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 Table of Contents  
REVIEW ARTICLE
Year : 2021  |  Volume : 8  |  Issue : 1  |  Page : 8-13

Use of immunosuppressants in vitiligo during COVID-19 pandemic: a quick review


1 Department of Dermatology, Venereology and Leprology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Dermatology, LHMC and Associated KSCH and SSK Hospital, New Delhi, India

Date of Submission12-Feb-2021
Date of Decision01-Mar-2021
Date of Acceptance04-Mar-2021
Date of Web Publication07-Apr-2021

Correspondence Address:
Muthu Sendhil Kumaran
Department of Dermatology, Venereology and Leprology, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh 160012
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/pigmentinternational.pigmentinternational_

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  Abstract 


Owing to the recent coronavirus (COVID-19) pandemic, there is a concern regarding the use of systemic immunosuppressive agents. There are no guidelines at present regarding the use of immunosuppressants. The main aim at this time should be to keep the dermatoses under control without exposing the patient to increased risk of infection and the consequent morbidity. In vitiligo, immunosuppressive agents are utilized in stabilization of progressive disease. An informed decision regarding the use of immunosuppressive agents can be made only after understanding the immune response to coronavirus, reviewing the mechanism of action of drug and evidence from previous studies on risk of infection. This review briefly discusses the mechanism of action and the safety data of various immunosuppressants used in vitiligo.

Keywords: Immunosuppressants, immunosuppression, unstable vitiligo, vitiligo


How to cite this article:
Mehta H, Soufila K, Kumar S, Sarkar R, Kumaran MS. Use of immunosuppressants in vitiligo during COVID-19 pandemic: a quick review. Pigment Int 2021;8:8-13

How to cite this URL:
Mehta H, Soufila K, Kumar S, Sarkar R, Kumaran MS. Use of immunosuppressants in vitiligo during COVID-19 pandemic: a quick review. Pigment Int [serial online] 2021 [cited 2021 May 9];8:8-13. Available from: https://www.pigmentinternational.com/text.asp?2021/8/1/8/313125




  Introduction Top


Vitiligo, although considered by many as a cosmetic disease, is associated with considerable psychological impact and social stigma, especially in darker skin types. Despite significant advances, vitiligo treatment still remains a daunting challenge for clinicians and requires the use of several systemic and topical immunosuppressive drugs.[1] However, in the backdrop of current coronavirus disease (COVID-19) pandemic, there is a rising apprehension among dermatologists as well as patients about the use of immunosuppressive agents and biologics. At present, Centers for Disease Control and Prevention and the World Health Organization does not give any specific guidelines on this. As a dermatologist, the priority should be to provide the best possible treatment to the vitiligo patients, delicately balancing the risk of immunosuppression with the risk of progression of disease. In this review, we will assess the pros and cons of the use of various immunosuppressive drugs in vitiligo.

There are certain general rules that should be considered before deciding to start, continue, or withdraw an immunosuppressive agent. A good understanding of the infectious pathway, normal immunological response, and abnormal immune response (cytokine storm) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) is extremely important.[2] A review of mechanism of actions of the drug and evidence from previous studies on risk of infection will aid the physician in reaching a decision. A drug that is pan-immunosuppressive or has a nonspecific action with a long half-life is better avoided because in case of an unlikely event of SARS-CoV2 infection, the reversal of immunosuppression may not be fast enough.[3] However, unnecessary fear and undertreatment should be avoided to prevent a possible exacerbation of the underlying disease.

Decision regarding immunosuppression should be made on individual basis as there are no solid guidelines and data at present.[4] The severity of primary disease and the presence of comorbidities need to be thoroughly analysed. General prevalence of COVID-19 in patients’ locality and facilities for self-isolation should be taken into account. Patient profile is another important consideration. In general, children have a Th2 skewed immunity, making them more susceptible to infections. However, they are often asymptomatic and silent carriers, and serious complications are rare. On the contrary, there is a gradual immunosenescence attainment as the person ages, with a decreased ability to respond to new antigens.[5] Often they also have multiple comorbidities, making them more prone to complications from viral infections.

