Objective

To identify the autoantigen recognized by the autoantibody that is associated with clinically amyopathic dermatomyositis (C-ADM) and rapidly progressive interstitial lung disease (ILD).



Methods

An anti–CADM-140 antibody–positive prototype serum sample was used to screen a HeLa cell–derived complementary DNA (cDNA) library. Selected cDNA clones were further evaluated by immunoprecipitation of their in vitro–transcribed and in vitro–translated products using anti–CADM-140 antibody–positive and anti-CADM-140 antibody–negative sera. The lysates of COS-7 cells transfected with the putative antigen were similarly tested. An enzyme-linked immunosorbent assay (ELISA) to detect the anti–CADM-140 antibody was established using a recombinant CADM-140 antigen, and its specificity and sensitivity for C-ADM and rapidly progressive ILD were assessed in 294 patients with various connective tissue diseases.



Results

By cDNA library screening and immunoprecipitation of in vitro–transcribed and in vitro–translated products, we obtained a cDNA clone encoding melanoma differentiation–associated gene 5 (MDA-5). The anti–CADM-140 antibodies in patients' sera specifically reacted with MDA-5 protein expressed in cells transfected with full-length MDA-5 cDNA, confirming the identity of MDA-5 as the CADM-140 autoantigen. The ELISA, using recombinant MDA-5 protein as the antigen, showed an analytical sensitivity of 85% and analytical specificity of 100%, in comparison with the “gold standard” immunoprecipitation assay, and was useful for identifying patients with C-ADM and/or rapidly progressive ILD.



Conclusion

Given that RNA helicase encoded by MDA-5 is a critical molecule involved in the innate immune defense against viruses, viral infection may play an important role in the pathogenesis of C-ADM and rapidly progressive ILD. Moreover, our ELISA using recombinant MDA-5 protein makes detection of the anti–CADM-140 antibody routinely available.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.24621

RNA helicase encoded by melanoma differentiation-associated gene 5 is a major autoantigen in patients with clinically amyopathic dermatomyositis: Association with rapidly progressive interstitial lung disease

Interstitial lung disease associated with the idiopathic inflammatory myopathies: what progress has been made in the past 35 years?

The idiopathic inflammatory myopathies (IIMs)--DM and PM--have been historically defined by broad clinical and pathological criteria. These conditions affect both adults and children with clinical features including muscle weakness, skin disease, internal organ involvement and an association with cancer in adults. Using a clinico-serological approach, DM and PM can be defined into more homogeneous subsets. Over the last few years, myositis-specific autoantibodies (MSAs) have been better characterized including autoantibodies directed against the aminoacyl tRNA-synthetase enzymes, the signal-recognition particle and the Mi-2 protein. In addition, clinically significant novel autoantibodies--anti-CADM-140, anti-SAE (small ubiquitin-like modifier activating enzyme), anti-p155/140 and anti-p140--have been described in the adult and juvenile disease spectrum. MSAs are directed against cytoplasmic or nuclear components involved in key regulatory intracellular processes including protein synthesis, translocation and gene transcription. The striking association between unique serological profiles and distinct clinical phenotypes suggests that target autoantigens may play a role in disease induction and propagation. In this review, we discuss the clinical utility and pathogenic significance of MSAs in disease expression.

Myositis-specific autoantibodies: their clinical and pathogenic significance in disease expression

Objectives. Various autoantibodies are detected in the sera of PM/DM patients. Some of them are specific to PM/DM patients and closely associated with clinical manifestations of the diseases. Recently, the anti-CADM-140 antibody was reported to be found specifically in clinically amyopathic DM (C-ADM) patients and to be associated with acute interstitial lung disease (ILD). We assessed the clinical significance of the anti-CADM-140 antibody and then investigated the autoantigen recognized by the anti-CADM-140 antibody. Methods. Autoantibodies were screened in 192 patients with various CTDs and 21 healthy controls using immunoprecipitation with [ 35 S]methionine-labelled HeLa cells. Immunoabsorbent column chromatography was used to purify an autoantigen that was subsequently subjected to peptide mass fingerprinting. Results. The anti-CADM-140 antibody was revealed to be specific to DM. Most of the anti-CADM-140positive patients were C-ADM although some of them showed apparent myositis. The anti-CADM-140positive patients frequently showed hyperferritinaemia and acute progressive ILD with poor prognosis. The anti-CADM-140 antibody was shown to recognize IFN induced with helicase C domain protein 1 (IFIH1), also known as the melanoma differentiation-associated gene 5 (MDA5), which is one of the RIG-I-like receptors and plays a role in innate immune responses. Conclusion. The anti-CADM-140 antibody was a marker of DM and intractable ILD and recognized IFIH1/MDA5, which is involved in innate immunity. These findings may give a new insight into the pathogenesis of DM.

