Efficacy and safety of tocilizumab in Japanese patients with systemic sclerosis and associated interstitial lung disease: A subgroup analysis of a global, randomised, controlled Phase 3 trial.

OBJECTIVES: The aim of this article is to investigate the efficacy and safety of tocilizumab in Japanese patients with systemic sclerosis. METHODS: Post hoc subgroup analysis of a global, randomised, controlled trial in patients treated with weekly tocilizumab 162 mg or placebo subcutaneously in a 48-week double-blind period (tocilizumab and placebo groups) followed by tocilizumab for 48 weeks in an open-label extension (continuous-tocilizumab and placebo-tocilizumab groups). RESULTS: Among 20 patients, 12 were randomised to tocilizumab (all had interstitial lung disease) and eight were randomised to placebo (six had interstitial lung disease). The modified Rodnan skin score improved in both treatment groups. The mean change in percent-predicted forced vital capacity was 3.3% [95% confidence interval (CI), -2.5 to 9.0] for tocilizumab and -3.8% (95% CI, -9.9 to 2.2) for placebo in the double-blind period and 2.0% (95% CI, -0.7 to 4.6) for continuous-tocilizumab and -1.4% (95% CI, -6.7 to 4.0) for placebo-tocilizumab in the open-label extension. Rates of serious adverse events per 100 patient-years were 19.3 for tocilizumab and 26.8 for placebo in the double-blind period and 0.0 for continuous-tocilizumab and 13.6 for placebo-tocilizumab in the open-label period. CONCLUSIONS: The efficacy and safety of tocilizumab in patients with systemic sclerosis were consistent between the Japanese subpopulation and the global trial population.

Perspective to precision medicine in scleroderma.

Systemic sclerosis (SSc) is a rare and heterogeneous disease with no relevant environmental trigger or significant responsible gene. It has been and will continue to be difficult to identify large enough patients to conduct classic population-based epidemiologic exposure/non-exposure studies with adequate power to ascertain environmental and genetic risk factors for these entities. The complexity of pathogenesis and heterogeneity are likely to require personalized/precision medicine for SSc. Since several potential drugs are currently available for specific patients if not whole SSc, classification of SSc seems to form the foundation for a better therapeutic strategy. To date, SSc has been classified based on the extent/severity of the affected area as well as some disease markers, including the autoantibody profile. However, such an analysis should also lead to improvements in the design of appropriately stratified clinical trials to determine the effects and prediction of targeted therapies. An approach based on drug response preclinically conducted using patients' own fibroblasts in vitro, can provide a precise disease marker/therapeutic selection for clinical practice. Because scleroderma dermal fibroblasts have a persistent hyper-productive phenotype occurring not only in person, but also in cell culture conditions. Thus, an accumulating approach based on disease markers ensures progression and de-escalation to re-establish a better life with a personally optimized drug environment after the onset of SSc.

A role for FcγRIIB in the development of murine bleomycin-induced fibrosis.

BACKGROUND: Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by excessive fibrosis. FcγRIIB is a low-affinity receptor for the Fc fragment of IgG. FcγRIIB is expressed on the surface of various leukocyte subsets and signals negative feedback pathways to down-regulate B-cell antigen receptor signaling. OBJECTIVE: The aim of the present study was to investigate the role of FcγRIIB in the development of a murine bleomycin-induced scleroderma model. METHODS: The experimental fibrosis model was generated by the intradermal injection of bleomycin into wild-type (WT) and FcγRIIB-deficient (FcγRIIB-/-) mice. We histologically assessed skin and lung fibrosis as well as inflammatory cell infiltration. Cytokine and chemokine expression levels were measured with RT-PCR. RESULTS: The severity of fibrosis in the skin and lung was significantly worse in FcγRIIB-/- mice than in WT mice. In the skin of bleomycin-treated mice, the numbers of CD8+ T cells, F4/80+ macrophages, MPO+ neutrophils, NK1.1+NK cells, and B220+ B cells were significantly higher in FcγRIIB-/- mice than in WT mice. The expression of TNF-α and IL-1ß was significantly higher in FcγRIIB-/- mice than in WT mice as was the expression of ICAM-1, CXCL2, and CCL3 in the affected skin. An adoptive transfer of splenic leukocytes from FcγRIIB-/- mice into WT mice showed exacerbated skin and lung fibrosis compared to WT mice without an adoptive transfer. CONCLUSION: These results indicate that FcγRIIB plays an inhibitory role in skin and lung fibrosis. Moreover, modulating FcγRIIB signaling has potential as a therapeutic approach for SSc.

