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 Table of Contents  
REVIEW ARTICLE
Year : 2017  |  Volume : 4  |  Issue : 2  |  Page : 78-84

Systemic therapy for melasma: Exploring newer options − A comprehensive review


1 Department of Dermatology, College of Medicine and Sagore Dutta Hospital, Kolkata, West Bengal, India
2 Department of Dermatology, Maulana Azad Medical College, New Delhi, India

Date of Web Publication1-Dec-2017

Correspondence Address:
Indrashis Podder
Department of Dermatology, College of Medicine and Sagore Dutta Hospital, Kolkata, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2349-5847.219672

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  Abstract 


Melasma is a chronic, hyperpigmentary disorder affecting the face, more commonly the females and has a significant psychological and social impact. Currently available treatment options such as prevention of ultraviolet radiation, topical lightening agents, chemical peels and light-based or laser therapies are useful in the short run but fail to produce a sustained improvement and complete clearance. The condition frequently recurs after successful treatment. Thus, the search is on for efficacious systemic agents which would help in maintaining remission and prevent relapses. Many of the oral agents provide improved results when used as adjuncts, with minimal side effects and may help to achieve quicker, better and long-lasting results. This article aims to review the efficacy, safety and tolerability of different systemic anti-melasma agents.

Keywords: Efficacy, melasma, safety, systemic agents


How to cite this article:
Podder I, Sarkar R. Systemic therapy for melasma: Exploring newer options − A comprehensive review. Pigment Int 2017;4:78-84

How to cite this URL:
Podder I, Sarkar R. Systemic therapy for melasma: Exploring newer options − A comprehensive review. Pigment Int [serial online] 2017 [cited 2017 Dec 14];4:78-84. Available from: http://www.pigmentinternational.com/text.asp?2017/4/2/78/219672




  Introduction Top


Melasma is a commonly acquired, chronic, circumscribed hyperpigmentary disorder mainly involving sun-exposed areas, especially the face in a symmetrical fashion. Females in the 3rd and 4th decade are most prone to develop this condition; however, Sarkar et al. reported a prevalence of 20.5% among Indian males.[1] It is more common in Fitzpatrick skin types IV, V and VI namely the Hispanic, Caribbean and Asian races as they live in areas exposed to intense ultraviolet (UV) radiation resulting in larger amounts of melanin production.[2] In India, melasma is the most common pigmentary disorder, with an incidence of approximately 10%;[3] often developing at a younger age having strong correlation with positive family history, thus, supporting the role of genetic factors in its development.[4]

Although the exact pathogenesis is unknown, dysfunctional melanogenesis plays a pivotal role. Two groups of factors seem instrumental: ’endogenous factors’ (genetic predisposition and cutaneous vasculature) and ’exogenous factors’ which may trigger the conditions such as sun exposure, pregnancy, use of oral contraceptives and steroids, ovarian tumours, intestinal parasitic infestation, deranged liver function, use of cosmetics and photosensitizing medications, inflammatory disorders of the skin and stressful events.[5] The significance of this condition owing to melanogenesis is due to the fact that it relapses frequently, is difficult to treat, and severely affects social and emotional well-being of patients.

The treatment of this condition remains challenging because its pathogenesis is poorly understood. Proper patient counselling, adequate sun protection measures and topical depigmenting agents (interfering with melanin synthesis) comprise the first line of therapy. Different types of chemical peels (e.g. glycolic, retinoic, etc.) are often added as second line therapy. Laser and other light-based therapies are being evaluated as potential therapies in refractory cases, although they carry the risk of worsening the condition in some cases.[6]

Recently, several systemic agents have been introduced for the treatment of melasma, most often as adjuncts to the established therapeutic modalities. A lot is known about topical skin whitening agents, but data are scarce regarding systemic skin whitening agents which are slowly gaining popularity. Moreover, their usage remains controversial and tricky because there are contradictory reports regarding their efficacy and adverse effects. This article aims to discuss the pros and cons of different systemic agents available for treating melasma along with the review of literature to promote their rational use. The commonly used systemic agents with their routes of administration are tabulated below [Table 1].
Table 1: Systemic agents being currently used for treatment of melasma and their routes of administration[5],[7],[8],[9],[10],[11],[12]]

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  Materials and methods Top


A literature search was performed using PubMed, Scopus, Medline, Embase and Cochrane databases. Key words searched included ’melasma’, ’hyperpigmentation’, ’systemic agents’, ’efficacy’, ’safety’ and ’skin-lightening agents’. Only English language articles have been considered without any time limitation. We have attempted to include all studies that analysed the role of systemic agents in the treatment of melasma.


