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Introduction/ObjectivesA 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).MethodWe 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).ResultsThe 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.ConclusionsDetection 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.

Autoantibodies to melanoma differentiation-associated gene 5 (MDA5) are specifically expressed in patients with dermatomyositis (DM) and are associated with a subset of DM patients with rapidly progressive interstitial lung disease (RP-ILD). Here, we examined the clinical utility of a newly developed enzyme-linked immunosorbent assay (ELISA) system for detecting these antibodies. Here we developed an improved ELISA for detecting anti-MDA5 antibodies. We then performed a multicenter clinical study involving 8 medical centers and enrolled 242 adult patients with polymyositis (PM)/DM, 190 with non-PM/DM connective tissue disease (CTD), 154 with idiopathic interstitial pneumonia (IIP), and 123 healthy controls. Anti-MDA5 antibodies in the patients' serum samples were quantified using our newly developed ELISA, and the results were compared to those obtained using the gold-standard immunoprecipitation (IP) assay. In addition, correlations between the ELISA-quantified anti-MDA5 antibodies and clinical characteristics were evaluated. In patients with PM/DM, the anti-MDA5 antibody measurements obtained from the ELISA and IP assay were highly concordant; the ELISA exhibited an analytical sensitivity of 98.2%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 99.5% (compared to the IP assay). Anti-MDA5 antibodies were detected in 22.7% of the DM patients, but not in any of the patients with PM, non-PM/DM CTD, or IIP. Clinically amyopathic DM, RP-ILD, arthritis, and fever were more prevalent in DM patients who were anti-MDA5 antibody-positive than in those who were antibody-negative (P ≤ 0.0002 for all comparisons). In addition, anti-MDA5 antibody-positive patients with RP-ILD exhibited higher antibody levels than those without RP-ILD (P = 0.006). Our newly developed ELISA can detect anti-MDA5 antibodies as efficiently as the gold standard IP assay and has the potential to facilitate the routine clinical measurement of anti-MDA5 antibodies in patients who suspected to have DM.

Dysphagia develops with low frequency in patients with dermatomyositis. Our objective was to determine the clinical and laboratory features that can estimate the development of dysphagia in dermatomyositis. This study included 92 Japanese patients with adult-onset dermatomyositis. The associations between dysphagia and clinical and laboratory features including disease-specific autoantibodies determined by immunoprecipitation assays were analyzed. Videofluoroscopy swallow study (VFSS) was performed for all patients with clinical dysphagia (n = 13, 14.1%) but not for patients without clinical dysphagia. Typical findings of dysphagia (pharyngeal pooling, n = 11 and/or nasal regurgitation, n = 4) was detected by VFSS in all patients with clinical dysphagia. Eleven patients with dysphagia (84.6%) had anti-transcription intermediary factor 1γ (TIF-1γ) antibody. By univariate analysis, the average age and the male to female ratio, internal malignancy, and anti-TIF-1γ antibody were significantly higher and the frequency of interstitial lung diseases and manual muscle testing (MMT) scores of sternomastoid and dertoid muscles were significantly lower in patients with dysphagia than in patients without dysphagia. Among patients with anti-TIF-1γ antibody, the mean age, the ratios of male to female and internal malignancy were significantly higher and mean MMT scores of sternomastoid muscle were significantly lower in patients with dysphagia compared with patients without dysphagia. By multivariable analysis, the risk of dysphagia was strongly associated with the existence of internal malignancy and ant-TIF-1γ antibody and was also associated with reduced scores of manual muscle test of sternomastoid muscle. Dysphagia was markedly improved after the treatment against myositis in all 13 patients. These findings indicate that dysphagia can develop frequently in patients with internal malignancy, anti-TIF-1γ antibody, or severe muscle weakness of sternomastoid muscle.

To identify similarities and differences in the clinical features of adult Japanese patients with individual anti-aminoacyl-tRNA synthetase antibodies (anti-ARS Abs). This was a retrospective analysis of 166 adult Japanese patients with anti-ARS Abs detected by immunoprecipitation assays. These patients had visited Kanazawa University Hospital or collaborating medical centers from 2003 to 2009. Anti-ARS Ab specificity included anti-Jo-1 (36%), anti-EJ (23%), anti-PL-7 (18%), anti-PL-12 (11%), anti-KS (8%), and anti-OJ (5%). These anti-ARS Abs were mutually exclusive, except for one serum Ab that had both anti-PL-7 and PL-12 reactivity. Myositis was closely associated with anti-Jo-1, anti-EJ, and anti-PL-7, while interstitial lung disease (ILD) was correlated with all 6 anti-ARS Abs. Dermatomyositis (DM)-specific skin manifestations (heliotrope rash and Gottron's sign) were frequently observed in patients with anti-Jo-1, anti-EJ, anti-PL-7, and anti-PL-12. Therefore, most clinical diagnoses were polymyositis or DM for anti-Jo-1, anti-EJ, and anti-PL-7; clinically amyopathic DM or ILD for anti-PL-12; and ILD for anti-KS and anti-OJ. Patients with anti-Jo-1, anti-EJ, and anti-PL-7 developed myositis later if they had ILD alone at the time of disease onset, and most patients with anti-ARS Abs eventually developed ILD if they did not have ILD at disease onset. Patients with anti-ARS Abs are relatively homogeneous. However, the distribution and timing of myositis, ILD, and rashes differ among patients with individual anti-ARS Abs. Thus, identification of individual anti-ARS Abs is beneficial to define this rather homogeneous subset and to predict clinical outcomes within the \"anti-synthetase syndrome.\"