Initial predictors of skin thickness progression in patients with diffuse cutaneous systemic sclerosis: Results from a multicentre prospective cohort in Japan.

OBJECTIVE: To identify initial parameters that predict worsening of skin thickening in patients with diffuse cutaneous systemic sclerosis (dcSSc) using a multicentre, prospective, observational cohort in Japan. METHODS: A total of 171 patients with dcSSc were selected from a prospective cohort database based on the following criteria: dcSSc, modified Rodnan total skin thickness score (mRSS) ≥7, disease duration <60 months, and valid mRSS data at one year. Worsening of skin thickness was defined as an increase in mRSS ≥3 points and an increase ≥25% from baseline to one year. Initial demographic and clinical parameters useful for predicting the progression of skin thickness were identified using univariate and multivariable analysis, and prediction models of skin thickening progression were built based on combinations of independent predictive parameters. RESULTS: Only 23 patients (13.5%) experienced worsening mRSSs at one year. Short disease duration, low mRSS, absence of nailfold bleeding, arthritis, and a high erythrocyte sedimentation rate at diagnosis were identified as predictors of subsequent worsening of the mRSS even after adjusting for the treatment. Assessment of the best predictive model revealed that patients with a disease duration ≤12 months and mRSS ≤19 had a risk of mRSS worsening within one year, with a sensitivity of 73.9% and specificity of 81.1%. CONCLUSION: Identification of predictors of subsequent worsening of skin thickness in dcSSc patients is useful for identifying patients who require intensive treatment with potential disease-modifying agents and for improving clinical trial design by characterizing eligible progressors in the Japanese population.

Long-term changes in nail fold capillary abnormalities and serum fibroblast growth factor 23 levels in dermatomyositis patients with anti-melanoma differentiating antigen 5 antibody.

Nail fold videocapillaroscopy (NVC) abnormalities are a characteristic finding of microangiopathy in dermatomyositis (DM). The aim of the present study was to examine long-term changes in NVC abnormalities and serum fibroblast growth factor 23 (FGF23) and vascular endothelial growth factor (VEGF) levels in DM patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody (Ab). Serum levels of FGF23 and VEGF were measured by enzyme-linked immunosorbent assay. NVC abnormalities were evaluated by capillaroscopy in 11 DM patients with anti-MDA5 Ab at baseline and after treatment. NVC abnormalities included irregularly enlarged capillaries, reduced capillaries, hemorrhages, capillary ramifications, disorganization of the vascular array, loss of capillaries and giant capillaries. Serum FGF23 levels were significantly decreased in patients with anti-MDA5 Ab (0.3 ± 0.3 pmol/L) compared with healthy controls (1.0 ± 0.6 pmol/L, P < 0.01). Serum FGF23 levels significantly increased after treatment (0.3 ± 0.3 vs 1.0 ± 0.7 pmol/L, P < 0.005), but serum VEGF levels were comparable between at baseline and after treatment. At baseline, irregularly enlarged capillaries were observed in 10 of 11 patients, but after treatment, they were significantly reduced in only two (91% vs 18%, P < 0.001). Hemorrhages were observed in all 11 patients at baseline, but disappeared in all after treatment (100% vs 0%, P < 0.001). These results suggest that NVC abnormalities are reversible by treatment and that serum FGF23 levels reflect the degree of microvascular damage in DM patients with anti-MDA5 Ab.

Nintedanib in patients with systemic sclerosis-associated interstitial lung disease: A Japanese population analysis of the SENSCIS trial.

