Use of systemic immunomodulatory therapies during the coronavirus disease 2019 (COVID-19) pandemic.

To the Editor: We read with great anticipation the American Academy of Dermatology's recent publication, “Guidance on the Use of Biologic Agents During COVID-19 Outbreak.” Although the immunopathophysiology behind these guidelines remains to be investigated, existing concepts may elucidate which agents require extra precautions to mitigate coronavirus disease 2019 (COVID-19) morbidity.

A key aspect of risk mitigation is prevention of SARS-CoV-2 infection in at-risk populations. Current evidence suggests that these populations include older adults, those with serious chronic medical conditions, and immunosuppressed patients with prior or active cancer. , Whether this last group includes patients receiving biological and small-molecule therapies remains to be seen. Nevertheless, the therapeutic efficacy of immunosuppressive and immunomodulatory medications is critical to the management of inflammatory and autoimmune conditions in dermatology.

Indeed, understanding the physiology and mechanisms of these agents can aid in discussion with patients. CD4+ T-cell immunity is critical to host defense against viral pathogens. Antiviral T-cell responses are initiated with the uptake of viral antigen in infected tissue, activation of T cells by viral recognition and pathogen signaling, and cytokine polarization toward a T-helper (Th) type-1 profile via interleukin (IL) 12 and type 1 interferon. Importantly, Th17, Th2, and regulatory (Treg) T-cell populations may also be generated to some degree to combat infection against certain viral pathogens. It stands to reason that the use of biologic therapies known to modulate and blunt Th1 responses, including tumor necrosis factor-α inhibitors, abatacept (CTLA-4 inhibitor), and ustekinumab (IL-12/23 inhibitor), may specifically require more stringent precautions to diminish risk of infection and prioritization of alternative therapeutic agents when possible. The effect of IL-17 inhibitors and dupilumab (IL-4 blockade), which predominately impair Th17 pathways and Th2 pathways, respectively, on SARS-CoV-2 remains unknown and, for now, also warrants caution. Additionally, the use of nonbiologic systemic therapies, such as cyclosporin, azathioprine, and methotrexate, warrants similar precautions because their therapeutic mechanisms create a state of generalized immunosuppression in the host.

Clinical data also paradoxically suggest that further deterioration in infected patients may be the result of a proinflammatory state created by cytokine storm. Similar pathogenesis was implicated in the disease biology of SARS-CoV and MERS-CoV infections. Specifically, higher concentrations of GCSF, IP10, MCP1, MIP1A, and tumor necrosis factor α were found in patients requiring intensive care unit admission compared with those with infection that did not require intensive care unit admission, suggesting a possible association between cytokine storm and disease severity.

The cytokine storm immunopathology of SARS-CoV-2 suggests that a subset of immunosuppressive therapies may begin to play a protective role in infected patients. By inhibiting the intensity of the cytokine storm, immunosuppressants may prevent lung tissue damage and further clinical deterioration. Directly counteracting the cytokine storm with glucocorticoids and anti–IL-6 treatment is under active investigation in China. Anti–IL-17 therapy was similarly investigated to combat morbidity of the influenza A (H1N1) virus pandemic in 2009, and a similar mechanism may become important in SARS-CoV-2.

As clinical evidence is collected to inform evidenced-based guidelines for the management of COVID-19, dermatologists should use their clinical judgement, the existing American Academy of Dermatology guidelines, and an understanding of pathophysiology to determine the appropriate risks/benefits of using systemic immunomodulating therapies.