaction and to identify the factors affecting their satisfaction. Despite the rise in medical costs for RA, little is known about the factors that influence patient satisfaction with the cost of treatment in RA patients., Methods: This is a multicenter observational study of Japanese RA patients from the FRANK Registry with data analyzed from March 2017 to August 2020. We collected data on demographic characteristics, clinical data, quality of life which was evaluated using the EuroQol 5-dimensional questionnaire (EQ5D), and patient satisfaction. The four categories of patient satisfaction were evaluated individually (i.e., cost, treatment efficacy, activities of daily living [ADL], and global treatment satisfaction). We analyzed the factors that affected each patient's satisfaction, such as age, sex, EQ5D, disease duration, disease activity, and treatment., Results: This study included 2235 RA outpatients (406 males, 1829 females). In RA patients, "very satisfied" and "satisfied" were given for nearly half of each satisfaction aspect (cost 49%; efficacy 72%; ADL 58%; global treatment 66%) at the time of the initial registration. To investigate the factors influencing each satisfaction, multivariate analysis has revealed that the use of b/tsDMARDs increased satisfaction of treatment effect (odds ratio [OR] 0.66) and ADL (OR 0.78) but decreased cost satisfaction (OR 2.21). Age (50-64 years; OR 0.91; 65-74 years, 0.55: ≥ 75 years, 0.35), female (OR 0.81), and history of musculoskeletal surgery (OR 0.60) all increased cost satisfaction. Patients with lower disease activity and higher EQ5D scores had higher levels of satisfaction in all areas., Conclusions: In this study, patient satisfaction in terms of cost, treatment effect, ADL, and overall treatment was generally higher, but some patients were dissatisfied. The cost of satisfaction increased with age and a history of musculoskeletal surgery, while it decreased with a lower EQ5D score and the use of b/tsDMARDs., (© 2022. The Author(s).)

Objective: Susceptibility genes that can account for characteristic features of SSc such as fibrosis, vasculopathy and autoimmunity remain to be determined. In mice, deficiency of Friend leukaemia integration 1 transcription factor (Fli1) causes SSc-like disease with these features. The human FLI1 gene contains (GA)n microsatellite, which has been shown to be associated with expression level. Because microsatellite polymorphisms are difficult to capture by genome-wide association studies, we directly genotyped FLI1 (GA)n microsatellite and examined its association with SSc., Methods: Genomic DNA from 639 Japanese SSc patients and 851 healthy controls was genotyped for (GA)n microsatellite using the fragment assay. The cut-off repeat number for susceptibility to SSc was determined by receiver operating characteristics (ROC) analysis. Association with susceptibility and clinical characteristics was examined using logistic regression analysis. FLI1 mRNA levels were determined using quantitative RT-PCR., Results: Based on the ROC analysis, (GA)n alleles with ≥22 repeats were collectively defined as L alleles and alleles with ≤21 repeats as S alleles. (GA)n L alleles were significantly associated with susceptibility to SSc (P = 5.0e-04, odds ratio 1.34, additive model). Significant association was observed both in diffuse cutaneous and limited cutaneous SSc. Among the SSc, (GA)n L alleles were significantly enriched in the patients with a modified Rodnan total skin thickness score ≥10 compared with those with a score <10. FLI1 mRNA levels were significantly decreased in healthy controls carrying (GA)n L alleles as compared with non-carriers., Conclusion: Extended repeat alleles of FLI1 (GA)n microsatellite may be associated with lower FLI1 mRNA levels and susceptibility to human SSc., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: To investigate the efficacy of suppressing joint destruction with subcutaneous tocilizumab (TCZ-SC) for Japanese rheumatoid arthritis (RA) patients in the real-world clinical setting. Methods: This 1-year prospective, multicenter study included 110 RA patients in whom TCZ-SC was newly initiated. Primary endpoint was the change from baseline in vdH-modified total Sharp score (mTSS) at week 52. Structural remission was defined as yearly mTSS of 0.5 or less. Disease activity was evaluated using the disease activity score (DAS28-ESR) and clinical disease activity index (CDAI). Results: At baseline, the patients' mean age was 58.6 years, and the mean disease duration was 10.6 years. The proportion of patients who were naïve for biologics was 44.5%, and 64.5% concomitantly received methotrexate. The yearly mTSS showed significant improvement from 9.41 before TCZ-SC initiation to -0.15 after 52 weeks. The structural remission rate was 76.1%. After 52 weeks, the DAS28-ESR and CDAI remission rates were 52% and 21%, respectively. Although the previous usage of biologics and baseline disease activity significantly affected the clinical remission, no factors with significant effects on structural remission were identified. Conclusion: These findings support the efficacy of TCZ-SC in suppressing disease activity as well as joint destruction over a 1-year period.