Medical management of vitiligo can be considered under two domains: arrest of disease progression and attainment of repigmentation. While phototherapy and topical agents can aid in repigmentation of disease, immunosuppressants are needed to stabilize progressive disease. Oral mini pulse of corticosteroids, methotrexate,[6] azathioprine,[7] mycophenolate mofetil (MMF),[8] cyclosporine,[9] apremilast,[10] and tofacitinib[11] have been used successfully in unstable vitiligo. We hereby review the mechanism of action and risk of immunosuppression with each of these agents. Even though some studies have reported that there is no increased risk of infection with immunosuppression alone, at present data regarding this are scarce. Therefore, immunosuppression should be started only in selected and absolutely necessary cases.

Oral mini pulse

Steroids have a profound effect on both innate and adaptive immune response by repression of nuclear factor kappa light chain enhancer of activated B cells (NF–ΚB) pathway and reduced production of inflammatory cytokines. Hence, they may accentuate the risk of various opportunistic infections. Meta-analysis of 71 trials found a relative risk of 1.6 for infections in patients on steroids, and the risk was dose dependent and minimal for a prednisolone equivalent dose <10 mg/day.[12] Other factors associated with high risk were older age, diabetes, and lower plasma albumin level. There are no particular contraindications to institution or discontinuation of systemic steroid therapy during the COVID-19 pandemic. Steroids can be started in necessary and selected cases and should be tapered as symptoms improve with the aim of maintaining at the least possible dose for disease control. Factors that increase the risk of infections include high dose, long-term treatment, and other concomitant immunosuppressive use. In the event of COVID-19, dose should be tapered rather than abruptly stopping steroids. Use of corticosteroids as oral mini pulse may minimize the immunosuppressive effects and can be considered in patients with rapid progression of disease. However, no studies evaluating the effect of oral mini pulse on the risk of COVID-19 have been conducted till now.

Methotrexate

Methotrexate inhibits dihydrofolate reductase, the enzyme involved in the conversion of dihydrofolate to tetrahydrofolate (a cofactor necessary for the synthesis of thymidylate and purine nucleotides), hence impeding DNA and RNA synthesis in immunologically active cells. It also inhibits cell division during the S phase by inhibition of the enzyme thymidylate synthase. Methotrexate also blocks migration of activated T cells into tissues. Another mechanism by which methotrexate decreases inflammation is via inhibition of amino-imidocarboxy-amido-ribonucleotide transformylase, resulting in increased concentration of the anti-inflammatory mediator adenosine. Production of pro-inflammatory mediator S-adenosyl methionine is suppressed by inhibition of methionine synthase.

Low-dose methotrexate has been used successfully to halt disease progression in vitiligo with efficacy similar to oral mini pulse of corticosteroids.[6] A modestly increased risk of infection in rheumatoid arthritis (RA) patients treated with methotrexate has been observed in some studies.[13] However, a meta-analysis assessing the use of methotrexate in non-RA inflammatory diseases (including psoriasis) found no increase in risk of total or serious infections.[14] A multicentre cohort study did not find any increase in COVID-19-related hospitalization or mortality in patients with recent exposure to methotrexate.[15] If a patient is being planned for methotrexate, screening for COVID-19 can be advised in high-risk areas. If a patient is already on methotrexate, and there is no signs or symptoms of infection/mild or asymptomatic infection, there is no evidence to support a preventive suspension at present. In case of serious infection, decision to stop treatment should be made after weighing the risk of flare of primary disease versus benefit.

