Understanding and managing anti-MDA 5 dermatomyositis, including potential COVID-19 mimicry

Abstract

Anti-Melanoma Differentiation-Associated gene 5 (MDA-5) Dermatomyositis (MDA5, DM) is a recently identified subtype of myositis characteristically associated with Rapidly Progressive Interstitial Lung Disease (RP-ILD) and unique cutaneous features. We reviewed PubMed, SCOPUS and Web of Science databases and selected 87 relevant articles after screening 1485 search results, aiming to gain a better understanding of the pathophysiology, clinical features, diagnosis, and treatment approaches of anti-MDA-5 DM described in the literature. The etiopathogenesis is speculatively linked to an unidentified viral trigger on the background of genetic predisposition culminating in an acquired type I interferonopathy. The clinical phenotype is highly varied in different ethnicities, with new clinical features having been recently described, expanding the spectrum of cases that should raise the suspicion of anti-MDA-5 DM. Unfortunately, the diagnosis is frequently missed despite excessive mortality, calling for wider awareness of suspect symptoms. RP ILD is the major determinant of survival, treatment being largely based on observational studies with recent insights into aggressive combined immunosuppression at the outset.

Keywords: Autoantibodies; Dermatomyositis; Genetic predisposition; Immunosuppression; Interstitial lung disease; Myositis; Phenotype.

Fig. 1

Flowchart of studies selected to inform the review

Fig. 2

Timeline depicting the discovery and evolution of the disease phenotype of anti-MDA5 DM. CADM clinically amyopathic dermatomyositis, RP rapidly progressive, ILD interstitial lung disease, MDA5 melanoma differentiation-associated gene 5, RA rheumatoid arthritis, ASSD anti synthetase syndrome

Fig. 3

Proposed pathogenesis of anti-MDA5 DM. In individuals with a particular genetic factors (HLA or non-HLA), an unknown viral trigger can lead to sensing of the viral double stranded Ribonucleic Acid (dsRNA) by cytoplasmic Pattern Recognition Receptors (PRR) like Melanoma Differentiation-Associated gene 5 (MDA5)/Retinoic Acid Inducible Gene-1 (RIG-1). This in turn results in activation of mitochondrial antiviral signaling protein (MAVS) which in conjugation with TNF Receptor associated factors (TRAF) recruits Tank binding kinase-1 (TBK-1) and IBK kinase (IKK). These then result in phosphorylation and activation of transcription factors-Interferon Regulatory factors (IRF) 3 and 7. These translocate into the nucleus and trigger type-1 interferon production. Virus induced cell injury and lysis, may result in release of viral-MDA5 complexes/MDA5. These complexes can be recognized by antigen presenting cells (APCs) and with a subsequent activation of helper T cells and B cells, production of autoantibody against MDA5. Activated cells and autoantibodies enter the systemic circulation and encounter autoantigens resulting in a systemic autoimmune response

Fig. 4

Prevalence of anti-MDA5 in adults and children with DM across various countries

Fig. 5

Periorbital edema in a patient with anti-MDA5 DM (top left). Chest radiograph (bottom left) showing patchy heterogeneous opacities involving both lung fields. Computed tomography (right) showing patchy consolidations with ground glass opacities involving both lung fields suggestive of an organizing pneumonia pattern