INTRODUCTION
While the world lives under the shadow of the novel coronavirus (COVID-19) pandemic, dermatologists wonder if the current situation calls for a temporary change in the management of skin conditions.
Immunosuppressive drugs are used ubiquitously in the modern treatment of inflammatory and autoimmune skin diseases like psoriasis, bullous diseases, connective tissue diseases, and many others. Treatment of these conditions is based on the suppression of the patient's immune system using steroids, steroid-sparing drugs, and biological agents.1
While the effects of the novel coronavirus on the body and its immune system are still being studied, there is overwhelming evidence that the virus could directly or indirectly affect the immune system. In one study, lymphocytopenia was reported in 83.2% of the admitted patients and might be associated with a worse prognosis.2 In another study, a steady decline in the lymphocyte counts was recorded in a group of patients who did not survive the infection.3
While the coexisting comorbid medical conditions (such as diabetes or heart disease) are considered as independent predictors of an adverse outcome of the novel coronavirus infection,4 it could be assumed that the chronic inflammatory and autoimmune skin diseases like psoriasis by themselves might imply an additional risk factor of developing more serious symptoms of the novel virus due to their chronicity and effects on the immune system.5
The use of immunosuppressive to treat these conditions can amplify this effect, and it might leave the patient vulnerable to more serious complications should an infection with the novel coronavirus be established. Hence, it may be wise to restrict temporarily the use of immunosuppressive agents including systemic steroids, steroid-sparing agents, and biologics in dermatology daily practice until more evidence is available about their safety in the current pandemic.6 As a relates point, the International Psoriasis Council declared an urgent statement on March 11, 2020 that the physician should be alert to the potentially harmful effects of COVID-19 infection on patients with psoriasis and to immediately discontinue or postpone immunosuppressant medications for psoriasis patients diagnosed with COVID-19 disease.7
Immunosuppressive drugs are used ubiquitously in the modern treatment of inflammatory and autoimmune skin diseases like psoriasis, bullous diseases, connective tissue diseases, and many others. Treatment of these conditions is based on the suppression of the patient's immune system using steroids, steroid-sparing drugs, and biological agents.1
While the effects of the novel coronavirus on the body and its immune system are still being studied, there is overwhelming evidence that the virus could directly or indirectly affect the immune system. In one study, lymphocytopenia was reported in 83.2% of the admitted patients and might be associated with a worse prognosis.2 In another study, a steady decline in the lymphocyte counts was recorded in a group of patients who did not survive the infection.3
While the coexisting comorbid medical conditions (such as diabetes or heart disease) are considered as independent predictors of an adverse outcome of the novel coronavirus infection,4 it could be assumed that the chronic inflammatory and autoimmune skin diseases like psoriasis by themselves might imply an additional risk factor of developing more serious symptoms of the novel virus due to their chronicity and effects on the immune system.5
The use of immunosuppressive to treat these conditions can amplify this effect, and it might leave the patient vulnerable to more serious complications should an infection with the novel coronavirus be established. Hence, it may be wise to restrict temporarily the use of immunosuppressive agents including systemic steroids, steroid-sparing agents, and biologics in dermatology daily practice until more evidence is available about their safety in the current pandemic.6 As a relates point, the International Psoriasis Council declared an urgent statement on March 11, 2020 that the physician should be alert to the potentially harmful effects of COVID-19 infection on patients with psoriasis and to immediately discontinue or postpone immunosuppressant medications for psoriasis patients diagnosed with COVID-19 disease.7
CONCLUSION
As the declaration of the novel coronavirus as a pandemic by the WHO is a trending topic nowadays, dermatologists around the world view with concern the impact of this pandemic on their daily practice.
While there is no overwhelming evidence for this recommendation, as the novel coronavirus seems to specifically target the immunity, and as the people with weak immunity are vulnerable to get more fatal outcomes, it is highly recommended to temporarily avoid the unnecessary use of immunosuppressive agents and use more conservative alternatives, unless they are used as a life-saving measure.
While there is no overwhelming evidence for this recommendation, as the novel coronavirus seems to specifically target the immunity, and as the people with weak immunity are vulnerable to get more fatal outcomes, it is highly recommended to temporarily avoid the unnecessary use of immunosuppressive agents and use more conservative alternatives, unless they are used as a life-saving measure.
