key: cord-333730-qsx0m68e
authors: Tsai, Y. C.; Tsai, T. F.
title: Oral disease-modifying antirheumatic drugs and immunosuppressants with antiviral potential, including SARS-CoV-2 infection: a review
date: 2020-09-03
journal: Ther Adv Musculoskelet Dis
DOI: 10.1177/1759720x20947296
sha: 
doc_id: 333730
cord_uid: qsx0m68e

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.

Infections are a common concern of immunosuppressive drugs. However, some immunosuppressants or disease-modifying antirheumatic drugs (DMARDs) show antiviral activity and may be safely used or even beneficial in patients with selected concomitant viral infections. Certain DMARDs may even be considered as an alternative treatment for recalcitrant infections. Moreover, the concomitant use of immunosuppressants and antiviral agents was proved to be more effective than antiviral agent monotherapy in some reports. 1 The antiviral property of immunosuppressants may act through (a) direct virucidal activity, (b) blockage of receptors, (c) inhibition of necessary molecules for viral replication in the hosts, or (d) amelioration of inflammatory symptoms. Also, control of inflammation may decrease the susceptibility or enhance host ability to defend against viral infection. The are indicated to treat and prevent malaria. They are also used as DMARDs for rheumatoid arthritis, lupus erythematosus, and porphyria cutanea tarda. In addition, the application for viral infections in off-label use has recently been investigated vigorously. The antiviral activity is through blocking the virus/cell fusion via increasing endosomal pH and hindering the glycosylation of cellular receptors ( Figure 2 ). 4 In vitro CQ revealed low half-maximal effective concentration (EC50) and high half-cytotoxic concentration (CC50) for COVID-19. 5 A preliminary study conducted in China showed benefits in pneumonia image, shortening of disease course, and promoting a virus-negative conversion compared with control group. 6 Then, four completed clinical studies demonstrated favorable outcomes in clinical and radiologic amelioration, while another two randomized controlled trials (RCTs) illustrated no statistically significant change compared with control arms. [7] [8] [9] [10] [11] [12] Based on the inhibitory effect of azithromycin against Ebola and Zika viruses in vitro, and the possibility of preventing from progressing to severe respiratory tract infections, two French trials which combined the use of azithromycin and HCQ revealed better efficacy. 7, 9 However, further studies are still needed to draw conclusions because most of these studies bear limitations including selection bias, allocation bias, or insufficient case numbers. Several multicenter, double-blind, and well-designed controlled trials are already underway to assess the efficacy and safety of CQ or HCQ in the treatment of COVID-19 pneumonia. In the absence of other confirmed effective therapy specific to SARS-CoV-2, both drugs are currently still listed in the treatment guidelines (Table 1) .

Baricitinib, blocking Janus kinase (JAK)1 and JAK2, is approved for rheumatoid arthritis and has been investigated in atopic dermatitis.

SARS-CoV-2 binds on the angiotensin-converting enzyme 2 (ACE2) receptors and enters lung cells through receptor-mediated endocytosis. Some of the numb-associated kinase (NAK) family members, AP2-associated protein kinase 1 (AAK1) and cyclin G-associated kinase (GAK), are hypothesized to regulate the ACE2-mediated endocytosis. Baricitinib demonstrated high affinity to AAK1 and In one controlled open-label study (n = 24), patients were given either baricitinib 4 mg/day plus lopinavir-ritonavir or antiretroviral plus hydroxychloroquine (control group) for 2 weeks. Significant improvement of symptoms and laboratory results, no intensive care unit transfer (versus 33% transfer in control cases), and 58% discharge from wards (versus 8% in control) was shown among the baricitinib-treated individuals. 14 In addition to antiviral property, baricitinib has been suggested as an approach for a cytokine storm syndrome, which features hypercytokinemia and multi-organ failure. Elevated ferritin and IL-6 in COVID-19 cases were predictive of a high mortality rate according to a China retrospective study. 17 Baricitinib inhibits cytokines including IL-2, IL-6, IL-10, interferon gamma (IFN-γ), and granulocytecolony-stimulating factor (G-CSF) 13, 18 and may bring the benefit of immune reconstruction which could be used in rapidly progressive diseases.