/pdf/the-rig-i-like-receptor-ifih1-mda5-is-a-dermatomyositis-nlhagc0y6g.pdf

The RIG-I-like receptor IFIH1/MDA5 is a dermatomyositis-specific autoantigen identified by the anti-CADM-140 antibody

Objective To clarify the association of clinical and prognostic features with dermatomyositis (DM)-specific autoantibodies (Abs) in adult Japanese patients with DM. Design Retrospective study. Setting Kanazawa University Graduate School of Medical Science Department of Dermatology and collaborating medical centers. Patients A total of 376 consecutive adult Japanese patients with DM who visited our hospital or collaborating medical centers between 2003 and 2008. Main Outcome Measures Clinical and laboratory characteristics of adult Japanese patients with DM and DM-specific Abs that include Abs against Mi-2, 155/140, and CADM-140. Results In patients with DM, anti–Mi-2, anti–155/140, and anti–CADM-140 were detected in 9 (2%), 25 (7%), and 43 (11%), respectively. These DM-specific Abs were mutually exclusive and were detected in none of 34 patients with polymyositis, 326 with systemic sclerosis, and 97 with systemic lupus erythematosus. Anti–Mi-2 was associated with classical DM without interstitial lung disease or malignancy, whereas anti–155/140 was associated with malignancy. Patients with anti–CADM-140 frequently had clinically amyopathic DM and rapidly progressive interstitial lung disease. Cumulative survival rates were more favorable in patients with anti–Mi-2 compared with those with anti–155/140 or anti–CADM-140 ( P Conclusion Dermatomyositis-specific Abs define clinically distinct subsets and are useful for predicting clinical outcomes in patients with DM.

https://jamanetwork.com/journals/jamadermatology/articlepdf/423519/dst05048_391_398.pdf

Clinical correlations with dermatomyositis-specific autoantibodies in adult Japanese patients with dermatomyositis: a multicenter cross-sectional study.

The aim of the study was to investigate the characteristics of adult clinically amyopathic dermatomyositis (CADM) with rapid progressive interstitial lung disease (ILD). Hospitalized patients with dermatomyositis (DM) and polymyositis (PM) between 1998 and 2005 in the Shanghai Renji Hospital were retrospectively studied. One hundred and forty-five patients were classified into CADM, classic DM or PM according to the modified Sontheimer's definition or Bohan-Peter's classification criteria. They were further stratified based on the presence or absence of clinical ILD. The Kaplan-Meier survival analysis and COX regression were performed. The predictive factors for ILD and other clinical properties of CADM-ILD were explored. The presence of clinical ILD was a significant risk factor for the poor outcome of DM/PM (OR = 4.237, CI 95%: 1.239-14.49, p = 0.021). Other risk factors are the presence of rashes and elevated urea nitrogen. Patients with DM/PM complicated by ILD had different clinical courses. Patients with CADM-ILD showed a rapidly progressive pattern with 6-month survival rate of 40.8%. The DM-ILD manifested a progressive pattern with a 5-year survival rate of 54%, while PM-ILD was chronic with 5- and 10-year survival rate of 72.4% and 60.3%, respectively. Better preserved muscle strength, elevated erythrocyte sedimentation rate, and hypoalbuminemia may herald ILD in DM/PM. Patients with CADM-ILD who later died had lower PO(2), higher lactate dehydrogenase, and prominent arthritis/arthralgia compared with those who survived. The presence of antinuclear antibody seems to be protective. Rapid progressive CADM-ILD is refractory to conventional treatment. ILD is a common complication in over 40% of our hospitalized DM/PM cohort and is also a prominent prognostic indicator. CADM is a special phenotype of DM/PM. CADM-ILD, which is usually rapidly progressive and fatal, requires further investigation.

/pdf/adult-clinically-amyopathic-dermatomyositis-with-rapid-4cb6hdj2qw.pdf

Yun Deng

Papers

Adult clinically amyopathic dermatomyositis with rapid progressive interstitial lung disease: a retrospective cohort study.