key: cord-1044705-69t4kkon
authors: Fagan, CNicole; Meah, Nekma; York, Katherine; Bokhari, Laita; Fletcher, Godfrey; Chen, Gang; Tobin, Desmond J.; Messenger, Andrew; Irvine, Alan D.; Sinclair, Rodney; Wall, Dmitri
title: Shedding light on therapeutics in alopecia and their relevance to COVID-19
date: 2020-12-16
journal: Clin Dermatol
DOI: 10.1016/j.clindermatol.2020.12.015
sha: 5ec79645f195a115031455cdca38a868778184bd
doc_id: 1044705
cord_uid: 69t4kkon

As of July 9, 2020, there were over 12 million confirmed cases of COVID-19 across the globe, with > 550,000 deaths. Many European countries including Belgium, the United Kingdom, Italy, and Spain have had the highest numbers of fatalities per capita.(1) This demonstrates the potential for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus to overwhelm even the most advanced healthcare systems despite extreme societal interventions. Since its emergence, SARS-CoV-2 has disseminated across the globe, impacting the structure of global societies, infrastructure and economies. Patients with alopecia are a diverse group who, for various indications, are prescribed a number of anti-microbials and anti-androgen treatments in addition to immunomodulatory therapies such as hydroxychloroquine, oral corticosteroids and a range of broad immunosuppressants. These drugs are being scrutinized for their capacity to potentially impact SARS-CoV-2 outcomes. We examine these treatments and highlight the critical role that patient registries will play in generating real-world evidence to assess their impact on COVID-19 outcomes.

The first reports of a cluster of viral pneumonias originating from the wet animal markets in Wuhan, Hubei province, China emerged in late December 2019. The implicated novel RNA virus was formally designated as severe acute syndrome coronavirus 2 (SARS-CoV-2). The majority of those infected are believed to be asymptomatic or to display only mild symptoms; however, morbidity and mortality are considerable in the 15% of individuals who have severe disease and the 5% of individuals who require critical care. 2 Rapid progression from complications such as acute respiratory distress syndrome (ARDS) can lead to death. 3 Dmitri Wall 6 Despite unparalleled mobilization of the global medical and scientific communities against the pandemic, no effective treatment or vaccine is available yet. Recently, the antiviral agent remdesivir, has been shown to be modestly effective in a well conducted clinical trial. 4 Likewise, preliminary results from a recent UK based trial have suggested that dexamethasone, a corticosteroid, has a moderate reduction of 28-day mortality in COVID-19 patients. 5 The rapid spread of SARS-CoV-2 across international borders highlights the need for a coordinated global response to improve outcomes. Experience from these epidemics and emerging evidence as COVID-19 spreads has stimulated drug trials exploring re-purposing of existing medicines, including antivirals and immunomodulating therapies to attenuate the destructive 'cytokine storm' associated with COVID-19. These repurposed therapies may be of benefit for SARS-CoV-2 at this time of immediate, acute, and widespread need, while we wait for targeted therapies to become available.

The factors that trigger severe disease in individuals are not yet well established. It is theorized that a pathologic excessive inflammatory response (including the so-called 'cytokine storm') may be a key player, and so this has led to trials of existing immunomodulatory drugs. 6, 7 In addition laboratory studies involving hydroxychloroquine and baracitinib have also demonstrated antiviral properties. Interestingly, the reported higher prevalence of severe disease in men and a low incidence in pre-pubertal children Dmitri Wall 7 suggests that androgens (and androgen receptor) could play a role in disease severity. 8 This highlights a possible role for anti-androgen medications. 9 Patient registries are a means of collecting data to monitor patients already taking immunomodulating and anti-androgen therapies that present an opportunity to establish the prevalence and severity of disease amongst this patient cohort. Patients being treated for various types of alopecia receive a wide range of therapies, including immunomodulating and anti-androgen drugs, and some will have been on long term treatment. Data obtained from monitoring the outcomes of treated alopecia patients during the COVID-19 crisis will help clarify if modulating the immune-mediated and androgen pathways influences the disease course and improves or increases morbidity and mortality. 7, 8 By simultaneously studying the outcomes of individuals suffering from alopecia currently not on these medicines, it will be possible to establish a large cohort of patients that can provide comparative data.

