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Objectives To evaluate the efficacy and safety of ustekinumab (UST) in a multicentre, randomised, double-blind, placebo-controlled trial in adult Japanese patients with active polymyositis (PM) and dermatomyositis (DM).Methods Fifty-one Japanese adults diagnosed with active PM/DM who did not respond adequately to one or more standard-of-care treatments were randomised 1:1 to receive UST (n=25) or placebo (n=26). Participants received body weight-range based intravenous administration of UST (6 mg/kg) or placebo at week 0 followed by 90 mg subcutaneous (SC) administration of UST or placebo every 8 weeks from week 8 to week 24. At week 24, placebo group crossed over to receive body weight-range based intravenous administration of UST, and thereafter, all participants received/were to receive SC administration of UST 90 mg every 8 weeks (week 32 through to week 72). The primary efficacy endpoint was the proportion of participants who achieved minimal improvement (≥20) in the International Myositis Assessment and Clinical Studies Total Improvement Score (IMACS TIS) at week 24.Results No statistically significant difference was seen in the proportion of participants who achieved minimal improvement (≥20) in IMACS TIS at week 24 between the treatment groups (UST 64.0% vs placebo 61.5%, p=0.94) based on the primary estimand of the primary endpoint analysis.Conclusions UST was safe and well tolerated but did not meet the primary efficacy endpoint in adult Japanese participants with active PM/DM based on the primary analysis at week 24 in the study.Trial registration number NCT03981744.

Abstract Background Abatacept is a recombinant fusion protein composed of the extracellular domain of cytotoxic T-lymphocyte antigen 4 and the Fc portion of immunoglobulin (Ig) G. The mechanism of action of abatacept in rheumatoid arthritis (RA) is believed to be competitive inhibition of T cell costimulation mediated by the binding of CD28 to CD80/CD86 on antigen-presenting cells, and recent studies have shown that abatacept induces reverse signaling in macrophages and osteoclast precursors in a T cell-independent manner. This study aimed to investigate the therapeutic effects of abatacept on circulating monocytes that contribute to RA pathogenesis. Methods Purified circulating monocytes derived from RA patients and controls were cultured in the absence or presence of abatacept or CD28-Ig for 24 h. The recovered cells were subjected to flow cytometry to evaluate the expression levels of cell surface molecules, and cytokines and chemokines in the culture supernatant were measured by multiplex bead arrays. The expression of candidate molecules was further examined by immunoblotting using total cellular extracts of the cultured monocytes. Finally, the effects of abatacept on cytokine production in monocytes stimulated with the immune complex of anti-citrullinated peptide antibodies (ACPAs) were examined. Results CD64/FcγRI was identified as a monocyte-derived molecule that was downregulated by abatacept but not CD28-Ig. This effect was observed in both RA patients and controls. The abatacept-induced downregulation of CD64/FcγRI was abolished by treatment with anti-CD86 antibodies but not anti-CD80 antibodies. Abatacept suppressed the production of interleukin (IL)-1β, IL-6, C-C motif chemokine ligand 2, and tumor necrosis factor-α in cultured monocytes stimulated with the ACPA immune complex. Conclusions The therapeutic effects of abatacept on RA are mediated, in part, by the downregulation of CD64/FcγRI on circulating monocytes via direct binding to CD86 and the suppression of immune complex-mediated inflammatory cytokine production.

