key: cord-0828576-dwwwvlpx authors: Schwartz, Robert A.; Pradhan, Swetalina; Murrell, Dedee F.; Jafferany, Mohammad; Olisova, Olga Yu.; Lomonosov, Konstantin M.; Lotti, Torello; Goldust, Mohamad title: COVID‐19 and Immunosuppressive therapy in Dermatology date: 2020-08-07 journal: Dermatol Ther DOI: 10.1111/dth.14140 sha: 0724dbba2a9ce0dabc4a8f946ea0f38995762328 doc_id: 828576 cord_uid: dwwwvlpx Coronavirus 2019 (COVID 19) was first detected in December 2019 in China. It has become a pandemic. With concern about therapies that may decrease immunity and enhance the severity of an indivduals's COVID‐19 infection, leading to a possibly fatal outcome, use of immunosuppressants has become an important concern. This work focuses on management of various skin diseases individuals lacking immunity to COVID‐19 but requiring a systemic immunosuppressant, keeping in view the challenge of the COVID 19 pandemic and that our knowledge of this virus and its effects on the immune system are incomplete including knowledge as to an individual's immunity after COVID‐19 infection. This article is protected by copyright. All rights reserved. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-Cov-2)-infection, delineated as COVID 19 , was first detected in December 2019. 1,2 On 11 March 2020 World Health Organization (WHO) declared COVID 19 as pandemic. 3, 4 There have been many proposed theories on the effect of this SARS-Cov-2 virus on the human immune system. In general low immunity allows rapid viral replication and delays viral clearance from the body. The amount of viral load is likely directly proportional to the damage to the organs, specifically lungs (Ref) . However, there is much to be learned about this specific virus and its effect upon and interaction with the immune system. We do know that many millions worldwide will get This article is protected by copyright. All rights reserved. COVID-19, a tiny percentage representing a huge of number of individuals will have a fatal outcome while the world awaits effective therapy or vaccination or the development of herd immunity. Various risk factors contributing to severe damage and mortality in COVID 19 patients include old age, obesity, diabetes mellitus, cancer and cardiovascular co-morbidities. 5 Many diseases in dermatology require immunosuppressants for treatment. They are usually given with proper monitoring of different blood parameters regularly. However, in the current scenario of COVID 19 pandemic, there have been a dilemma among dermatologists how to tackle the dermatological problems requiring immunosuppressive therapy because of the effects of drugs on immunity and the difficulty in regular monitoring blood parameters due to movements restrictions and safety concerns. The immunosuppressants have been categorized according to risk profile of COVID 19, taking into account their effect on body immunity. 6 The drugs with low risk are sulfasalazine, apremilast and hydroxychloquine, whereas methotrexate and azathioprine have intermediate risk. High risk drugs include cyclophosphamide, cyclosporine, leflunomide, mycophenolate mofetil, prednisolone and biologics. 3 The immunosuppressive drugs azathioprine, cyclosporine, cyclophosphamide and mycophenolate mofetil take 3 months for wash out from body. 7 Details of pharmacokinetics of biologic and non-biologic drugs have been discussed in In various studies regarding live vaccination in rheumatology patients on immunosuppressive therapy, recommendations have been made regarding delay of live vaccination depending on This article is protected by copyright. All rights reserved. specific immunosuppressant. [8] [9] [10] According to the recommendation, live vaccines should be delayed for at least: • 5 half-lives after the administration of biological agents or disease-modifying drugs (3-12 months), • 4 weeks after high-dose corticosteroid therapy (≥20 mg/day prednisone or equivalent, for longer than 2 weeks), Low-dose immunosuppressive therapy has been found to be relatively safe without increasing infection risk. 8, 9 Low-dose immunosuppressive therapy is defined as follows: • Low-dose corticosteroid (<20 mg/day of prednisone or equivalent, short or long term or alternating days), • Low-dose methotrexate (<0.4 mg/kg/week or <20 mg/week), • Low-dose azathioprine (<3 mg/kg/day), • Low-dose 6-mercaptopurine (<1.5 mg/kg/day) This article is protected by copyright. All rights reserved. Among all methotrexate, cyclosporine and retinoids are widely practised by dermatologists. Recently different biologicals targeting different pathways of disease are in market. Apremilast is the only oral biological approved for psoriasis; others are either given subcutaneously or intravenously. 11 Looking at current COVID 19 pandemic the treatment of psoriasis is individualized in different scenarios. a. New case: Start with topical corticosteroid or calcipotriol along with emollients. This article is protected by copyright. All rights reserved. b. Old case on systemic immunosuppressive: Stop systemic treatment and maintain on topicals and emollients. Advise the patient to stay at home for at least 3 months without any outside movement. Maintain proper hand hygiene. Discuss the risk and benefits of before starting treatment. If no contact history with COVID 19, healthy young adult without any other comorbidities can be started with apremilast with or without hydroxychloroquine and symptomatic treatment with NSAIDS for joint pain at least three months. The patient can be in touch over phone to avoid frequent visit to medical office or hospital. Systemic Acetretin with emollients The patient usually needs to be admitted for intravenous fluid support. Treatment may commence with acetretin/apremilast or a combination of these. If there is no response considering the disease severity patient can be shifted to cyclosporin/methotrexate after discussing the risk and benefits with the patient. Patient should use normal surgical mask 24 hour including the health care workers. Proper hand hygiene should be maintained by the patient. After discharge patient should stay confined in home or home quarantine for at least three months. This article is protected by copyright. All rights reserved. It is believed that proactive biologic discontinuation could lead to treatment failure via formation of anti-drug antibodies. Psoriasis, being a chronic disease, needs long term treatment and hence stoppage of biologic treatment would cause worsening of disease, increase the hospital visits and have negative psychological effects in COVID pandemic time. Psychological stress will again aggravate the disease. Due to chance of failure of biologic because of anti-drug antibody formation, the cost of treatment will increase in future due to of biologic switching. 