OBJECTIVE: We examined the efficacy and safety of nintedanib in Japanese patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) in the global Safety and Efficacy of Nintedanib in Systemic Sclerosis (SENSCIS) trial. METHODS: Randomised patients received oral nintedanib 150 mg (N = 34) twice daily or placebo (N = 36) until the last patient reached 52 weeks of treatment (up to 100 weeks). Data were analysed using a subgroup analysis model with Japanese and non-Japanese patients as subgroup variables. RESULTS: In Japanese patients, the adjusted annual rate of forced vital capacity (FVC) decline over 52 weeks was -86.2 mL/year (nintedanib) and -90.9 mL/year (placebo); treatment difference, 4.67 mL/year (95% confidence interval, -103.28, 112.63). Treatment effect heterogeneity between Japanese and non-Japanese patients was not detected (treatment-by-visit-by-subgroup interaction; p = .49). FVC decline was smaller for nintedanib versus placebo through 100 weeks in Japanese patients. The most commonly reported adverse events with nintedanib were gastrointestinal and liver disorder events; most were mild-to-moderate in severity. CONCLUSION: In both Japanese and non-Japanese patients with SSc-ILD, nintedanib slowed the progression of ILD, with no heterogeneity detected between the subgroups. The safety profile for nintedanib in Japanese patients was similar to that observed in patients with idiopathic pulmonary fibrosis (ClinicalTrials.gov: NCT02597933).

Clinical course of Japanese patients with early systemic sclerosis: A multicenter, prospective, observational study.

OBJECTIVES: To investigate the clinical course of Japanese patients with early diffuse cutaneous systemic sclerosis (dcSSc) and early SSc with interstitial lung disease (ILD). METHODS: We prospectively analyzed the clinical features of 207 Japanese patients with early dcSSc (n = 150) and limited cutaneous SSc (lcSSc) with ILD (n = 57) in 10 medical centers every year for 7 consecutive years. RESULTS: Mean modified Rodnan total skin thickness score (mRSS) was 18.3 and 67.4% of the cohort had ILD. Most patients started immunosuppressive therapy and vasodilators during 7 years (83.4% and 87.9%, respectively). Mean value of mRSS of total patients was significantly reduced from the initial registration after the first year. However, other parameters for physical function associated with skin sclerosis including fist closure, hand extension, and oral aperture were not so ameliorated during the study period. Health Assessment Questionnaire-disability index and serum KL-6 levels were constant throughout the course. Percent vital capacity and the presence of ILD, clinically suspected pulmonary arterial hypertension, and digital ulcers were gradually exacerbated during the period. CONCLUSION: In Japanese early dcSSc patients and SSc patients with ILD, mRSS was continuously reduced during 7 years of follow-up, but there was little improvement of physical disability and organ involvement.

A case of anti-BP230 antibody-positive bullous pemphigoid receiving DPP-4 inhibitor.

Bullous pemphigoid (BP) is a cutaneous autoimmune blistering disorder. Recently, it has been reported that dipeptidyl peptidase-4 inhibitors (DPP4i) is associated with the development of BP (DPP4i-BP). Patients with DPP4i-BP have autoantibodies (autoAbs) preferentially targeting full-length BP180, but not the BP180NC16a domain. In this report, we described a case of anti-BP230 antibody (Ab)-positive BP receiving DPP4i. A 78-year-old male with a medical history of type 2 diabetes receiving vildagliptin at 100 mg daily for 38 months was referred to our hospital with itching blisters on his body and extremities. Skin biopsy showed subepidermal bulla with eosinophil infiltration. Direct immunofluorescence staining revealed a linear staining pattern with complement C3 and IgG at the subepidermal basement membrane zone. By laboratory testing, autoAbs against BP180NC16a and full-length BP180 were negative by enzyme-linked immunosorbent assay (ELISA); however, anti-BP230 Abs were positive by ELISA (index: 123.91). His HLA genotype was DQB1*04:01 and 05:01. Based on these results, we diagnosed the patient with anti-BP230 Abs-positive BP associated with DPP4i. To the best of our knowledge, this is the first case of DPP4i-BP with only anti-BP230 Abs. Further accumulation of DPP4i-BP cases is needed to clarify the relationship between overall features of DPP4i-BP and anti-BP230 Abs.

