1. Calcutta National Medical College and Hospital, West Bengal, India; anan.gopal@gmail.com
2. Calcutta National Medical College and Hospital, West Bengal, India; nanditashetty90@gmail.com

*             Correspondence: anan.gopal@gmail.com

Keywords: efficacy, safety, mometasone furoate, adapalene gel, alopecia areata

1. INTRODUCTION

Alopecia Areata (AA) is a common autoimmune disease caused by damage of hair follicles by the cells (T lymphocytes) [1]. Alopecia Areata is taken as heterogeneous disease clinically having very typical symptoms but its etiology is not typical and characterized as enigma [2]. The T cell activation using immune pathways for the disease are still not clear and this limits the targeted therapy used for treating the Alopecia Areata [3]. The lesions of Alopecia Areata are pathologically characterized as intra-follicular and also peri-follicular cell infiltrates mainly directed towards the anagen hair bulbs. The composition of such infiltrate is mainly composed of activated CD8 as well as CD4 T-cells along with Langerhans cells and the macrophage cells [4].  The Worldwide incidence of Alopecia Areata in the life of an individual is rated as 2% and also sex predominance is not documented as well [5]. The usual occurrence is very common during the 30s or their 40s but it can occur at any age. The earlier the occurrence, the result is the disease severity characterized by more area involved. The entire scalp could be affected among 1 to 2 percent cases designated as Alopecia Totalis [6].  The hair loss at the scalp area in round circle of about 1 to 4 cm and majority of the affected patients reports such rapid onset at single or multiple places. The treatment options also vary widely for such patients suffering from Alopecia Areata. The appropriate option for treatment is not known as each available option had certain advantages as well as disadvantages [7]. Many treatment modalities both topical and systemic are available. The topical modalities are steroids, immunotherapy, minoxidil, anthralin, retinoids and superficial cryotherapy. Systemic treatments include oral corticosteroids (40mg per day) and other options include immunosuppressants such as azathioprine, Cyclosporine, methotrexate. Topical retinoids are irritants and induce hair growth by unknown mechanism [8]. As the treatment of alopecia areata is dependent on age of patient as well as the extent and duration of scalp involvement, so each case must be dealt with a customized individual basis approach [9]. Mometasone is a medium-strength corticosteroid. It decreases swelling (inflammation), itching, and redness. This medication is used to treat skin conditions such as eczema, psoriasis and utricaria. This medication is available in several forms including cream, ointment, and lotion [10]. Adapalene (3rd generation synthetic topical retinoid analogue mainly derived from naphthenic acid) plays a crucial role in the treatment of acne. Retinoid have vitamin A like activity which helps to regulate cell turnover [11]. As no local study regarding this treatment for alopecia Areata is available so this review will help us to evaluate efficacy of combination of mometasone furoate 0.1% cream and adapalene 0.1% gel and will provide directions for future researchers.