However, there are competing ideas about the interference of JAK inhibitors with IFN-mediated antiviral activities. IFNs prohibit viral spreading in the early phase of infections. In animal models of SARS and Middle East respiratory syndrome (MERS), IFN-α and IFN-β showed benefit at the early stage but were harmful at the late phase. Patients with severe SARS who died of hypoxemia revealed high IFN-α, -γ, while those discharged DMARDs, disease-modifying anti-rheumatic drugs.

journals.sagepub.com/home/tab 5 from hospital had low IFN-α, -γ. Therefore, some experts suggested baricitinib's use in the situation of hyperinflammation and cytokine syndrome, rather than in those with mild diseases.

In fact, clinical trials have commenced to evaluate the optimal timing, duration, and safety of baricitinib in viral infections, including SARS-CoV-2. [19] [20] [21] Cyclosporine A Cyclosporine A (CsA) is indicated for rheumatoid arthritis, psoriasis, organ transplants to prevent injection, and keratoconjunctivitis sicca. It is also used in severe atopic dermatitis, chronic urticaria, pyoderma gangrenosum Kimura disease, acute systemic mastocytosis, and ulcerative colitis. CsA inhibits lymphocyte function, mainly T cells, by forming a complex with cyclophilin. Cyclophilin-CsA complex binds on the calcineurin, which blocks the dephosphorylation of nuclear factor of activated T cells (NF-AT). This interferes with entry of NF-AT into the T-cell nucleus and further suppresses cytokine production such as IL-2. severe COVID-19. Experimentally, CsA targets cyclophilin D to inhibit mitochondrial permeability transition pore (MPTP) opening and rescues mitochondria from apoptosis. [22] [23] [24] Moreover, melanoma-differentiation-activated protein 5 (MDA5), an RLR helicase and putative cytoplasmic receptor of SARS-CoV-2, is also the target antigen of clinically amyopathic dermatomyositis (CADM). Patients with MDA5 plus CADM have higher risks of developing rapidly progressive interstitial lung diseases and respiratory failure, while this could be reversed by calcineurin inhibitors. Based on these hypothetical functions, CsA was proposed as a modulator for cytokine storm syndrome in COVID-19 infections. 25

Mycophenolic acid (MPA), an active metabolite of mycophenolate mofetil (MMF), inhibits inosine monophosphate dehydrogenase (IMPDH), an essential enzyme in the de novo purine synthesis pathway. IMPDH inhibition especially influences T and B lymphocytes because they use almost a de novo pathway to synthesize (minimally use a salvage pathway). MMF and MPA are utilized in organ transplantation, Crohn's disease, and as steroid-sparing agents for conditions such as pemphigus, Behçet's disease, and lupus erythematosus. Although they were associated with higher risk of opportunistic infections including herpes zoster, cytomegalovirus (CMV), and BK virus (BKV) nephropathy, literature also revealed its possible benefit for HIV and influenza virus. 26, 27 In vitro: MMF showed low EC50 (0.47 μmol/l) in SARS-CoV-2-infected Vero E6 cells, while the EC50 of remdesivir, as a positive control, was 0.77 μmol/l. Besides, MMF probably inhibited SARS-CoV-2 through IMPDH and especially dihydroorotate dehydrogenase (DHODH). DHODH is another essential enzyme for pyrimidine synthesis, and MMF might control viral infection by depleting the intracellular pyrimidine pools. 28 Thalidomide Thalidomide, a derivative of glutamic acid, is approved for erythema nodosum leprosum and is also used in many conditions such as prurigo nodularis, pyoderma gangrenosum, Bechet's disease, lupus erythematosus and erythema multiforme. It exerts anti-inflammatory effect through cereblon E3 ubiquitin ligase as the primary target and thus inhibits chemotaxis of leukocytes, monocytes as well as the production of tumor necrosis factor (TNF)-alpha, IL-8, and IL-12.