  Discussion Top


The different varieties of systemic therapy for melasma are briefly discussed below along with the review of literature.

Tranexamic acid

Tranexamic acid (trans-4-aminomethyl cyclohexane carboxylic acid) (TA) is probably the most studied systemic agent being used for the treatment of melasma. It is a plasmin inhibitor, commonly used as a haemostatic agent owing to its antifibrolytic action. It is also being promoted as a systemic skin-whitening agent probably related to its antiplasmin activity. Its first usage in the treatment of melasma dates back to 1979.[13] It has been reported to be efficacious as oral medication, localized intradermal microinjection[5] or intravenous formulation (not available in India).[14]

Several mechanisms of action have been proposed for this medication, and those have been tabulated below [Table 2].[5],[8],[14],[15],[16]
Table 2: Mechanism of action of tranexamic acid in melasma

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Several authors have demonstrated the efficacy of oral TA in melasma [Table 3]. The standard dose of TA is 500 mg/day as single or two divided doses and the duration of therapy ranging from 2 to 6 months.
Table 3: Use of oral tranexamic acid for treatment of melasma

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Fortunately, side effects reported with oral TA are few and are generally mild in nature including nausea, diarrhoea, abdominal pain, skin rashes, alopecia, drowsiness and menstrual irregularities, usually reversible on discontinuation of the drug. Careful screening for personal and familial risk factors for thromboembolism is recommended before initiation.[22] The drug is contraindicated in the presence of coagulation disorders, pregnancy and lactation to avoid any catastrophe,[14] although potentially life threatening side effects namely deep vein thrombosis, pulmonary embolism and myocardial infarction have not been reported at this low dose.[22],[23] However, a variable relapse rate ranging from 9 to 27% has been reported after stopping the medication.[14],[18],[22]

Glutathione

Glutathione, a low molecular weight thiol-peptide plays an important role in maintaining the intracellular redox balance, itself being a powerful antioxidant. Recently, it is being promoted as a systemic skin-lightening agent for the treatment of several conditions including melasma. However, its use remains debatable due to lack of evidence base studies as well as several adverse effects being reported.

Glutathione exerts its hypopigmentary effect by several mechanisms namely direct (by binding with the copper-containing active sites) and indirect (via antioxidant effect leading to exhaustion of free radicals and peroxides) inhibition of tyrosinase enzyme (the key enzyme for melanogenesis).[9] It also switches the production of eumelanin to pheomelanin by the formation of sulfhydryl-dopa conjugates.[24] Additionally glutathione has been shown to scavenge UV radiation-induced reactive oxygen species generated in epidermal cells.[25] Its antioxidative action also helps to lighten melasma, as several studies have confirmed the role of oxidative stress in melasma.[26],[27]

Glutathione may be used orally (20–40 mg/kg/day in two divided doses) or intravenously (600–1200 mg). However, the intravenous route is not recommended because of safety concerns. The duration of therapy is not specified, although most studies have recommended 12 weeks to obtain results.

Several studies have demonstrated the efficacy of glutathione as a skin-lightening agent [Table 4].
Table 4: Efficacy of systemic glutathione in treating melasma

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Although there are few studies regarding the efficacy of oral glutathione, intravenous glutathione has not been studied till date. But the usage of this drug remains debatable as several adverse effects have been reported, especially with the parenteral formulation. Another deterrent to its use remains the high cost. Adverse effects reported with long-term use of systemic glutathione have been tabulated below [Table 5].
Table 5: Adverse effects reported with systemic glutathione (intravenous > oral)[9]

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These adverse effects have prompted the Food and Drug Administration of Philippines to issue a public warning regarding the safety of the off-label use of glutathione injection as a skin-lightening agent.[9]

L-Cysteine peptide

L-Cysteine peptide is another remarkable antioxidant which may be used for the treatment of melasma owing to its skin-lightening property. It is claimed to be 3–5 times more potent than glutathione.[7] High concentration of this molecule inhibits the tyrosinase enzyme (rate limiting enzyme for melanogenesis) and promotes pheomelanin synthesis by forming cysteinyl-dopa. L-Cysteine may be obtained from natural sources such as poultry, yoghurt, egg yolks, red peppers, garlic, onions, broccoli, Brussel sprouts, oats and wheat germ.

