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      CID‐19 pulmonary infection in erythrodermic psoriatic patient with oligodendroglioma: safety and compatibility of apremilast with critical intensive care management

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          Abstract

          Dear Editor, Novel coronavirus 2019 (SARS‐CoV2) pandemic has particularly affected Italy, with a profound impact on the therapeutic strategy for complex disorder such as psoriasis, whose extensive skin damage might expose to an increased infective risk compared to the general population. 1 , 2 , 3 , 4 Psoriasis treatment relies on immunosuppression, and although most experts agree that the benefit‐to risk‐ratio is in favour of maintaining selective biological therapies, and small molecules such as apremilast, they recommend dismission if severe COVID‐19 symptoms occur. 5 , 6 We report a patient with erythrodermic psoriasis, with contraindication to most treatments because of a recurrent brain oligodendroglioma, who was under apremilast therapy while contracting SARS‐CoV‐2 pneumonia. The 45‐year‐old obese (BMI 36.33) white man, with a decennial history of severe psoriasis and arthritis, treated with all traditional and biological drugs had to start chemotherapy with temozolomide, for the brain oligodendroglioma not operable recurrence. Its psoriasis had worsened to erythroderma (Fig. 1), only partially controlled by prednisone 50 mg/day, and in agreement with the neuro‐oncologist, apremilast 30 mg orally twice a day was started. The patient gradually improved, allowing prednisone tapering to a minimal dose of 12.5 mg daily. On February 19, 2020, he was enough stabilized to travel to Milan, Northern Italy, to be evaluated for brain radiotherapy. On February 26, he developed a severe cough with high fever (TC 40°C) and a chest X‐Ray revealed bilateral interstitial pneumonia with positive swab to SARS CoV2. After referral to the Infective Disease Unit, the patient started treatment with Lopinavir/Ritonavir400/100 mg twice a day and intravenous Ceftriaxone 2 g/day. He was discharged on March 3, clinically healed after two consecutive negative SARS‐CoV‐2 swabs. Apremilast had never been stopped during the COVID‐19 hospitalization, with acceptable control of the psoriasis, limited to mild scaling and erythema, especially on the trunk (Fig. 2). Figure 1 Severe erythrodermic psoriasis (PASI 45) before apremilast treatment. Figure 2 The patient improvement under apremilast treatment, after the COVID‐19 recovery. The fact that patient with a severe form of psoriasis contracted the COVID‐19 pneumonia, while on treatment with apremilast is worth of some considerations. First of all, the information of apremilast safety, not interfering with the infection, as the drug was not interrupted during the whole course of the infection. Our patient had several risk factors for a worst outcome: obesity, recent chemotherapy, persistence of brain oligodendroglioma and viral contagion in a nosocomial setting. By converse, the infection recovered rapidly and the patient was discharged 6 days after the onset of symptoms. Apremilast has previously demonstrated a long‐term safety profile in the setting of serious infections such as HIV, HBV and HCV. 7 , 8 However, therapeutic strategy during severe COVID‐19 pneumonia are still in the process of definition, and it was quite surprising apremilast was maintained. We cannot rule out that apremilast anti‐inflammatory activity might have played a role in the rapid recovery. The selective inhibition of the enzyme phosphodiesterase 4 (PDE4) allows higher levels of cyclic AMP, which decreases the production of inflammatory cytokines such as tumour necrosis factor‐alpha (TNF‐α). 7 Interestingly, the efficacy of apremilast has been reported in acute lung injury caused by the anticancer proteasome inhibitor carfilzomib, characterized by an exaggerated inflammatory response. 9 Another experiment in mouse has documented an inhibitory effect of apremilast on the release of profibrotic cytokine from macrophages, including interleukin‐6. 10 During COVID19, pneumonia has been documented a ‘cytokines storm’, with markedly higher levels of IL‐6, and TNF‐α, suggesting the use of interleukin‐6 receptor blocker tocilizumab in severe cases. 11 Recently, another Italian psoriasis patient contracting COVID‐19 under IL‐23 inhibitor treatment (guselkumab) has been reported, and completely recovered from the infection. 12 From our experience, apremilast confirms its safety in very critical patients with severe infections, including COVID‐19. Its efficacy in our sub‐erythrodermic psoriasis was not completely satisfactory, but other treatments were contraindicated for the recurrent brain oligodendroglioma. Further studies are warrant to explore the intriguing immune modulating activities of this very manageable drug. Acknowledgement The patient in this manuscript has given written informed consent to the publication of his case details. Funding source none.

