Environmental Triggers for Connective Tissue Disease

The Case of COVID-19 Associated With Dermatomyositis-Specific Autoantibodies

Maria De Santis; Natasa Isailovic, Francesca Motta; Caterina Ricordi; Angela Ceribelli; Ezio Lanza; Elena Azzolini; Salvatore Badalamenti; Antonio Voza; Carlo Selmi


Curr Opin Rheumatol. 2021;33(6):514-521. 

In This Article

The Evolving Scenario of COVID-19 and Autoimmune Diseases

Although there is growing evidence of the role of autoimmunity in the severity of COVID-19, the prevalence of serum autoantibodies, their influence on clinical outcomes, and the implications on patient management remain elusive. We report herein that over 50% of hospitalized patients with COVID-19 are positive for ANA with 20% of these manifesting additional autoantibodies commonly identified in CTD and other autoimmune diseases, in both cases associated with lung involvement and with a potential mechanistic link based on the target antiviral signaling antigens, namely anti-Scl-70/TOPO1, RIG1, MDA5, and E2/E3.

Variable prevalence rates have been described for autoantibodies in COVID-19, as represented by retrospective studies in Chinese patients with severe COVID-19 having positive ANA (50%), anti–52 kDa SSA/Ro (20%), and anti–60 kDa SSA/Ro (25%)[24] or in Italian patients with 45% being positive for at least one autoantibody associated with poorer prognosis.[5] Furthermore, among 29 critically ill COVID-19 patients from Greece almost 70% of patients had ANA (34.5%), antiphospholipid antibodies (antiβ2 glycoprotein I 34.5% and anticardiolipin 24.1%), p-antineutrophil cytoplasm antibodies (ANCA) (6.9%), and c-ANCA (6.9%).[25] A recent meta-analysis confirmed that the presence of 'latent autoimmunity', defined as the isolated presence of autoimmune antibodies without sign or symptoms fulfilling classification criteria for autoimmune disease, correlates with a more critical disease and longer hospital stay, and the most represented antibodies in this condition include ANA (43%), rheumatoid factor (57%), and antiphospholipid antibodies (57%). This is in agreement with our data, as patients with COVID-19 and ANA are more frequently females and have a more severe lung impairment, requiring more frequently supplemental oxygen and antiviral therapy, which partially accounts for the longer hospital stay also associated. We hypothesize that in the context of an acute viral infection as the one induced by COVID-19, autoantigens can be exposed leading to the loss of tolerance and to the development of less-specific autoantibodies, such as ANA, which may worsen the tissue damage created by the inflammatory response to the virus.

Regarding more specific autoantibodies, Chang et al.[26] reported that 50% of patients had autoantibodies recognizing autoantigens associated with CTD, namely transient autoantibodies against MDA5 and Jo1, and permanent autoantibodies against Scl70/TOPO1. Our data confirm the significant correlation between positive anti-MJ/NXP2, anti-RIG1, anti-MDA5, and anti-Scl70/TOPO1 and the severity of COVID-19, mainly in terms of pulmonary disease at lung imaging without any sign of a de novo or preexisting rheumatic disease.

Additional rare specificities have been recently reported in a review by Liu et al.,[7] for which autoantibodies against contactin-associated protein 2 (anti-Caspr2), ganglioside GD1b (anti-GD1b) and myelin oligodendrocyte glycoprotein (anti-MOG) have been shown in case reports or retrospective studies with unclear meaning in the COVID-19 disease onset and manifestations such as neurological impairment.[27,28]

In our cohort of COVID-19 patients, all the antigens recognized by patients' autoantibodies are relevant to the pathogenesis of SARS-CoV-2 viral infection. First, MDA5 is the main sensor of SARS-CoV-2 infection in lung cells,[29] in which interferon-induced genes, such as the one encoding for the different components MDA5 and RIG1, are upregulated during COVID-19.[30,31] Second, double-stranded RNA (dsRNA) molecules are produced during coronavirus infections and are recognized by pattern recognition receptors, such as the RLR, which in turn undergo a conformational change that allows their interaction with mitochondrial antiviral signaling (MAVS) protein located in the outer mitochondrial membrane. MAVS is a fundamental signaling molecule to link the upstream viral RNA recognition by RLR to downstream activation of the NF-kB transcription pathway. In MDA5- or MAVS-knockout cells, the number of cells infected by the Coronavirus was higher due to a significant decrease in interferon production.[32] Third, both Scl-70/TOPO1 and MJ/NXP2 are important players in host responses to viruses, being involved in activating inflammatory response against infectious agents and in RNA metabolism,[33,34] respectively. Fourth, the mitochondrial dysfunction observed during COVID-19 and its possible role in host defense escape mechanisms fit with the observed prevalence of antibodies directly against mitochondrial antigens (E2/E3) without an association with pulmonary and liver disease severity.

We speculate that the SARS-CoV-2 infection may lead to the hyper-expression of proteins involved in the response against the virus, with more severe and longer infection further contributing to this process. This may on the one hand indicate a stronger antiviral response against the more severe infection and on the other hand that the underlying virus-induced immune modification, leading to the development of autoantibodies to specific proteins involved in the antiviral response in a subset of patients, may worsen the lung damage or even induce long-term complications. Moreover, such a complexity in the immune landscape of COVID-19 can possibly account both for the inter-individual variability of the disease manifestation and for the persistence of symptoms time after healing (known as 'long COVID').

We currently live a moment in which vaccination campaigns against COVID-19 are playing a fundamental role in the prevention of this disease. A recent report on a case of myositis related to COVID19 vaccination has been published,[35] with muscle inflammation related to the site of vaccine injection and not with systemic involvement, and also this aspect plays a key role to avoid COVID-19 inflammatory and autoimmune disease manifestations.