key: cord-356040-qdpkidn8 authors: Ghazawi, Feras M.; Lim, Megan; Dutz, Jan P.; Kirchhof, Mark G. title: Infection risk of dermatologic therapeutics during the COVID‐19 pandemic: an evidence‐based recalibration date: 2020-07-03 journal: Int J Dermatol DOI: 10.1111/ijd.15028 sha: doc_id: 356040 cord_uid: qdpkidn8 Recommendations were made recently to limit or stop the use of oral and systemic immunotherapies for skin diseases due to potential risks to the patients during the current severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) COVID‐19 pandemic. Herein, we attempt to identify potentially safe immunotherapies that may be used in the treatment of cutaneous diseases during the current COVID‐19 pandemic. We performed a literature review to approximate the risk of SARS‐CoV‐2 infection, including available data on the roles of relevant cytokines, cell subsets, and their mediators in eliciting an optimal immune response against respiratory viruses in murine gene deletion models and humans with congenital deficiencies were reviewed for viral infections risk and if possible coronaviruses specifically. Furthermore, reported risk of infections of biologic and non‐biologic therapeutics for skin diseases from clinical trials and drug data registries were evaluated. Many of the immunotherapies used in dermatology have data to support their safe use during the COVID‐19 pandemic including the biologics that target IgE, IL‐4/13, TNF‐α, IL‐17, IL‐12, and IL‐23. Furthermore, we provide evidence to show that oral immunosuppressive medications such as methotrexate and cyclosporine do not significantly increase the risk to patients. Most biologic and conventional immunotherapies, based on doses and indications in dermatology, do not appear to increase risk of viral susceptibility and are most likely safe for use during the COVID‐19 pandemic. The limitation of this study is availability of data on COVID‐19. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also named 2019 novel coronavirus disease COVID-19, is the causative agent of the ongoing pandemic. 1 and MIP-1a. 5, 6 This is consistent with the reported elevation of proinflammatory cytokines in SARS 7 and MERS infections. 8 The massive inflammatory cell infiltration and elevated proinflammatory cytokine/chemokine responses result in acute lung injury and ARDS. 4, 9, 10 Part 2: Infectious risks associated with biologics: evaluating cytokine knockout data and reviewing data from randomized controlled trials (RCTs) and biologic treatment registries Infecting TNF-a À/À , TNF receptor 1 (R1) À/À , and TNFR2 À/À mice with mouse hepatitis virus-3 (MHV-3, belongs to the coronavirus family) revealed that a deficiency of either TNF-a or TNFR1 decreased morbidity and mortality (Table 1) . 11 TNF receptors 1/2 knock-out mice infected with SARS-CoV were protected from infection-related morbidity. 12 Collectively, TNF-a promotes the deleterious effects of coronavirus infection presumably through excessive inflammation. From clinical trials ( The B-lymphocyte antigen CD20 is highly expressed on B cells starting at the pre-B-cell stage and on mature B cells, and it is downregulated during terminal differentiation into plasma cells. While the precise function of CD20 is not fully elucidated, IgM expression in immature and mature B cells from CD20-deficient mice was markedly reduced compared to wildtype. 16 Furthermore, reduced humoral immunity to adeno-associated viral antigens was demonstrated in CD20-deficient mice. 17 A patient who lacked CD20 expression due to homozygous mutations reported intermittent respiratory infections, associated with persistent hypogammaglobulinemia and strong reductions in circulating memory B cells. 18 No significant differences in URTI, nasopharyngitis, bronchitis, cough, and sinusitis between rituximab (anti-CD20) 19 and placebo were demonstrated in a double-blind RCT for rheumatoid arthritis (RA). 20 However, in a prospective, open-label RCT, it was noted that lung infections/ pneumonia were higher in the rituximab treatment arm by more than twofold (11% vs. 5% in control, no confidence intervals were presented). 21 The role of CD20 + cells in presenting antigen to T cells and in generation of antibodies to protect from new infections remains unclear. The IL-12/IL-23 common pathway plays a key role in the induction of inflammation in adaptive immune responses, where IL-12 induces a Th1 immune response with a downstream induction of cytokines such as TNF, interferon (IFN)-c, and IL-23 promotes a Th17 immune response through the induction of inflammatory cytokines such as IL-17 and IL-22. 