The main clinical features of COVID-19 are fever, dry cough, and dyspnea. 10 Anosmia and ageusia have also been widely reported. Approximately 80% of those infected run a mild disease course, 15% infected develop a severe illness, and 5% require critical care due to respiratory failure and ARDS. 2 These individuals may require mechanical ventilation and often multi-organ support. Those following a severe disease trajectory tend to be of older age with coexisting underlying disease, 10, 11 although the virus can cause death in young people without co-morbidities. The significant capacity for mortality, even in healthy Dmitri Wall 8 individuals, has triggered broad scale and unprecedented public health interventions to curb the spread of SARS-CoV-2.

As a respiratory virus SARS-CoV-2 initially infects the lungs, targeting type 2 pneumocytes, however, the virus been found in many organs and tissues including skin and testis. SARS-CoV-2 enters the cell by binding to the angiotensin converting enzyme-2 (ACE2) surface receptor. 12 To enter the cell via ACE2 the viral spike protein must first be primed by the host protein transmembrane protease serine 2 (TMPRSS2). 13 To date, androgens are the only identified promoter for the TMPRSS2 gene, binding to the androgen response element and promoting transcription of the gene. 14 Like TMPRSS2, ACE2 is also regulated by the androgen receptor (AR), although not exclusively. 15 As the primed spike protein is reliant on both TMPSS2 and ACE2 for pathogenesis, this highlights an association between androgens and SARS-CoV-2. 8 Evidence suggests COVID-19 and its SARS and MERS predecessors are characterized by an hyperinflammatory response and 'cytokine storm' syndrome. 6, 16 This aberrant immune response likely contributes to lung damage and death. 17 Observational reports of COVID-19 patients show similarities between severe SARS-CoV-2 infection and other hyperinflammatory states like secondary hemophagocytic lymphohistiocytosis and macrophage activating syndrome. 17 Early reports of COVID-19 patients showed elevated interleukin (IL)-1B, interferon gamma (IFN-y), IFN-y inducible protein 10 (IP-10), and monocyte chemoattractant protein-1 (MCP1), activating type 1 T cell responses. 10 In addition higher levels of granulocyte-colony stimulating factor (GCSF), IP-10, macrophage inflammatory protein-1A (MIP1A), and tumor necrosis factor-alpha (TNF-a) were seen in Dmitri Wall 9 those admitted to ICU. 10 In a separate study, levels of IL-6 and serum ferritin were higher in non-survivors and an increase in these markers correlated with severity of disease. 17 Severely-affected COVID-19 patients are those with underlying conditions that impair the immune response or cause chronic low grade systemic inflammation, such as obesity, type 2 diabetes, and atherosclerosis. 18 In older adults, increased production of type 2 cytokines and age dependent defects in the function of T-cells and B-cells may lead to increased viral replication and a prolonged proinflammatory state, leading to a poorer outcome. 17 Similarly to MERS, the outcome of COVID-19 infection may depend on a balance of both host and SARS-CoV-2 induced immune signaling cascades. 16 Therapies that could modulate the interaction between the virus and the host responses may improve morbidity and mortality in COVID-19 patients.

Alopecia can be characterized as scarring or non-scarring. Non-scarring hair loss includes androgenetic alopecia (AGA; syn. male pattern hair loss [MPHL] or female pattern hair loss

[FPHL]), telogen effluvium and alopecia areata (AA). While AA is believed to be among the most common autoimmune conditions in humans, with an estimated lifetime risk of 1.7-2.1%, 19, 20 AGA is even more prevalent, progressively increasing with age. Half of all men are affected by 50 years of age and 30% of women by 50 years of age. Individuals with all forms of alopecia can find hair loss extremely distressing, as hair is seen as a core element of identity and culture. In women with breast cancer, chemotherapy-induced alopecia can be considered to be more emotionally difficult than the mastectomy. 21, 22 Whilst in patients with alopecia areata, there is an association with suicidal ideation and youth suicide. 23 Scarring alopecias include lichen planopilaris and its variants, frontal fibrosing alopecia, folliculitis decalvans, dissecting cellulitis of the scalp, discoid lupus erythematosus, and localized scleroderma. In contrast to non-scarring alopecia, scarring alopecias result in permanent hair loss. Prompt treatment with a broad range of immunomodulatory and systemic therapies is recommended to arrest the disease process. 24 Recently, drugs that are used for hair disease, such as anti-androgens, anti-microbials and the immunomodulatory drugs hydroxychloroquine, corticosteroids, ciclosporin, and Janus kinase (JAK) inhibitors have been considered for use in the treatment of COVID-19. 5, 8, 9, 12, [25] [26] [27] [28] [29] [30] [31] In particular, the use of hydroxychloroquine and corticosteroids has been controversial since the start of the pandemic. There are no data available yet on the value of methotrexate in COVID-19 disease, although it could be theorized that it is to be avoided given its association with pulmonary toxicity. 32

Hydroxychloroquine Hydroxychloroquine is frequently used to treat a number of cicatricial alopecias including discoid lupus erythematosus and lichen planopilaris. [33] [34] [35] Since the start of the outbreak, chloroquine and hydroxychloroquine have been under intense clinical scrutiny in scientific and mass media as possible therapeutic and prophylactic treatments for COVID-19.

