key: cord-254580-nhpjvgt4
authors: Ricardo, Jose W.; Lipner, Shari R.
title: Considerations for Safety in the Use of Systemic Medications for Psoriasis and Atopic Dermatitis during the COVID‐19 pandemic
date: 2020-05-27
journal: Dermatol Ther
DOI: 10.1111/dth.13687
sha: 
doc_id: 254580
cord_uid: nhpjvgt4

Coronavirus disease 2019 (COVID‐19), is responsible for at least 2,546,527 cases and 175,812 deaths as of April 21, 2020. Psoriasis and atopic dermatitis are common, chronic, inflammatory skin conditions, with immune dysregulation as a shared mechanism; therefore, mainstays of treatment include systemic immunomodulating therapies. It is unknown whether these therapies are associated with increased to COVID‐19 susceptibility or worse outcomes in infected patients. In this review, we discuss overall infection risks of non‐biologic and biologic systemic medications for psoriasis and atopic dermatitis, and provide therapeutic recommendations. In summary, in patients with active infection, systemic conventional medications, the JAK inhibitor tofacitinib, and biologics for psoriasis should be temporarily held until there is more data; in uninfected patients switching to safer alternatives should be considered. Interleukin (IL)‐17, IL‐12/23 and IL‐23 inhibitors are associated with low infection risk, with IL‐17 and IL‐23 favored over IL‐12/23 inhibitors. Pivotal trials and postmarketing data also suggest that IL‐17 and IL‐23 blockers are safer than TNF‐blockers. Apremilast, acitretin and dupilumab, have favorable safety data, and may be safely initiated and continued in uninfected patients. Without definitive COVID‐19 data, these recommendations may be useful in guiding treatment of psoriasis and atopic dermatitis patients during the COVID‐19 pandemic. This article is protected by copyright. All rights reserved.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel human coronavirus, with 2,546,527 confirmed cases of coronavirus disease 2019 (COVID-19) and 175,812 deaths worldwide (April 21, 2020). 1 It was declared a pandemic by the World Health

Organization. An overall case fatality rate of 3.61% has been reported, 2 however, inaccuracies may exist because those who are asymptomatic or suffer from mild disease may never receive confirmation.

Psoriasis and atopic dermatitis (AD) are common, chronic, inflammatory skin diseases, affecting 2-3% of the general population and 7% of adults in the United States (US), respectively. 3, 4 Disease mechanisms are multifactorial, with immune dysregulation important for both conditions, and mainstays of treatment immune-modulation. 5 Systemic therapy is preferred for psoriasis treatment in patients with Body Surface Area>10%, involvement of sensitive areas or topical therapy failure. 6 Systemic treatment is recommended for AD patients with severe disease or recalcitrant to topical therapy. 7 Immunocompromised patients are highly vulnerable to infections, which is particularly concerning in the context of the COVID-19 pandemic.

In this review, we summarize the current literature regarding overall infection risks with systemic immunomodulating agents for psoriasis and AD, and provide evidence-based treatment recommendations during the COVID-19 pandemic.

Systemic corticosteroids are immunosuppressive medications used to treat AD flares, but very rarely psoriasis. They have been shown to increase infection risk. In a systematic review of 101 studies on AD children (n=6,817) treated with systemic corticosteroids ≥15 days, infection rate was 8.7%, with 21 associated deaths. 8 In a meta-analysis of corticosteroid use in patients with influenza pneumonia (10 studies, n=6548), compared with placebo, corticosteroids were associated with higher mortality, longer intensive care unit length of stay and a higher rate of secondary infection. 9 Therefore, oral corticosteroids should be avoided, weighing the risks of disease flare vs. SARS-CoV-2 infection, to prevent COVID-19 susceptibility. Before discontinuation, dose tapering may be considered to avoid a negative effect on respiratory symptoms.