We aimed to dissociate the autoantibody response against the Ro52 protein in patients with anti-synthetase or anti-melanoma differentiation-associated gene 5 (MDA5) antibodies to explore the potential roles of different anti-Ro52 autoantibody responses in disease subclassification. This study used a single-center, prospective myositis cohort involving 122 consecutive patients with anti-synthetase antibodies identified by RNA immunoprecipitation (RNA-IP) and 34 patients with anti-MDA5 antibodies detected using enzyme immunoassay (EIA). Anti-Ro52 antibodies were measured using commercial EIA kits, while anti-Ro/SSA antibodies were identified using RNA-IP. Clinical features and outcomes were stratified according to two different patterns of autoantibody responses against Ro52, including “isolated anti-Ro52”, defined by positive anti-Ro52 and negative anti-Ro/SSA antibodies, and “anti-SSA-Ro52”, defined by positive anti-Ro52 and anti-Ro/SSA antibodies. Isolated anti-Ro52 positivity was the most prevalent autoantibody response in patients with both anti-synthetase (40/122; 32.8%) and anti-MDA5 antibodies (8/34; 23.5%). Isolated anti-Ro52 or anti-SSA-Ro52 positivity was associated with Gottron’s sign in patients with anti-synthetase antibodies, while in patients with anti-MDA5 antibodies, isolated anti-Ro52 positivity was associated with respiratory insufficiency at initial presentation and poor overall survival. Isolated anti-Ro52 positivity could be a potential biomarker for patient stratification; however, the clinical significance of dissociating isolated anti-Ro52 positivity from overall anti-Ro52 positivity was not evident.

ObjectiveTo investigate histologic features of immunological components in the primary tumor site of patients with cancer-associated myositis (CAM) by focusing on tumor-infiltrating lymphocytes (TILs) and tertiary lymphoid structures (TLSs), which play major roles in antitumor immunity.MethodsCancer-associated myositis patients were selected from the single-center idiopathic inflammatory myopathy cohort based on the availability of primary tumor specimens obtained before the introduction of immunomodulatory agents. Control cancer subjects without CAM were selected from the cancer tissue repository at a ratio of 1:2 matched for demographics and cancer characteristics of CAM cases. A series of immunohistochemical analyses was conducted using sequential tumor sections. TLS was defined as an ectopic lymphoid-like structure composed of DC-LAMP+ mature dendritic cells, CD23+ follicular dendritic cells (FDCs) and PNAd+ high endothelial venules. TLS distribution was classified into the tumor center, invasive margin, and peritumoral area.ResultsSix CAM patients and 12 matched non-CAM controls were eligible for the study. There was no apparent difference in the density or distribution of TILs between the groups. TLSs were found in 3 CAM patients (50%) and 4 non-CAM controls (33%). TLSs were exclusively located at the tumor center or invasive margin in CAM cases but were mainly found in the peritumoral area in non-CAM controls. FDCs and class-switched B cells colocalized with follicular helper T cells were abundantly found in the germinal center-like area of TLSs from CAM patients compared with those from non-CAM controls.ConclusionThe adaptive immune response within TLSs in the primary tumor site might contribute to the pathogenic process of CAM.

ObjectiveTo stratify patients with polymyositis/dermatomyositis-associated interstitial lung disease (ILD) who were initially treated with an intensive regimen consisting of high-dose corticosteroids, a calcineurin inhibitor, and intravenous cyclophosphamide (triple-combo therapy) into subgroups based on mortality outcomes by a cluster analysis using a large-scale multicenter retrospective cohort of Japanese patients with myositis-associated ILD (JAMI).MethodsTwo-step cluster analysis of preclustering and subsequent hierarchical clustering was conducted in 185 patients who received triple-combo therapy in an unbiased manner. Initial predictors for mortality previously reported in patients with myositis-associated ILD were used as variables and included age, sex, disease duration, classification of myositis, requirement of supplemental oxygen, anti-aminoacyl tRNA synthetase (ARS) antibody, anti-melanoma differentiation-associated gene 5 (MDA5) antibody, and serum levels of C-reactive protein (CRP) and Krebs von den Lungen-6 (KL-6). The cluster model was further applied to 283 patients who received conventional regimens consisting of corticosteroids with or without a single immunosuppressive agent (dual-combo therapy or monotherapy). Cumulative survival rates were compared using Kaplan-Meier analysis, and the log-rank test was used to test for significant differences between two groups.ResultsWe developed a cluster model consisting of 6 clusters, which were categorized by age at onset, clinically amyopathic dermatomyositis, CRP, KL-6, requirement of supplemental oxygen, anti-ARS antibody, and anti-MDA5 antibody. This model was judged to be of good quality based on the silhouette measure of cohesion and separation of 0.6. These clusters were regrouped into three subsets based on low (50%) mortality rates. The performance of the clustering was generally replicated in patients who received initial dual-combo therapy or monotherapy. Survival benefits of triple-combo therapy over dual-combo therapy or monotherapy were not observed in any of the clusters.ConclusionWe successfully developed a cluster model that stratified patients with myositis-associated ILD who were treated with initial triple-combo therapy into subgroups with different prognoses, although this model failed to identify a patient subgroup that showed survival benefits from triple-combo therapy over dual-combo therapy or monotherapy.