2. LITERATURE REVIEW

The term alopecia, used by physicians dating back to Hippocrates, originates from the Greek word for fox, “alopex,” and was so-named due to fur loss seen in fox mange. “Areata” is derived from the Latin word, “area,” meaning a vacant space or patch. The Alopecia Areata was clinically described originally in “A Practical Synopsis of Cutaneous Disease” written by Thomas Bateman in year 1817 and apprenticed to Robert Willan (dermatologist) [12]. On the other hand, Bateman defined it as “bald patches, mainly circular,” and having characteristic of hair regrowth that is consisting of “softer and lighter in color than before.” The Bateman give it name of “porrigo decalvans,” means “depilating scalp disease [13, 14]. Alopecia Areata (AA) is a complex autoimmune condition that causes non-scarring hair loss. It typically presents with sharply demarcated round patches of hair loss and may present at any age [15]. Alopecia Areata (AA) is immune-mediated chronic condition having acute characteristics of non-scarring onset of hair loss mainly ranged from patchy areas with small circumscribed scalp areas, towards complete scalp hair loss and then continues to full body hair loss. The pathophysiology of the disease was recently scarcely known by the scientists although AA is very commonly affecting the adults as well as children. The suggestions currently known are that immune privilege (IP) collapses from the hair follicle possibly because of external as well as genetic factors triggering the disease onset [16, 17]. Many dermatologists have observed 25% of all cases of alopecia due to AA, making it among the most common causes of hair loss. About 0.1 to 0.2% of the population is affected worldwide and the lifetime risk is 1.7% [18].  In the United States and the United Kingdom, AA represents for 25% of all alopecia patients presenting to dermatologists, while in China and India, it accounts for 3.8% and 0.7% of all new outpatient respectively. It is equally common in both sexes and can affect anyone of any age or with any hair color. Some studies have even found a slight masculine predominance. Ages ranged from 4 months for the youngest to late 70s for the eldest have been reported. Twenty percent of the cases were in children, and sixty percent of the AA patients received their first patch before the age of twenty. AA can affect people at any age, but it is more common in children. The highest incidence is between the age of 30–59 years. In 8.7–20% of cases, close relatives had been likely impacted. Seventy to eighty percent of people who develop AA do so before the age of 40(48%). This makes AA the most common reason of hair loss in otherwise young individuals. GPs are often the first point of contact for patients, however they may not know enough about the condition to give adequate care or recommend patients to a specialist [19]. AA scored higher than melanoma (138/176) as compared to non-melanoma skin cancer (150/176) and psoriasis (144/176) among others. Despite recent increases, National Institute of Health funding for AA remains shockingly low considering the impact of the condition [20]. The hair follicle has significant feature of having immune privilege mainly given by surface molecules suppressed to present CD8+ T-cell lymphocytes from auto antigens with later termed as MHC Class-I and in some cases as generated by inhibiting local environment signaling the cells to develop AA by breaking down the immune privilege [21]. The hair follicles are continually recycled during the various stages of the hair growth cycle. In a typical growth cycle, the follicle goes through three stages: telogen, anagen, and catagen [22 23]. The phases of hair growth cycles are reduced or altered in AA patients. Hair follicles in the anagen phase, which are responsible for creating melanin, are the primary targets of the inflammatory infiltration seen in this condition. T cells, natural killer cells, dendritic cells and mast cells, are all part of the complex inflammatory cell infiltration. When the anagen hair follicles are attacked by the inflammatory cells, they are hurriedly transitioned into the catagen phase [23].

Figure 1: Hair cycle in alopecia areata

