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Cite this article as: Spanopoulou C, Kassimos D, Cassimos D. Potential Role of Anti-Complement Agents in the Treatment of COVID-19Related ARDS. Mediterr J Rheumatol 2020;31(Suppl 2):304-5. To the Editor, The current COVID-19 pandemic has caused hundreds of thousands of deaths with fatality figures continuing to rise. Lung injury has been the leading cause of mortality with nearly 90% of deaths resulting from ARDS. This condition is a serious immunological complication, characterised by widespread lung inflammation causing severe hypoxaemia, refractory to oxygen treatment. To date, no pharmacological treatment has been approved for the management of ARDS. So far, mechanical ventilation with the application of positive end-expiratory pressure (PEEP) has been the standard of care.1 As it has recently been established, hyperinflammation, also described as “cytokine storm”, holds a significant role in the pathogenesis of severe COVID-19. In patients admitted to intensive care units (ICU), higher levels of cytokines have been detected in plasma samples, with the cytokine storm being proportional to disease severity. This observation raises the possibility of using immunosuppressive medications in the treatment of patients with signs of respiratory failure. Given the inflammatory excess implicated in SARS-CoV-2-induced ARDS, numerous clinical trials are investigating the use of cytokine inhibitors targeting specific inflammatory markers such as IL-1β, IL-6, IFNg and TNFa. Of those, tocilizumab, a recombinant humanised monoclonal antibody that acts as an IL-6 receptor antagonist, has been reported to improve the clinical outcome of patients with COVID-19-related lung disease. In addition, JAK-STAT signalling inhibitors, approved for rheumatoid arthritis and myelofibrosis, have been suggested for the prevention of cytokine storm in COVID-19 and other severe viral infections. Lastly, corticosteroids and intravenous immunoglobulin are also being evaluated as candidate therapeutic agents.2 Further investigations on the role of the complement in the initiation of the cytokine storm are required. Prior research on highly pathogenic viruses like SARS-CoV has indicated an exaggerated complement activation, and a subsequent cytokine storm, to be implicated in the pathogenesis of lung injury.3 Therefore it is fair to hypothesize that blockade of complement signalling could be a promising treatment strategy for the alleviation of SARS-CoV-2-induced ARDS. The complement system is a key element of innate immunity whose dysregulation is involved in various pathologic conditions including inflammatory, autoimmune, and infectious diseases. Anaphylatoxin C5a is one of the most potent proinflammatory mediators. Its strong chemoattractant properties are involved in the recruitment of neutrophils and macrophages which promotes vascular leakage and protein accumulation in the airways, thus contributing to tissue damage.4 Based on earlier reports, bronchoalveolar lavage fluid collected from patients infected with H1N1 virus has been found to include increased levels of C5a. Reversely,

Potential Role of Anti-Complement Agents in the Treatment of COVID-19-Related ARDS