key: cord-0929076-u8h0py48 authors: Elmas, Ömer Faruk; DemirbaŞ, Abdullah; Kutlu, Ömer; BaĞcıer, Fatih; Metin, Mahmut Sami; Özyurt, Kemal; Akdeniz, Necmettin; Atasoy, Mustafa; Türsen, Ümit; Lotti, Torello title: Psoriasis and COVID 19: A narrative review with treatment considerations date: 2020-06-17 journal: Dermatol Ther DOI: 10.1111/dth.13858 sha: 95e3d284dd1ea1769182439db47e9d7546dd0fe1 doc_id: 929076 cord_uid: u8h0py48 COVID‐19 is a highly contagious respiratory infection caused by severe acute respiratory syndrome coronavirus 2. COVID‐19 outbreak, has been declared a pandemic by the World Health Organization on March, 2020. The pandemic has affected the management of psoriasis, not only for those who are under treatment but also for those who are about to begin a new therapy to control their disease. An increasing number of studies in the current literature have focused on the relationship between psoriasis and COVID 19 from different perspectives. This narrative review includes searching the PubMed and Web of Science databases using the keywords "psoriasis,”, “psoriatic arthritis”, "coronavirus", "COVID 19" and "SARS‐Cov‐2". The search was supplemented by manual searching of reference lists of included articles. A total of 11 relevant original investigations and 6 case studies was identified. The search was updated in May 2019. Due to the absence of randomized controlled trials, it is not likely to have a robust evidence‐based approach to psoriasis management in the era of COVID‐19. However, current literature may provide some clues for safety considerations. Conventional immunosuppressive therapies such as methotrexate and cyclosporine, and anti TNF agents should not be preferred due to increased risk of infection, especially in high‐risk areas. The use of cyclosporine may pose additional risk due to the side effect of hypertension, which has been reported to be associated with susceptibility to severe COVID‐19. Considering that current literature has provide no conclusive evidence that biologics increase the risk of COVID‐19, withdrawal of these agents should be reserved for patients with COVID 19 symptoms. The treatment approach should be personalized, considering the advantages and disadvantages for each case separately. This article is protected by copyright. All rights reserved. Psoriasis is a common chronic inflammatory skin disease associated with significant morbidity extending beyond the cutaneous manifestations 1 . The disease affects about 2-3% of the population worldwide, and its' management requires qualified professionals to provide highquality care. 2,3 COVID-19 is a highly contagious respiratory infection caused by severe acute respiratory syndrome coronavirus 2. COVID-19 outbreak, which caused thousands of deaths, has been declared a pandemic by the World Health Organization on March, 2020 4 . The pandemic has been reported to modify the course of many diseases, and psoriasis is not exempt from the impact of the outbreak 5, 6 . This narrative review includes searching the PubMed and Web of Science databases using the keywords "psoriasis,", "psoriatic arthritis", "coronavirus", "COVID 19" and "SARS-Cov-2". This article is protected by copyright. All rights reserved. The COVID 19 pandemic has altered the approach to all patients necessitating close contact during a visit, including dermatologic consultations. The health care system was overwhelmed in many countries, and many centers couldn't cope with the vast number of patients. Patients with psoriasis were not exempt from this situation and had only limited access to required health care settings in many countries. Many centers were able to maintain scheduled treatments for only selected patients 3 . Limited availability of dermatology care services caused exacerbation of pre-existing cases of psoriasis, while new cases failed to be diagnosed. "Stay at home" orders issued by many authorities to limit the spread of the infection were another reason for fewer patients applying for outpatient services 7 . Emotional stress is another factor that may act as a catalyst for the onset and aggravation of psoriasis 8 . Kutlu and Metin suggested that the burden of stress prompted by the COVID-19 pandemic might raise the number of psoriasis cases demanding dermatology visits 9 . A recent web-based study investigating the association of outdoor activity restriction and income loss with patient-reported outcomes of psoriasis during the COVID-19 pandemic showed that 43.7% of 926 patients described moderate-to-much worsening of psoriasis. Outdoor activity limitation was found to be positively correlated with the worsening of psoriasis, stress, and anxiety and depression. Likewise, income loss was associated with the exacerbation of psoriasis, stress, and anxiety and depression 10 . Maximizing the psycho-social support available to patients with