1 INTRODUCTION

The severity of coronavirus disease 2019 (COVID-19), caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), ranges from asymptomatic to catastrophic, and possibly death.1 The most severe manifestations of COVID-19 are thought to result from immune dysregulation and cytokine storm.2, 3 The risk of contracting COVID-19 and the range of subsequent prognoses for patients receiving immunosuppressive (IS) therapy have not been clearly established; however, observational studies of patients who have an immune-mediated inflammatory disease (IMID) have demonstrated slightly increased to no change in COVID-19 susceptibility relative to the general population.4-8 Despite this, there remain significant concerns about IS therapy compromising immunity and potentially affecting COVID-19 susceptibility and morbidity. While the safety profile of anti-cytokine biologic agents has been shown to be favorable,5 the safety of conventional disease-modifying antirheumatic drug use during COVID-19 remains more ambiguous.9-11 Currently, many providers advocate for an individualized approach to determine a therapy’s continuation, reduction, or discontinuation.12, 13

Concerns remain regarding the impact of IS on the SARS-CoV-2 vaccine response, which has been recently reviewed by Gresham et al.14 They concluded that COVID-19 vaccines can be regarded as safe and are generally well-tolerated by dermatological patients on standard IS therapy doses, a finding which has since been verified by a large multicenter observational study by Furer et al.10 Although safe, IS therapy may impact the efficacy and durability of the vaccine response, as reduced vaccine-induced antibody responses and seroconversion rates have been observed with common dermatological IS therapies such as rituximab, glucocorticoids, abatacept, and mycophenolate mofetil (MMF).10, 15, 16 Thus, while vaccination provides some level of protection among this patient cohort, susceptibility to COVID-19 will likely remain elevated relative to the vaccinated general population.

In this review, we aim to examine the risk of COVID-19 associated with the use of conventional IS therapeutics in dermatology, including apremilast, azathioprine (AZA), cyclosporine, methotrexate, MMF, Janus kinase (JAK) inhibitors, systemic glucocorticoids, and intravenous immunoglobulin (IVIg). Most biologics have been shown to be safe during COVID-19 and have been reviewed elsewhere.14 While each IS medication has been implicated in carrying an increased risk for various viral infections, IS medications collectively have not been reviewed for their effects during COVID-19 in dermatology patients with IMID. Here, we focus on viral infection risk, with a special emphasis on the risk of SARS-CoV-2 and other coronavirus infections, and provide drug management recommendations with considerations based on available data (Table 1).

TABLE 1. Summary of immunosuppressive drug management and recommendations Medication Mechanism Infection risk: key points Evidence (author, study type, patient population) Evidence qualitya US Clinical Trials (Trial ID) Recommendation for adjustment during pandemic Recommendation for adjustment if COVID-19 positive Mycophenolate mofetil (MMF) Inhibits inosine-5′-monophosphate dehydrogenase, decreasing de novo production of guanosine nucleotides preferentially required for lymphocyte replication

Conflicting studies about susceptibility to COVID-19

Cohort study has shown increased severity of infection in patients on mycophenolate mofetil therapy30

Increased survival in MERS-CoV patients

Kridin et al.,99 observational study, bullous pemphigoid and pemphigus

Balestri et al.,100 observational study, pemphigus

Veenstra et al.,9 observational study, IMID

FAI2R Consortium, cohort study, COVID-19 patients with autoimmune rheumatic diseases30, 101

Boyarsky et al.,102 prospective cohort study, solid organ transplant patients receiving mRNA vaccine

B None Continue Lower or temporarily discontinue therapy Methotrexate Inhibits nucleic acid synthesis by inhibiting dihydrofolate reductase

Modest increase in rates of URI

No significant difference in COVID-19 patient outcomes in 3 studies

Sadeghinia and Daneshpazhooh,103 systemic review, psoriasis

Yousaf et al.104 observational study, IMID

Veenstra et al.,9 observational study, IMID

Soldevila et al.,105 review, IMID

B NCT04610567 and NCT04352465 Continue Lower or temporarily discontinue therapy Cyclosporine Inhibition of interleukin-2 transcription, thereby suppressing T-cell activation

Mixed results with risk of developing infection

May have antiviral activity

Ghazawi et al.,106 narrative review, psoriasis

Di Lernia et al.,107 retrospective observational study, psoriasis and atopic dermatitis