The immune privilege collapses in healthier hair follicles thus converting them to a condition termed as Alopecia Areata. The condition could develop in genetically predisposed person having some pro-inflammatory signals like substance P as well as IFN gamma usually known for regulating MHC class I present in epithelium of hair follicles in humans exposed previously in follicular associated antigens towards pre-existing CD8+ T cells that are auto reactive. The triggers reported are commonly are physical stress, viral infections, vaccines, emotional stress and using drugs [24, 25]. Receptor, Janus kinase (JAK), and signal transducer and activator of transcription (STAT) are the main actors in the JAK-STAT signaling pathway. IFNs, ILs, and other cytokines and hormones are examples of ligands that the cell surface receptor binds to. The JAK family of tyrosine kinases includes JAK1, JAK2, and JAK3 in addition to tyrosine kinase 2. (TYK2). In response to signals from ligands, JAK phosphorylates a tyrosine in its own protein, activating its kinase function and allowing it to phosphorylate a STAT protein. The STAT component is phosphorylated to cause dimerization and activation of STATs. After being activated, STATs move to the nucleus, where they induce transcription of DNA. This action ultimately results in the activation of genes [26].  Gene expression is a fundamental step because it activates cytokines, which mediate cellular functions. The IFN signaling route led to the discovery of the JAK-STAT signaling pathway. Since then, it has been discovered that many cytokines can activate the JAK-STAT pathway, resulting in a wide range of gene expression. Keeping both innate and adaptive immunity strong requires the JAK-STAT pathway to function properly. Myeloproliferative neoplasms and severe combined immunodeficiency are two examples of haematological and immune-related illnesses that can be caused by a missing or malfunctioning JAK component [27]. In light of the fact that the JAK-STAT pathway is crucial in mediating the CD8+ NKG2D+T cell response, a component of AA pathogenesis, It appear to be a promising alternative for the therapy of AA. Inhibiting this route also stimulates the hair development cycle, which improves the efficacy of treatments for hair loss. The following sections will go into greater detail on the topic of the JAK-STAT pathway, the hair growth cycle, JAK pathway and AA [27, 28]. Hair thinning in AA patients may be attributable to an abnormality in one of the follicle growth phases, namely a rushed shift from the anagen to the catagen or telogen phase. It has been hypothesized that genetic, immunologic, and environmental variables may all have a role in the development of AA, despite the fact that the aetiology of AA is not well recognized [29-31]. Emotional or physical stress, such as that experienced after a loss or an injury, is frequently cited as the cause of AA. The severity of AA and its possible onset are both influenced by the surrounding environment. Although stress is commonly listed as a cause of AA, the evidence from human research is mixed. Medications, fever, illnesses and vaccines are some others. Vaccination against a wide range of human diseases, such as Clostridium tetani, hepatitis B virus, HPV and herpes zoster virus has been associated with a small increase in the incidence of AA. In contrast, a study found that swine flu infection either caused or aggravated AA. Soy products have been linked to AA in the mouse model, and recent research highlights a connection among AA and Vitamins A and D. Multiple environmental factors may affect the progression of the condition [32]. In alopecia areata there is a reduced antigen-presenting cell activity and down regulation of major histocompatibility complex class I (MHC I) and class II (2 macroglobulin) molecules. There is production of immunosuppressive molecules like transforming growth factor and melanocyte-stimulating hormone which create an immune privilege zone in the normal hair follicle [17].  AA is strongly linked to autoimmune disorders like vitiligo. Those who suffer from Alopecia Areata (AA) or Alopecia Universalis (AU) are at a higher risk, while those who have vitiligo are at 4 times higher risk. Patients with thyroid illness (2.3%), type 1 diabetes (3.2%), rheumatoid arthritis (0.9%), pernicious anaemia (10-60%), and vitiligo (4.1%) have all been found to be at increased risk for developing AA [33]. Observational studies have found a strong association between AA and genetics (10%-42%). The incidence is predicted to be between 0% and 8.6% in adults with a family history, and between 10% and 51.6% in children. Men were more likely to report a favorable family history than women. The fact that AA strikes in pairs of identical twins, between siblings, and in multigenerational families suggests a genetic component [34]. The linkage has been found between AA and the numerous SNPs (Single Nucleotide Polymorphs) when genome-wide studies have been conducted. The stronger predictor found, in recent meta-analysis, for AA was HLADR (Human Leukocyte Antigen DR) present on chromosome number 6. The genes of HLA class II are very closely related to CD4+ & CD8+ T-cells effecting crucially on AA. The commonly known protein BIM or BCL2 that helps in controlling autophagy is also helping in determining the disease etiology. The genes encoding the natural killer cells like receptor D ligands as well as JAK pathway also increase significantly the vulnerability of AA. TREGS (T-regulatory