Preventing COVID-19-induced pneumonia with anticytokine therapy

Immune-mediated disorders are a group of disabling conditions that affect millions of individuals worldwide.¹ These pathologies include, but are not limited to, rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, and inflammatory bowel diseases. Each of these diseases has a unique epidemiology and pathophysiology, despite sharing several pathways of tissue damage, which rely on an excessive cytokine response. Indeed, cytokine blockers, such as infliximab, adalimumab (anti-tumor necrosis factor [TNF]), and ustekinumab (anti-interleukin [IL]-12/IL-23 [p40 subunit]), used for the treatment of psoriasis, rheumatoid arthritis, and inflammatory bowel diseases, are used with success for inducing and maintaining remission. Unfortunately, however, the use of these therapies enhances the risk of bacterial and viral infections, and of viral reactivation in cases with previous viral infection.² With the recent emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the increasing incidence of associated coronavirus disease 2019 (COVID-19) in countries where immune-mediated disorders are frequent, the use of these drugs poses major challenges for clinicians. Studies so far suggest that most patients infected with SARS-CoV-2 remain asymptomatic or develop mild symptoms, but approximately 15–20% of patients develop severe respiratory distress syndrome or septic shock.³ The treatment of these critically ill patients is particularly difficult, as no specific antiviral drug or vaccine is currently recommended.

Morbidity and mortality associated with COVID-19 are highest in the elderly and among people with comorbidities. Individuals with comorbidities could theoretically include patients with immune-mediated disorders taking cytokine blockers, as these drugs inhibit the function of molecules involved in the host defence against pathogens. Surprisingly, however, no increase of SARS-CoV-2-driven pneumonia has been documented in such patients so far. Therefore, the question arises as to whether patients with immune-mediated disorders on cytokine inhibitors represent a privileged group who are resistant to COVID-19 disease. Analysis of the cytokine profile characterising severe cases of COVID-19 suggests this assumption might be the case.

SARS-CoV-2-induced pneumonia is marked by hyperactivation of effector T cells and excessive production of inflammatory cytokines, particularly IL-6.⁴ This reaction, known as a cytokine storm, was initially described as a life-threatening complication in patients receiving antibody-based immune therapy. In addition to IL-6, other cytokines (ie, IL-1, TNF, and interferon-γ), which are produced during the cytokine storm, contribute to the pathological process that leads to plasma leakage, vascular permeability, and disseminated intravascular coagulation. In the case of viral infection, these events increase dissemination of the virus, thus providing a metabolic milieu in which a fatal outcome might result. In line with these events, blockade of IL-6 function with a monoclonal antibody against its receptor (eg, tocilizumab) is useful for the initial treatment of patients with a so-called cytokine storm,⁵ and preliminary evidence suggests that such a therapy can help to prevent the detrimental inflammatory response in some cases of SARS-CoV-2-induced pneumonia (unpublished).

Most cytokines secreted during a cytokine storm and in COVID-19 are also produced in high amounts during exacerbations of immune-mediated disorders, and represent major therapeutic targets. We speculate that patients with immune-mediated disorders taking IL-6 inhibitors, or compounds that suppress immune pathways leading to IL-6 production or mediation of IL-6 signalling, might be somewhat protected against SARS-CoV-2-driven pneumonia. Although we are waiting for direct data in support of this hypothesis, clinicians should advise patients with immune-mediated disorders about the necessity to stay on their treatment with cytokine blockers, and patients with immune-mediated disorders should stay on medication unless discussed with their doctor. In addition, clinicians should stress that such treatments do not confer protection against infection, and therefore patients with immune-mediated disorders should adopt self-isolating behaviour designed to prevent social contact and the spread of SARS-CoV-2.