Objectives: To clarify differences in incidences of articular and extra-articular involvement in patients with polymyalgia rheumatica (PMR) using FDG-PET/CT. Methods: Twenty PMR patients were enrolled in this retrospective study. We compared frequency, degree, and patterns (diffuse or non-diffuse) of abnormal FDG accumulation in the proximal and distal articular structures (PAS, DAS), and extra-articular synovial structures (ESS). Regional analyses were performed for the large joints (shoulder, hip, and knee). Results: The incidences of positive FDG accumulation were significantly higher in the PAS (96.7%) and ESS (91.4%) than in the DAS (31.8%, p  < .0001), although, the incidence in the knees (96.2%) was exceptionally high. PAS (2.79 ± 0.61) and ESS (2.52 ± 0.85) had significantly higher visual scores than DAS (0.89 ± 1.33, p  < .0001). Shoulder, hip, and knee joints each had a different accumulation pattern. Strong FDG accumulation was frequently observed in the medial-to-subscapular part of the shoulder joints, the lateral part of the hip joints, and the medial part of the knee joints. Conclusion: ESS were found to be the main affected areas in PMR patients as well as PAS. DAS involvement occurred with low frequency except in the knee joints. Each large joint showed a different accumulation pattern and its own characteristically strongly affected areas.

Objectives: To evaluate the safety of sifalimumab in Japanese patients with systemic lupus erythematosus (SLE). Methods: This phase 2, open-label study consisted of a 52-week initial stage (Stage I) and a long-term extension (Stage II). In Stage I, sequential cohorts of patients received ascending doses of sifalimumab (intravenous [IV] 1.0, 3.0, and 10.0 mg/kg or subcutaneous 100 mg every 2 weeks; IV 600 and 1200 mg every 6 weeks). In Stage II, patients enrolled before June 2012 received the same dose of sifalimumab as during Stage I for up to 157 weeks or sifalimumab 600 mg IV every 4 weeks if they enrolled later. The safety of sifalimumab was assessed by adverse events (AEs). Results: Thirty patients enrolled in Stage I and 21 patients entered Stage II. The majority of patients experienced AEs (96.7% in Stage I and 100% in Stage II); most were mild or moderate in severity. Serious AEs occurred in 30.0% and 57.1% of patients in Stage I and II, respectively; most were instances of SLE flares. The proportion of patients in Stage I and II who had AEs leading to discontinuation was 10.0% and 28.6%, respectively. Conclusion: Sifalimumab was well tolerated in Japanese patients with SLE.

Genome-wide association studies of systemic lupus erythematosus (SLE) in Chinese and Korean populations demonstrated strong association of single nucleotide polymorphisms (SNPs) located in the GTF2I-NCF1 region, rs73366469 (GTF2I), rs117026326 (GTF2I), rs80346167(GTF2IRD1) and rs201802880 (NCF1). This region has also been associated with susceptibility to Sjögren syndrome and rheumatoid arthritis; however, association studies with systemic sclerosis (SSc) and ANCA-associated vasculitis (AAV) have not been reported. Here we made an attempt to confirm their associations with SLE in the Japanese population, to find the primarily associated SNP, and to investigate whether these SNPs are also associated with susceptibility to SSc and AAV. By genotyping these four SNPs on 842 SLE, 467 SSc, 477 AAV patients and 934 healthy controls, striking association was confirmed in Japanese SLE. In addition, these SNPs were significantly associated with susceptibility to SSc, but not with AAV. Conditional logistic regression analysis revealed that the association of NCF1 rs201802880, a missense SNP encoding p.Arg90His, can account for the association of other SNPs by linkage disequilibrium. These results suggested that GTF2I-NCF1 region is associated with susceptibility to multiple autoimmune rheumatic diseases but not with AAV, and the primarily associated variant may be the missense SNP in NCF1.

