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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.

Interstitial lung disease is one of the most important causes of mortality in patients with polymyositis or dermatomyositis. Understanding the risk factors for development and progression of interstitial lung disease is crucial to improving clinical outcomes.

Purpose of Review This review aims to evaluate recent findings on the role of environmental factors in the development and clinical presentation of idiopathic inflammatory myopathies (IIMs). Recent Findings A targeted literature review was conducted to identify reports relevant to the association between environmental factors and IIMs published over the past three years. There has been an increasing number of publications dealing with the association of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or vaccination with the development of IIMs, highlighting the significant role of the antiviral immune response in the pathogenesis of the disease. Traditional environmental factors associated with the pathogenic process of IIM subclassifications included drugs such as statins and immune checkpoint inhibitors, ultraviolet radiation, smoking, air pollutants, and vitamin D deficiency. Correlations of seasonality and residence with the onset of certain IIM subtypes suggest a potential role of environmental triggers in the pathogenic process. An interplay between genetic predisposition and various environmental factors might contribute to the development of IIMs as well as the heterogeneous clinical and serological presentation of IIMs. Summary The growing evidence on the role of environmental factors in the development of IIMs provides important clues to elucidate the pathophysiology of these disease entities. The mechanisms underlying the interactions between genetic predisposition and environmental factors should be investigated in the future.

ObjectivesTo 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.MethodsFor 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.ResultsIn 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).ConclusionsAnti-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.

Anti-melanoma differentiation-associated gene 5 (MDA5)-positive dermatomyositis (DM) is often complicated by rapidly progressive interstitial lung disease (RP-ILD), leading to early mortality. Previous studies on the pathogenesis of anti-MDA5-positive DM highlighted type I interferons (IFNs), while recent investigations reported the significance of a type III IFN, IFN-λ3. We investigated a range of cytokines, including type I/II/III IFNs, in serum samples from anti-MDA5-positive DM patients collected at diagnosis before treatment introduction. Elevations of IFN-β and λ3 were identified as the hallmark of anti-MDA5-positive DM, in comparison with other myositis subtypes, systemic lupus erythematosus, and COVID-19 pneumonia. The elevation of IFN-λ3 was associated with decreased CD56 dim CD16 pos NK cells in circulation. The unique cytokine profile with type I/III IFN upregulation in anti-MDA5-positive DM was replicated in independent validation cohorts. A cluster analysis using serum type I/III IFN levels identified three subgroups in anti-MDA5-positive DM: mild elevations of IFN-α/β and λ3; a marked increase in IFN-λ3 alone; and pronounced elevations of IFN-α/β with mild to moderate increase in IFN-λ3. Patients in the cluster with a marked elevation of IFN-λ3 alone tended to present with RP-ILD and decreased survival. The combination of serum type I/III IFN levels could serve as a prognostic biomarker in anti-MDA5-positive DM.

To 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). Two-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. We 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 (<10%), moderate (10-50%), and high (>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. We 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.

Background Patients with Dermatomyositis (DM) having anti-melanoma differentiation-associated gene 5 (MDA5) antibodies occasionally develop rapidly progressive interstitial lung disease (RP-ILD), a serious inflammatory complication; however, no genetic biomarker has yet been identified for this condition. This study aimed to identify interferon-induced with helicase C domain 1 (also known as MDA5) gene ( IFIH1 ) variants associated with a high risk of DM-associated RP-ILD. Methods A total of 204 patients with DM were enrolled from six institutions. Whole-exome sequencing was performed on nine patients with DM-associated interstitial lung disease (ILD) who were positive for anti-MDA5 antibodies, and six single-nucleotide polymorphisms (SNPs) were identified: p.Val194Ala (no reference SNP ID), rs1990760, rs3747517, rs12479043, rs10930046, and rs141134657. Allele frequencies of eight IFIH1 variants—including these six SNPs plus rs117608083 and rs183412282—were analyzed using Sanger sequencing. Statistical analyses included allele frequency comparisons and genotype-based assessments (dominant and recessive models), and the Armitage trend test. Results Among the 204 patients with DM, 109 (53.4%) had classic DM and 95 (46.6%) had clinically amyopathic DM. A total of 174 patients (85.3%) had ILD, and 62 (30.4%) were positive for anti-MDA5 antibodies. Among the 204 patients with DM, low minor allele frequencies (MAFs) for rs12479043 and rs10930046 were significantly ( p  < 0.05) associated with high rates of ILD and anti-MDA5 antibodies. Among the 174 patients with ILD, a low MAF for rs141134657 was significantly ( p  < 0.05) associated with a high incidence of acute onset of ILD within 3 months, in accordance with allele, genotype, and Armitage trend tests, but not the recessive model. A low MAF for rs141134657 tended to be associated with high serum C-reactive protein levels in accordance with the additive and dominant models, but the result was not significant. None of the analyzed IFIH1 variants were significantly associated with serum levels of ferritin, KL-6, and lactate dehydrogenase. Conclusion This study identified genetic biomarkers associated with the risk of RP-ILD in patients with DM. These findings suggest that analysis of IFIH1 variants may serve as a valuable tool for predicting the development of RP-ILD in this patient population.

Background Cytomegalovirus (CMV) can cause life-threatening diseases in immunosuppressed patients. Some of the patients with connective tissue disease develop CMV infection, and approximately half of this group has been reported to have received pulsed-methylprednisolone (p-MPSL) therapy. This study aimed to identify predictors of the onset of CMV infection in patients receiving p-MPSL therapy for connective tissue disease. Methods This was a retrospective, multicenter cohort study. We included patients who received p-MPSL therapy for connective tissue disease and had CMV antigenemia measured between April 2011 and December 2020. Peripheral blood cell data before the start of p-MPSL therapy and at the start of steroid tapering were collected in addition to baseline characteristics, including age, sex, and body mass index. CMV infection was defined as detection of one or more CMV antigen-positive cells (CMV-positive). The study examined and compared the CMV-positive group with the CMV-negative group. Logistic regression analysis was used to explore the factors associated with CMV antigen positivity. Receiver operating characteristic curve analysis was used to identify the cut-off values for the factors associated with CMV antigen sensitivity. Results Of the 200 patients included, 87 had antigen positivity. Logistic regression analysis showed that age ≥ 65 years [adjusted odds ratio (aOR): 2.75, 95% confidence interval (CI): 1.54–4.92] and platelet count less than 30.20 × 10 4 /µL [aOR: 4.38, 95%CI: 2.21–8.68] at baseline were significantly associated with CMV antigen positivity. Lymphocyte count < 1440 /µL [aOR: 5.36, 95% CI: 1.96–14.65], neutrophil-to-lymphocyte ratio (NLR) ≥ 3.42 [aOR: 7.31, 95% CI: 2.52–21.22], and platelet-to-lymphocyte ratio (PLR) ≥ 145.28 [aOR:6.10, 95% CI: 2.24–16.64] at the start of steroid tapering also increased the OR for CMV infection. The areas under the receiver operating characteristic curves for lymphocytes, NLR, and PLR were 0.742, 0.693, and 0.673 respectively. Conclusion Platelet count, lymphocyte count, NLR, and PLR may be crucial predictors of the onset of CMV infection in patients with connective tissue disease. These easily obtainable factors may be clinically useful as predictors of CMV infection. A potential research area would be to validate the parameters in a prospective patient population.

Surfactant 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. We 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. Seventy-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 [greater than or equal to]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 <127.6 ng/mL survived. Serum 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.