psoriasis during the pandemic may play a significant role in controlling disease activity. This article is protected by copyright. All rights reserved. Patients with COVID 19 may show characteristics of hyperinflammation caused by the overproduction of cytokines. Biomarkers of inflammation such as C-reactive protein and ferritin have been found significantly elevated in patients with Covid-19 11 . Given the crucial role of inflammation in the pathogenesis of psoriasis, it can be suggested that hyperinflamation status caused by COVID-19 may also alter the course of psoriasis. In their series of 52 patients, Kutlu and Metin found that 9.6% of patients with COVID-19 who were previously admitted to the dermatology outpatient clinic had psoriasis. They concluded that patients with psoriasis may be more vulnerable to COVID 19 9 . Ozaras et al reported a case of psoriasis worsened possibly due to COVID 19. The authors implied that hyperinflamation status generated by COVID 19 itself might exacerbate psoriasis. 12 At this time there are no medications that have been proven to be effective for the prevention or treatment of COVID-19. However, various antiviral agents, immunotherapies, and vaccines continue to be investigated as potential therapeutics. Hydroxychloroquine has been licensed since 1955 for the prevention and treatment of malaria 13 . The studies suggest that HCQ may have antiviral effects. Notwithstanding the absence of obvious evidence, Food and Drug Administration (FDA) allowed emergency use of HCQ in hospitalized patients without alternative treatment options 14 . Psoriasis has been reported to be induced or aggravated by HCQ. Most recently, Kutlu and Metin reported a 71-year-old patient with COVID-19 to have an aggravation of pre-existing psoriasis following HCQ and oseltamivir administration 5 . Although the precise causes of this effect are not entirely understood, it has been reported that HCQ may increase the production of IL-17 resulting in This article is protected by copyright. All rights reserved. A single-blind, randomized-controlled study has shown that azithromycine may be a potential therapeutic option for chronic plaque psoriasis via its effects on superantigen producing Group A streptococcus, and by its possible immunomodulatory effect on epidermal langerhans cells and keratinocytes 18 . In another study, Huang et al found that azithromycin inhibits TLR7 signaling in dendritic cells and improves the imiquimod-induced Psoriasis-like cutaneous inflammation in mice 19 . It can be hypothesized that the use of azithromycin in COVID 19 cases with pre-existing psoriasis may alleviate psoriatic lesions. However, it is obvious that more observations and prospective studies are needed to confirm or reject this hypothesis. Acitretin Acitretin has anti-inflammatory properties and inhibits cell differentiation without immunosuppressive effects. In their cohort study, Dommasch et al found that patients with psoriasis on acitretin treatment showed no increased risk of viral or respiratory infection 20 . Caselli et al showed that retinoids may have antiviral effects on human herpesvirus 21 . The effects of retinoids on SARS-Cov-2 remains unknown. Although acitretin has not been proven safe in patients with COVID-19, it can be preferred during the pandemic because it has no immunosuppressive effects. Both methotrexate and cyclosporine are associated with an increased risk of infection. The overall frequency of contracting pneumonia in patients with psoriasis using methotrexate has been reported to be 0.8% 22 Unexpectedly, Wilde AH reported that cyclosporine strongly inhibits in-vitro replication of MERS-coronavirus, while its in-vivo effects remain unknown 24 . Despite the impact of these immunosuppressive agents on the course of COVID-19 is clearly unknown, several dermatology societies have recommended to withdrawn or suspend immunosuppressive treatments in the case of COVID-19 diagnosis till the patient recovers from the infection. However, the decision has been left to the cooperation between the patient and physician in charge, considering the advantages/disadvantages for each case separately 25, 26 . This article is protected by copyright. All rights reserved. Biologics inhibit immune-mediated pathways including distinct cytokines. Therefore, they may pose a possible risk of enhanced sensitivity to infections. However, there is no clear evidence supporting the withdrawal of biologics for most patients with psoriasis due to the risk of infection. Some authors have not recommended the withdrawal of TNFα inhibitors and anti-IL biologics due to "likely moderate risk" in the case of mild viral symptoms 27 31 . In a cross-sectional, questionnairebased study, the authors found that COVID 19 knowledge prevents biologics discontinuation. This article is protected by copyright. All rights reserved. avoid their