Objectives: To identify the determinant of patients' perspectives of quality of life (QOL) and working status out of analysis-derived components underlying a set of assessment measures of the status of patients with rheumatoid arthritis (RA)., Methods: From the NinJa database in Japan (2012-2014), 1455 RA patients with DAS28 > 3.2 were recruited. Components explaining RA status were derived from principal component analysis of 15 assessment measures. Multivariate regression was used to examine the relative contribution of each identified component to the EuroQOL-5 Dimension Questionnaire score and working status., Results: Among the identified components (patient symptoms, physical disability, evaluated symptoms, patient distress, inflammatory marker, and serological marker), patient distress showed highest contribution to EuroQOL for both male (44.6%) and female patients (39.3%). Physical disability was associated with significantly less participation in paid work in male (odds ratio [OR]; 0.63) and both household and paid work in female (OR; 0.82 and 0.54, respectively), though patient distress showed the strongest association with less participation in both household and paid work in female (OR; 0.64 and 0.45, respectively)., Conclusion: The approach to latent patient distress using psychological screening tools, concurrently with the treatment to control the activity of arthritis, can be help to improve health-related QOL (HRQOL) including work participation.

Aim: The purpose of this study was to assess 5-year changes in physical function and factors associated with improvement among patients with rheumatoid arthritis (RA) in daily clinical practice, focusing on the effect of treatments, including biologic agents, in the early stage of disease course., Methods: The National Database of Rheumatic Diseases by iR-net in Japan (NinJa) was searched for patients with disease duration ≤ 2 years and modified health assessment questionnaire (mHAQ) > 0 between 2004 and 2007, so that 510 patients were included in the final analysis. Multivariate-logistic regression analyses were used to identify predictors of 5-year mHAQ disability score improvement., Results: Median mHAQ score was 0.40 at baseline and decreased to a median 0.17 after 5 years. Seventy-four percent of the patients were treated with methotrexate (MTX) and 25% with biologic agents, with early use of biologic agents (within 2 years of RA onset) increasing over time. Multivariate analyses identified higher baseline Disease Activity Score of 28 joints - C-reactive protein and early use of MTX (within 1 year of RA onset) and of biologic agents (within 2 years) as significantly associated with improved mHAQ; odds ratios of the early treatment were 1.83 (P = 0.01) for MTX and 2.23 (P = 0.04) for biologic agents, respectively., Conclusion: Five-year mHAQ improved in early RA patients in the NinJa database. In daily clinical management of RA, likewise in clinical trials, early administration of MTX or biologic agents is able to improve physical function outcome., (© 2016 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Objective: To determine whether tofacitinib can be discontinued in patients with RA who achieve low disease activity (LDA)., Methods: RA patients with LDA after tofacitinib treatment in a phase III and long-term extension study were enrolled in this multicentre, non-randomized, open, prospective, observational study. The decision of discontinuation or continuation of tofacitinib was determined based on patient-physician decision making with informed consent. The primary endpoint was the proportion of patients who remained tofacitinib-free at post-treatment week 52. Clinical outcome was compared between those who continued and those who discontinued tofacitinib. The last observation carried forward method was used for patients who could not discontinue tofacitinib before week 52., Results: Of 64 patients, 54 discontinued and 10 continued tofacitinib therapy. At post-treatment week 52, 20 of the 54 patients (37%) of the discontinuation group remained tofacitinib-free without disease flare. Disease activity at post-treatment week 52 was higher in the discontinuation group than the continuation group. Among the discontinuation group, the RF titre at baseline was significantly lower in patients who remained tofacitinib-free than those who did not (40 vs 113 U/ml). In fact, a higher proportion of patients with lower RF remained tofacitinib-free at week 52 compared with those with higher RF at baseline. In patients who could not achieve tofacitinib-free status, re-initiation of tofacitinib or other biologics improved disease activity., Conclusion: It is possible to discontinue tofacitinib without flare in about a third of patients with RA. A low RF predicts maintenance of LDA after discontinuation of tofacitinib., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Objective: Knowing the risk of hospitalized infection associated with individual biological agents is an important factor in selecting the best treatment option for patients with rheumatoid arthritis (RA). This study examined the comparative risk of hospitalized infection between biological agents in a routine care setting., Methods: We used data for all RA patients who had first begun biological therapy at rheumatology divisions of participating community hospitals in Japan between January 2009 and December 2014. New treatment episodes with etanercept, infliximab, adalimumab, abatacept, or tocilizumab were included. Patients were allowed to contribute multiple treatment episodes with different biological agents. Incidence rates (IRs) of hospitalized infection during the first year of follow-up were examined. Cox regression analysis was used to calculate hazard ratios (HRs) for overall hospitalized infection and for pulmonary hospitalized infection, adjusting for possible confounders., Results: A total of 1596 new treatment episodes were identified. The incidence of overall hospitalized infection during the first year was 86 with 1239 person-years (PYs), yielding a crude IR of 6.9 per 100 PYs (95% confidence interval [CI], 5.6-8.6). After correction for confounders, no significant difference in risk of hospitalized infection was observed between treatment groups: adjusted HRs (95% CI) were 1.54 (0.78-3.04) for infliximab, 1.72 (0.88-3.34) for adalimumab, 1.11 (0.55-2.21) for abatacept, and 1.02 (0.55-1.87) for tocilizumab compared with etanercept. Patient-specific factors such as age, RA functional class, body mass index (BMI), prednisolone use, and chronic lung disease contributed more to the risk of hospitalized infection than specific biological agents. The incidence of pulmonary hospitalized infection was 50 and a crude IR of 4.0 per 100 PYs (95% CI, 3.1-5.3). After adjustment for confounders, adalimumab had a significantly higher HR for pulmonary hospitalized infection compared with tocilizumab: an adjusted HR (95% CI) was 4.43 (1.72-11.37) for adalimumab. BMI, prednisolone use, diabetes mellitus, and chronic lung disease were also significant factors associated with the risk of pulmonary hospitalized infection., Conclusions: The magnitude of the risk of overall hospitalized infection was not determined by the type of biological agents, and patient-specific risk factors had more impact on the risk of hospitalized infection. For pulmonary hospitalized infections, the use of adalimumab was significantly associated with a greater risk of this complication than tocilizumab use.