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          The cytokine release syndrome (CRS) of severe COVID-19 and Interleukin-6 receptor (IL-6R) antagonist Tocilizumab may be the key to reduce the mortality

          Highlights • Pathogenesis of cytokine release syndrome in severe COVID-19 patients • The key role of IL-6 in cytokine release syndrome • Propose possible drugs IL-6R antagonist Tocilizumab for severe COVID-19
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            COVID-19 and immunomodulator/immunosuppressant use in dermatology

            To the Editor: We read with great interest the Commentary by Lebwohl et al 1  recently published in the Journal of the American Academy of Dermatology. The authors provided a pertinent overview of infection risk associated with commonly used biologics to treat psoriasis in light of the current coronavirus disease 2019 (COVID-19) outbreak. We agree that this time has been particularly concerning for patients taking immunomodulators/immunosuppressants who are unsure of their risk for severe disease. In response to the previous commentary, the goal of this letter is to expand and provide the latest information about COVID-19 along with considerations for addressing patient concerns surrounding dermatology-related immunomodulator/immunosuppressant use. Theoretical data from previous coronavirus outbreaks has suggested a strong role for type I interferon, B-cell–released antibodies, tumor necrosis factor-α, and other cytokines in the viral immune response (Fig 1 ).2, 3, 4 Interleukin (IL) 17 cytokines are important for immune cell recruitment to infection sites to promote clearance, while also activating downstream cascades of cytokines and chemokines. 4 IL-1 promotes fever and the differentiation of T-helper cells to IL-17–producing T cells. Tumor necrosis factor-α promotes dendritic cell differentiation, leukocyte recruitment, and mediates fever. 4 Antibodies produced by plasma cells help to neutralize the virus, limit infection, and prevent future infections. Disruption of B-cell differentiation into plasma cells could limit antibody production. 3 Fig 1 COVID-19 viral immune response and targets of common dermatologic immunomodulators and immunosuppressants. (Left) (1) Person-to-person transmission of COVID-19 occurs though direct contact with respiratory secretions of infected individuals. 2 The virus invades host cells by binding to their receptors and fusing with the cell membrane. (2) It is hypothesized that once inside the body, the lung epithelial cells become the primary target, where the receptor binding domain of the virus spikes bind to angiotensin-converting enzyme 2 (ACE2) receptors of ACE2-expressing target cells. (3) Although not confirmed, it is believed the virus dampens the initial type 1 interferon (IFN) responses, which contributes to uncontrolled viral replication. (4) Once the virus is identified, macrophages present viral components to activate and induce (5) differentiation of T cells and B cells. (6) Activated B cells differentiate into plasma cells that produce antibodies important for neutralizing viruses. (7) The resulting inflammatory cytokines and antibodies continue to stimulate the production of additional cytokines and antibodies, which may contribute to the “cytokine storm” noted in those with severe disease. (8) The inflammatory cytokines and antibodies also promote the influx of neutrophils, monocytes, and macrophages along with additional inflammatory cytokines. (Right) The drug targets for common dermatologic immunomodulators and immunosuppressants have also been included in this diagram. FGF, Basic fibroblast growth factor; GCSF, granulocyte-colony stimulating factor; GMCSF, granulocyte-macrophage colony-stimulating factor; IL, interleukin; IP10, interferon γ-induced protein 10; IRF, interferon regulatory factor; MCP1, monocyte chemoattractant protein 1; MIP1A, macrophage inflammatory protein 1-α; NFAT, nuclear factor of activated T cells; NF-κB, nuclear factor-κB; PDE4, phosphodiesterase 4; PDGF, platelet-derived growth factor; PKA, protein kinase A; T H , T-helper cell; TNF, tumor necrosis factor; VEGFA, vascular endothelial growth factor A. Created with Biorender.com. Broad immunosuppression across multiple cytokine axes with immunosuppressants has the potential to increase susceptibility, persistence, and reactivation of viral infections. Immunosuppressants decrease cytokines that recruit and differentiate immune cells needed to clear the infection. In addition, inflammatory mediators can become hyperactivated, resulting in a “cytokine storm,” which is the primary cause of death in severe disease. 3 Whether withdrawal of broadly immunosuppressive therapies may increase the risk of precipitating cytokine storm is unknown. Therefore, classic immunosuppressants may present the most concerning risk for those affected by COVID-19 (Table I ). Immunomodulators, such as biologics, that do not target vital domains within the viral immune response may dampen, but not significantly affect viral clearance. Table I Considerations for commonly used immunomodulators and immunosuppressants for dermatologic conditions Drug class Mechanism of action Drug name Risk Comments/considerations∗ Classic immunosuppressants Inhibits NF-κB Corticosteroids Likely concerning risk Consider stopping when viral symptoms present especially with known or potential exposure Calcineurin inhibitor Tacrolimus Cyclosporine  Antimetabolites Inhibits DNA replication Mycophenolate mofetil Azathioprine Methotrexate Immunomodulators  Monoclonal antibodies TNF-α inhibition Infliximab Likely moderate risk Continue if viral symptoms are mild, consider stopping if viral symptoms worsen or high fever develops  Receptor fusion protein Etanercept  Monoclonal antibodies Certolizumab  Monoclonal antibodies Adalimumab  IL receptor modulators IL inhibition Anakinra (IL-1)  Monoclonal antibodies Dupilumab (IL-4) Likely low risk Continue unless severe symptoms present  Monoclonal antibodies Brodalumab (IL-17) Likely moderate risk Continue if viral symptoms are mild, consider stopping if viral symptoms worsen or high fever develops  Monoclonal antibodies Secukinumab (IL-17a)  Monoclonal antibodies Ixekizumab (IL-17a)  Monoclonal antibodies Ustekinumab (IL-12/23)  Monoclonal antibodies Guselkumab (IL-23)  Monoclonal antibodies Anti-CD20 antibody Rituximab Likely concerning risk Consider stopping when viral symptoms present especially with known or potential exposure. PDE4 inhibition Apremilast Likely low risk Continue unless severe symptoms present IL, Interleukin; NF-κB, nuclear factor κB; PDE4, phosphodiesterase 4. ∗ General considerations only, medication use should be considered based on each individual patient's risk and disease profile. Currently, there are no data describing the benefits or risks of stopping immunomodulators/immunosuppressants during the COVID-19 outbreak. However, each medication's mechanism of action, administration method/frequency, and pharmacokinetics/pharmacodynamics are important to consider. Nonbiologic medications, including small molecule inhibitors and immunosuppressants, are typically easier to stop and restart within days to weeks due to shorter half-life. Meanwhile, biologics generally have a longer half-life and include a risk of antidrug antibody formation with treatment cessation and subsequent continuation. However, biologics also tend to be more targeted and less involved in the previously mentioned components of the viral immune response. General medication considerations are included in Table I. Although patient dependent, clinicians may consider weaning patients with stable disease off of immunosuppressants. Shared decision making is needed when deciding on a treatment plan that includes immunomodulators/immunosuppressants during the COVID-19 outbreak. Patients with existing comorbidities may require more conservative measures. 5 Physicians should continue to consult with the Centers for Disease Control and Prevention Information for Healthcare Providers, which is updated daily (https://www.cdc.gov/coronavirus/2019-nCoV/hcp/index.html). Once again, we thank the authors for raising awareness of patient concerns during this evolving outbreak.
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              Dermatologists and SARS‐CoV‐2: The impact of the pandemic on daily practice