Methotrexate and cyclosporine are amongst the most frequently used systemic medications for psoriasis and AD, with both associated with increased infection rates. There was a 58% higher overall infection risk with cyclosporine vs. methotrexate in the BIOBADADERM registry (Spanish Registry of Adverse Events for Biological Therapy in Dermatological Disease) including 2153 psoriasis patients. 10 In a head-to-head comparison of methotrexate (n=50) versus cyclosporine (n=47) in moderate to severe AD adults, infections rates were 32% and 24%, respectively. 11 While methotrexate and cyclosporine are associated with decreased infection rates and favored over treatment with systemic corticosteroids, 12 their impact on susceptibility to/severity of COVID-19 is unknown and, if essential, precautions should be taken to avoid infection. Of interest, cyclosporine has anti-coronavirus activity in vitro, but the effect in humans is unknown. 13 The systemic retinoid, acitretin, is anti-inflammatory and inhibits cell differentiation; it is Food and Drug Administration (FDA)-approved for psoriasis. 14 It does not suppress the immune system to the extent of the other conventional treatments for psoriasis. In an observational cohort study, there was no increased rate of overall serious infections among acitretin-treated psoriasis patients vs. methotrexate; acitretin increased risk of cellulitis compared to methotrexate (propensity score-adjusted hazard ratio [HR], 1.76; 95% CI, 1.11-2.80), possibly due to skin fragility and staphylococcus aureus colonization. 15 Therefore, acitretin has not shown increased viral/respiratory infection risk and can be safely used during the pandemic. Retinoids have been shown to inhibit human herpesvirus eight replication, their effect on SARS-CoV-2 remains to be established. 16 

This article is protected by copyright. All rights reserved.

Azathioprine is used off-label in the US for AD treatment in patients recalcitrant or who have contraindications to cyclosporine and methotrexate. In 12 AD children treated with azathioprine, there were no associated infections. 17 In a double-blind, placebo-controlled, crossover study of 37 AD adults treated with azathioprine, there were five cases of upper respiratory infections (URIs) (14%), two cases folliculitis (5%), and one report each impetigo (3%) and sore throat (3%). 18 In a retrospective analysis of 232,611 systemically-treated adults with AD (six months), there were increased risks of serious and opportunistic infections with azathioprine (RR=1.89) and prednisone (RR=1.78) compared with methotrexate, with a reduced risk with cyclosporine (RR=0.87). 12 Therefore, azathioprine may increase susceptibility to infections, and if essential, exposure to COVID-19 should be minimized.

Apremilast, an orally administered phosphodiesterase four inhibitor is FDA-approved for moderate to severe plaque psoriasis and has been used off-label for AD. [19] [20] [21] Although it does modulate immunologic cascades, this pathway does not seem to particularly increase susceptibility to infection. In a pooled safety analysis of two randomized, controlled trials (RCTs) involving psoriasis patients treated with apremilast (n=1184), URIs and nasopharyngitis occurred in 19.2% and 16.6% of patients, respectively; serious infections (urinary tract infection n=2; appendicitis n=3; pneumonia=2) occurred in 1.4%. 22 Furthermore, in an observational cohort study including systemically treated psoriasis patients, overall serious infections were decreased with apremilast vs. methotrexate (HR, 0.50; 95% CI, 0.26-0.94). Thus, apremilast seems to be a safe alternative for uninfected psoriasis patients during the pandemic, but specific COVID-19 data is needed.

Data regarding infection risks of nonbiological therapies for psoriasis and AD is summarized in table 1.

Biologic medications are widely used for psoriasis and AD patients, with limited data regarding infection risk. Since biologics inhibit immune-mediated pathways involving specific cytokines, there is at least theoretical risk of increased susceptibility to and severity of infection. A common reason for discontinuation of biologics is infection. 23 Among the targeted cytokines for these biologics, tumor necrosis factor-alpha (TNF-α) plays a crucial role in the immune response against intracellular pathogens and formation of granulomas, 24 and Interleukin (IL) -12 and IL-23 are involved in cell-mediated immunity by inducing interferon-γ. 25 IL-23 also induces T-helper 17 cell differentiation and IL-17secretion, fundamental in providing immunity against bacteria, viruses, fungi and parasites. 26, 27 IL-4 and IL-13 play key roles in the immune response against helminth infections. 28

Five classes of biologic therapies are used for psoriasis or AD: TNF-α inhibitors (table 2) , IL-17 inhibitors, an IL-12/23 inhibitor, IL-23 inhibitors, an IL-4/13 inhibitor, and a Janus kinase (JAK) inhibitor (table 3) .

This article is protected by copyright. All rights reserved.