Hydroxychloroquine is generally considered to have a more favorable side effect profile than chloroquine, though both have raised concerns due to their arrhythmogenic potential. 28 Both drugs have an anti-inflammatory role, as they reduce T-cell activation and Dmitri Wall 11 alter the cytokine profile. They also have a synergistic antiviral role. They interfere with the glycosylation of the ACE-2 cellular receptor of SARS-CoV and alter entry into the cell by increasing the endosomal pH, thereby limiting fusion. 36 During the SARS-CoV-1 epidemic, in vitro studies of chloroquine and hydroxychloroquine showed efficiency against the virus ,and this has been mirrored in SARS-CoV-2. 37 In the SARS-CoV-2 pandemic, early clinical reports from China suggested positive outcomes in patients treated with chloroquine. 38, 39 Hydroxychloroquine used alone or in combination with azithromycin suggested that the viral load may be reduced; however, the relevance of this in affecting disease severity is yet to be confirmed. 29, 40 Unfortunately, these studies were not adequately-powered and stemmed mainly from off-label use of the drugs. patients. 42 The WHO SOLIDARITY trial, another randomized controlled trial, has released preliminary data that confirms there is no reduction of death with the use of hydroxychloroquine. 43 Both the RECOVERY and SOLIDARITY trials have thus concluded that there is no benefit and have since stopped enrollment in the hydroxychloroquine arm of the trials.

The high-level endorsements of hydroxychloroquine utility by America and China has led to shortages, which may impact on the general availability of the drugs for approved use in hair disorders. Until further evidence emerges, widespread use of hydroxychloroquine cannot be recommended; however, it would be prudent to monitor alopecia patients currently taking these drugs, as this may provide further insight about the potential benefits of therapeutic or prophylactic use in the context of COVID-19.

Glucocorticoids are used in inflammatory hair diseases, as they disrupt autoimmune mechanisms and cause a widespread dampening down of immune responses. 34, [44] [45] [46] Like hydroxychloroquine, the use of steroids has been controversial in the context of COVID-19.

While corticosteroids might presumably reduce severe, immune-mediated lung inflammation seen in COVID-19 patients, they may also reduce host responses and so limit viral clearance. 47 They have frequently been used in ARDS, but they are not proven to reduce mortality due to variable results between individual trials. 48 In a review of six studies examining steroids and ARDS, there was insufficient evidence to support the use of corticosteroids. 48 Corticosteroids were widely used during the earlier outbreaks of SARS and MERS. In one systematic review of SARS patients treated with steroids, 25 out of 29 studies were inconclusive ,and the remaining 4 reported possible harm. 49 In a retrospective study of Dmitri Wall 13 MERS patients, those given steroids were more likely to have invasive interventions and had no difference in 90-day mortality. 50 Despite considerable, but inconsistent evidence, steroids were used in China at the beginning of the COVID-19 outbreak. An expert consensus from the Chinese Thoracic Society, all of whose members were involved in treating COVID-19 patients, argues that a short course of low to moderate dose steroids for critically ill patients should not be ruled out. 51 Interestingly, a small retrospective cohort study of 201 patients from Wuhan identified that methylprednisolone appeared to reduce mortality in COVID-19 patients with ARDS. 52 Preliminary results from the UK based randomized RECOVERY (Randomized Evaluation of COVid-19 thERapY) trial showed that dexamethasone reduces 28 day mortality by 17% in hospitalized COVID-19 patients. The greatest benefit was seen in ventilated patients, reducing deaths by one third, and by one fifth in patients receiving oxygen only. 5 Taken together this suggests that corticosteroids may be of benefit in those with severe disease, however current WHO guidelines advises against the use of steroids in COVID- 19. 47 Cyclosporine Cyclosporine (CYA), a calcineurin inhibitor, is a mainstay of steroid-sparing treatment in hair disorders and has a well-established side effect profile. 34, 45, 53, 54 As an immunosuppressant, it limits the transcription of IL-2 and other cytokines in activated T-cells. 55 Individuals taking cyclosporine are at risk for developing serious infections; however, it has an effect on cytokine profiles; in theory, it could be of benefit in preventing the pathologic hyperinflammation observed in COVID-19. Cyclosporine had previously been used to treat the cytokine storm in secondary hemophagocytic lymphohistocytosis, which has a similar Dmitri Wall 14 cytokine profile to SARS-CoV-2 infection. 6, 56 In contrast to targeted biologics ,such as anti-IL-6 (which have been put forward as a treatment for the cytokine storm in COVID-19 patients), CYA is more affordable. In vitro studies showed that CYA at low doses inhibits MERS-CoV and SARS-CoV replication; 57,58 however, given the risk of serious complications, such as nephrotoxicity and hypertension in already compromised individuals, robust preclinical studies would need to confirm if CYA is beneficial in SAR-CoV-2 infection prior to its use.