Idiopathic inflammatory myopathies (IIMs) are characterized by muscle inflammation caused by exacerbated autoimmunity reactions. Patients with IIMs also have extramuscular lesions, such as skin rash, arthritis, interstitial lung disease (ILD), and cardiomyopathy. ILD is one of the leading causes of mortality in patients with IIMs. Thus, physicians need to manage patients with IIM-associated ILD (myositis-ILD) appropriately to prevent the development and progression of ILD. Predictive factors for morality should be considered at the time of making decisions on therapeutic strategies for myositis-ILD. There have been numerous prognostic factors associated with mortality or pulmonary dysfunction. According to the latest research, which contains the large database analysis enrolling 499 incident cases of myositis-ILD with the comprehensive measurement of myositis-specific autoantibodies (MSAs), the presence of anti-melanoma differentiation-associated gene 5 antibody, age ≥60 years, C-reactive protein ≥1 mg/dL, and pulse saturation oxygen

A 47-year-old man was referred to our hospital with a 1-month history of fever and dyspnea after inhalation of insecticide in a confined space. We diagnosed rapidly progressive interstitial pneumonia. High-dose methylprednisolone, tacrolimus, and intermittent infusion of cyclophosphamide were administered. His condition rapidly deteriorated; therefore, extracorporeal membrane oxygenation therapy was performed. Unfortunately, he died 69 days after admission. Although typical skin findings suggestive of dermatomyositis were absent, anti-melanoma differentiation-associate gene (anti-MDA5) antibody was positive. Our findings suggest that in patients with hyperferritinemia and rapidly progressive interstitial lung disease (RP-ILD) demonstrating random ground glass shadows and peripheral consolidations by high-resolution computed tomography (HRCT) even if skin manifestations related to dermatomyositis are not complicated, we should assume anti-MDA5 antibody-positive interstitial pneumonia. Keywords: Anti-melanoma differentiation-associated gene 5 antibody, Rapidly progressive interstitial pneumonia, Clinical amyopathic dermatomyositis, Extracorporeal membrane oxygenation

Objectives To investigate whether the onset of polymyositis (PM)/dermatomyositis (DM)-associated interstitial lung disease (ILD) is influenced by season and residence in the context of myositis-specific autoantibodies.Methods For patients with PM/DM-associated ILD enrolled in a multicentre cohort, 365 and 481 patients were eligible for seasonal and geographical analysis, respectively, based on the availability of reliable clinical information. The patients were divided into three groups: (1) anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive patients, (2) anti-aminoacyl tRNA synthetase (anti-ARS) antibody-positive patients and (3) patients negative for those antibodies. Seasonality was assessed by the Rayleigh test. Distance from residence to the nearest waterfront was measured on Google Map and was compared between groups by the exact Wilcoxon rank-sum test.Results In anti-MDA5-positive patients, the disease developed more frequently in October–March (p=0.03), whereas a seasonal relationship was not found in the remaining two patient groups. Residence at disease onset in anti-MDA5-positive patients was significantly closer to the waterfront, especially to freshwater, compared with that in anti-ARS-positive or anti-MDA5-/ARS-negative patients (p=0.003 and 0.006, respectively).Conclusions Anti-MDA5-associated ILD occurred predominantly from October to March in individuals residing near freshwater, suggesting an environmental influence on the onset of this disease subset.