12 Also, it is hypothesized that stoppage of biologic will lead to higher pro-inflammatory states and could worsen the cytokine storm in COVID 19 affected patients. 13 Therefore, discontinuation of biologics to prevent COVID 19 infection should be personalized. Pemphigus vulgaris produces painful oral and skin erosions that can be sources of entry to infectious organisms. If the patient is not treated, the severity of pemphigus may increase, making the patient more vulnerable to secondary infection and possible sepsis. Currently the CDC is advising maintenance of proper hand hygiene, avoidance of fomite contact to prevent transmission of COVID 19. However eroded skin being as a risk factor for COVID 19 is unknown. To prevent disease progression and possible sepsis, pemphigus patients need treatment with options mostly immunosuppressive. Systemic corticosteroids are considered first line drugs. Others medications useful are rituximab, cyclophosphamide, azathioprine, and mycophenolate mofetil. Intravenous immunoglobulin and plasmapheresis can also be tried. 14 The treatment of pemphigus vulgaris will vary depending upon the situations. However, it is advised to maintain immunomodulatory This article is protected by copyright. All rights reserved. therapy when needed since unjustified withdrawal could lead to uncontrolled disease activity resulting in high morbidity and mortality. 15 The patients needs to be admitted. Proper skin care with barrier dressings. In addition to oral corticosteroids at 1mg/kg/day, intravenous immunoglobulin can be considered rather than starting conventional immunosuppression. .If CDA is achieved, slow tapering of the GCD may proceed. Where IVIG is not available, conventional immunosuppression such as MMF may be given as well. Under pre-COVID-19 times, rituximab would have been the first choice but given its irreversible long term immunosuppression and precautions around viral infections, it is not advised to be started at present. 16 Patients need to use masks 24 hours during hospital stay and at home. After discharge patients need to remain home-quarantined for three months and follow up with teledermatology, ideally. The only to visits to the hospital should be if the disease flares up. If no skin lesions, DCP can be withheld during the COVID 19 pandemic and the patient can be started with prednisolone <20mg/day. Oral cyclophosphamide also needs to be stopped because the combination of oral steroid and cyclophosphamide will cause more immunosuppression. This article is protected by copyright. All rights reserved. Once the disease is controlled taper prednisolone rapidly to < 20mg/day prednisolone. Ideally, avoid other immunosuppressants. If the disease remains uncontrolled IVIg can be added if feasible. If disease is not controlled on <0.2mg/kg/day, consider entry into a phase 3 RCT which is enrolling globally with a short acting reversible BTK inhibitor vs placebo, the PEGASUS trial (NCT02704429). BTK inhibitor PRN1008 works via reversible covalent binding and therefore has a self-limited immunomodulatory effect. Start with low dose corticosteroid <20 mg/day prednisolone for< 2weeks followed by stoppage and maintain with topicals. After stopping systemic treatment patients should be supplied with ample topical therapy, and guidance on the amount needed to prevent flares until systemic therapy can be reinstated. Judicious use of emollients and antihistamines. Patients to be in home quarantine for three months. Low dose methotrexate <20 mg/week can also be given. Short course oral corticosteroid for< 2 weeks followed by stoppage and maintain with topicals with judicious use of emollient and antihistamine. Steven Johnson Syndrome and Toxic epidermal necrolysis: Various treatments including corticosteroids, cyclosporine, tacrolimus, intravenous immunoglobulin and plasmapheresis haven tried in SJS/TEN, none of which have proven efficacy 22 , with systemic steroids and oral cyclosporine being used most widely. 23 However in the current scenario of COVID 19 pandemic, options are being reevalauted with intravenous immunoglobulin beign preferred treatment to arrest the activity of disease. Another promising alternative is plasmapheresis. This article is protected by copyright. All rights reserved. Dermatomyositis may produce severe muscle inflammation or myositis leading to severe muscle pain, weakness and sometimes dysphagia, dysphonia, and dyspnea due to weakened esophageal and respiratory muscles. 24 High dose oral prednisone may be initiated early to improve muscle weakness. 25, 26 The dose of prednisolone varies between 0.5 and 2 mg/kg/day for initial treatment. 27 In situations where prednisone cannot be used, second-line agents such as methotrexate and azathioprine may be appropriate. Rituximab, intravenous immunoglobulin (IVIG), and other biologics are useful in those who developed resistance to therapy. In patients experiencing steroid-related toxicity, a steroid-sparing agents such as methotrexate, azathioprine, cyclophosphamide, cyclosporine, mycophenolate mofetil, leflunomide, chlorambucil, and tacrolimus can be tried. 28 Though corticosteroids are first line treatment, to avoid immunosuppression because of risk of COVID 19, intravenous immunoglobulin should be considered first choice. After control of myositis low dose immunosuppressive therapy can be started. This article is protected by copyright. All rights reserved. Corticosteroids need to be tapered off and other immunosuppressive to be stopped. Treatment of dermatologic disorders requiring a long term immunosuppressant is challenging at this point of time due to COVID 19 pandemic. In the absence of any effective treatment or vaccine for COVID 19 infection, lots of patients are losing their life. Hence, before giving treatment to any disease condition, physicians need to weigh the risk benefit ratio of giving immunosuppressive drug. It is advisable to consider other options. If immunosuppressive treatment is to be given, it should be with low dose and minimum duration. In addition, patients who do not have immunity to COVID 19 should take protection according to CDC guidelines and consider home quarantine as a member of a vulnerable population until there is effective vaccination or treatment or herd immunity has been reached. This article is protected by copyright. All rights reserved. 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