Glowacka et al.,39 review, viral diseases including MERS, HIV, and hepatitis C

Veenstra et al.,9 observational study, IMID

B NCT04412785 and NCT04492891 Continue Consider continuing Azathioprine (AZA) Inhibition of purine synthesis by acting as an analog and interfering with DNA and RNA production

Moderately increased risk of pneumonia and infections requiring hospitalization

Poor outcomes in patients who contracted COVID-19

Bernatsky et al.,48 case–control study, rheumatoid arthritis

Berth-Jones et al.,49 double-blind RCT, atopic dermatitis

Veenstra et al.,9 observational study, IMID

Sukanjanapong et al.,108 retrospective cohort, pemphigus

Schram et al.,109 observational study, atopic dermatitis. Meggitt et al.,50 RCT, atopic dermatitis

B None Monotherapy acceptable; avoid use in conjunction with systemic steroids Discontinue Intravenous immunoglobulin (IVIg) MOA is not completely understood. Proposed mechanisms involve enhanced immunoregulatory elements

Has high antiviral activity against other viruses

Has been used in conjunction with other systemic agents for treatment of SARS-infected patients (inconclusive data regarding efficacy)

van Schaik et al.,110 RCT, non-dermatological condition

Tabarsi et al.,62 RCT, severe COVID-19

Huang et al.,111 observational cohort study, non-severe COVID-19

B NCT04616001, NCT04411667, and NCT04480424 Continue Consider continuation Apremilast Inhibits phosphodiesterase 4 activity, increasing immunomodulatory cAMP levels 1184 patient trial found that in patients taking apremilast for ≥3 years, 19.2% developed URI, 16.6% developed nasopharyngitis, and 0.2% developed pneumonia66

Stein Gold et al.,112 prospective database, psoriasis

Dauden et al.,113 prospective cohort study database, psoriasis

Queiro Silva et al.,114 case series, psoriasis

Gisondi et al.,6 narrative review, psoriasis

B NCT04590586 Consider continuation on case-by-case basis due to its increased risk of URI Discontinue JAK inhibitors Targets intracellular signal transduction for cytokines signaling

In clinical trials, very low viral or bacterial infection incidence among study participants

Ruxolitinib and baricitinib underwent a clinical trial for evaluation to treat COVID-19, with baricitinib receiving approval for COVID-19 related pneumonia as a treatment in some countries30, 115-117

Cantini et al.,118 open label clinical trial for barticinib, COVID−19

Holcomb et al.,119 cross-sectional study, IMID

Kvist-Hansen et al., review, psoriasis120

Kalil et al., RCT, COVID−1976

Marconi et al., RCT, COVID−1977

B NCT0440286, NCT04404361, and NCT04933799 (there are 22 studies as of 4 August 2021, 10 are active, five terminated/withdrawn, four completed, three unavailable) Continue Continue baricitinib, ruxolitinib, and tofacitinib; consider stopping higher doses of upadacitinib Systemic CS Suppression of multiple cytokines, chemokines, and peripheral leukocytes

Low CS doses may be advantageous in COVID-19 to decrease severity of infection

Higher doses may increase susceptibility to acquiring COVID-19 and having poorer outcomes

Dexamethasone found to decrease mortality in COVID-19-positive patients who require oxygen with or without ventilatory support98

WHO REACT Working Group,121 meta-analysis, critically ill patients

The RECOVERY Collaborative Group,122 open-label clinical trial, hospitalized patients

D’Silva et al.,101 cohort study, COVID-19 patients with autoimmune rheumatic diseases

Gianfrancesco et al.,5 case series, rheumatic disease patients with COVID-19

B 11 studies total: eight active and three completed Low-dose CS permissible; recommend tapering higher CS doses to 10 mg daily or lower as feasible Low-dose CS treatment is standard in COVID-19 requiring supplemental oxygen Abbreviations: cAMP, Cyclic adenosine monophosphate; CoV, Coronavirus; CS, Corticosteroids; HIV, human immunodeficiency virus; IMID, Immune-mediated inflammatory disease; JAK, Janus kinase; MERS, Middle Eastern respiratory syndrome; MOA, Mechanism of action; RCT, Randomized controlled trial; SARS, severe acute respiratory syndrome; URI, Upper respiratory infection. US clinical trials as of July 2021. aAdapted from previously described quality of evidence summary.123 Category A includes systematic reviews or cohort studies with uniform results applicable to most dermatology patients on immunosuppressive therapy; category B includes systematic reviews or cohort studies with non-uniform results not applicable to all dermatology patients on immunosuppressive therapy; category C includes consensus guidelines, case reports or case series, and expert opinions. 2 MYCOPHENOLATE MOFETIL