ObjectiveSurfactant protein D (SP-D) is considered a serum biomarker of various forms of interstitial lung disease (ILD). In this study, we examined the utility of SP-D as a predictive biomarker for mortality in patients with ILD associated with polymyositis/dermatomyositis (PM/DM) using large-scale multicentre cohort data.MethodsWe enrolled 381 patients with incident PM/DM-associated ILD in a multicentre retrospective cohort based on the availability of serum SP-D at the baseline. Demographic and clinical characteristics as well as the presence of autoantibodies to melanoma differentiation-associated gene 5 (MDA5) and aminoacyl tRNA synthetase were measured at the time of diagnosis, and follow-up survival data were collected prospectively.ResultsSeventy-eight patients died during the median observation period of 18 months, and the majority of patients died of ILD. The SP-D levels at baseline were significantly lower (P = 0.02) in a non-survivor subset than in a survivor subset among the entire enrolled patients. However, the SP-D levels were higher in the non-survivor subset than in the survivor subset based on the stratification by anti-MDA5-positive, anti-ARS-positive and, double-negativity, although there was an only statistically significant difference (P = 0.01) in the double-negative group. Surprisingly, the SP-D levels were within the upper limit of normal, 110 ng/mL, in 54 (87%) of 62 anti-MDA5-positive patients who died. In the double-negative group, the mortality rates were significantly higher (P = 0.002) in a subset with SP-D ≥127.6 ng/mL, the cut-off value for mortality calculated by the receiver operating characteristic curve, than the other subset. All of patients with SP-D ConclusionSerum SP-D levels behave differently among patients with stratified by anti-MDA5 antibody, anti-ARS antibody and both negativity in PM/DM-associated ILD. Its use in clinical practice should be applied with caution on the basis of the presence or absence of anti-MDA5 antibody or anti-ARS antibody.

Abstract Background Some patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) also have positivity of rheumatoid factor (RF). However, the clinical significance of this occurrence remains unknown in AAV patients. The aim of this study was to clarify an association between the presence of RF and clinical features in patients with AAV. Results Forty-seven patients diagnosed with AAV who were not complicated with RA were enrolled in this study. We compared clinical manifestations of AAV between an RF-positive subset (n = 29) and an RF-negative subset (n = 18). The Birmingham Vasculitis Activity Score (BVAS) was higher (P = 0.026) in the RF-positive subset than in the RF-negative subset. The levels of CRP and ESR were higher in the RF-positive patients (P = 0.020 and P = 0.007, respectively) compared to the RF-negative subset. IgM-RF titers were significantly correlated with the BVAS (r = 0.50, P = 0.0004). In addition, the IgM-RF titers had significant correlations with the levels of CRP (r = 0.41, P = 0.004), ESR (r = 0.39, P = 0.016), IgM (r = 0.36, P = 0.016) and IgG (r = 0.37, P = 0.015). The frequency of commencement of dialysis therapy, usage of mechanical ventilation and mortality were higher in the RF-positive subset than in the RF-negative subset. Conclusions In patients with AAV, RF titers were significantly correlated with disease activity and the levels of inflammatory markers. The presence of RF could be a poor prognostic factor in patients with AAV.

BACKGROUND:Accumulating evidence has shown that several non-HLA genes are involved in the susceptibility to polymyositis/dermatomyositis. This study aimed to investigate the involvement of C8orf13-BLK, one of the strongest candidate genes for autoimmune diseases, in susceptibility to polymyositis/dermatomyositis in the Japanese population. A possible gene-gene interaction between C8orf13-BLK and STAT4, which we recently showed to be associated with Japanese polymyositis/dermatomyositis, was also analyzed. METHODS:A single-nucleotide polymorphism in C8orf13-BLK (dbSNP ID: rs13277113) was investigated in the Japanese population using a TaqMan assay in 283 polymyositis patients, 194 dermatomyositis patients, and 656 control subjects. RESULTS:The C8orf13-BLK rs13277113A allele was associated with overall polymyositis/dermatomyositis (P