Objective: Upper limit of methotrexate (MTX) for patients with rheumatoid arthritis (RA) was recently increased from 8 to 16 mg/week in Japan. We therefore examined the effect of concomitant MTX dose on the efficacy of adalimumab (ADA) in clinical practice., Method: Sixty-one consecutive RA patients treated with ADA were followed for minimum 52 weeks and retrospectively compared by MTX dose; patients receiving concomitant MTX of 10 mg/week or more (MTX ≥10 mg group) and <10 mg/week (MTX <10 mg group). Disease activity and remission were evaluated by the disease activity score 28 (DAS28) criteria., Results: The MTX ≥10 mg group consistently showed better improvement in DAS28 and resulted in more patients (52.8%) with DAS28-remission compared with the MTX <10 mg group (26.1%). Multivariate analysis showed that MTX ≥10 mg had a significant effect on DAS28 remission with odds ratio of 5.12. ADA retention rate was 72.2% in MTX ≥10 mg group compared with 52.0% in MTX <10 mg group. Discontinuation of ADA due to adverse events were comparable in the MTX ≥10 mg and MTX <10 mg groups (11.1% vs. 12.0%)., Conclusions: These findings support the critical role of concomitant MTX in the efficacy of ADA, and recommend use of MTX ≥10 mg in Japanese RA patients.

Background: The relationship between the histological pattern and survival in systemic sclerosis-associated interstitial lung disease (SSc-ILD) is unclear. In patients with SSc-ILD, we investigated whether the clinical data obtained by non-invasive examinations could be used for prognostic evaluation, and attempted to clarify whether complicating acute exacerbation (AE) and the selection of pharmacological therapy were associated with survival., Methods: Thirty-five patients with SSc-ILD, who had not been diagnosed by surgical lung biopsy were analyzed, retrospectively. The HRCT findings were evaluated by 2 radiologists and classified into "CT-UIP" or "CT-inconsistent with UIP" patterns based on whole lung interpretations. HRCT scores were calculated based on the extent of abnormality evidenced by HRCT. The log-rank test was used to determine variables, including clinical parameters and histories., Results: Twelve (34%) of the 35 patients died during a median follow-up period of approximately 7.9 years. The log-rank test showed that a higher mortality was associated with higher age, a CT-UIP pattern, a higher score for ground-glass attenuation with traction bronchiectasis on HRCT, and complicating AE, whereas a lower mortality was significantly associated with the use of immunosuppressants. A CT-UIP pattern was significantly associated with a higher incidence of later AE., Conclusion: Treatment with immunosuppressants was associated with a longer survival, and complicating AE is a predictor of shortened survival in SSc-ILD patients. Among the clinical parameters determined by non-invasive examinations, a CT-UIP pattern and the extent of fibrotic lesions on HRCT, but not a histological pattern of UIP, may be predictors of shortened survival., (Copyright © 2016 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