Mycophenolate mofetil (MMF) is an immunosuppressant derived from mycophenolic acid, which has antiviral activity.13 It has demonstrated utility in treating multiple inflammatory dermatological diseases, autoimmune bullous dermatoses, and many other IMID.17

Coronavirus proteases are responsible for the maturation and dampening of interferon-β release from host cells, and some researchers hypothesize that inhibiting these viral proteases may be a viable treatment strategy for COVID-19.18, 19 In vitro studies have found that mycophenolic acid inhibits proteases in the Middle Eastern respiratory syndrome coronavirus (MERS-CoV) as well as SARS-CoV.18, 20 Several other in vitro studies have shown that mycophenolic acid or MMF inhibits SARS-CoV.21-23

A 2014 retrospective chart review of patients with MERS-CoV demonstrated increased survival in patients treated with MMF.24 MMF has also shown activity against hepatitis C virus and HIV.25 In contrast, patients receiving MMF have increased rates of cytomegalovirus and BK polyomavirus infections, as well as bacterial upper respiratory tract infections (URI).26, 27 Patients taking MMF are also at increased risk of developing herpes zoster and herpes simplex viruses.26

However, the solid organ transplantation literature suggests that patients taking MMF are at higher risk of COVID-19. Imam et al.28 reviewed 15 studies reporting on 120 liver transplant patients with COVID-19 taking IS drugs, including tacrolimus, MMF, and prednisone. They reported that 48.4% of patients were maintained on MMF and that 14.3% of patients had their MMF treatment reduced. Overall, 28.6% of patients needed intensive care unit admission and 13.6% died. However, whether these patients had their MMF maintained or reduced was not clarified. Another study comparing 111 liver transplant patients observed that patients who had higher MMF doses had a dose-dependent increased risk of COVID-19 severity.29 COVID-19 severity was also linked to MMF use in a study of 694 patients with rheumatic disease; patients were six-times more likely to develop severe disease (p = 0.015),30 which was mirrored by the findings in a study at our institution.9

In conclusion, studies of SARS-CoV-2 infection in dermatology patients who are taking MMF are limited; however, there is no definitive evidence to support decreasing or discontinuing MMF therapy in non-infected individuals. However, in patients infected with SARS-CoV-2, we recommend that providers discontinue MMF therapy to avoid worse outcomes.

3 METHOTREXATE

Methotrexate inhibits purine synthesis and therefore slows cell division in rapidly proliferative cells, such as lymphocytes. In dermatology, methotrexate is commonly used to treat psoriasis, atopic dermatitis, and mycosis fungoides, among many other IMID.17 The evidence regarding methotrexate’s IS profile is mixed.

Conway et al.31 conducted a meta-analysis of respiratory events in patients who were taking methotrexate for non-rheumatoid arthritis and conditions such as psoriasis, psoriatic arthritis, and inflammatory bowel disease. Among 1630 patients, there were 504 documented respiratory adverse events. Compared with other IS agents used to treat rheumatoid arthritis, methotrexate was found not to lead to an increased risk of adverse respiratory events (relative risk [RR], 1.03; 95% confidence interval [CI], 0.9–1.17). Additionally, the study found no increased risk of non-infectious (RR, 1.07; 95% CI, 0.58–1.96) or infectious (RR, 1.02; 95% CI, 0.88–1.19) respiratory adverse events with methotrexate use.31 Distinction between viral and bacterial infections was not made. West et al.32 conducted a meta-analysis examining the safety profile of methotrexate in conditions including psoriasis, palmoplantar psoriasis, and psoriatic arthritis. Across all patients, URI, pneumonia, and severe infections were reported at a weighted incidence of 10.2%, 0.8%, and 1.6% respectively.32

Methotrexate use has rarely been linked to more severe COVID-19 symptoms, with only one case–control study on psoriasis reporting an increased hospitalization risk independently associated with use (adjusted odds ratio, 2.30; 95% CI, 1.11–4.78; p = 0.025).8 Methotrexate use has also been associated with a mildly impaired immune response to an mRNA-based vaccine in a rheumatic disease patient cohort; however, the authors stopped short of recommending postponing or withholding treatment.10 Conversely, a study of 104 psoriasis patients found no significant difference in COVID-19 severity between the 13 COVID-19 patients taking methotrexate (10–22.5 mg/week) and those psoriasis patients who were not receiving systemic or biologic treatment.33 A retrospective cohort analysis that was conducted at our home institution found no significant association of methotrexate use with SARS-CoV-2 infection rates, percentage of COVID-19-positive patients who required hospital admission, need for ventilator use, or mortality.9