cells), autophagy & apoptosis also seems to be involved in developing AA but further researches are needed to pin down the precise mechanisms [35]. This disease significantly affects the quality of life of the patients. Hair loss, depending on its intensity and duration, is a major source of stress. The psycho-social effects of AA on patients and their loved ones have been shown to be quite substantial. Major depressive illness, chronic anxiety, and social phobia all have a high prevalence rate among AA members. Affected individuals especially the young people have been reported to have a low Health-Related Quality of Life (HRQoL). It can lead to great distress and emotional disturbance for the patients [36, 37]. The manifestations of alopecia Areata vary widely from person to person, and even within the same person. The illness is clinically categorized into many subtypes based on the areas of skin affected, the pattern of hair loss, and the severity of hair loss. Patchy AA characterised by single or several circular areas of baldness on the scalp, is the most prevalent clinical manifestation of alopecia Areata. These hairless patches can appear singly or join together to produce larger areas. Within the lesions, the skin seems smooth and healthy. A minor edema may be perceptible, but there is no erythema or other evidence of inflammation. A lesion’s width can remain stable or develop depending on the disease’s activity, and spontaneous remission followed by complete or partial regrowth is also a possibility. If left untreated, AA’s patchy hair loss can develop into alopecia totalis (AT) or alopecia universalis (AU) [38]. There are a many types of alopecia Areata of the scalp, each corresponding to a specific pattern of hair loss. Hair loss in the temporal and occipital regions of the scalp forms a band-like bald spot that takes the form of a snake (“ophis” means “snake). By contrast, sisaipho, also known as inverse ophiasis type, causes thinning of hairs in the central part more than androgenetic alopecia. DAA (Diffuse alopecia Areata), also known as AAI (alopecia Areata incognita), is usually a non-patchy type of Alopecia Areata (AA) that is commonly wrongly diagnosed or detected significantly later than the more prevalent forms. Diffuse alopecia Areata is characterised by widespread balding, and it affects primarily young to middle-aged women. One school of thought holds that DAA and AAI are two distinct diseases. Other aberrant hair regrowth patterns have been recorded, however they are extremely rare [39-41]. Androgenic alopecia, as suggested by its name showed a clear predisposition genetically and is excessive response was likely shown to androgen. The polygenic disorder having variable penetrance of pattern alopecia, and genes of both maternal and paternal side were involved. Androgenic alopecia is definitely a familial predisposition with sons was 5-6 times higher in having relative risk if baldness was present in fathers. It is a disease that causes loss of hairs due to increase sensitivity of scalp hair follicles to di-hydrotestosterone. It occurs in a well-defined pattern, male pattern hair loss and female pattern hair loss. In males the loss of hairs begins at the upper region of the temples and extends throughout with time forming characteristics M shaped pattern. The key difference between androgenic alopecia and AA is that it occurs due to increased sensitivity of scalp hair follicles to di-hydrotestosterone, while AA is an autoimmune disease. Androgenic alopecia mainly characterized by having trichoscopic abnormalities predominance in the frontal region as compared to the occipital region. The hair follicles miniaturization using trichoscopy showed that it is heterogeneous at hair shaft thick region that is >20% observed hair shafts become thinner than terminal shafts and there is also increased percentage of vellus thin hairs (i.e., >10% of them) [42]. The commonly known imitator is called syphilis that could present in the form of wide ranging clinical symptoms thus mimicking the other important diseases. On the other hand, atypical manifestations can commonly overlap the different stages. The secondary syphilis signs showed that SA (syphilitic alopecia) is usually less frequent and its prevalence range documented as 2.8% – 22.1%. Such prevalence is typically underestimated as possibility of subtle presentation is evident along with the diagnosis difficulty. The definition of SA is essential while alopecia becomes the only possibility and muco-cutaneous signs are present. The clinical appearance suggests that the SA is classified as: 1) diffuse alopecia mainly characterized of diffused hair loss; 2) moth-eaten (patchy alopecia) mainly having small irregular patches distributed unevenly/evenly over the scalp area; and 3) combined mix form (both diffused hair loss & moth-eaten patches like). The