Objectives: The management of elderly-onset rheumatoid arthritis (EORA) is challenging due to progressive functional disability, increased comorbidities, and high drug-related risks. EORA is defined as disease onset after 60years since 1985. We assessed whether this cut-off age was optimal in a progressively ageing society. Methods: This study used two cohorts of consecutive rheumatoid arthritis (RA) patients: the Nippon Medical School (NMS) cohort (n = 204) and the Keio cohort (n = 296). Clinical findings independently correlated with the age of RA onset were selected as 'EORA features' from previously reported EORA characteristics using univariable and multivariable regression analyses. Receiver operating characteristic curve analysis was conducted to determine the cut-off age that best selected patients with all EORA features. Results: Acute onset, negative anti-cyclic citrullinated peptide antibody, and high erythrocyte sedimentation rate were selected as 'EORA features' in both cohorts. Patients with all EORA features were more numerous with age and almost exclusively older than 65 years. The optimal EORA cut-off age was 73 years with an area under the curve (AUC) of 0.82 in the NMS cohort and 68 with an AUC of 0.93 in the Keio cohort. In the NMS cohort, Health Assessment Questionnaire-Disability Index and comorbidities in patients with disease onset between 60 years and the projected cut-off age were similar to those in younger-onset RA, but differed from those in patients with disease onset older than the projected cut-off age. Conclusion: The optimal EORA cut-off age was greater than the conventional definition, but this needs to be validated in different patient populations. [ABSTRACT FROM AUTHOR]

Objective: Rare disease. Background: Systemic vasculitides constitute heterogenous conditions affecting many organs and systems through blood vessel inflammation. Although there are some classifications for vasculitis, several vasculitides are "unclassified" because they cannot be clearly assigned to one of the known entities. Case Report: We report an autopsy case of a 67-year-old Japanese man who presented with fever, ocular pain, erythema, chest pain, and headache. The disease caused episcleritis, thrombophlebitis, extensive deep vein thrombosis, multiple pulmonary nodules and masses, hypertrophic pachymeningitis, and hyper-intensity areas in brain parenchyma on magnetic resonance images. Histopathology of the pulmonary nodule confirmed vasculitis affecting medium-to-small veins and arteries without necrotizing vasculitis or granulomatous inflammation. We diagnosed the patient with unclassified vasculitis based on the clinicopathological characteristics. Steroids in combination with immunosuppressants were used, but the disease was refractory and relapsing. The disease activity was eventually controlled with rituximab, but the patient died of bronchopneumonia. On autopsy, lung and brain findings indicated healed vascular inflammation. Conclusions: This is the first case report of unclassified vasculitis, which is characterized as medium-to-small-sized arteritis and phlebitis, causing episcleritis, thrombophlebitis, deep vein thrombosis, pulmonary vasculitis, and intracranial vasculitis. The clinical conditions share some similarities with granulomatosis with polyangiitis and Behçet's disease; however, they meet no classification criteria of any specific vasculitis. More cases need to be analyzed to confirm our findings. [ABSTRACT FROM AUTHOR]

Objectives: To compare the quantitative performance for measuring anti-MDA5 antibody titer of two enzyme-linked immunosorbent assay (ELISA) systems: an in-house ELISA and the commercial MESACUPTM anti-MDA5 test. Methods: Anti-MDA5 antibody titer was measured in sera from 70 patients with dermatomyositis using an in-house ELISA and the MESACUPTM anti-MDA5 test side-by-side. For the commercial ELISA kit, serum samples diluted 1:101 were used according to the manufacturer's protocol, but serial dilutions of sera were also examined to identify the optimal serum dilution for quantification. Results: The anti-MDA5 antibody titers measured by the in-house and commercial ELISAs were positively correlated with each other (r=0.53, p=.0001), but the antibody titer measured by the commercial ELISA was less sensitive to change after medical treatment, and 37 (80%) of 46 anti-MDA5-positive sera had antibody titer exceeding the quantification range specified by the manufacturer (-150 index). Experiments using diluted serum samples revealed that diluting the sera 1:5050 improved the quantitative performance of the MESACUPTM anti-MDA5 test, including a better correlation with the in-house ELISA results and an increased sensitivity to change. Conclusion: We improved the ability of the commercial ELISA kit to quantify anti-MDA5 antibody titer by altering its protocol. [ABSTRACT FROM AUTHOR]