Methotrexate has been shown to inhibit replication of SARS-CoV-2 in the kidney Vero E6 cell line. Recently, Safavi and Nath suggested using methotrexate in patients with COVID-19 to attenuate the cytokine storm.34 To our knowledge, no clinical prospective or retrospective studies have investigated methotrexate as an adjunct medication to decrease cytokine storm risk in COVID-19 patients. At high doses, methotrexate can decrease T-cell interleukin (IL)-6 and tumor necrosis factor (TNF)-α levels in addition to decreasing monocyte proliferation and shifting them toward a less inflammatory cytokine profile.35 Additionally, through binding of the high-mobility group box 1 protein, methotrexate can inhibit macrophage cytokine production.35

Although there is an increased infection risk with methotrexate use, the reported infection rates, especially for URI, have been modest among patients treated for dermatological conditions. Methotrexate use in psoriasis patients has been associated with an increased hospitalization risk from COVID-19, but not increased mortality;8 however, other studies have not identified an increased risk, and most data suggest that methotrexate therapy is safe unless the patient is infected with SARS-CoV-2. Thus, for COVID-19 patients, lowering or temporarily discontinuing methotrexate therapy should be considered, as any potential benefit as an adjunct medication for COVID-19 has not been validated through rigorous clinical trials.

4 CYCLOSPORINE

Cyclosporine inhibits calcineurin signaling via the formation of a complex with cyclophilin, thereby blocking translocation of nuclear factor of activated T cells (NFAT) from the cytosol to the nucleus. This leads to a downstream decrease in IL-2, impacting T-cell activation and proliferation.36 In dermatology, cyclosporine is US Food and Drug Administration (FDA)-approved for treating psoriasis and is commonly used off-label for other IMID. Although cyclosporine is immunosuppressive, infection risk with its use is not well-defined.

Some studies have suggested that cyclosporine does not cause reactivation of viral infections and may carry lower risk of URI compared to other immunosuppressants such as MMF,37 whereas other studies have shown increased rates of infection. Dávila-Seijo et al.38 examined the crude rates of infection with different systemic drugs in moderate to severe psoriasis. Cyclosporine led to an increased overall rate of infection (adjusted RR, 1.58; 95% CI, 1.17–2.15) and a significant risk of serious life-threatening infection (adjusted RR, 3.12; 95% CI, 1.1–8.8). However, the viral or bacterial nature of infections was not delineated.

Cyclosporine inhibits replication of several RNA viruses, including coronaviruses and influenza virus.39-41 In vitro studies have shown that cyclosporine strongly inhibits MERS-CoV replication,42 but more recently, Li et al.41 demonstrated strong inhibition of MERS-CoV in vivo in human lung and bronchus explant culture models with use of cyclosporine. In a pilot study of 209 patients hospitalized with COVID-19, Galvez-Romero et al.43 showed that the patient cohort treated with cyclosporine A (1–2 mg/kg/day for 7 days) in addition to clarithromycin, enoxaparin, and I.V. methylprednisone had decreased mortality and fewer hospitalization days than patients treated with I.V. methylprednisone alone.

Pfefferle et al.44 used a genome-wide yeast two-hybrid interaction screen to demonstrate that cyclophilins and immunophilins interact with the SARS-CoV non-structural protein 1. Through an in vitro model, they demonstrated that upregulation of non-structural protein 1 led to indirect activation of NFAT and its downstream NFAT/calcineurin pathway.44 With the addition of cyclosporine A, dose-dependent inhibition of replication of all coronavirus genera was observed, including SARS-CoV.44

Cyclosporine has shown antiviral effect against coronaviruses in human epithelial airway cells in vitro, particularly SARS-CoV, suggesting that there may be a benefit to continued use of cyclosporine during COVID-19.45 One case report of a pregnant woman with a significant ulcerative colitis flare and concomitant COVID-19 demonstrated flare improvement without progression of COVID-19 symptoms with I.V. cyclosporine therapy.46 However, further data and human trials are needed to validate these findings. Based on a literature review, consideration should be given to the continuation of cyclosporine during severe COVID-19 for the potential to decrease the exuberant immune response. However, close monitoring is necessary given cyclosporine’s side-effect profile, especially nephrotoxicity.