Characteristics of Japanese patients with eosinophilic fasciitis: A brief multicenter study.

Eosinophilic fasciitis is a relatively rare cutaneous fibrotic condition affecting the deep fascia of the extremities, with or without peripheral blood eosinophilia. To examine the characteristics of Japanese patients with eosinophilic fasciitis, we conducted a brief, multicenter, retrospective survey at seven university hospitals. In total, 31 patients were identified as having eosinophilic fasciitis, among whom 30 patients fulfilled the Japanese diagnostic criteria. The male : female ratio was 2.3:1, and the mean age was 47.7 years. Three of the patients were under 20 years old. The possible triggering factors included muscle training, sports, walking or sitting for a long time, physical work, insect bite and drug. Co-occurrence of morphea was observed in nine cases (29%), and malignancies were associated in three (two hematological malignancies and one internal malignancy). Immunological abnormalities in the serum showed positive antinuclear antibody, positive rheumatoid factor, increased aldolase levels and increased immunoglobulin G levels. The patients were treated with either monotherapy or combination therapy by oral prednisolone (20-80 mg/day), methotrexate (6-10 mg/week), cyclosporin (100-150 mg/day), mizoribine, infliximab and phototherapy. Methylprednisolone pulse therapy was performed in six cases. By contrast, spontaneous improvement due to resting only was observed in two cases, and skin hardening was improved by withdrawal of the anticancer drug in one case. This study suggests several characteristics of Japanese patients with eosinophilic fasciitis, namely male predominance, rare pediatric occurrence, immunological abnormalities and coexistence with morphea. Systemic prednisolone is the first-line therapy, but pulse therapy is occasionally required for severe cases. The triggering events of physical stress are not so frequent as have previously been reported, and various factors or even unknown factors may be associated with the induction of eosinophilic fasciitis.

Association of functional (GA)n microsatellite polymorphism in the FLI1 gene with susceptibility to human systemic sclerosis.

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.

Clinical features of Japanese systemic sclerosis (SSc) patients negative for SSc-related autoantibodies: A single-center retrospective study.

OBJECTIVE: To examine the clinical features of systemic sclerosis (SSc) patients negative for SSc-related autoantibodies (autoAbs). METHODS: Serum samples were collected from 546 SSc patients. The presence of antinuclear antibody (ANA) was screened by indirect immunofluorescence (IIF) staining using HEp-2 cells. SSc-related autoantibodies were identified by specific IIF staining, enzyme-linked immunosorbent assay, or immunoprecipitation assay. Clinical features were analyzed among patients negative for ANA/SSc-related autoAbs, anticentromere Abs (ACA), anti-topoisomerase I (anti-topo I) Abs, and anti-RNA polymerase (anti-RNAP) Abs. RESULTS: Of the 546 SSc patients, 26 (4.8%) were negative for ANA and 29 (5.3%) were ANA-positive but negative for SSc-related autoAbs. Regarding clinical features, patients negative for ANA/SSc-related autoAbs (n = 55) had a significantly shorter disease duration, higher proportion of the diffuse type, contracture of phalanges, diffuse pigmentation, higher modified Rodnan total skin thickness score (mRSS), and lower incidence of telangiectasia than those with ACA (n = 224). On the other hand, younger disease onset, lower mRSS, and lower incidence of scleroderma renal crisis were observed in patients negative for ANA/SSc-related autoAbs than in those with anti-RNAP Abs (n = 52). Although pitting scars were less common in patients negative for ANA/SSc-related autoAbs than in those with anti-topo I Abs (n = 144), their clinical features were similar. CONCLUSION: Patients negative for ANA/SSc-related autoAbs form a clinically distinct subset among SSc patients.

Performance evaluation of a commercial line blot assay system for detection of myositis- and systemic sclerosis-related autoantibodies.