SA trichiscopic findings that are known nowadays mainly based on case series consisting of 6 cases (one diffuse & 5 moth-eaten type SA) [43-45]. A full medical and family history, as well as a physical examination of the patient’s scalp, face, and any other areas of the body (including the nails), are essential components of an accurate diagnosis of AA. Skin scraping, dermoscopy and the hair-pull test are essential companion procedures if there is any clinical suspicion then additional tests are needed, such as a fungal culture, scalp biopsy, or serology for other autoimmune illnesses or infectious diseases (such as syphilis) [16]. There is strong association of alopecia Areata to a variety of illnesses like thyroid disease of autoimmune nature, psoriasis, vitiligo, lupus erythematosus, and also rheumatoid arthritis. Multiple evidences suggested that these disorders may share molecular pathways, including genetic investigations, retrospective analyses, and systematic reviews. Patients suffering from alopecia Areata have an increased risk towards thyroid illness (autoimmune), thyroid autoantibodies if comes positive, aberrant thyroid function tests reporting (findings), and also thyroid malfunctioning. The correlation seen between the disease (AA) and thyroid antibody test positivity (TPO-Ab, TG-Ab) appears to be stronger than the correlation among AA and a laboratory or clinical thyroid problem. Additionally, a higher prevalence of atopic diathesis, including allergic rhinitis, allergic conjunctivitis, atopic dermatitis, and asthma, has been documented in AA patients. Research into whether or not AA increases the risk of developing diabetes mellitus has yielded conflicting results. The insufficiency of Vitamin D, deficiency of iron (anaemia), Down syndrome, metabolic syndrome and also Helicobacter pylori infection, and these all appeared to be seen more commonly among people having the disease (AA). Depression and anxiety disorders are the most common mental disorders that are significantly related with AA [46]. In children under the age of 10 years, atopic dermatitis is a common co-existing condition, whereas in adults over the age of 60 years, diseases like thyroiditis and dermatitis appeared being most common in same conditions. In comparison to patients with patchy AA, those with AT/AU are much more likely to experience at least one related condition [47]. When making a clinical diagnosis of AA, it is not standard practice to prescribe routine blood tests and screening for autoimmune illnesses to all patients. However, in cases of thyroid family history, down syndrome and atopy, as well as thyroid function routinely screened should be done among pediatric patients [48]. The courses of Alopecia Areata is characterized by unpredictable and fluctuating hair loss, might include relapse, significant hair loss persistency or remissions. The long-term development of AA does not appear to be influenced by therapeutic measures. About half of patients will recover on their own within a year after the first episode. The relapse rate, however, has been reported to be as high as 85% and, when monitored over the long term, can reach 100%. The degree of disease is the most important indicator of prognosis (that is, extent of hair loss). Poor prognostic markers include the clinical presentation related to AT, ophiasis pattern, AU as well as nail involvement. These features are associated with a low likelihood of successful hair regrowth, treatment resistance, and relapse. An higher chance of developing AT/AU is also associated with nail involvement. Prior to the introduction of diphenylcyclopropenone (DPCP), only about 10% of cases of AT and AU were known to have been successfully treated [49]. The onset at earlier age is mainly associated to disease severity as well as its poor prognosis. Whereas, disease activity and its severity, current episode duration, relapse rates always decreases with older age. Therapy resistance, delays between onset of the disease and therapeutic care, and persistent hair loss are all additional indicators that predict a bad prognosis. Other factors that have been linked to more severe disease and a bad prognosis include a positive AA family history, the atopic and autoimmune disease presence, & the Down syndrome presence. The evidence for a positive trend in atopy’s past is inconclusive [50]. Most recent treatments used for AA tried restricting or modifying the immune system’s activities, but these approaches have yielded mixed results and substantial relapse rates, particularly in the more severe cases. It is challenging to determine the efficacy of therapy because of the unexpected progression of the condition and its frequent reduction limits seen during the treatment first year. In addition, the current therapy alternatives as reported in literature showed no affect towards the long-term