Using cyclosporine in the COVID era: An emergent need for caution
Authors: Ananta Khurana, Khushboo Sethia
Journal: Journal of the American Academy of Dermatology (2020)

To the Editor: We read the paper "Cyclosporine therapy during the COVID-19 pandemic is not a reason for concern" by Rudnicka et al1Rudnicka L. Goldust M. Glowacka P. et al.Cyclosporine therapy during the COVID-19 pandemic is not a reason for concern [e-pub ahead of print].J Am Acad Dermatol. 2020; 83: e151-e512Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar and wish to highlight some interpretations that can encourage complacency in the use of a drug where caution is needed. As rightly pointed out, there are in vitro data showing inhibitory effects of cyclosporine A (CsA) on coronaviruses (CoVs); along with many other classes of virus, prominently hepatitis C virus and HIV.2de Wilde A.H. Zevenhoven-Dobbe J.C. van der Meer Y. et al.Cyclosporin A inhibits the replication of diverse coronaviruses.J Gen Virol. 2011; 92: 2542-2548Crossref PubMed Scopus (199) Google Scholar CsA binds to cyclophilins, a family of ubiquitous proteins present in all prokaryotes and eukaryotes. Functional interactions between viral proteins (chiefly the nonstructural protein 1) and members of cyclophilin family form an important part of the virus-host interaction.2de Wilde A.H. Zevenhoven-Dobbe J.C. van der Meer Y. et al.Cyclosporin A inhibits the replication of diverse coronaviruses.J Gen Virol. 2011; 92: 2542-2548Crossref PubMed Scopus (199) Google Scholar Genome-wide analysis of protein-protein interactions between severe acute respiratory syndrome (SARS)-CoV and human host proteins identified both cyclophilins and FK506-binding protein (FKBP) as interaction partners for SARS-CoV proteins.3Pfefferle S. Schöpf J. Kögl M. et al.The SARS-coronavirus-host interactome: identification of cyclophilins as target for pan-coronavirus inhibitors.PLoS Pathog. 2011; 7: e1002331Crossref PubMed Scopus (330) Google Scholar The exact function of cyclophilins' viral pathogenicity is not known, but they are probably essential for viral growth and replication. The immunosuppressive action of calcineurin inhibitors (CNIs), on the other hand, relies on calcineurin inhibition by the CsA-cyclophilin A complex, which blocks the translocation of nuclear factor of activated T cells to the nucleus and prevents the transcription of cytokine genes, prominently interleukin 2. Thus, the antiviral effect of CsA, via binding cyclophilin, largely occurs a step upstream of that essential for their immunosuppressive effect. Trials of some novel cyclophilin inhibitors and nonimmunosuppressive analogs of CsA have been undertaken for potential use in hepatitis C virus and other viral infections.4Gallay P.A. Cyclophilin inhibitors: a novel class of promising host-targeting anti-HCV agents.Immunol Res. 2011; 52: 200-210Crossref Scopus (31) Google Scholar There are well-researched aspects regarding the intricacies of the interaction of viruses with host cells. Interestingly, mycophenolic acid and 6-thioguanine also have in vitro activity against CoVs, but again, the clinical implications are unclear.5Hart B.J. Dyall J. Postnikova E. et al.Interferon-β and mycophenolic acid are potent inhibitors of Middle East respiratory syndrome coronavirus in cell-based assays.J Gen Virol. 2014; 95: 571-577Crossref PubMed Scopus (180) Google Scholar,6Chen X. Chou C.Y. Chang G.G. Thiopurine analogue inhibitors of severe acute respiratory syndrome-coronavirus papain-like protease, a deubiquitinating and deISGylating enzyme.Antivir Chem Chemother. 2009; 19: 151-156Crossref PubMed Scopus (69) Google Scholar Another important point to consider for clinical use of immunosuppressives during the ongoing pandemic is the effect on host antiviral immune responses.7Khurana A. Saxena S. Immunosuppressive agents for dermatological indications in the ongoing COVID 19 pandemic: rationalizing use and clinical applicability [e-pub ahead of print].Dermatol Ther. 2020; https://doi.org/10.1111/dth.13639Date accessed: June 11, 2020Crossref Scopus (6) Google Scholar The cytotoxic T lymphocytes and natural killer cells are the most important immune cells in this regard, along with antibody-dependent cellular cytotoxicity and certain cytokines, prominently interferons.7Khurana A. Saxena S. Immunosuppressive agents for dermatological indications in the ongoing COVID 19 pandemic: rationalizing use and clinical applicability [e-pub ahead of print].Dermatol Ther. 2020; https://doi.org/10.1111/dth.13639Date accessed: June 11, 2020Crossref Scopus (6) Google Scholar CsA not only suppresses the helper T cells and precursors of cytotoxic T lymphocytes but also causes depression of innate immune response via an inhibitory effect on natural killer cells. Increased risk of viral infections, such as multiple viral warts and Epstein-Barr virus reactivations in transplant patients, and of cytomegalovirus infections in transplant recipients and ulcerative colitis patients taking CsA is probably related to this.7Khurana A. Saxena S. Immunosuppressive agents for dermatological indications in the ongoing COVID 19 pandemic: rationalizing use and clinical applicability [e-pub ahead of print].Dermatol Ther. 2020; https://doi.org/10.1111/dth.13639Date accessed: June 11, 2020Crossref Scopus (6) Google Scholar Further, animal models have demonstrated an inability to mount an effective immune response to viral infections with administration of CsA.8Kim J.H. Perfect J.R. Infection and cyclosporine.Rev Infect Dis. 1989; 11: 677-690Crossref PubMed Scopus (68) Google Scholar Thus, the prominent interference with host antiviral responses by CsA should not be ignored. Further, none of the immunosuppressives have so far been conclusively shown to be beneficial for the "cytokine storm" associated with severe coronavirus disease 2019 (COVID-19) infection, and use on that premise is speculative. Hence, we believe that the use of immunosuppressive drugs requires a guarded approach during the ongoing pandemic, with initiation only in most essential cases and with continued close monitoring for infectious adverse effects. Cyclosporine therapy during the COVID-19 pandemicJournal of the American Academy of DermatologyVol. 83Issue 2PreviewTo the Editor: The rapid dissemination of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and COVID-19 pandemic raised concerns related to possible risks associated with the immunosuppressive treatment of autoimmune diseases.1,2 Cyclosporine is an immunosuppressive drug that acts selectively on T cells by inhibiting calcineurin phosphorylase. It is widely used in dermatology, rheumatology, nephrology, ophthalmology, and transplantation. Full-Text PDF