INTRODUCTION/OBJECTIVES: A line blot (LB) assay is a multi-analyte platform capable of simultaneously detecting multiple anti-nuclear antibody specificities. Here, we evaluated the performance of a commercial LB assay developed for the identification of myositis- or systemic sclerosis (SSc)-related autoantibodies (autoAbs). METHOD: We screened 300 serum samples from patients with various connective tissue diseases using an LB assay and compared the results of myositis- or SSc-related autoAbs with those identified by RNA and protein immunoprecipitation (IP) assays or indirect immunofluorescence (IIF). RESULTS: The IP assays revealed anti-Jo-1 Abs in 14 patients, anti-EJ Abs in 12, anti-PL-7 Abs in 8, anti-PL-12 Abs in 4, anti-Mi-2 Abs in 6, anti-SRP Abs in 8, anti-topoisomerase I Abs in 54, anti-RNA polymerase III Abs in 24, anti-U3 RNP Abs in 9, anti-Th/To Abs in 9, anti-Ku Abs in 14 and anti-hUBF Abs in 4, whereas IIF identified anti-centromere in 35. Good agreement between the IP assays and the LB assay was found only for anti-Jo-1 and anti-centromere antibodies. When a cut-off was adjusted to reconcile with the results of IP assays, the detection performance of LB assay was improved for anti-EJ, anti-PL-7, anti-PL-12, anti-SRP, anti-topoisomerase I and anti-RNA polymerase III Abs. However, the results of anti-Mi-2, anti-U3 RNP, anti-Th/To, anti-hUBF and anti-Ku Abs remained discordant between the LB assay and IP assays at all cut-off levels. CONCLUSIONS: Detection of myositis- or SSc-related autoAbs using a commercial LB assay requires great caution since it can yield analytically false-positive or false-negative results. Key Points • A line blot (LB) assay is a multi-analyte platform capable of simultaneously detecting multiple antibodies with anti-nuclear specificities. • Detection of myositis- or systemic sclerosis-related autoantibodies using a commercial LB assay requires great caution since it can yield analytically false-positive or false-negative results.

CD22 and CD72 contribute to the development of scleroderma in a murine model.

BACKGROUND: Systemic sclerosis (SSc) is a systemic autoimmune disease that is characterized by excessive fibrosis. CD22 and CD72 are B cell-specific cell surface molecules that negatively regulate B cell function. OBJECTIVE: The aim of the present study was to investigate the roles of CD22 and CD72 in a murine scleroderma model. METHODS: The experimental fibrosis model was generated by subcutaneous injection of bleomycin or hypochlorous acid (HOCL) into wild-type (WT), CD22-deficient (CD22-/-), CD72-deficient (CD72-/-) and CD22 and CD72 double-deficient (CD22-/-/CD72-/-) mice. We histologically assessed skin fibrosis and inflammatory cell infiltration. Cytokine and chemokine expression levels were measured by real-time polymerase chain reaction. RESULTS: The severity of fibrosis in the skin and lung was significantly less in CD22-/-, CD72-/-, and CD22-/-/CD72-/- mice than in WT mice in the bleomycin-induced model. In the skin of bleomycin-treated mice, the numbers of CD3+ T cells, CD8+ T cells, and F4/80+ macrophages were significantly lower in CD22-/-, CD72-/-, and CD22-/-/CD72-/- mice than in WT mice. The expression levels of mRNAs for IL-6, TNF-α, TGF-ß, CTGF, IL-1ß, IL-13, CXCL2, and ICAM-1 were significantly lower in CD22-/-, CD72-/-, and CD22-/-/CD72-/- mice than in WT mice. In the HOCL-induced model, both skin and lung fibrosis were ameliorated in CD22-/-, CD72-/- and CD22-/-/CD72-/- mice compared to WT mice. CONCLUSION: These results indicate that CD22 and CD72 likely play crucial roles in skin and lung fibrosis. Moreover, the inhibition of CD22 and CD72 function has potential as a therapeutic approach to SSc.

Availability of EuroQol-5-Dimensions-5-Level (EQ-5D-5L) as health-related QOL assessment for Japanese systemic sclerosis patients.