Using Benevolent AI (Artificial intelligence) software, researchers at the Imperial College, London, identified baracitinib, a Janus kinase inhibitor as a potential treatment for COVID-

protein. The numb-associated kinases (NAK), AP2-associated protein kinase 1 (AAK1) and cyclin G-associated kinase (GAK) are known regulars of endocytosis. AAK1 and GAK are potential therapeutic targets, preventing the virus from entering the cells via receptormediated endocytosis. Baracitinib, a JAK inhibitor, currently in a phase 3 clinical trial for the treatment of severe alopecia areata, is a high affinity inhibitor of AAK1 and binds GAK. 31, 59 It was granted breakthrough therapy status for alopecia in March 2020 by the FDA. 60 Originally 6 potential AAK1 inhibitors were identified by Artificial Intelligence, but baracitinib, given its once daily dosing and acceptable side effect profile, was considered the most favorable therapeutic option. 31 Baracitinib exerts its anti-inflammatory properties via the JAK 1 / 2 pathway and is approved for use in rheumatoid arthritis. The anti-inflammatory properties may limit the Dmitri Wall 15 hyperinflammatory response and subsequent 'cytokine storm' in SARS-CoV-2 infection. A RCT currently being conducted by the National Institutes of Allergy and Diseases (NIADH) aims to explore this further. In the Adaptive COVID-19 Treatment Trial (ACCT 2) baracitinib will be combined with remdesivir, an antiviral that has been tested already in COVID-19 patients (ACTT) by NIADH. Preliminary results from the ACTT trial indicates a 31% faster time to recovery in those receiving remdesivir vs. placebo in COVID-19 patients. 4 It is postulated that these drugs act synergistically to reduce viral entry, replication, and hyperinflammation without interacting with the relevant CYP drug-metabolizing enzymes. 59

Methotrexate (MTX) is a longstanding immunosuppressive drug used in a number of dermatoses, including those affecting the hair follicle. 45, 46, [61] [62] [63] Along with other immunosuppressants, patients currently taking MTX are in theory more susceptible to serious infections including COVID-19. The guidelines from the British Association of Dermatologists recommends that patients currently taking immunosuppressant drugs to self-isolate and to temporarily stop methotrexate use, if they contract COVID-19. 64 Methotrexate, a folate analogue, exerts its anti-inflammatory effects by increasing intracellular adenosine. In addition, it reduces homing of T-cells and decreases the production of pro-inflammatory cytokines. 65 At present, there is no scientific evidence examining the interaction between SARS-CoV-2 and methotrexate. It is possible that the immunosuppressive effects of methotrexate could prevent the virus-induced cytokine storm by inhibiting the expression of certain cytokines; however, as a known side effect of methotrexate is pulmonary toxicity, it is not currently a Dmitri Wall 16 drug being investigated for repurposing. 32 Monitoring patients with alopecia on methotrexate during the pandemic is important, as it will allow clinicians to determine if there is an increased risk of contracting the virus, and if this is associated with a worse outcome.

Androgenetic alopecia hair loss is due to a genetically determined sensitivity to androgens.