Case report: A 45-year-old woman with critical symptoms of COVID-19 was treated by thalidomide 100 mg every 24 h. After the first day use of thalidomide, clinical conditions including oxygen index improved. Cytokines such as IL-6, IL-10, IFN-γ all decreased to normal range. 15 Proposed mechanisms are as follows: thalidomide inhibits NF-κB, which further suppresses the production of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and IL-8, and prevents the cytokine surge. It also regulates immune function by activating T cells and T-cell receptors. Moreover, the sedative and antiemetic property of thalidomide helps anxious patients calm down, which reduces oxygen consumption. 15 Now, at least one clinical trial has been conducted to investigate the efficacy and safety of thalidomide as an adjuvant therapy for COVID-19 pneumonia. 29

Part II: DMARDs with antiviral potential other than SARS-CoV-2 Many oral DMARDs have inherent antiviral activity and could be the treatment of choice for patients with coexisting immune-based diseases and infections. Especially when the infection is still in progression, choosing DMARDs with anti-microbial evidence would bring double benefits for better infection control without sacrificing underlying disease management. The antimicrobial mechanisms of DMARDs are often distinct from their immunomodulatory pathway, and the efficacy is different in viral species (Tables 2, 3 

Leflunomide is approved for rheumatoid arthritis and psoriatic arthritis (not in the United States). Leflunomide inhibits the synthesis of pyrimidine via acting on the mitochondrial enzyme DHODH; therefore, rapidly dividing cells, especially lymphocytes, are suppressed. On the other hand, leflunomide showed antiviral activity at least for CMV, BKV, and HIV. It works by teriflunomide, the active metabolite of leflunomide, which disrupts nucleocapsid tegumentation, and thus prevents virion assembling, rather than influences the de novo pyrimidine synthesis pathway. 97 Herpes simplex virus A case report with perianal HSV-2 lesions in an acyclovir-resistant HIV patient significantly improved with leflunomide 40 mg, twice a day. 98 Another HIV patient with HSV-1/HSV-2 pseudo-tumors on the perineum and scrotum only slightly improved with valacyclovir, foscarnet, and imiquimod. After 9 months of leflunomide, complete regression of the lesions was noted. Leflunomide has both immunomodulation and antiviral activities in the HSV pseudotumors because pseudotumor formation is an immune reconstruction phenomenon in HIV patients. 99 Human immunodeficiency virus An RCT (n = 18) demonstrated leflunomide decreased the activation and cycling of CD4+ T cells. The expression of HIV co-receptors CCR5 and CXCR4 was also reduced compared with placebo. 102

Three patients with atopic dermatitis treated with azathioprine developed multiple verrucae and molluscum contagiosum. Due to treatment resistance, azathioprine was switched to leflunomide (100 mg loading 3 days, then 20 mg/day). All the lesions subsided in three patients within 2 months of leflunomide treatment. 103 Multiple recalcitrant verrucae in three and molluscum in one of renal allograft recipients cleared after switching from MMF to leflunomide. 104 Leflunomide can serve as a potential option for patients with skin warts or molluscum concomitant with immune conditions that require immunosuppressants. Leflunomide was regarded as an add-on treatment for multi-drug-resistance CMV infection.