occurrence of the condition, therefore there is still a pressing need for novel, more effective medications. As researchers learn more about the disease’s pathophysiologic underpinnings, they are able to design more specific treatments [51]. When administered sparingly, topical corticosteroids have a low side-effect profile and are therefore frequently utilized as being first-line of action among the children having very limited patchy areas of AA. In more extreme cases, they are indicated as a complementary treatment. These days, a wide variety of generic formulations of corticosteroids, including solutions, shampoos, and foam preparations, are readily available for topical use. In a trial with 43 patients, 84% of those having patchy condition of AA demonstrated >80% hair grown back among them after utilizing a lotion containing 0.05% clobetasol propionate, while only 57% of those with androgenetic alopecia and 80% of those with atopic alopecia saw any improvement. Clobetasol propionate 0.05% was shown to be effective in a trial of individuals with long-term AT and AU, however only 28.4% patients reported successfully treatment results, while only 18.5% patients had their hair regrowth maintained. For mild to moderate AA, betamethasone valerate foam is another useful therapy [52]. Topical corticosteroids of moderate potency (such as mometasone furoate or methylprednisolone aceponate) are recommended for children younger than 12 years old because of their high therapeutic index. Folliculitis, skin atrophy might occur, but these effects are usually temporary and treatable [53]. Intra-lesional corticosteroids injection administration alone or in conjunction with topical corticosteroids can be used as the initial line of treatment. Triamcinolone acetonide is a great choice for a corticosteroid. There are typically 3–5 sessions spread out over the course of 4–6 weeks. However, if no negative effects are shown after the initial injection, additional injections might be given if necessary. Every session, triamcinolone acetonide tiny drops (10 mg/ml) (look like crystal suspension) are diluted using either saline solution or local anesthetic in proportion of 1:1 and administered intralesional to prevent atrophy. To slow the spread of lesions, the injections are made using a very fine needle such as 27 G, primarily inside the lesion borders. Do not inject more than 1.5-2 mg of triamcinolone acetonide per cm². These injections should not exceed 1 mg/cm², and only qualified medical professionals should administer them near the eyebrows and beard. Hair regrowth often begins between 4 and 8 weeks after treatment has ended, while some patients may not see any results until after many months [54]. Only in cases of mild to moderate AA have intralesional steroid injections been studied, although results have shown a hair regeneration rate of 56%-97%. But on a look back among 10 patients having severe AA (SALT score of > 50%), the documented therapeutic response was almost 60%. Patients with active illness may derive greater benefit from intra-lesional injections. Recent comprehensive review and meta-analysis among the intra-lesional triamcinolone acetonide used in the patchy areas of AA found comprehensively that the hair regrowth rates at 5 and 10 mg/mL concentrations were comparable, while lower rates occurred at concentrations 5 mg/mL. Unfortunately, there is a dearth of data on relapse rates in the published literature. Mild discomfort experienced while the injection administered and the skin atrophy developed, that is usually considered reversible, are the most prevalent adverse effects. There is a chance of increased intraocular pressure when injecting between the brows [55]. Pulse and systemic therapy of corticosteroids have been used to treat AA. Studies report a wide range of therapy approaches. Consequently, it is challenging to make meaningful comparisons between outcomes, given that efficacy ranges from 28% to 84% and that response rates for AT and AU ophiasis are quite low [56]. Relapse rates were found to range from 25% to 75%, depending on the length of time patients were monitored [57]. Forty percent of those given prednisolone responded significantly to oral pulse therapy, while twenty-five percent relapsed within three months. Although there have been no reports of major or long-term side effects of pulse therapy, even in youngsters, the well-known side effects of steroids provide a barrier to their widespread and long-term usage in AA [58]. When treatment of moderately – severely affected patients with AA in adults having SALT score of >30%, the corticosteroids taking orally, either separately or in conjunction of using corticosteroids of topical nature, that was generally accepted being first-line therapy. A 1 mg/kg initial dose is prescribed as per body weight and finally tapered off over the period of