Anti-TNF-α therapies inhibit a crucial immunological pathway, therefore an immunosuppressive effect and increased infection risk are expected. There is an FDArequired black box warning of infection susceptibility. 29 However, assessing infection risk is challenging because RCTs are often not adequately powered to detect rare events and ineligibility criteria may exclude up to 30% of real-world patients. 30 Certolizumab increased risks of all infections, URIs and nasopharyngitis by 5%, 2% and 2%, respectively. 29 Additionally, anti-TNF-α therapy is associated with latent tuberculosis reactivation, even with chemoprophylaxis; infliximab is associated with increased risk of herpes zoster. 34, 35 Therefore, based on available data, anti-TNF-α biologics should be held Similarly, an 11% increased risk in overall infections with secukinumab was reported based on pivotal trials, with most attributable to yeast infections; URIs were increased slightly for secukinumab, but not for ixekizumab or brodalumab. 29 Since IL-17 plays an important role in immunological response against candida infections, there is a theoretical increased risk of yeast infections with anti-IL17 therapies. 40 In a pooled analysis from 10 phase two and three clinical studies on 3,430 psoriasis patients treated with secukinumab 300 mg (n=1,1410), 150 mg (n=1,395) and etanercept (n=323), candida infections were reported in 2.9%, 1.5% and 1.2% of subjects, respectively. 41 All infections were mild, resolved spontaneously or responded to standard treatment, without causing treatment discontinuation. 41 Overall, increased infection risk has been shown with IL-17 inhibitors, but yeast infections may constitute a large proportion of that increase; URIs are particularly uncommon. Therefore, IL-17 inhibitors may be safely prescribed and continued, unless the patient is symptomatic or positive for SARS-CoV-2.

Ustekinumab inhibits IL-12 and IL-23, with IL-12 playing an important role in protection against viral infections. 29, 42, 43 However, no increased susceptibility to infection with ustekinumab has been reported. In a pooled analysis of four phase two/three studies of 3, 117 This article is protected by copyright. All rights reserved. 

Contrary to IL-12/23 inhibitors, anti-IL-23 therapies do not target IL-12, and IL-12 plays a key role fighting viral infections. 29, 45 Reduced risks of salmonella, candida and mycobacterium infections were seen in IL-23p19-targeted vs. IL-12/23p40-targeted animal models. 46-49 Nonetheless, RCTs on IL-23 inhibitors have shown conflicting results regarding infection risks. In a phase III, double-blinded, placebo-controlled study on 837 psoriasis patients randomized to treatment with guselkumab, adalimumab or placebo, overall, candida, and serious infections, occurred at comparable rates across treatment groups. 50 In 798 risankizumab-treated psoriasis patients, there was increased overall infection risk in two This article is protected by copyright. All rights reserved.

phase three studies. 51 The most common infections were URIs, urinary tract infections and influenza. 51 Two cases of latent tuberculosis were reported in the risankizumab group; both patients tested negative at baseline. 51 Data assessing infection risk with tildrakizumab is sparse. Lebwohl et al reported an increase in nasopharyngitis (4%) with tildrakizumab compared with placebo. 29 Risk, however, is low and comparable to placebo. Therefore, based on available data, IL-23 inhibitors may be continued/initiated, unless the patient is symptomatic or positive for SARS-CoV-2.

Tofacitinib is a small molecule inhibitor of tyrosine kinases of the Janus family, preferentially JAK1 and JAK3, downregulating cytokines crucial for lymphocyte development; therefore, there is potential for increased risks of intracellular bacterial and viral infections. 52 It has been hypothesized, nonetheless, that fluctuations in plasma levels of JAK inhibitors throughout the day may preserve immunogenicity against infectious pathogens. 53 Tofacitinib carries an FDA-required black box warning for serious infections. In one placebo-controlled phase three trial of 422 patients with psoriatic arthritis, randomized to treatment with 5-mg or 10-mg tofacitinib, adalimumab, or placebo, nasopharyngitis (in 7%, 12% and 10%, respectively) and URIs (in 9%, 11%, and 8%, respectively) were the most common adverse events. 54 There were three cases of serious infections (influenza, appendicitis and pneumonia) and four cases of herpes zoster in the tofacitinib-treated group. 54 Similarly, in two randomized, placebo-controlled studies of 745 and 741 psoriasis patients treated with tofacitinib 5-mg and 10-mg, respectively, nasopharyngitis and URIs were the most common infections, and 5 serious infections (pneumonia, herpes zoster and erysipelas in the 5-mg group; and appendicitis, pneumonia and pyelonephritis in the 10-mg group) were reported in tofacitinib-treated patients. 55 Furthermore, herpes zoster was reported in 12 tofacitinib-treated patients versus none in the placebo groups. 55 Thus, tofacitinib has an association with increased infection risk in psoriasis/psoriatic arthritis patients. Tofacitinibtreated patients may be more susceptible to COVID-19, strict protective measures are recommended to minimize viral exposure.