Higher expression of the androgen receptor (AR) may correlate with increased disease severity in COVID-19 patients. 8 Evidence for this comes from epidemiologic studies, as well as reports of AR in TMPRSS and ACE2 expression. 13, 15 Severe disease in COVID-19 patients has shown a greater male vs female predominance (52% vs 48%). Pre-pubescent children are at very low risk of severe disease, representing only 0.6% of cases in a study of 1,099 patients in China. 66 Ethnic differences in the outcomes of COVID-19 have also been reported, with more African Americans having worse outcomes compared to Caucasians. Although confounding factors are likely to contribute to these differences, genetic variations of the AR between different ethnic groups could explain the increased susceptibility to severe complications of COVID-19; 9 likewise, genetic variants in AR expression in women and children could explain the lower rate of severe COVID-19 seen in these populations. 9 For example, polymorphisms in the CAG repeat in exon 1 of the AR may account for some of these racial and gender differences ,as CAG polymorphisms correlate with the incidence of other androgen-mediated diseases, such as androgenetic alopecia and prostate cancer. 67, 68 Studies of expression of CAG polymorphisms in hospitalized COVID-19 patients could be of value in determining, if this hypothesis is true. 9 Dmitri Wall 17 To better understand if there is an association between AR expression and severity of COVID-19 infection, it is important to record the outcomes of individuals with increased AR expression/sensitivity, such as men with androgenetic alopecia. 9 If true, there are several classes of drugs used in androgenetic alopecia that may be of use in SARS-CoV-2 infection.

Examples of such androgen receptor antagonists include spironolactone, 69,70 flutamide, 71 bicalutamide, 72 cyproterone acetate, 73 and the 5-alpha reductase inhibitors finasteride and dutasteride. [74] [75] [76] [77] [78] These drugs, which are widely available and have a well-understood safety profile, could be rapidly repurposed for use in COVID-19 patients.

SARS-CoV-2 is a newly emergent pathogen, about which relatively little is known currently.

It is associated with considerable morbidity, mortality, and profound socioeconomic disruption. As such, there is a critical need for effective therapies to become available on a large scale. As measures designed to limit its spread are gradually withdrawn, the threat of a second, more devastating, wave of illness looms, highlighting the continued need for worldwide research and collaboration.

The rapidly evolving nature of COVID-19 disease and the manner in which new therapies and novel applications of existing therapies could be applied (i.e., beyond their conventional use), stresses the need to collect data in a harmonized manner. The role of patient registries is fundamental to enabling this. The emergence of a number of collaborative, international patient registries is of significant interest , including for alopecia (SECURE-Alopecia; securederm.com/secure-alopecia/). 79 These registries focus on collecting anonymized data regarding outcomes of patients with specific conditions, such as inflammatory bowel disease, cirrhosis, atopic dermatitis, psoriasis ,and all forms of alopecia who have contracted COVID-19. 80 This will generate relatively well-harmonized datasets in a large cohort of patients who have contracted COVID-19 while on immunomodulatory therapies. This initiative will allow us to compare outcomes with alopecia patients who have not been treated. Data collected will provide real-world evidence to assess the safety and effectiveness of the potential treatments described in this article.

The emergence of three highly infective SARS coronaviruses in the last twenty years has shown the value of international networks and the necessity for coordinated rapid responses. Identifying and repurposing approved therapies with known pharmacokinetics, proven safety profiles and acceptable side effects could be of paramount importance, until such time as an effective vaccine is available.

Therapies used for alopecia may have a positive effect on the outcomes of COVID-19.

Immunomodulators such as hydroxychloroquine, ciclosporin, and the JAK inhibitor baracitinib may augment the cytokine storm and pathological lung inflammation leading to death. Hydroxychloroquine and baracitinib may also exert an antiviral effect in SARS-CoV-2 infection. Recently, the positive effect of hydroxychloroquine proposed in earlier studies has been questioned, as more data indicate there is no benefit. Official reporting of 2 large prospective, randomized, placebo-controlled clinical trials is currently awaited. The role of the AR in the severity of COVID-19 disease needs to be elucidated further. If proven, antiandrogens, such as finasteride and spironolactone, could be used to reduce the risk of severe disease. Until recently, evidence for the use of glucocorticoids was inconclusive or even suggests harm; however, the results of the UK RECOVERY trial have disputed this, suggesting a benefit for the use of dexamethasone in COVID-19 patients. Methotrexate, although an immunomodulator, is not currently a candidate drug for repurposing in SARS-CoV-2 infection given its potential pulmonary side-effects.

Patients with alopecia are a diverse group, for whom a wide range of systemic therapies are prescribed. They offer a meaningful opportunity to collect real-world data that will better inform the global community, through pooled observations from multinational real-world patient registries, and so not only help inform care of alopecia, but also offer a chance to establish risk factors and candidate interventions that may modulate disease course and save lives.

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