HLA-G plays a role in fetal-maternal tolerance as well as immunoregulation, and has been suggested to be involved in autoimmune diseases and cancers. HLA-G encodes two potentially functional polymorphisms in the 3' untranslated region, 14bp insertion/deletion (14bp indel, rs371194629) and a single nucleotide polymorphism rs1063320, previously reported to affect HLA-G expression level or splicing isoform and to be associated with susceptibility to systemic lupus erythematosus (SLE). However, the results of SLE association studies are inconsistent, probably due to the small sample size of each study and lack of consideration of linkage disequilibrium (LD) with HLA-class II haplotypes in each population. In this study, we performed association studies of these polymorphisms on 843 patients with SLE and 778 healthy controls in a Japanese population, in many of whom HLA-DRB1 alleles have been genotyped at the four-digit level. LD was detected between DRB1*13:02, protective against multiple autoimmune diseases in the Japanese, and the rs1063320 G (D' = 0.86, r2 = 0.02) and with 14bp del (D' = 0.62, r2 = 0.01), but not between SLE-susceptible DRB1*15:01 and HLA-G. Although significant association with overall SLE was not detected, 14bp ins allele was significantly associated with SLE with the age of onset <20 years, when compared with healthy controls (P = 0.0067, PFDR = 0.039, OR 1.44, additive model) or with SLE patients with the age of onset ≥20 (P = 0.033, PFDR = 0.0495, OR 2.09, additive model). This association remained significant after conditioning on DRB1*13:02 or DRB1*15:01. On the other hand, significant association was detected between rs1063320 C and anti-RNP antibody and anti-Sm antibody positive SLE, which was dependent on negative LD with DRB1*13:02. eQTL analysis showed reduced HLA-G mRNA level in 14bp ins/ins individuals. In conclusion, our observations showed that HLA-G 14bp ins allele represents a genetic contribution on early-onset SLE independent of DRB1.

Objective: Several studies on associations between human leukocyte antigen (HLA) allele frequencies and susceptibility to systemic sclerosis (SSc) have been reported. Anti-centromere antibodies (ACA) and anti-topoisomerase I antibodies (ATA) are found in SSc patients. Here, we sought to identify HLA alleles associated with SSc in Japanese, and explored their associations with SSc phenotypes including the presence of autoantibodies., Methods: Associations of HLA-DRB1, DQB1, and DPB1 were analyzed in 463 Japanese SSc patients and 413 controls., Results: We found that DRB1*13:02 (P = 0.0011, Pc = 0.0319, odds ratio [OR] 0.46, 95% confidence interval [CI] 0.29-0.73), DRB1*14:06 (P = 6.60X10-5, Pc = 0.0020, OR 0.05, 95%CI 0.01-0.41), DQB1*03:01 (P = 0.0009, Pc = 0.0150, OR 0.56, 95%CI 0.40-0.79), and DPB1*02:01 (P = 5.16X10-6, Pc = 8.77X10-5, OR 0.52, 95%CI 0.39-0.69) were protectively associated with SSc. In addition, these four alleles seemed to be independently associated with the protection against the susceptibility of SSc. On the other hand, we could not find predisposing alleles for overall SSc. With respect to SSc subsets, a tendency for these four alleles to be protectively associated was observed. However, there was a significant association between DRB1*01:01, DRB1*10:01, DQB1*05:01, and DPB1*04:02 and the susceptibility to SSc with ACA. On the other hand, the presence of DRB1*15:02, DQB1*06:01, DPB1*03:01, and DPB1*09:01 was associated with SSc with ATA., Conclusion: Thus, the present study has identified protective associations of the four HLA class II alleles with overall Japanese SSc and predisposing associations of HLA class II alleles with Japanese SSc subsets.