Although stray reports have demonstrated its efficacy, proper scientific evidence is lacking to recommend the use of this product for the treatment of melasma.

Polypodium leucotomos extract

P. leucotomos extract, derived from the tropical South American P. leucotomos fern is a systemic sun-protecting agent. It has been used in oral form to treat several dermatological conditions namely psoriasis, atopic dermatitis and polymorphic light eruption with varying degrees of efficacy.[23] Recently, some studies have shown its efficacy in the treatment of melasma [significant reduction in melasma area severity index (MASI) and melasma associated quality of life (MelasQoL) scores] probably due to its collagen-remodelling role (inhibition of metalloproteinase enzyme) in sun-damaged skin.[30],[31] It is also a powerful anti-oxidant and anti-inflammatory agent.[10] However, Ahmed et al. reported no significant improvement with polypodium when compared to placebo.[32] No significant adverse effect has been reported till date with 480–1200 mg/day for 3 months.[23],[30],[31]

Thus, P. leucotomos is well tolerated but not significantly better than placebo in the treatment of melasma.

Oral antioxidants

Oral antioxidants viz. vitamins A, C and E have been found to be beneficial in the treatment of melasma when used as adjuncts along with topical therapy and oral proanthocyanidin. Handog et al.[33] demonstrated significant improvement of melasma (mexametric analysis and improved MASI scores) when oral antioxidants were used as adjuncts, in comparison to placebo. The antioxidants were taken twice daily for 8 weeks to obtain the desired results. Isolated use of vitamins C and E has also been beneficial in some patients, although their combined usage provided better result. Mild and reversible side effects such as abdominal pain and metallic taste have been reported rarely.[33]

Pycnogenol/procyanidin

Pycnogenol, a standardized plant extract obtained from the bark of pine tree Pinus pinaster has recently generated huge interest in the management of melasma. It contains procyanidin as its main active ingredient (65–75%) apart from other catechins, epicatechins and ferrulic acid.[8] It is a powerful antioxidant (more powerful than vitamins E, C) and anti-inflammatory agent acting by doubling the intracellular synthesis of anti-oxidative enzymes and scavenging free radicals. It has also been demonstrated to reduce UV-induced erythema by inhibiting the expression of nuclear factor-κß.[34] Ni et al. demonstrated a significant reduction in pigment intensity and melasma area in almost 80% of Chinese patients taking the drug (25 mg thrice daily for 30 days). The study also highlighted the high bioavailability of this agent and absence of any serious side effect (clinical and laboratory parameters) apart from metallic taste. Additionally, several other associated symptoms such as fatigue, constipation, body ache and anxiety also showed remarkable improvement.[35]

Melatonin

Melatonin, a hormone synthesized by the pineal gland is a powerful antioxidant and free radical scavenger which reduces the generation of UV-induced free radicals. In addition, it also interferes with the pigmentary action of some hormones namely alpha-melanocyte stimulating hormone (α-MSH), oestrogen and progesterone. These properties have generated interest in melatonin as a safe and effective therapy to combat melasma. Hamadi et al. have substantiated this view by demonstrating the efficacy of both topical and oral melatonin in the treatment of melasma, when used as an adjunct with other topical therapies.[36] They also demonstrated the safety of oral melatonin up to a dose of 3 mg/day given for 90 days, except for the occurrence of mild, transient drowsiness in some patients.

Herbal extracts

Rhus vernciflua stokes (RVS) is an oral herbal medicine, recently being investigated as a systemic therapy for melasma. Animal studies have demonstrated its inhibitory action on melanin synthesis by blocking the tyrosinase enzyme in a dose-dependent manner. Moreover, α-MSH-induced generation of microphthalmia-associated transcription factor and tyrosinase were also significantly inhibited in B16F1 melanoma cells treated with RVS.[12] However, human studies are lacking till date. Khan et al.[37] have also reported the efficacy of Hippophae rhamnoides and Cassia fistula extracts as skin-lightening agents in Asian patients with melasma. So, these herbal extracts may be tried as adjuvant skin-lightening agents in hyperpigmentation disorders namely melasma in the near future.