Background: Some patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) also have positivity of rheumatoid factor (RF). However, the clinical significance of this occurrence remains unknown in AAV patients. The aim of this study was to clarify an association between the presence of RF and clinical features in patients with AAV. Results: Forty-seven patients diagnosed with AAV who were not complicated with RA were enrolled in this study. We compared clinical manifestations of AAV between an RF-positive subset (n = 29) and an RF-negative subset (n=18). The Birmingham Vasculitis Activity Score (BVAS) was higher (P = 0.026) in the RF-positive subset than in the RF-negative subset. The levels of CRP and ESR were higher in the RF-positive patients (P = 0.020 and P = 0.007, respectively) compared to the RF-negative subset. IgM-RF titers were significantly correlated with the BVAS (r = 0.50, P = 0.0004). In addition, the IgM-RF titers had significant correlations with the levels of CRP (r= 0.41, P = 0.004), ESR (r = 0.39, P = 0.016), IgM (r = 0.36, P = 0.016) and IgG (r = 0.37, P = 0.015). The frequency of commencement of dialysis therapy, usage of mechanical ventilation and mortality were higher in the RF-positive subset than in the RF-negative subset. Conclusions: In patients with AAV, RF titers were significantly correlated with disease activity and the levels of inflammatory markers. The presence of RF could be a poor prognostic factor in patients with AAV. [ABSTRACT FROM AUTHOR]

Objective. Hyperferritinemia is frequently accompanied by rapidly progressive (RP) interstitial lung disease (ILD) with polymyositis (PM)/dermatomyositis (DM). To clarify the mechanism of RP-ILDwith hyperferritinemia, we investigated the associations between serumferritin levels and various cytokines in patients with PM/DM. Methods. This retrospective study included 38 patients admitted to our hospital with PM/DM. Levels of serum ferritin and cytokines (IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, IL-17, IL-18, TNF-α, IFN-α, IFN-γ, and IP-10) were measured. Disease activity was evaluated using the tool proposed by the International Myositis Assessment and Clinical Studies Group. We analyzed the associations between disease activity and levels of serum ferritin and cytokines. Results. The levels of serumferritin, IL-8, IL-10, IL-18, and TNF-α, were significantly correlated with disease activity. In a multivariate analysis, IL-6 (t = 3.6, p = 0.0010), IL-8 (t = 4.8, p < 0.0001), and IL-10 (t = 5.7, p < 0.0001) significantly contributed to serum ferritin levels. The levels of serum ferritin, IL-6, IL-8, and IL-10, were higher in the RP-ILD subset than in the non-ILD subset or the chronic ILD subset. Conclusion. IL-6, IL-8, and IL-10 are significant contributors to hyperferritinemia in PM/DM. The regulation of these cytokines might offer a possible treatment strategy for RP-ILD with PM/DM. [ABSTRACT FROM AUTHOR]

Periaortitis is a rare vascular manifestation and is often associated with retroperitoneal fibrosis. Herein, we describe a case of periaortitis accompanied by retroperitoneal fibrosis in a patient who developed acute kidney insufficiency due to bilateral ureteral stenosis. Ultrasonography at presentation detected thickness of the outer layer of the bilateral common iliac artery and right internal and external iliac arteries, consistent with periaortitis. Moreover, follow-up ultrasound images revealed subsiding of the thickness of the arterial wall in response to treatment with corticosteroids. Because of its noninvasiveness and handiness, ultrasonography has become popular for the assessment of large vessels in clinical practice, particularly monitoring for affected lesions. Computed tomography, magnetic resonance imaging, and positron emission tomography are currently used for the diagnosis and monitoring of periaortitis, but in this case, ultrasonography was utilized in the diagnosis and monitoring of periaortitis as a supportive imaging modality, as the use of contrast agents was contraindicated because of renal insufficiency. [ABSTRACT FROM AUTHOR]