Background/Purpose: Anti-MDA5 autoantibody associated syndrome is a novel entity within the spectrum of autoimmune myositis. It has been described as a clinical mimic of the anti-synthetase syndrome, but is associated with a characteristic cutaneous phenotype and, unlike anti-synthetase syndrome, has been associated with rapidly progressive interstitial lung disease (RPILD). This clinical picture has been primarily reported in Asians and has a poor prognosis, especially in the presence of elevated ferritin. However, in North American cohorts these associations are not as clear due to a paucity of data. 

The primary goal of our study was to define clinical, biochemical and radiological features predictive of anti-MDA5-associated RPILD that would justify empirical treatment, pending confirmation of anti-MDA5 autoantibody status. 

Methods: We retrospectively analyzed the clinical features of 7 patients (pts) who presented with features suggestive of anti-MDA5-associated RPILD and who were subsequently confirmed (or strongly suspected in one case) to have anti-MDA5 autoantibody, using a novel line immunoassay (Euroline, Euroimmun, Lubeck, Germany) in 3 pts. 

Results: Six of the 7 pts were men; five were Caucasian. Six pts presented with dyspnea, and RPILD developed in all 7 pts. Anti-MDA5-associated cutaneous signs appeared within one month of respiratory symptoms in 6 (86%) pts, but were recognized at initial presentation in 2 pts. These included palmar or lateral finger papules (n=4), skin ulcerations (n=2), and mechanic’s hands (n=4). Gottron papules and sign were sometimes psoriasiform. Shawl and V-signs were not seen, whereas periungueal erythema was always present.

Profound weight loss over 1 to 2 months (mean 21.9 lbs, range 14-37 lbs) and articular symptoms occurred in all pts. One pt had Raynaud phenomenon. Four pts were clinically amyopathic; only 1 pt had CK levels >500 U/L. Hepatic enzymes were elevated in 6 (86%) pts. The ANA test was negative for nuclear and cytoplasmic staining on HEp-2 substrate. Imaging at initial presentation showed ground glass opacities with consolidation in 6 (86%) pts, isolated ground glass opacities in 1 pt, and reticulations in 4 pts, in a bibasilar peripheral distribution in 6 pts.

Four (57%) pts died. Time from hospitalization to death ranged from 6 to 41 days. Time from initial symptoms to death ranged from 6 weeks to 4 months. Survivors received mycophenolate mofetil with or without tacrolimus, concomitantly with corticosteroids. Hyperferritinemia (>1000 mcg/L, n=4 pts) upon admission was associated with a fatal outcome (n=4 deaths).  

Conclusion:  In an inpatient setting, anti-MDA5-associated ILD can be a rapidly progressive condition with a high mortality. Cutaneous findings are subtle and may follow the respiratory symptoms. Dyspnea, cutaneous findings, profound weight loss, articular symptoms, normal or low CKs with elevated AST/ALT, and absence of nuclear and cytoplasmic fluorescence on ANA testing should alert the clinician to the possibility of anti-MDA5-associated RPILD. Hyperferritinemia is associated with a poor outcome. Early institution of immunosuppressive therapy may prove lifesaving.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-anti-mda5-autoantibody-phenotype-defining-clinical-biochemical-and-radiological-features-suggestive-of-anti-mda5-associated-rapidly-progressive-interstitial-lung-disease/