Azathioprine

Azathioprine inhibits the de novo purine synthesis, hence diminishing cell proliferation. The exact mechanism of immunosuppressant and anti-inflammatory action of this purine analogue is not known, but is likely related to its incorporation into DNA and RNA. It also supresses the function of T lymphocytes, B lymphocytes, natural killer cells, and antigen presenting cells. A recent randomized controlled trial found azathioprine to be inferior to oral mini pulse of corticosteroids in terms of both arresting disease progression and induction of repigmentation.[7] It can be useful as an alternative to corticosteroids in rapidly progressive disease or in cases where corticosteroids are contraindicated. In atopic dermatitis patients, cyclosporine had 58% higher risk of infection in comparison to methotrexate.[16] In the same study, azathioprine doubled the risk of infection and MMF tripled the risk. Increased incidence of infections with azathioprine therapy has also been reported in patients of airborne contact dermatitis[17] and inflammatory bowel disease.[18] However, in a cohort of 40 patients with urticaria, no infection was observed with azathioprine.[19] Increased incidence of mucocutaneous candidiasis, reactivation of herpes zoster, dermatophytosis, cellulitis, upper and lower respiratory tract infections, and tuberculosis has been reported when azathioprine is used in combination with steroids for dermatological indications.[20]

The half-life of azathioprine is 5 hours, but immunosuppression with this agent may be maintained for up to 3 months. In addition, the mechanism of action is not specific, putting the patient at increased risk of viral infections. The risk of infection with azathioprine increases with duration of therapy and severity of leukopenia. If a patient is planned for azathioprine, screening for COVID-19 can be advised. If the patient is already on treatment, in case of mild or no infection, treatment can be continued with close monitoring of leukocyte count since lymphopenia may worsen the prognosis of COVID-19.[21] In case of serious infections, treatment suspension can be considered after assessing the risk versus benefit.

Mycophenolate mofetil

MMF is an inhibitor of inosine monophosphate dehydrogenase (IMPDH) enzyme that supresses the de novo pathway of purine synthesis. It selectively inhibits the proliferation of activated lymphocytes. It also inhibits recruitment and chemotaxis of lymphocytes by modulating the expression of cell adhesion molecules. A reduction in antibody production by activated B cells has also been demonstrated with MMF. A recent prospective, randomized study found MMF to be useful in active vitiligo, albeit with less efficacy as compared to oral mini pulse of corticosteroids.[8] The half-life of mycophenolic acid is 17.5 hours and the duration of immunosuppression after stoppage is up to 3 months. MMF has been associated with increased risk of infections, particularly at doses >2 g/day. Fatal infections have been observed in posttransplant cases, but risk in dermatologic patients is less clear. An increased risk of viral infections, particularly herpes, has been observed, although the duration or severity of these infections was not increased.[22],[23] Inhibition of IMPDH may be responsible for antiviral action of the drug as well, which has been demonstrated in vitro against influenza virus, Zika virus, and West Nile virus.[24] Few studies, however, have demonstrated the inefficacy of MMF in inhibiting viral replication of SARS-CoV, although it did not significantly increase it.[24] Treatment with MMF has been continued without worsened prognosis in cases of COVID-19 in anecdotal reports,[25] but large cohort studies assessing the safety of this agent during this pandemic are lacking.