In vitro anti-CMV properties of leflunomide were not through blocking the replication of viral DNA, so it is effective even in patients with direct antiviral drug-resistance history. 105 disseminates to the urinary-tract system and lives there persistently. A sudden increase of BK-virusassociated nephropathy is related to the administration of potent immunosuppressants such as MMF and tacrolimus. Leflunomide is now generally accepted as a second choice after reduction of immunosuppressive agents. However, in a phase II RCT (n = 46), viremia was decreased in the group of leflunomide active metabolites, but no significant improvement of renal function was noted. 108

Treatment options for RSV are limited to supportive care or ribavirin with only marginal effectiveness. Leflunomide showed a potent, dose-dependent anti-RSV activity in cell cultures. 92 Also, pulmonary viral loads were prominently reduced in cotton rats, even if there was a 3-day delay of leflunomide administration after viral inoculation. 109 Leflunomide offers a dual benefit of both viral-load reduction and anti-inflammatory effects that attenuate the destruction of cytokine-related diseases.

Tofacitinib, a JAK1 and JAK3 inhibitor, is indicated in rheumatoid arthritis, ulcerative colitis, and psoriatic arthritis. It is also used off label for vitiligo and alopecia areata. Tofacitinib treats inflammatory diseases by interfering with the activation of the JAK/signal transducers and activators of transcription (STAT) pathway, which inhibits gene transcription, and cytokine production is thereby reduced.

HTLV-1, a retrovirus, has been linked to diseases such as adult T-cell lymphoma/leukemia (ATLL), HTLV-1-associated myelopathy (HAM), and uveitis. Ex vivo and animal studies revealed positive results of tofacitinib for ATLL and HAM. 110 HTLV-1-encoded tax protein activates IL-2, -9, -15, which further trigger JAK3-STAT5 pathway. Accumulating data demonstrated a major role of JAK3 in the pathophysiology of ATLL. 114 As a result, tofacitinib targeting JAK3 has been suggested as a therapeutic strategy in future studies.

Hydroxyurea, a deoxyribonucleic acid (DNA)synthesis inhibitor, belongs to the antineoplastic medications. However, it may be used as a second-line drug for psoriasis and palmoplantar pustulosis 115 based on the ability to slow down the rapid division of keratinocytes. Bone marrow suppression is the major and common adverse effect of hydroxyurea.

Hydroxyurea demonstrated promising results in reducing HIV RNA viral loads in five placebocontrolled clinical trials. Among all the trials, hydroxyurea was combined with didanosine, a nucleoside analog reverse-transcriptase inhibitor (NRTI). However, one should be reminded that decreased CD4 counts were noted in some studies. Therefore, close follow up of hematologic change is required in daily practice. [65] [66] [67] [68] [69] In vitro studies demonstrated the antiviral modes of hydroxyurea. First, hydroxyurea depletes deoxynucleoside triphosphate (dNTP) pools, which impedes DNA synthesis and in turn slows down the production of viral DNA. Second, hydroxyurea enhances NRTI phosphorylation and reduces resistance to NRTIs. This may partially explain the benefits of adding hydroxyurea to NRTI for viral control. Finally, cytotoxic effect of hydroxyurea makes cellular division of CD4+ T cells decline. This enables hydroxyurea to block HIV proliferation, because HIV could only replicate in dividing CD4+ T cells. 64 

Although the mode of action of hydroxyurea for HCV, HBV, HSV, and B19V is unknown, viral replications were inhibited by hydroxyurea in in vitro studies. 70, [74] [75] [76] Small-scaled clinical trials showed significant reduction of HCV RNA levels and HBV viral loads in chronic HCV and HBV carriers, respectively. 71, 72 However, there is a case report of an elderly patient with essential thrombocythemia experiencing reactivation of HBV during treatment with hydroxyurea. 73 A retrospective review of children with sickle cell anemia demonstrated decreased requirement of blood transfusion and attenuation of clinical symptoms when using hydroxyurea in patients with B19V infection. 77

Minocycline, a second-generation of tetracyclines, is frequently used for bacterial infections, acne, and rheumatoid arthritis. The small size and lipophilic nature facilitate its penetration into blood-brain barrier easily. The neuroprotection and anti-inflammation effects 116, 117 brought interest in the treatment of virus-induced encephalitis such as HIV, Japanese encephalitis virus (JEV), and reovirus. The antiviral property is not clearly known but seems to be diverse, including neuroprotective, antiapoptotic, interference of viral protein expression, and anti-inflammatory effects.