Miscellaneous agents

Apart from these, several miscellaneous agents such as hyaluronic acid, green tea, ellagic acid-rich pomegranate extract, coumarin extracts from the plant Angelica dahurica, epidermal growth factor and combinations of multiple natural extracts namely natural collagen extracts, bearberry extract, Glycyrrhiza glabra extract, grape seed extract, lycopene, kelp, olive leaf extract, hawthorn, jujube, sea buckthorn, starch, coix seed, pearl extracts, etc. have been used over time for the treatment of melasma owing to their skin-whitening properties in the form of food or dietary supplements. Although there are few animal studies supporting the use of green tea polyphenol,[38] ellagic acid-rich pomegranate extract[39] and coumarin extracts from the plant A. dahurica,[40] human trials are scarce or absent.[8] Yamakoshi et al. demonstrated the skin-lightening property of proanthocyanidin-rich grape seed extract in the treatment of melasma on Japanese women.[11] Thus, most of these agents are used as over-the-counter adjuncts without much credible scientific evidence.

Oral agents used topically

Two agents come alongside with this category − ascorbic acid/vitamin C and zinc. Although oral vitamin C has been used effectively, some concerns have been raised regarding its bioavailability and unstable nature. So, a topical preparation containing vitamin C has been used successfully in the treatment of melisma which showed significant lightening of melasma at the end of 16 weeks.[41] No adverse effect has been reported.

Zinc is another oral agent, which has been used successfully in the treatment of several pigmentary disorders owing for its ability to reduce melanin synthesis apart from having peeling and exfoliating properties. Although Sharquie et al.[42] have demonstrated the efficacy of adjuvant topical ZnSO4 cream in improving melasma, Yousefi et al.[43] reported greater improvement with hydroquinone than topical zinc (although MASI reduced significantly in both groups). However, there is no study yet regarding the role of oral zinc in treatment of melasma. No complication has been reported except occasional and transient burning sensation. Thus, further studies are needed to validate the role of topical zinc as an effective adjuvant in melasma.

Problems with systemic anti-melasma agents

Although most of these systemic agents are devoid of serious adverse effects, probably with the exception of glutathione, their use as a skin-whitening agent for the treatment of melasma is not yet approved by the United States Food and drug administration (USFDA).[7] However, their unregulated use by untrained people may lead to several lethal complications such as sepsis, air embolism, transmission of human immunodeficiency virus and Hepatitis B (parenteral formulations). Use of counterfeit agents may also prove fatal by increasing the risk of severe infections. Predisposition for skin cancers is a theoretical risk because these agents are known to promote the formation of pheomelanin, which is known to damage the deoxyribonucleic acid of melanocytes; however there are no human studies to substantiate this risk.[7] As with other systemic agents, hypersensitivity and hepato-renal dysfunction are notable contraindications for their use. Lack of long-term studies, except for TA, is a deterrent for determining their optimum dosage and delayed side effects.

Economic considerations

These systemic agents are being widely marketed under the ambiguous category of cosmeceuticals (products having both pharmaceutical and cosmetic properties), despite lack of evidence to demonstrate their absolute efficacy, except for TA (which is supported by several studies). India is a growing market for skin-whitening agents as fairness is considered to be a good virtue in our social and cultural circles. Presently, the Indian dermatology market is worth a staggering 1642 crore rupees ($ 410 million), and fairness-directed skin-lightening cosmetic market accounts for almost 61% of the total dermatology market [1000 crore ($ 250 million)].[7] All the pharmaceutical houses are trying to cash-in on this huge market and coming up with newer skin-lightening systemic agents, without adequate tests and research, and trying to promote them by false marketing gimmicks and advertisements. Many untrained individuals are also using them without any regulation for the lure of money, thus, jeopardizing the health of patients.


  Conclusion Top


As we can see, a plethora of systemic agents are available today in the market with claims of improving melasma belonging to varied categories of pharmaceutical agents, cosmetics and food supplements. This article aims to review all these varieties of products available along with review of relevant literature to rationalize their use. The authors have found TA to be the most useful systemic anti-melasma agents with several studies supporting its safety and efficacy. The other agents have also been found effective to varying degrees. However, all these agents provide best result when combined with topical and conventional therapies (sun protection measures). Thus, we opine topical therapy and sun protection measures remain the cornerstone for the treatment of melisma, yet these systemic agents may be added as adjuncts only in recalcitrant cases for improved results. Most of the agents have been found to be safe, except for the parenteral preparations (glutathione). Thus, the unregulated use of parenteral anti-melasma agents should be strongly discouraged. Further large-scale trials/studies are needed for longer durations to validate the use of these systemic agents for the treatment of melasma, thus, enriching our therapeutic armamentarium.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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