loss of compliance 32 . In a multicenter study, the authors reported that 23 patients with psoriasis on biologics had COVID-19 symptoms but they did not stop treatment. The authors did not observe a more severe course of suspected COVID-19 signs in patients who maintained treatment 33 The patient was completely asymptomatic, although he continued the treatment as previously scheduled 37 . Considering the interference of IL-17/23 pathway may have beneficial outcomes in COVID -19, ixekizumab is being investigated for the treatment of COVID -19 infection 36 . In a large cohort study including 1193 patients with psoriasis on biologics and small molecules, the authors found that patients on biologics were at greater risk to test positive for COVID-19 and to be hospitalized. However, they reported no increased risk of intensive care unit admission or death 38 . In a retrospective multicenter study including 206 patients with psoriasis This article is protected by copyright. All rights reserved. on biologics, the authors found no significant number of hospitalizations or deaths from COVID-19 39 . In another retrospective study, including 980 patients with psoriasis on biologics, the authors have found no early signal of an increased hospitalization or death from COVID-19 40 . Finally, in a telephone consultation-based study including 168 patients with psoriasis on biologics, the authors did not observe a high frequency of COVID-19 or related symptoms 41 . Current literature has shown no conclusive evidence that biological agents increase the risk of COVID-19. Therefore, preventive withdrawal of treatment should be avoided and reserved for patients with COVID 19 symptoms. The cessation of biologics may also be considered for patients having contact with a confirmed case of COVID-19. Unnecessary biologic withdrawal may cause a worsening of psoriasis, increased disease burden, unfavorable impact on the quality of life, and raised health care costs. Moreover, the subsequent return to biologic therapeutics can be related to switching toward more expensive drugs because of the limited efficiency of biologics in the same patient after their interruption 42 . Psoriasis and psoriatic arthritis (PsA) share many treatments, including methotrexate, biologics, small molecules, and cyclosporine. Valenti et al described a case of psoriasis and PsA managed with adalimumab every two weeks for about two years, that rapidly recovered from COVID- Although there is a slight risk of infections with these therapies, many rheumatologic societies including European League Against Rheumatism, and American College of Rheumatology are against the improper withdrawal of immunosuppressants and immunomodulatory therapies for PsA due to the risk of disease flare which may be associated with more adverse events than the treatment itself. Exacerbation of PsA may induce systemic inflammation and immunological disturbance which are responsible for increased sensitivity to infections in the setting of systemic polyarthritis. Moreover, an active disorder requires a medical reassessment, which is best to be avoided during the pandemic due to the higher risk of contamination in the hospital. On the other hand, if any symptoms suggestive of COVID 19 occur, the discontinuation of immunosuppressive and immunomodulatory therapies should be considered on a case by case basis 44 . It should be noted that almost all available data originate from the pre-COVID-19 area and they should be interpreted with caution 45 . Nonsteroid anti-inflammatory agents are also frequently used in PsA. WHO announced that there is no evidence of any relationship between the use of nonsteroid anti-inflammatory agents and COVID-19 mortality. Until more data is available, nonsteroid anti-inflammatory agents shoud not be discontinued in patients with PsA 46 . The COVID 19 pandemic has negatively affected the management of many diseases, and psoriasis is not exempt from this situation. Patients' inability to access adequate health care services and stress burden caused exacerbations in psoriasis cases. We believe that it is essential to closely monitor patients with psoriasis and provide alternative health care tools, such as telephone consultations and teledermatology, when necessary. Providing psycho-social support to the patients and their families may also have beneficial effects in controlling the disease activity. We recommend that classical immunosuppressive agents such as methotrexate, This article is protected by copyright. All rights reserved. cyclosporin, and TNF alpha inhibitors should be avoided especially in high-risk areas. Considering that current literature has provide no conclusive evidence that biologics increase the risk of COVID-19, withdrawal of these agents should be reserved for patients with COVID 19 symptoms. 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