Objective: To assess the functional disability in Japanese patients with systemic sclerosis (SSc) using the EuroQol-5-Domain-5-Level health questionnaire (EQ-5D-5L), which was developed in Europe to demonstrate the cost utility of treatments for non-specific diseases.Methods: The EQ-5D-5L and Disability Index of the Health Assessment Questionnaire (HAQ-DI), which is a questionnaire for the quality of life for rheumatic diseases, were completed by 109 Japanese patients with SSc, and the clinical findings and laboratory data were collected at the same time.Results: There was a correlation between the EQ-5D-5L score and HAQ-DI score. The EQ-5D-5L index score was affected by the % of predicted vital capacity (%VC), pulmonary arterial hypertension, and renal crisis. The %VC and renal crisis were also indicated as factors reducing the quality of life in the HAQ-DI. There was no difference in the EQ-5D-5L score between the SSc subtypes or among autoantibodies.Conclusion: Our single-center study demonstrated the EQ-5D-5L to be a valuable assessment tool for functional disability in Japanese SSc patients, similarly to the disease specific HAQ-DI.

Anti-transcriptional intermediary factor 1-γ antibody as a biomarker in patients with dermatomyositis.

The presence of anti-transcriptional intermediary factor (TIF)1-γ antibody (Ab) is associated with cancer in adult patients with clinically amyopathic dermatomyositis (CADM) or dermatomyositis (DM). In this study, we examined whether anti-TIF1-γ Ab levels are associated with disease activity in patients with CADM/DM. Anti-TIF1-γ Ab levels were examined in 23 patients with CADM or DM (CADM, n = 6; DM, n = 17). Baseline characteristics and outcomes were recorded, and serial measurements of anti-TIF1-γ Ab levels were obtained. Of the 23 patients with detectable anti-TIF1-γ Ab, 16 (70%) had an internal malignancy, while two (9%) had interstitial lung disease. Mean initial anti-TIF1-γ Ab levels (134 ± 47 index) were significantly decreased after 24 months (54 ± 45 index, P < 0.0001) and remained decreased thereafter. Anti-TIF1-γ Ab became negative (index value, <32) in 10 patients (43%) and remained positive (index value, ≥32) in 13 patients (57%) during the clinical course. The frequency of remission in the anti-TIF1-γ Ab-negative conversion group (100%) was significantly higher than in the sustained positive group (0%, P < 0.0001). Furthermore, mortality in the anti-TIF1-γ Ab-negative conversion group (0%) was significantly lower than that in sustained positive group (69%, P < 0.001). This study indicates that anti-TIF1-γ Ab levels are a useful and relevant surrogate marker of disease activity during follow-up monitoring.

Human leukocyte antigen in Japanese patients with idiopathic inflammatory myopathy.

Objective: The human leukocyte antigen (HLA) is the strongest genetic risk factor for idiopathic inflammatory myopathy (IIM), and different HLA alleles have been reported to be associated with IIM susceptibility among different ethnic groups. In this study, we have investigated HLA alleles associated with IIM in Japanese patients.Methods: Genotyping of HLA-DRB1 and DPB1 were performed in 252 Japanese IIM patients (166 dermatomyositis [DM] and 86 polymyositis [PM] patients) and the association was analyzed with comparison to controls (n = 1026 for DRB1 and n = 413 for DPB1).Results: DRB1*08:03 was associated with IIM (p = 1.60 × 10-5, pc = .0005, odds ratio [OR] 2.11, 95% confidence interval [CI] 1.52-2.92) and DM (p = .0004, pc = .0128, OR 2.06, 95%CI 1.40-3.02). DPB1*05:01 was also associated with IIM (p = .0001, pc = .0021, OR 1.96, 95%CI 1.38-2.77) and DM (p = .0005, pc = .0075, OR 2.05, 95%CI 1.37-3.08). DRB1*09:01 (p = .0012, pc = .0368, OR 0.35, 95% CI 0.18-0.69) and DPB1*04:01(p = .0004, pc = .0057, OR 0.05, 95% CI 0.00-0.85) were protectively associated with PM. Two locus analyses suggested that DRB1*09:01 and DPB1*04:01 were independently associated with PM.Conclusion: Protective associations of HLA were detected in Japanese PM patients.