DISCLOSURE
The author has no relevant conflicts of interest.
REFERENCES
1. Leis-Dosil VM, Prats-Caelles I. Practical management of immunosuppressants in dermatology. Actas Dermo-Sifiliográficas (English Edition). 2018 Jan 1;109(1):24-34.
2. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H, Lei CL, Hui DS, Du B. Clinical characteristics of coronavirus disease 2019 in China. New Engl J Med. 2020 Feb 28. DOI: 10.1056/NEJMoa2002032
3. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, Zhao Y. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus–infected pneumonia in Wuhan, China. JAMA. 2020 Feb 7.
4. Munster VJ, Koopmans M, van Doremalen N, van Riel D, de Wit E. A novel coronavirus emerging in China—key questions for impact assessment. New Engl J Med. 2020 Feb 20;382(8):692-4.
5. Takeshita J, Grewal S, Langan SM, Mehta NN, Ogdie A, Van Voorhees AS, Gelfand JM. Psoriasis and comorbid diseases: implications for management. J Am Acad Dermatol. 2017 Mar 1;76(3):393-403.
6. Conforti C, Giuffrida R, Dianzani C, Di Meo N, Zalaudek I. COVID-19 and psoriasis: is it time to limit treatment with immunosuppressants? A call for action. Dermatologic Therapy. 2020 Mar 11:e13298.
7. International Psoriasis Council, Statement on the Coronavirus (COVID-19) Outbreak, March 11, 2020. https://www.psoriasiscouncil.org/blog/Statement-on-COVID-19-and-Psoriasis.htm
2. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H, Lei CL, Hui DS, Du B. Clinical characteristics of coronavirus disease 2019 in China. New Engl J Med. 2020 Feb 28. DOI: 10.1056/NEJMoa2002032
3. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, Zhao Y. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus–infected pneumonia in Wuhan, China. JAMA. 2020 Feb 7.
4. Munster VJ, Koopmans M, van Doremalen N, van Riel D, de Wit E. A novel coronavirus emerging in China—key questions for impact assessment. New Engl J Med. 2020 Feb 20;382(8):692-4.
5. Takeshita J, Grewal S, Langan SM, Mehta NN, Ogdie A, Van Voorhees AS, Gelfand JM. Psoriasis and comorbid diseases: implications for management. J Am Acad Dermatol. 2017 Mar 1;76(3):393-403.
6. Conforti C, Giuffrida R, Dianzani C, Di Meo N, Zalaudek I. COVID-19 and psoriasis: is it time to limit treatment with immunosuppressants? A call for action. Dermatologic Therapy. 2020 Mar 11:e13298.
7. International Psoriasis Council, Statement on the Coronavirus (COVID-19) Outbreak, March 11, 2020. https://www.psoriasiscouncil.org/blog/Statement-on-COVID-19-and-Psoriasis.htm
AUTHOR CORRESPONDENCE
Mohammed Shanshal MBChB FABMS Doctor.dermatology30@yahoo.com
Response: Is the Coronavirus (COVID-19) Pandemic an Indication to Temporarily Modify Dermatological Management Plans?
We should all be concerned about the impact of COVID-19 on our patients and should examine the potential impact of the drugs we use on susceptibility to infection and severity of infection.
We do not believe that we can lump all drugs together under the category of “immunosuppressive.†In fact, we run the risk of harming our patients if we tell them to stop all biologic therapies. Dupilumab is the perfect example. It should not be called an immunosuppressive agent and in fact, in the package insert it is referred to as an immunotherapy. The word “immunosuppressive†(or the word “viralâ€) does not appear in its package insert. In a study from our lab, dupilumab reduced the elevated levels of IL-4 found in lesional skin of patients with atopic dermatitis to levels found in non-lesional skin, and there is no evidence that it reduces cytokines to levels below normal.1 Moreover, many of our patients with atopic dermatitis also have asthma, which should be considered a risk factor for severe COVID-19 infection, and asthma is also treated effectively by dupilumab. Withholding that treatment may be detrimental. Omalizumab is also used to treat asthma and similar concerns should be considered.