22 Mice defective in both IL-12/23 (p40 À/À ) and IL-12 alone (p35 À/À ) were infected with a murine coronavirus (MHV). 23 IL-12 and IL-12/23 knockout mice had similar survival to wild-type animals. 23 Therefore, IL-12 does not seem to contribute to antiviral function or survival. Mice deficient in IL-23 alone (p19 À/À ) were infected with murine coronavirus, and viral control was similar to wild-type mice, demonstrating that IL-23 does not significantly confer protection from infection. 24 This was also demonstrated thorough neutralization of mice using anti-IL-23p19specific and anti-IL-12/23p40 antibodies, followed by infection of mice with MHV. 25 In the absence of IL-12/23 signaling, specific antiviral T-cell response was intact. 25 Clinical trials using IL-12/23 or IL-23 inhibitors demonstrated no significant increase in respiratory adverse events (Table 2) . Furthermore, the PSOLAR study reported that ustekinumab had no increased risk of serious infections. 13 Of note, a recent case study reported COVID-19 in a patient during IL-23 inhibitor (guselkumab) treatment for psoriasis, and the patient had a good outcome. 26 IL-17 is a proinflammatory cytokine with important roles in Tcell activation and neutrophil mobilization and activation. 27 IL-17 expression is induced during influenza infection as part of the Th1 immune response that contributes to viral clearance. 28 However, a growing body of evidence suggests that IL-17 is also associated with promotion of viral infections and tissue pathology. This is thought to occur through direct suppression including TNF-a, IL-1b, and IL-6. 32 In humans, chronic mucocutaneous candidiasis has been attributed to the disruption of Th1 and Th17 pathways. This was illustrated in patients with identified mutations in IL-17RA and STAT1 genes. 33 These patients have no increased risk of viral infections. 34 Clinical trials using IL-17 inhibitors demonstrated no significant increase in respiratory adverse events (Table 2) . A recent case report reported a patient receiving therapy with an IL-17 inhibitor (ixekizumab) who was completely asymptomatic but tested positive for COVID-19. 35 ity. 38 The use of anakinra in clinical trials was associated with a slightly higher frequency of serious infectious episodes, primarily pneumonia (2.1% vs. 0.4%, comparative risk 5.25), than the placebo group. 39 It appears that normal IL-1 expression/ function is required to mount an optimal antiviral immune response. IL-4 is a key regulator in humoral and Th2 adaptive immunity. Mouse models demonstrated that the constitutive overexpression of IL-4 prior to RSV infection delayed viral clearance, increased the density of the lymphocytic infiltrate in the lungs, and diminished induction of primary cytotoxic T lymphocyte responses. 40 Conversely, IL-4 À/À mice cleared RSV readily after primary infection, with minimal pathology. 40 Cyclosporine is a calcineurin inhibitor that blocks IL-2 signaling and T-cell proliferation. 52, 53 The most common infectious side effects from cyclosporine were flu-like symptoms seen in 15% of patients enrolled in an RCT for chronic idiopathic urticaria. 54 Psoriasis registries examining cyclosporine reported infection Trials that combined MMF with corticosteroids had significantly higher rates of infections, up to 59%. 62 MMF is reported to increase patients' susceptibility to viral infections, 63 and an increase in nasopharyngitis and URTIs was noted comparing prednisone plus MMF to prednisone monotherapy in pemphigus vulgaris. 62 Of note, MMF was used to treat eight patients with MERS with a 100% survival rate; however, when analyzing the severity of illness and treatment, MMF was given to less severely ill patients. 64 Azathioprine Azathioprine inhibits purine synthesis and downregulates B-cell and T-cell function. 65, 66 Documented types of infection with use of azathioprine include lower respiratory tract infections (LRTI) and URTI, which had rates of 5% and 5-20%, respectively. 67, 68 Thirty-six percent of patients in one study had infections of moderate intensity. 69 There were no registries evaluating the prevalence of infections during azathioprine therapy for dermatologic uses. One systematic review evaluating the off-label use of azathioprine found mild infections reported in 0.36% of patients and severe infections in only 0.30% of patients 70 (Table 3 ). The use of methotrexate (MTX), 71 a folic acid antagonist that inhibits nucleotide synthesis, 72 infection were similar to the placebo group. 