In microglial cell culture, minocycline reduced viral replication by 71-96%. 78 In vivo, macaque monkeys treated with minocycline showed less destruction of axons and less replication of viruses in the central nervous system. The experiment suggested that the antiviral effect of minocycline was through reducing the activation of monocytes and hence, viral replication was blocked. 79 Nevertheless, two double-blind, randomized, placebo-controlled human studies revealed that under minocycline 100 mg twice daily, there was no difference in cognitive function compared with placebo. 80, 81 Japanese encephalitis virus Minocycline showed high efficacy in animal models and in vitro studies for the treatment of JEV. 82 33, 34 Four clinical trials showed positive results of HIV control, either in the reduction of immune activation or lowering the vertical transmission. [35] [36] [37] [38] However, another two trials (one RCT, one single-arm) revealed no efficacy. 39, 40 As for dengue, 41-44 chikungunya, [45] [46] [47] influenza A viruses, [48] [49] [50] [51] and HCV, 52,53 paradoxical outcomes were found in the literature. Therefore, the utilization of CQ in these viral diseases still needs further investigation.

The major concern of Zika virus infection is that it can transmit from placenta to fetus and cause microcephaly or congenital defects. CQ prevented Zika virus internalization in cell cultures and reduced morbidity or mortality in mice. In addition, it prevented fetal mice from microcephaly. 54 Therefore, CQ might be a potential treatment waiting for clinical verification.

HCQ had been reported to downregulate the expression of IFN genes and reduce the production of type I IFNs. This phenomenon was noted in vitro 118 and in human studies of autoimmune diseases. 119 Since IFNs are crucial in innate immunity to defend viral infections, the usage of HCQ may raise concerns about the counter effects in viral control. Nevertheless, opposite results were also presented: HCQ activated IFNβ signaling pathways in cell studies of dengue virus. 120 

Betaretrovirus is regarded as one of the environmental factors triggering the recurrence of primary biliary cirrhosis (PBC) after liver transplantation. Earlier and more severe recurrence of PBC occurred with tacrolimus compared with CsA as an immunosuppressant. This may be partially explained by the antiviral activity of CsA.

According to an in vitro study, it was suggested that CsA interrupted viral replication through inhibiting viral protein synthesis, gag and envelope assembly, and particle budding. 63

The combination of MMF and highly active antiretroviral therapy improved the control of viral replication and delayed viral-load rebound in a randomized pilot study (n = 17 The effectiveness of thalidomide for KS might be related to anti-angiogenesis, and experts hypothesized the modulation of the immune system to trigger an antiviral action.

The treatment of immune-based diseases has been revolutionized by the introduction of target therapy, mainly biologics. Compared with biologics, conventional synthetic DMARDs exert broad-spectrum functionality. DMARDs work through immunosuppressive and antiinflammatory effects with the possibility of higher infection risk. However, many none-biologic DMARDs demonstrate antiviral activities instead. Although in most instances, the antiviral activity of DMARDs is based on in vitro or small-scale controlled studies, this property would be useful in the choice of DMARDs for patients with concomitant viral infections. Also, the combinational use of antiviral drugs and DMARDs has been shown to be more effective and less resistant in the control of some viral infections. Furthermore, in the face of novel viral infection, such as SARS-CoV-2, screening of existing chemicals, including DMARDs, may prove to be fruitful.

Dr Tsen-Fang Tsai has conducted clinical trials or received honoraria for serving as a consultant for AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, EliLilly, Galderma, GSK-Stiefel, Janssen-Cilag, Leo-Pharma, Merck, Novartis, Pfizer Inc., and UCB Pharma. Dr Ya-Chu Tsai has delivered speeches held by AbbVie, EliLilly, Janssen-Cilag, Leo-Pharma, Novartis, Pfizer.

The authors received no financial support for the research, authorship, and/or publication of this article. 

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