We do not have any data on whether biologic therapies for psoriasis render patients more susceptible to COVID-19 infection. We do, however, have data from placebo-controlled pivotal trials on the occurrence of upper respiratory tract infections in patients on all of the approved biologic therapies for psoriasis.2 A recent review of these showed only small numbers of infections that did not differ substantially from the placebo rates. Numbers were slightly higher for TNF blockers (although not for etanercept), which do carry boxed warnings on risk of infection. Boxed warnings regarding infection do not appear for antibodies to IL-12/23, IL-23, or IL-17 or for apremilast or acitretin. Methotrexate and cyclosporine are certainly immunosuppressive and do carry boxed warnings. Ustekinumab, which blocks both IL-23 and IL-12, does not show an increase in respiratory tract infections, but it should be pointed out that IL-12 plays an important role in immunity to viral infections. Nonetheless, the PSOLAR registry, which followed patients on ustekinumab and other psoriasis treatments for years, showed the lowest incidence rate of serious infections in patients treated with ustekinumab compared to all other therapies or to patients not on methotrexate or biologic therapies.3 Discontinuing biologic therapies does have some drawbacks other than recurrence of psoriasis. If patients are doing well and hold their therapy until their disease recurs, the response is not always recaptured in retreated patients. For example, if certolizumab pegol is discontinued and responders are retreated upon recurrence of the disease, 13.5% to 32.4% of responders lose their PASI-75 response on retreatment.4 The same data showing a reduction in response exists for many, if not most of the biologics used to treat psoriasis and atopic dermatitis. Furthermore, severe psoriasis including erythrodermic psoriasis can be debilitating and could constitute a risk factor for worse outcomes.5
We must apply common sense to every patient scenario. At Mount Sinai, we do not routinely discontinue dupilumab, omalizumab, or IL-17 or IL-23 blockers. We have offered many of our patients on TNF-blockers the opportunity to switch to other treatments, but every patient must be considered individually. For example, one of our patients, a 28-year-old female of childbearing potential who is not at high risk because of her age and health, opted to stay on certolizumab pegol. Her psoriasis and psoriatic arthritis responded very well, and she was comfortable on this drug because, if she were to become pregnant, it would not cross the placenta. In our view, that was a reasonable decision. The point is that every patient’s circumstance is different and must be handled on a case by case basis. Across the board, discontinuation of all biologic therapies for all dermatology patients could do more harm than good despite the hazards of COVID-19 infection. In fact, the increased systemic inflammation that the patients with AD and psoriasis may experience upon discontinuation of their drugs may put them in increased risk of complications of COVID-19 infection and associated morbidities such as asthma exacerbation.
Mark Lebwohl MD and Emma Guttman-Yassky MD PhD Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY
We do not believe that we can lump all drugs together under the category of “immunosuppressive.†In fact, we run the risk of harming our patients if we tell them to stop all biologic therapies. Dupilumab is the perfect example. It should not be called an immunosuppressive agent and in fact, in the package insert it is referred to as an immunotherapy. The word “immunosuppressive†(or the word “viralâ€) does not appear in its package insert. In a study from our lab, dupilumab reduced the elevated levels of IL-4 found in lesional skin of patients with atopic dermatitis to levels found in non-lesional skin, and there is no evidence that it reduces cytokines to levels below normal.1 Moreover, many of our patients with atopic dermatitis also have asthma, which should be considered a risk factor for severe COVID-19 infection, and asthma is also treated effectively by dupilumab. Withholding that treatment may be detrimental. Omalizumab is also used to treat asthma and similar concerns should be considered.