5 AZATHIOPRINE

Azathioprine (AZA) is an antimetabolite drug used to treat many dermatological conditions, including IMID, autoimmune bullous dermatoses, and pyoderma gangrenosum.17 The enzymes hypoxanthine-guanine phosphoribosyltransferase and thiopurine methyltransferase convert AZA to its active metabolites, mercaptopurine and thioguanine, which inhibit purine synthesis.47

Current infection data describing patients receiving AZA therapy do not delineate viral versus bacterial etiologies, making it challenging to assess morbidity from SARS-CoV-2 infection. Bernatsky et al.48 performed a large case–control study of rheumatoid arthritis patients on AZA to assess serious infection risk, defined as any infection requiring hospitalization. The study concluded that patients taking AZA were at a moderately increased risk of developing infections requiring hospitalization and contracting pneumonia (RR, 1.5; 95% CI, 1.2–2.0 and RR, 1.3; 95% CI, 0.9–1.8, respectively).48 Berth-Jones et al.49 performed a double-blind, randomized, placebo-controlled crossover trial with 2.5 mg/kg/day AZA for 3 months in patients with severe atopic dermatitis. A total of five of 24 patients (21%) who received AZA developed a URI, compared to two of 25 patients (8%) in the placebo group. In 2006, a double-blind placebo study on AZA safety for moderate to severe atopic dermatitis reported that of 41 patients who received AZA at 1 mg/kg/day or 2.5 mg/kg/day, two patients (5%) had a lower respiratory tract infection and two patients had a URI. In the placebo group (n = 20), no patients developed a lower respiratory tract infection and one patient (5%) developed a URI.50 More recently, our group observed that three of 25 patients (12%) taking AZA with concern of possible COVID-19 were infected with SARS-CoV-2. All three of these patients required hospital admission and ventilator support, and one patient died.9

Azathioprine monotherapy-associated infection data are limited; however, current studies suggest that AZA moderately increases infection risk. We advise continuation of AZA during the COVID-19 pandemic as monotherapy, with strong caution against the use of AZA with corticosteroids (CS). If patients are infected with SARS-CoV-2, we recommend discontinuation.

6 INTRAVENOUS IMMUNOGLOBULIN

Intravenous immunoglobulin (IVIg) is plasma-derived immunoglobulin (Ig)G from healthy human donors, and it has been used for its immunomodulatory and anti-inflammatory effects in several dermatological conditions, including autoimmune bullous disorders, dermatomyositis, Stevens–Johnson syndrome, and Kawasaki syndrome.51 IVIg is also used for maintaining antibody levels in genetic conditions associated with impaired antibody production, such as hypogammaglobinemia and common variable immunodeficiency.52-54 Thus, while it is unknown to what degree IVIg may truly dampen the immune system because of its use in conditions where it helps to reconstitute antibody production, its apparent action in decreasing severity of autoimmune conditions qualifies it for discussion among IS therapy. IVIg’s immunomodulatory effects result from many mechanisms that are not fully elucidated, but are thought to suppress the proliferation of antigen-specific T cells and extracellular matrix adhesion of T cells. The Fc portion of IVIg may bind directly to and downregulate inflammatory cytokines such as IL-2 and IL-6.51, 55 Additionally, IVIg may bind to and neutralize autoantibodies and may bind the Fc- receptor on innate immune effector cells, thereby blocking activation of the immune response.56 In vitro studies have shown that IVIg has high antiviral activity against several viruses, including parvovirus B19 and Epstein–Barr virus.57

Although IVIg has been used for SARS-CoV infection and COVID-19, it has largely been used as an adjunct treatment with other medications; consequentially, the safety and efficacy of isolated IVIg for coronavirus infection has not been studied.58-61 Cao et al.58 recently suggested the use of high-dose IVIg at 0.3–0.5 g/kg for 5 days as a treatment for COVID-19 at the onset of respiratory distress. They reported improvement of fever, respiratory distress, and radiological findings in three patients with this treatment. However, antiviral therapy with oseltamivir and lopinavir/ritonavir was concomitantly used in two of the three patients, and systemic CS were used in one patient, confounding the results.58 A randomized controlled trial (RCT) of 52 patients treated with 400 mg/kg IVIg concluded that this treatment was not effective in the management of severe COVID-19, with no significant differences in mortality rate or mechanical ventilation compared to control patients, all of whom were treated with additional antiviral therapies. However, length of hospital stay may have been reduced with early IVIg intervention and intensive care unit admission.62

There is a dearth of RCT and studies that have investigated the safety and efficacy of IVIg in individual viral infections and the rate of viral infection during IVIg use. However, IVIg in combination with other therapies for the treatment of COVID-19 and SARS-CoV has demonstrated either neutral or positive outcomes. Therefore, continuation of IVIg during COVID-19 infection can be considered, and preemptive discontinuation of IVIg is not recommended.