almost eight days, followed by corticosteroid application again for upcoming three weeks, has been reported as significantly successful for using in daily practice; and such course must be repeatedly given for at least three or four times. Although pulse therapy administered orally or intravenously may appear to be ineffective while the patient is experiencing the acute phase of disease, and during the hair cycle remains disrupted and results in hair falling, it could actually promote as well as decrease its period until hair regrowth begins again [59]. Recently published meta-analysis and the comprehensive review demonstrated that the hair regrowth response rate to DPCP therapy was 65.4% (73.6% rate at patchy AA and 55.5% among AT/AU areas), and widely range between different studies from 5%-85.5%, but regarding the complete hair regrowth response rate was only 31.3%. Among patients receiving maintenance treatment showed relapse rate=38.3% in comparison to 49.0% of those who did not. The therapeutic responses of AT/AU are lower than those of patchy AA, with AU being the lowest. Only 17.5% of participants with AT/AU in a big experiment saw their hair grow back, whereas 62.6% had relapses within three years. Although clinical trials demonstrate poor response and significant relapse rates when DPCP is used in children, it is still an option [60]. Typically, the minimum age is 12 years old, but it might be lower or higher. Hyperpigmentation, depigmentation, flu-like symptoms, and occipital or cervical lymphadenopathy are among the possible negative side effects. Less common side effects include those similar to erythema multiforme, such as fever and headache [61]. Anthralin can be used instead of DPCP for extended AA or AT due to its lower risk of adverse effects, which is especially beneficial when treating young patients but is not limited to them. Anthralin’s topical treatment results in irritating dermatitis, which, for reasons that have not been determined, stimulates hair growth. The benefit is that it can be used in the comfort of one’s own home, with concentrations ranging from 0.5% to 1%, and with application times varying from ten minutes to overnight. Once the slight dermatitis caused by the anthralin has cleared up, the dosage or duration is increased. On average, patients experience improvement after 4 months of treatment, at which point they should continue receiving care for even longer [62]. Response rates demonstrated among patients having patchy AA was 74%, and among those having severe AA as well as AT ranges from 17-38%, but there are only a small number of trials on the efficacy of anthralin as monotherapy. And in 33% of cases, children with AA had full hair regeneration, according to a research. Contact causes significant irritability and also discoloration of the fair hair, clothing and skin. Self-treatment is an option for many people, and unlike topical sensitization therapies, it is not linked to any permanent immune system changes [63]. Response rates to methotrexate (MTX) in severe AA range from 38-64%, however using methotrexate with orally administered corticosteroids gave comprehensively improve outcomes. Relapse rates after stopping MTX treatment are significant, despite the fact that the drug is typically given over extended time periods. The majority of investigations, including those involving children, found either no adverse outcomes or only mild ones. It must be utilized only among patients having considerably severe disease that is resistant to traditional medications and also used having high psychological load because to the lack of clear evidence on the efficacy and safety of this method. Adolescents between the ages of 13 and 18 are safe to receive MTX treatment, according to most experts [64]. Cyclosporine either alone or in combination with other treatments, appear to be affective in mild and severe AA. However, because of the dangers it poses, it shouldn’t be used for AA. Dapsone does not work, and azathioprine and sulfasalazine are not suggested, for the treatment of AA. There is little to no encouraging data indicating that apremilast or simvastatin/ezetimibe is effective treatments. Failure of tumour necrosis factor (TNF) inhibitors to effectively treat AA has been reported, and in some cases, anti-TNF therapy has been linked to the onset of AA in previously undiagnosed patients [64]. Dupilumab has been observed to cause hair regrowth in individuals with coexisting AA who were previously treated against moderately or severely affected atopic dermatitis, but these results remain contradictory. However, there are cases of people developing AA for the first time after dupilumab treatment. Interestingly, AA may also be induced in MS patients receiving treatment with the monoclonal antibodies alemtuzumab and ocrelizumab [65]. Tofacitanib or Xrljanz, is a non-FDA approved