We do not have any data on whether biologic therapies for psoriasis render patients more susceptible to COVID-19 infection. We do, however, have data from placebo-controlled pivotal trials on the occurrence of upper respiratory tract infections in patients on all of the approved biologic therapies for psoriasis.2 A recent review of these showed only small numbers of infections that did not differ substantially from the placebo rates. Numbers were slightly higher for TNF blockers (although not for etanercept), which do carry boxed warnings on risk of infection. Boxed warnings regarding infection do not appear for antibodies to IL-12/23, IL-23, or IL-17 or for apremilast or acitretin. Methotrexate and cyclosporine are certainly immunosuppressive and do carry boxed warnings. Ustekinumab, which blocks both IL-23 and IL-12, does not show an increase in respiratory tract infections, but it should be pointed out that IL-12 plays an important role in immunity to viral infections. Nonetheless, the PSOLAR registry, which followed patients on ustekinumab and other psoriasis treatments for years, showed the lowest incidence rate of serious infections in patients treated with ustekinumab compared to all other therapies or to patients not on methotrexate or biologic therapies.3 Discontinuing biologic therapies does have some drawbacks other than recurrence of psoriasis. If patients are doing well and hold their therapy until their disease recurs, the response is not always recaptured in retreated patients. For example, if certolizumab pegol is discontinued and responders are retreated upon recurrence of the disease, 13.5% to 32.4% of responders lose their PASI-75 response on retreatment.4 The same data showing a reduction in response exists for many, if not most of the biologics used to treat psoriasis and atopic dermatitis. Furthermore, severe psoriasis including erythrodermic psoriasis can be debilitating and could constitute a risk factor for worse outcomes.5
We must apply common sense to every patient scenario. At Mount Sinai, we do not routinely discontinue dupilumab, omalizumab, or IL-17 or IL-23 blockers. We have offered many of our patients on TNF-blockers the opportunity to switch to other treatments, but every patient must be considered individually. For example, one of our patients, a 28-year-old female of childbearing potential who is not at high risk because of her age and health, opted to stay on certolizumab pegol. Her psoriasis and psoriatic arthritis responded very well, and she was comfortable on this drug because, if she were to become pregnant, it would not cross the placenta. In our view, that was a reasonable decision. The point is that every patient’s circumstance is different and must be handled on a case by case basis. Across the board, discontinuation of all biologic therapies for all dermatology patients could do more harm than good despite the hazards of COVID-19 infection. In fact, the increased systemic inflammation that the patients with AD and psoriasis may experience upon discontinuation of their drugs may put them in increased risk of complications of COVID-19 infection and associated morbidities such as asthma exacerbation.
Mark Lebwohl MD and Emma Guttman-Yassky MD PhD Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY
REFERENCES
1. Guttman-Yassky E, Bissonnette R, Ungar B, et al. Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis. J Allergy Clin Immunol. 2019;143(1):155–172.
2. Lebwohl M, Rivera-Oyola R, Murrell DF. Should biologics for psoriasis be interrupted in the era of COVID-19? J Amer Acad Dermatol 2020, in press.
3. Kalb RE, Fiorentino DF, Lebwohl MG, et al. Risk of serious infection with biologic and systemic treatment of psoriasis: Results from the Psoriasis Longitudinal Assessment and Registry (PSOLAR). JAMA Dermatol. 2015;151:961–969.
4. Reich K, Ortonne JP, Gottlieb AB, et al. Successful treatment of moderate to severe plaque psoriasis with the PEGylated Fab' certolizumab pegol: results of a phase II randomized, placebo-controlled trial with a re-treatment extension. Br J Dermatol. 2012;167(1):180–190.
5. Green MS, Prystowsky JH, Cohen SR, Cohen JI, Lebwohl MG. Infectious complications of erythrodermic psoriasis. J Am Acad Dermatol. 1996;34:911–914.
2. Lebwohl M, Rivera-Oyola R, Murrell DF. Should biologics for psoriasis be interrupted in the era of COVID-19? J Amer Acad Dermatol 2020, in press.
3. Kalb RE, Fiorentino DF, Lebwohl MG, et al. Risk of serious infection with biologic and systemic treatment of psoriasis: Results from the Psoriasis Longitudinal Assessment and Registry (PSOLAR). JAMA Dermatol. 2015;151:961–969.
4. Reich K, Ortonne JP, Gottlieb AB, et al. Successful treatment of moderate to severe plaque psoriasis with the PEGylated Fab' certolizumab pegol: results of a phase II randomized, placebo-controlled trial with a re-treatment extension. Br J Dermatol. 2012;167(1):180–190.
5. Green MS, Prystowsky JH, Cohen SR, Cohen JI, Lebwohl MG. Infectious complications of erythrodermic psoriasis. J Am Acad Dermatol. 1996;34:911–914.