Cyclosporine

Cyclosporine is a calcineurin inhibitor and a potent immunosuppressant. Binding of cyclosporine to cyclophilin forms a complex that inhibits calcineurin, resulting in reduced activity of the transcription factor, nuclear factor of activated T cells (NFAT), downregulating transcription of a number of cytokines, most significantly interleukin-2. It also inhibits cellular trafficking by reducing production of interferon gamma and intracellular adhesion molecule-1. It has been used successfully in stable vitiligo post melanocyte transfer to enhance repigmentation.[26] A pilot study assessing use of cyclosporine in unstable vitiligo found it effective in halting disease progression.[9] Low-dose cyclosporine (up to 3 mg/kg/day) normally used in dermatology is usually not associated with any serious infections. In a cohort of 2845 patients of psoriasis, risk of infections with cyclosporine was more than that of methotrexate,[27] but no accentuated risk was reported on use as monotherapy in a cohort of chronic refractory urticaria.[19] Screening for COVID-19 can be advised if a patient is newly planned for cyclosporine. If a patient is already on cyclosporine, and there is no signs or symptoms of COVID-19, there is no evidence to support preventive suspension at present.[28] In case of serious COVID-19, there is a hypothetical beneficial effect of continuing cyclosporine. Protective effects of cyclosporine have been reported in beta-coronavirus[29] and hepatitis C virus (HCV)[30]; these viruses use cyclophilins as chaperones and NFAT as the chief signalling pathway, which can be targeted by cyclosporine. In severe disease, mitochondrial stress response and dysfunctional immune response of macrophages infected with COVID-19 are the causes of host cell damages. Cyclosporine can cause inhibition at various levels along this abnormal response pathway and confer protection upstream of the cytokine storm.[31] No studies have assessed the action of cyclosporine on SARS-CoV2. Theoretically, patients receiving cyclosporine therapy for autoimmune dermatological conditions may be benefitted by its antiviral action. However, this antiviral action may hamper the mounting of immune response against SARS-CoV2 and may prevent the development of natural immunity against reinfection. Increased risk of human papilloma virus and Epstein-Barr virus infections in patients receiving cyclosporine has been well documented in the literature.[32] Increased risk of cytomegalovirus reactivation has been observed in posttransplant cases and ulcerative colitis.[33],[34] A guarded approach is therefore advised, prescribing cyclosporine in only the most essential cases where immunosuppression is necessary and benefits of therapy outweigh the risks.

Apremilast

Apremilast is a small molecule inhibitor of the enzyme phosphodiesterase-4 (PDE-4). PDE-4 is an intracellular enzyme that degrades cyclic adenosine monophosphate (cAMP) and is present predominantly in various effector immune cells, monocytes, neutrophils, and dendritic cells. Although impressive efficacy of apremilast in vitiligo was noted in a case series,[10] a later randomized controlled trial failed to replicate these findings.[35] No increase in risk of serious infections has been noted in psoriasis and psoriatic arthritis in long-term follow-up studies.[36] Consequently, suspension or avoidance of treatment with apremilast has not been recommended. The current literature suggests a minimal risk of infection with apremilast use and therefore low potential for harm with apremilast therapy in COVID-19 infection. A case series reported no increased risk on continuation of apremilast in COVID-19 positive patients.[37]

Janus kinase (JAK) inhibitors

Tofacitinib is an inhibitor of JAK1/3, which are tyrosine kinases involved in transduction of cytokine-mediated signals and consequently transcription of proteins involved in inflammation. It has been used as both oral and topical therapies in patients with vitiligo.[11],[38],[39] Ruxolitinib acts by inhibiting JAK1/2, resulting in blockade of signal transducer and activator of transcription pathways, reducing the production of multiple pro-inflammatory cytokines including interferon gamma, IL-12, or IL-23, ultimately resulting in the suppression of TH17 pathway. Serious bacterial, mycobacterial, fungal, viral, and other opportunistic infections have been reported with the use of tofacitinib and ruxolitinib. Venous thromboembolism has been reported with tofacitinib therapy. However, recent studies have shown direct antiviral and anti-inflammatory effects of ruxolitinib and baricitinib in COVID-19. At this time, there are insufficient data to comment upon the magnitude of harm or benefit of JAK inhibitors during the current SARS-CoV2 pandemic.


  Conclusion Top


Data on safety of immunosuppressants during this pandemic are scarce and treatment has to be decided on case-to-case basis, assessing the risk versus benefit ratio. Low-dose corticosteroids as mini pulse and apremilast have probably the minimum risk of immunosuppression and can be considered safe in cases of unstable vitiligo. Risk is intermediate with azathioprine and methotrexate, while it is highest with cyclosporine, JAK inhibitors, and mycophenolates. Mechanism of action and potential utility of various agents are summarized in [Table 1].
Table 1 Mechanism of action and utility of various immunosuppressants in patients with unstable vitiligo

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Conflicts of interest

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