7 APREMILAST

Apremilast is a phosphodiesterase-4 inhibitor approved to treat psoriasis. Inhibiting phosphodiesterase-4 increases intracellular cyclic adenosine monophosphate levels, thereby modulating the activity of innate and adaptive immune cells.63 At least one clinical trial is testing apremilast for use in COVID-19 patients, and one case report has suggested that apremilast might have had a protective effect with a patient exposed to SARS-CoV-2.64 Additionally, apremilast demonstrates a favorable safety profile in infections such as HIV, hepatitis B virus, and hepatitis C virus.65

Upper respiratory tract infections have been well documented as common, mild to moderate adverse effects of apremilast. The ESTEEM 1 and 2 trials were large, phase III, double-blind RCT examining both the safety and efficacy of apremilast for 1184 patients with mild to moderate psoriasis.66 URI occurred in 19.2% (n = 227), nasopharyngitis in 16.6% (n = 196), and pneumonia in 0.2% (n = 2) of patients.66 Similarly, the PALACE trials, phase III double-blind RCT assessing the safety and efficacy of apremilast, noted URI and nasopharyngitis as common, mild to moderate side-effects.67, 68 Another RCT observed a dose-dependent increase in URI with apremilast use. The study noted that 10% of patients developed URI at the 10 mg dose, 14% developed URI at the 20 mg dose, and 16% developed URI at the 30 mg dose, compared to the 6% of patients who developed URI in the placebo group.69

Recently, a case report described a 45-year-old man with brain oligodendroglioma and erythrodermic psoriasis who was taking apremilast 30 mg two times daily and prednisone 12.5 mg daily and who developed SARS-CoV-2 pneumonia.70 The patient did not discontinue apremilast and recovered after 6 days of treatment with lopinavir/ritonavir 400/100 mg two times daily and I.V. ceftriaxone 2 g/day.70

There is a slightly increased risk of respiratory infection with apremilast. A national task force on psoriasis treatment during the COVID-19 pandemic concluded that apremilast and other psoriasis treatments were not known to significantly alter contracting COVID-19 or developing worse symptoms, although data are still emerging on this topic.71 At the moment, preemptive discontinuation of apremilast should be considered on a case-by-case basis, and discontinuation is recommended in the setting of SARS-CoV-2 infection. However, further research is needed to determine whether apremilast might be beneficial for dampening the exaggerated immune response and cytokine storm commonly found in SARS-CoV-2 infection.

8 JAK INHIBITORS

The JAK family of enzymes is responsible for signal transduction via the JAK–STAT pathway and plays a critical role in numerous pro-inflammatory pathways.72 Thus, JAK inhibitors may serve as an effective tool in combatting the cytokine storm in patients with SARS-CoV-2 infection.73 There have been several clinical trials evaluating the potential role of ruxolitinib and baricitinib in the management of COVID-19 (ChiCTR2000029580).74, 75 Baricitinib, an oral JAK inhibitor that is used for atopic dermatitis and rheumatoid arthritis, has been approved in Japan for COVID-19-related pneumonia. In a double-blind, randomized, placebo-controlled trial of 1033 subjects, hospitalized adults treated with baricitinib, remdesivir, and CS had a 1-day faster recovery time compared with remdesivir and corticosteroids alone (95% CI, 1.01–1.32; p = 0.03). Moreover, subjects receiving non-invasive ventilation or high-flow oxygen had an 8-day faster recovery time compared with subjects treated only with remdesivir and corticosteroids (rate ratio for recovery, 1.51; 95% CI, 1.10–2.08).76 Separately, in the COV-BARRIER phase III clinical trial, hospitalized COVID-19 subjects treated with baricitinib in combination with remdesivir and systemic corticosteroids did not show a significant difference in disease progression compared with standard treatment of remdesivir and systemic corticosteroids alone; however, the 28-day all-cause mortality was lower in the baricitinib group (hazard ratio, 0.57; [95% CI, 0.41–0.78]; nominal [p = 0.0018]).