76 A review of infectious risks in rheumatoid arthritis (RA) patients indicated that although MTX has previously been implicated not only with increased risk of infection but also increased severity, the evidence was not clear. 77 The review concluded that MTX appears to be associated with minimal, if any, increased infection risk in the RA population. 77 Hydroxychloroquine is an antimalarial medication that inhibits lysosomal functions and interferes with a myriad of immune pathways. 78 Its exact mechanism in many dermatologic processes has never been fully elucidated. Hydroxychloroquine has been shown to have a favorable side effect profile in terms of infection risk in many clinical trials. 79, 80 It is currently under investigation in numerous phase 2 clinical trials as treatment for COVID-19 as it may inhibit viral fusion to the host cell and inhibit viral assembly and release. 81 Apremilast is a phosphodiesterase 4 (PDE4) inhibitor, 82 with side effects including nasopharyngitis and URTI. 83 The incidence of URTI in the apremilast-treated groups is comparable to placebo ranging from 4.8 to 26.0% and 4.4 to 14.0%, with higher rates being accounted for from one study examining apremilast in palmoplantar psoriasis (Table 3 ). Overall, rates of infection were not increased in patients treated with apremilast. [84] [85] [86] [87] [88] [89] A recent case was reported of a patient with erythrodermic psoriasis, with contraindication to most treatments due to a recurrent brain oligodendroglioma who had psoriasis Thalidomide Thalidomide, 91 an immunomodulatory drug with a range of activity that is not fully characterized, 92 is effective for various refractory dermatoses, but its side effect profile is unfavorable, and risks of teratogenicity and neuropathy often preclude its use. 91 Table 3 highlights four RCTs where there was no increased risk of infection in thalidomide compared to placebo. Prolonged use of oral corticosteroids is generally avoided due to side effects. 93 None of the following studies reported infection as an adverse reaction. 94 Immunosuppression is not a comorbidity that is commonly reported in COVID-19 patients despite it commonly being referred to as a risk factor. 104 The limited data do not suggest increased risk of severe complications compared to the general population. Lei et al. 105 reported two heart transplant patients in China who survived COVID-19 infections. Two reported renal transplant patients who contracted COVID-19 and succumbed to the illness had similar clinical courses compared to non-transplant patients. 106 Transplant recipients may practice more stringent physical distancing practices compared to the general population, resulting in falsely low numbers. The literature surrounding SARS and transplant recipients is sparse. Risk factors for severe SARS included hypertension, diabetes, coronary heart disease, hepatitis, and pregnancy with a mortality rate with ≥1 risk factor compared to none of 54.5% vs. 7.5%; P < 0.01. 107 There is no evidence that suggests transplant recipients had poorer outcome in the SARS epidemic. A retrospective cohort study of a MERS outbreak in Korea revealed that the number of affected immunosuppressed patients was low and did not identify any transplant patients. 108 Immunosuppression was not identified as a poor prognostic factor in MERS infection. 109 Immunomodulatory regimens have revolutionized the treatment of dermatological diseases. With the current COVID-19 pandemic, it is imperative to examine the evidence and conduct a risk-benefit analysis for each patient. There may be patients who require more or less treatment, for instance some patients with existing comorbidities may require a more conservative Figure 1 A pictorial representation of COVID-19 risk assessment of dermatologic treatments where green represents "safe" and red represents "higher risk" approach. 110 The greatest risk of infections in biologics appear to occur with CD20 inhibition (Fig. 1) . For non-biologic immunotherapies, the greatest risk of infection appears to occur with the use of high doses of oral corticosteroids. A slight increased infection risk is seen with cyclosporine, although cyclosporine has been shown to inhibit coronavirus replication and did not increase susceptibility in transplant patients. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): the epidemic and the challenges COVID-19 and psoriasis: is it time to limit treatment with immunosuppressants? 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