Sphingosine-1-phosphate (S1P), a lipid mediator, regulates lymphocyte migration between lymphoid tissue and blood. Furthermore, S1P participates in several physiological phenomena including angiogenesis, inflammation, immune regulation, and neurotransmitter release. Moreover, S1P/S1P receptor signaling involves in systemic sclerosis (SSc) pathogenesis. This study aimed to investigate whether the selective S1P 1 receptor modulator cenerimod attenuates murine sclerodermatous models. Cenerimod was orally administered to murine sclerodermatous chronic graft versus host disease (Scl-cGVHD) mice, either from day 0 to 42 or day 22 to 42 after bone marrow transplantation. Bleomycin-induced SSc model mice were administered cenerimod from day 0 to 28. Early cenerimod administration inhibited, and delayed cenerimod administration attenuated skin and lung fibrosis in Scl-cGVHD mice. Cenerimod suppressed the infiltration of CD4 + T cells, CD8 + T cells, and CD11b + cells into the inflamed skin of Scl-cGVHD mice as opposed to control mice. In contrast, cenerimod increased the frequency of regulatory T cells in the spleen and skin of Scl-cGVHD mice. Additionally, cenerimod attenuated the mRNA expression of extracellular matrix and fibrogenic cytokines in the skin. Furthermore, cenerimod attenuated bleomycin-induced fibrosis in the skin and lung. Hence, the selective S1P 1 receptor modulator cenerimod is a promising candidate for treating patients with SSc and Scl-cGVHD.

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.

Systemic sclerosis (scleroderma) is a connective tissue disease characterized by excessive extracellular matrix deposition in the skin and visceral organs. Serum IL-6 levels are reported to be elevated in human scleroderma and chronic graft-versus-host disease (cGVHD) patients. IL-6 blockade using anti-IL-6 receptor mAb (anti-IL-6R mAb) results in amelioration of the pathologic symptoms of some autoimmune diseases such as rheumatoid arthritis and juvenile idiopathic arthritis. In this study, we examined the effects of anti-IL-6R mAb on either prevention or treatment of murine sclerodermatous cGVHD (Scl-cGVHD). We found that serum IL-6 levels in Scl-cGVHD mice gradually increased after bone marrow transplantation. Administration of anti-IL-6R mAb attenuated the development of severe Scl-cGVHD and fibrosis and resulted in an increase in CD4+CD25+FoxP3+ regulatory T cells. However, treatment of established Scl-cGVHD with anti-IL-6R mAb showed no effects on disease severity. The effects of anti-IL-6R mAb were mostly inhibited by anti-CD25 mAb. Together, our results indicate that IL-6 has an important role in the pathogenesis of Scl-cGVHD. IL-6 blockade may be an effective approach for preventing Scl-cGVHD and treating cGVHD and scleroderma in humans.

To assess the utility of circulating adhesion molecule levels as a prognostic indicator of disease progression in systemic sclerosis (SSc) patients with early onset disease. Ninety-two Japanese patients with early onset SSc presenting with diffuse skin sclerosis and/or interstitial lung disease were registered in a multicentre, observational study. Concentrations of intercellular adhesion molecule (ICAM) -1, E-selectin, L-selectin, and P-selectin in serum samples from all patients were measured by enzyme-linked immunosorbent asssay (ELISA). In 39 patients, adhesion molecule levels were measured each year for four years. The ability of baseline adhesion molecule levels to predict subsequent progression and severity in clinical and laboratory features were evaluated statistically. At their first visit, serum levels of ICAM-1, E-selection, P-selectin were significantly elevated and serum L-selectin levels were significantly reduced in patients with SSc compared with healthy controls. Overall, serum ICAM-1 levels at each time point were significantly inversely associated with the %vital capacity (VC) of the same time and subsequent years by univariate analysis. The initial serum ICAM-1 levels were significantly inversely associated with the %VC at the fourth year by multiple regression analysis. The initial serum P-selectin levels were significantly associated with the health assessment questionnaire disability index (HAQ-DI) at the fourth year by multiple regression analysis. Initial adhesion molecule levels were not significantly associated with other clinical features including skin thickness score. Baseline adhesion molecule levels were not significantly associated with subsequent rate of change of clinical parameters. In patients with SSc, serum levels of ICAM-1 and P-selectin may serve as prognostic indicators of respiratory dysfunction and physical disability, respectively. Further longitudinal studies of larger populations are needed to confirm these findings.

An 83‐year‐old man with muscle involvement and interstitial lung disease (ILD) was diagnosed with anti‐OJ antibody (Ab)‐positive polymyositis (PM). He did not have Raynaud's phenomenon, heliotrope rash, Gottron's sign, fever, arthralgia, or mechanic's hand. A literature review of 21 anti‐OJ Ab‐positive patients described that the diagnoses were as follows: 10 with PM, five with dermatomyositis, five with ILD, and 1 with overlap syndrome of PM and rheumatoid arthritis. Myositis was observed in 16, ILD in 19, and skin rash in 5. Physicians need to be aware of the existence of patients with anti‐OJ Ab who have myositis and ILD. Physicians need to be aware of the existence of patients with anti‐OJ Ab who have myositis and ILD, even if they do not have Raynaud's phenomenon, fever, arthralgia, or mechanic's hand.

Objective\\nSeveral 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.\\nMethods\\nAssociations of HLA-DRB1, DQB1, and DPB1 were analyzed in 463 Japanese SSc patients and 413 controls.\\nResults\\nWe 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.\\nConclusion\\nThus, 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.