Oral disease-modifying antirheumatic drugs and immunosuppressants with antiviral potential, including SARS-CoV-2 infection: a review

Abstract

There have been several episodes of viral infection evolving into epidemics in recent decades, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the latest example. Its high infectivity and moderate mortality have resulted in an urgent need to find an effective treatment modality. Although the category of immunosuppressive drugs usually poses a risk of infection due to interference of the immune system, some of them have been found to exert antiviral properties and are already used in daily practice. Recently, hydroxychloroquine and baricitinib have been proposed as potential drugs for SARS-CoV-2. In fact, there are other immunosuppressants known with antiviral activities, including cyclosporine A, hydroxyurea, minocycline, mycophenolic acid, mycophenolate mofetil, leflunomide, tofacitinib, and thalidomide. The inherent antiviral activity could be a treatment choice for patients with coexisting rheumatological disorders and infections. Clinical evidence, their possible mode of actions and spectrum of antiviral activities are included in this review article. Lay summary Immunosuppressants often raise the concern of infection risks, especially for patients with underlying immune disorders. However, some disease-modifying antirheumatic drugs (DMARDs) with inherent antiviral activity would be a reasonable choice in the situation of concomitant viral infections and flare up of autoimmune diseases. This review covers DMARDs of treatment potential for SARS-CoV-2 in part I, and antiviral mechanisms plus trial evidence for viruses other than SARS-CoV-2 in part II.

COVID-19: autoimmunity, multisystemic inflammation and autoimmune rheumatic patients

“…Among the JAK inhibitors, baricitinib has antiviral effects by blocking viral entry through ACE2 into the cell (63). Baricitinib also exerts anti-inflammatory effects leading to the reduction of MIS and restoration of immune regulation (63,64). Baricitinib in combination with remdesivir significantly improved clinical status and reduced time to recovery in severe COVID-19 patients requiring respiratory therapy (Stages 2b-3).…”

Leflunomide: Traditional immunosuppressant with concurrent antiviral effects

“…Early studies reported that leflunomide inhibited CMV infection mainly by disrupting nucleocapsid tegumentation, thus preventing virion assembly, while subsequent studies demonstrated that leflunomide minimally inhibited the de novo pyrimidine synthesis pathway but instead, interfered with cell signaling pathways and gene expression. 30,36 Here we discuss studies showing that leflunomide had variable effects on different viral infections in different cell types. A summary of the anti-viral effect and the proposing mechanisms of leflunomide is shown in Table 2.…”

“…Approved in 1998 in the United States, leflunomide is used for the treatment of rheumatoid arthritis (RA), 4–10 lupus nephritis (LN), 11–15 primary Sjögren's syndrome (pSS), 16–18 psoriasis/psoriatic arthritis (PsA), 19–23 granulomatosis with polyangiitis (GPA), 24–27 giant cell arteritis (GCA) 28 and Takayasu arteritis (TA) 29 as a disease‐modifying drug. Leflunomide also exerts broad antiviral activity 30 on herpes simplex virus (HSV)‐1/2, cytomegalovirus (CMV), Epstein–Barr virus (EBV), human herpesvirus‐8 (HHV‐8), human papillomavirus (HPV), polyomavirus, retrovirus, picornavirus, arenavirus, paramyxovirus, and flavivirus 2,3,31,32 in vitro and/or in vivo , commonly in the immunosuppressed transplant recipients. Furthermore, cytokine storms can be present in viral infection, 33,34 but anti‐inflammatory therapy may lead to exacerbation of infection.…”

Antivirális és gyulladásellenes kezelési lehetőségek COVID–19-ben

“…A Janus-kináz (JAK)-gátlók közül a baricitinib a JAK1 és JAK2 izoformákat gátolja, emiatt több citokin (például IL2, IL4, IL6, interferon-γ) szignalizációját gátolja [41,42]. Antivirális hatása révén a vírus sejtbe történő penetrációját is gátolja [43]. Kisebb vizsgálatokban COVID-19-ben csökkentette az IL6-szintet, valamint normalizálta a lymphocytaszámot, ezen belül a CD4 + és CD8 + T-sejt-, valamint B-sejt-számot [42].…”

“…A JAK-gátlók közül a már említett baricitinib remdesivirrel ajánlott [42,43]. Egyébként ebbe a csoportba tartozik a ruxolitinib JAK2-gátló is, melyet hematológiai malignitások kezelésére alkalmaznak.…”