Dupilumab targets IL-4 and IL-13, elements of the type two immune response. 56 As type one and type two immune responses cross-regulate each other, suppression of type one immunity can potentially facilitate uncontrolled or persistent viral and bacterial infections. 57

Nonetheless, Dupilumab has been associated with a reduced infection rate in AD patients. A pooled analysis of seven RCTs on dupilumab-treated AD adults showed a decreased risk of serious infections, skin infections and herpes infections (eczema herpeticum or herpes zoster) in the dupilumab groups compared with placebo. Furthermore, by also treating asthma, dupilumab may theoretically decrease risk for COVID-19 infected patients for severe respiratory disease. 56 Therefore, current evidence suggests continuing and initiating dupilumab treatment in AD patients during the COVID-19 pandemic.

It is difficult to make definitive conclusions about susceptibility to SARS-CoV-2 infection in psoriasis or AD patients on systemic treatments, solely based on general infection risk data. Furthermore, the majority of studies included patients with mean age of approximately 40 years; therefore, these recommendations may not be applicable to older individuals, who on average have higher COVID-19 associated mortality. There is also a potential role for some of these medications as treatments of COVID-19 but this remains largely unknown. In We suggest the following algorithms for treatment of psoriasis and AD during the COVID-19 pandemic (Figures 1, 2) . This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. 

Coronavirus COVID-19 Global Cases by the

Cross-Country Comparison of Case Fatality Rates of COVID

Sleep disturbances in adults with eczema are associated with impaired overall health: a US population-based study

National Health and Nutrition Examination Surveys

Atopic dermatitis and psoriasis: two different immune diseases or one spectrum?

Recategorization of psoriasis severity: Delphi consensus from the International Psoriasis Council

Systemic Treatment of Adult Atopic Dermatitis: A Review

Systematic Review of the Toxicity of Long-Course Oral Corticosteroids in Children

The effect of corticosteroids on mortality of patients with influenza pneumonia: a systematic review and meta-analysis

Infections in Moderate to Severe Psoriasis Patients Treated with Biological Drugs Compared to Classic Systemic Drugs: Findings from the BIOBADADERM Registry

Methotrexate Versus Cyclosporine in Adults with Moderate-to-Severe Atopic Dermatitis: A Phase III Randomized Noninferiority Trial

Comparative Safety of Systemic Immuno-modulatory Medications in Adults with Atopic Dermatitis

Suppression of coronavirus replication by cyclophilin inhibitors

A review of its pharmacology and therapeutic use

Risk of Serious Infection in Patients Receiving Systemic Medications for the Treatment of Psoriasis

Retinoic acid analogues inhibit human herpesvirus 8 replication

Adalimumab therapy for moderate to severe psoriasis: A randomized, controlled phase III trial

Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the treatment of patients with moderate to severe psoriasis with randomized withdrawal and retreatment: Results from the phase III, double-blind, placebo-and active comparator-controlled VOYAGE 2 trial

Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomised trial

Secukinumab in plaque psoriasis--results of two phase 3 trials

Infliximab monotherapy provides rapid and sustained benefit for plaque-type psoriasis

Infliximab induction and maintenance therapy for moderate-to-severe psoriasis: a phase III, multicentre, double-blind trial

A randomized comparison of continuous vs

year in the treatment of moderate-to-severe plaque psoriasis

Certolizumab pegol for the treatment of patients with moderate-to-severe chronic plaque psoriasis: pooled analysis of week 16 data from three randomized controlled trials

Guselkumab versus secukinumab for the treatment of moderate-to-severe psoriasis (ECLIPSE): results from a phase 3, randomised controlled trial

Longterm safety profile of ixekizumab in patients with moderate-to-severe plaque psoriasis: an integrated analysis from 11 clinical trials

Ixekizumab Treatment for up to 5 Years in Adult Patients with Moderate-to-Severe Psoriasis: Results from Greater Than 17,000 Patient-Years of Exposure

A prospective phase III, randomized, double-blind, placebo-controlled study of brodalumab in patients with moderate-to-severe plaque psoriasis