The role of antirheumatics in patients with COVID-19

Abstract

The COVID-19 pandemic has resulted in more than 2 million deaths globally. Two interconnected stages of disease are generally recognised; an initial viral stage and a subsequent immune response phase with the clinical characteristics of hyperinflammation associated with acute respiratory distress syndrome. Therefore, many immune modulators and immunosuppressive drugs, which are widely used in rheumatological practice, have been proposed as treatments for patients with moderate or severe COVID-19. In this Review, we provide an overview of what is currently known about the efficacy and safety of antirheumatic therapies for the treatment of patients with COVID-19. Dexamethasone has been shown to reduce COVID-19 related mortality, interleukin-6 inhibitors to reduce risk of cardiovascular or respiratory organ support, and baricitinib to reduce time to recovery in hospitalised patients requiring oxygen support. Further studies are needed to identify whether there is any role for glucocorticoids in patients with less severe COVID-19. Although evidence on the use of other antirheumatic drugs has suggested some benefits, results from adequately powered clinical trials are urgently needed. The heterogeneity in dosing and the absence of uniform inclusion criteria and defined stage of disease studied in many clinical trials have affected the conclusions and comparability of trial results. However, after the success of dexamethasone in proving the anti-inflammatory hypothesis, the next 12 months will undoubtedly bring further clarity about the clinical utility and optimal dose and timing of other anti-rheumatic drugs in the management of COVID-19.

Figure 1

COVID-19 disease course and therapeutic windows of opportunity for DMARDs Schematic depicts the evolution of a severe SARS-CoV-2 infection and therapeutic windows of opportunity for the indicated DMARDs according to the timing of the different ongoing immunopathological processes from the initial viral inoculum to multi-organ failure. (A) SARS-CoV-2 binds to the host receptor ACE2 (yellow and green receptors), and viral docking is eased by TRMPSS2 (blue co-receptor) cleaving viral spike protein. (B-C) In the asymptomatic phase, host cell infection, viral diffusion in the human body, and virion production predominate. Mucosal and local innate immunity (natural killer cells, neutrophils and monocyte-macrophages) react to viral replication, causing cytopathic effects and pro-inflammatory mediators release, and the onset of signs and symptoms occurs. (D) Cellular immunity (B cells, CD4 T cells, CD8 T cells) develop locally and systemically, and symptoms and signs increase in severity. (E) An imbalance between effective and hyper-activated immune responses can result in cytokine storm, which deteriorates lung injury, precipitating or determining respiratory insufficiency. (F) At this stage, potentially protective neutralising antibodies could also trigger antibody-dependent enhancement and the activation of the classical pathway of complement system, enhancing viral replication and further proinflammatory cytokine release. (G) The imbalance between inflammation and coagulopathy as well as SARS-CoV-2 infection of endothelial cells and pericytes determine concurrent micro- and macro-thrombotic events enhancing organ damage. (H) These uncontrolled processes trigger reinforcing and self-maintaining pathological loops (dashed arrows) that eventually lead to systemic cellular and organ dysfunction resulting in multi-organ failure. ACE2=angiotensin-converting enzyme 2. DMARD=disease-modifying anti-rheumatic drug. TNF=tumour necrosis factor. TRMPSS2=transmembrane protease serine 2.

Figure 2

COVID-19 hyperinflammation criteria AST=aspartate aminotransferase. BUN=blood urea nitrogen. HRCT=high-resolution CT. RT-PCR=reverse transcriptase PCR. *Criteria are met when patients fulfill all the entry criteria and at least one criterion per each cluster. †A score of two or more criteria met distinguished patients along multiple clinical endpoints: median length of hospital stay, requirement for intensive care unit, requirement for mechanical ventilation, and hospital deaths.