              Abstract Since the first case of “pneumonia of unknown aetiology” was diagnosed at the Wuhan Jinyintan Hospital in China on 30 December 2019, what was recognised thereafter as “severe acute respiratory syndrome coronavirus 2” (SARS‐CoV‐2) has spread over the four continents, causing the respiratory manifestations of Coronavirus disease‐19 (COVID‐ 19) and satisfying the epidemiological criteria for a label of “pandemic.” The ongoing SARS‐CoV‐2 pandemic is having a huge impact on dermatological practice including the marked reduction of face‐to‐face consultations in favour of teledermatology, the uncertainties concerning the outcome of COVID‐19 infection in patients with common inflammatory disorders such as psoriasis or atopic dermatitis receiving immunosuppressive/immunomodulating systemic therapies; the direct involvement of dermatologists in COVID‐19 care for patients assistance and new research needs to be addressed. It is not known yet, if skin lesions and derangement of the skin barrier could make it easier for SARS‐CoV‐2 to transmit via indirect contact; it remains to be defined if specific mucosal or skin lesions are associated with SARS‐CoV‐2 infection, although some unpublished observations indicate the occurrence of a transient varicelliform exanthema during the early phase of the infection. SARS‐CoV‐2 is a new pathogen for humans that is highly contagious, can spread quickly, and is capable of causing enormous health, economic and societal impacts in any setting. The consequences may continue long after the pandemic resolves, and new management modalities for dermatology may originate from the COVID‐19 disaster. Learning from experience may help to cope with future major societal changes.
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                Author and article information

                Contributors
                atzoril@unica.it
                Journal
                J Eur Acad Dermatol Venereol
                J Eur Acad Dermatol Venereol
                10.1111/(ISSN)1468-3083
                JDV
                Journal of the European Academy of Dermatology and Venereology
                John Wiley and Sons Inc. (Hoboken )
                0926-9959
                1468-3083
                04 June 2020
                : 10.1111/jdv.16625
                Affiliations
                [ 1 ] Dermatology Clinic Department of Medical Sciences and Public Health University of Cagliari Cagliari Italy
                Author notes
                [*] [* ] Correspondence: L. Atzori. E‐mail: atzoril@ 123456unica.it

                Author information
                https://orcid.org/0000-0002-8105-1402
                https://orcid.org/0000-0002-2227-581X
                Article
                JDV16625
                10.1111/jdv.16625
                7272987
                32385859
                4e453da8-2566-4533-9e38-4a5055fe0af7
                © 2020 European Academy of Dermatology and Venereology

                This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.

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                Figures: 2, Tables: 0, Pages: 2, Words: 2893
                Categories
                Letter To The Editor
                Letters to the Editor
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                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.3 mode:remove_FC converted:05.06.2020

                Dermatology
                Dermatology

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