treatment for hair loss secondary to alopecia areata. This janus kinase inhibitor (JAK inhibitor) interferes with the immune system to prevent the autoimmune disease alopecia Areata. Tofacitanib encourages hair regrowth and healthy hair follicles. Tofacitanib is a JAK inhibitor it suppresses the effects of the interferon and cytokines. During last 2 years, newly invented treatment technique that is JAK inhibitor is used commonly known as Ruxolitinib & Tofacitinib (oral medications). The AA patients if treated with such medicine give favorable outcomes and hair regrowth (almost 50%) was seen in 53 to 82% proportion. The JAK inhibitor theory showed that it commonly inhibits the basic interleukin-15 & interferon-gamma in hair follicle as well as white blood cell signals thus reducing the hair follicle damaging. Studies using psoralen plus ultraviolet A (PUVA) have shown mixed results, with some patients responding and others not. Low success rates mean that this technique cannot be advised, especially as repeatedly as well as prolonged treatments that results in unacceptable higher cumulative ultraviolet a doses. A systematic review and meta-analysis of the research into the efficacy of excimer laser for treating AA was published not too long ago. With 50.1% patients had reported clinically significant having hair regrowth, it seems to generate a positive treatment response; nonetheless, the evidence basis is weak [66]. The minoxidil usage for the treatment of alopecia Areata patches is commonplace in clinical practice. It is important to remember, though, that topical minoxidil does not have any anti-inflammatory impact. As a co-medication with other therapies that can halt or reverse the inflammatory infiltration, it is most often used to promote hair growth [67]. There is still some debate regarding whether or not oral zinc and vitamin D are effectively treating the alopecia Areata, and the research primarily comprises of tiny case-control studies and case-reports with contradictory findings. Serum zinc levels were lower in patients with resistant AA compared to newly diagnosed AA, however zinc insufficiency is uncommon in the AA population as a whole. Zinc’s immunological properties are primarily responsible for the recommendation of oral supplementation in AA. In addition, the severity of AA, its response to treatment, and the length of time it has been around all linked negatively with lower serum zinc levels. Researchers tested that use of oral zinc sulphate (approx. 5 mg/kg/day) in treating the alopecia Areata among the 100 patients via a double-blinded, cross-over research, and found that after 3 months, roughly 60% of patients had total hair regrowth, in comparison to just 10% among the group utilizing placebo. So, it may be safe and useful to take the oral supplement daily (50–100 mg) including zinc gluconate and aspartate, and zinc sulphate in 2 to 3 months [68]. It has been demonstrated through research that retinoic acid (RA) is essential for hair growth, specifically in the production of hair follicles and in patterning via the home box (Hox) gene proteins (Hox C8 as well as C6). For instance, RA has an effect on the skin’s craniofacial and neural crest development. It appears that RA both up- and down-regulates the home box genes, which in turn affects hair follicle development, initiation, differentiation, and inhibition. Follicular hair cells are vulnerable affecting the RA and these RA receptors genes had been found among nearly all parts of the hair follicles. Because of retinoic acid’s positive effects showed on the hair growth, the topical retinoids both tretinoin as well as bexarotene have shown effective for treating both alopecia Areata as well as androgenic alopecia (AGA). Synthetic adapalene is an analogue of naphthenic acid that has been used topically for medical purposes from the third generation. Due to the anti-inflammatory properties of combination drugs and the capacity in blocking critical pathophysiological mechanisms resulting in development the condition of acne, adapalene has emerged as one of the essential lagents of acne treatment. Adapalene has been shown to be effective in treating acne, however unlike tretinoin and bexarotene, which are both topical retinoids, no studies have reported its effectiveness in treating alopecia areata or androgenetic alopecia [69]. With the success seen with topical tretinoin and bexarotene, it is reasonable to assume that adapalene will prove to be a successful drug in the treatment of AA as well [70].

3. CONCLUSION

It is concluded that from the review of this study, we may conclude that combination of 0.1% mometasone furoate cream and adapalene gel in treating Alopecia Areata was more safe and efficacious for managing Alopecia Areata as compared to 0.1% mometasone furoate cream alone

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