JAAD ONLINE: NOTES & COMMENTS
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 publi-
cation, ‘‘Guidance on the Use of Biologic Agents
During COVID-19 Outbreak.’’1 Although the immu-
nopathophysiology 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.2,3 Whether this last
group includes patients receiving biological and
small-molecule therapies remains to be seen.
Nevertheless, the therapeutic efficacy of immuno-
suppressive and immunomodulatory medications is
critical to the management of inflammatory and
autoimmune conditions in dermatology.
Indeed, understanding the physiology and mech-
anisms of these agents can aid in discussion with
patients. CD41 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 cyto-
kine polarization toward a T-helper (Th) type-1
profile via interleukin (IL) 12 and type 1 interferon.4
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- inhibitors, abata-
cept (CTLA-4 inhibitor), and ustekinumab (IL-12/23
inhibitor), may specifically require more stringent
precautions to diminish risk of infection and prior-
itization of alternative therapeutic agents when
possible.5 The effect of IL-17 inhibitors and dupilu-
mab (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 nonbio-
logic systemic therapies, such as cyclosporin,
azathioprine, and methotrexate, warrants similar
precautions because their therapeutic mechanisms
J AM ACAD DERMATOL
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.2 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
were found in patients requiring intensive care unit
admission compared with those with infection that
did not require intensive care unit admission, sug-
gesting a possible association between cytokine
storm and disease severity.2
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 gluco-
corticoids and antieIL-6 treatment is under active
investigation in China.2 AntieIL-17 therapy was simi-
larly investigated to combat morbidity of the influenza
A (H1N1) virus pandemic in 2009, and a similar
mechanism may become important in SARS-CoV-2.6
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.
Payal Shah, BS, and John G. Zampella, MD
From the Ronald O. Perelman Department of
Dermatology, New York University School of
Medicine, New York.
Funding sources: None.
Conflicts of interest: None disclosed.
IRB approval status: Not applicable.
Reprints not available from the authors.
Correspondence to: John G. Zampella, MD, FAAD,
The Ronald O. Perelman Department of
Dermatology, New York University School of
Medicine, Preston Robert Tisch Center for Men’s
Health, 555 Madison Ave, New York, NY 10022
E-mail: john.zampella@nyulangone.org
JUNE 2020 e203
e204 Notes & Comments
REFERENCES
1. American Academy of Dermatology. Guidance on the use of
biologic agents during COVID-19 outbreak. Available at:
https://assets.ctfassets.net/1ny4yoiyrqia/PicgNuD0IpYd9MSO
wab47/023ce3cf6eb82cb304b4ad4a8ef50d56/Biologics_and_CO
VID-19.pdf. Accessed March 18, 2020.
2. Huang C, Wang Y, Li X, et al. Clinical features of patients
infected with 2019 novel coronavirus in Wuhan, China. Lancet.
2020;395(10223):497-506.
3. Liang W, Guan W, Chen R, et al. Cancer patients in SARS-CoV-2
infection: a nationwide analysis in China. Lancet Oncol. 2020;
21(3):335-337.
J AM ACAD DERMATOL
JUNE 2020
4. Swain SL, McKinstry KK, Strutt TM. Expanding roles for CD4(1)
T cells in immunity to viruses. Nat Rev Immunol. 2012;12(2):
136-148.
5. Ma W-T, Yao X-T, Peng Q, Chen D-K. The protective and
pathogenic roles of IL-17 in viral infections: friend or foe? Open
Biol. 2019;9(7):190109.
6. Li C, Yang P, Sun Y, et al. IL-17 response mediates acute lung
injury induced by the 2009 pandemic influenza A (H1N1) virus.
Cell Res. 2012;22(3):528-538.
https://doi.org/10.1016/j.jaad.2020.03.056