WHATS NEW IN THE TREATMENT OF MELASMA?
Authors : Dr. Sweta Rambhia .
Whats new in the treatment of Melasma.
Melasma is a common disorder of hyperpigmentation affecting millions of people worldwide. It is thought to be triggered or exacerbated by sun exposure and hormones, but much remains to be understood about its pathogenesis.
Melasma is an acquired disorder of symmetrical hyperpigmentation appearing as light brown to dark, light brown to dark macules and patches on the face, especially the forehead, malar areas, and chin. It is sometimes referred to as chloasma or the mask of pregnancy. 1
Several clinical patterns of melasma have been described, but many patients have a mixture of these patterns.2 The centrofacial pattern is the most common and consists of lesions on the forehead, cheeks, nose, upper lip, or chin. The malar pattern describes lesions located primarily on the cheeks and nose. The mandibular pattern consists of lesions on the ramus of the mandible.
Although melasma of the forearms has been described, this entity is not always present in patients3 with facial melasma and has not been well characterized. Melasma can be further classified based on a Wood’s lamp examination to help identify the location of the pigment.
ETIOPATHOGENESIS
The Melasma Area and Severity Index
The Melasma Area and Severity Index (MASI) was created by Kimbrough-Green et al 4 in an attempt to standardize the subjective evaluation of melasma. It is calculated by dividing the face into four areas: the forehead, right malar area, left malar area, and chin. Each area is weighted such that the forehead, right malar area, and left malar area are 30% each, and the chin is 10%. Scoring for darkness (D) of pigment when compared with normal skin and homogeneity (H) of the pigment in the specified area (A) is then performed. A numerical value for area of involvement, ranging from 1 (\10% of the area involved) to 6 (90-100% of the area involved) is assigned. The total score is calculated as follows:
MASI= 0.3 A(D+H) forehead +0.3A(D+H) right malar +0.3 A(D+H) left malar + 0.1 chin (D +H) The range of scores is 0 to 48. The MASI score is the most commonly used measurement technique.
Differential Diagnosis
TREATMENT OPTIONS FOR MELASMA
The treatment of melasma includes topical formulations, chemical peels, lasers and light sources. While no single therapy has proven to be of benefit to all patients hence combinations of modalities can be used to optimize management in difficult cases.
SUNSCREENS
A broadspectrum UVA- and UVB-protective sunscreen with an SPF of at least 30 along with a physical block, such as titanium dioxide or zinc oxide, should be used by patients with melasma and should be reapplied every 2 to 3 hourly . Patients should also be instructed to wear protective hats and clothing when outdoors and to practice sun avoidance .
Topical treatments:
Phenolic Compounds
Hydroquinone: It is the mainstay and gold standard drug in the treatment of melasma .Available as 2 % and 4 %. It can be used alone or in combination with tretinoin and fluocinolone (Kligmans formula consisting of 5% hydroquinone, 0.1% tretinoin, and 0.1% dexamethasone, Modified kligmans regime consists of 2% hydroquinone ,1% hydrocortisone and 0.05 % tretinoin ) . Hydroquinone is thought to act by inhibition of tyrosinase, by binding to the enzyme or by interaction with copper molecules at the enzyme’s active site. This leads to altered melanosome formation and increased melanosome destruction, and even the inhibition of DNA and RNA synthesis. In a nonrandomized trial, 4% hydroquinone and broad-spectrum sunscreen was also shown to be efficacious in the treatment of melasma, with 89.5% of subjects showing a good to excellent response. 5 Some patients may develop hypersensitivity to hydroquinone6 .
Other side effects of hydroquinone are burning ,pruritus , itching , ochronosis , occupational vitiligo.
Mequinol:
Mequinol (4-hydroxyanisole) is a phenolic agent that is thought to act as a competitive inhibitor of tyrosinase without damaging melanocytes. It is available in concentration of 2% .It has lesser side effects compared to hydroquinone.
Arbutin:
Arbutin is a beta-D glucopyranoside derivative of hydroquinone that is derived from Uva ursi folium (the bearberry plant) and can also be found in cranberry and blueberry leaves. Its mechanism of action is inhibition of tyrosinase and 5,6-hydroxyindole-2-carboxylic acid (DHICA) polymerase and inhibition of melanosome maturation. Deoxyarbutin is a recently developed derivative of arbutin
Retinoids
Synthetic retinoid such as tretinoin is thought to have inhibitory effect on tyrosinase by inhibiting the enzyme’s transcription as well as on dopachrome conversion factor with a resulting interruption of melanin synthesis and also acts through induction of desquamation. Concentration of retinoid ranges from 0.025 to 00.1%.Associated side effects are erythema and peeling and post inflammatory hyperpigmentation.
Topical steroid Fluocinolone acetonide 0.01 % is used mainly as a triple combination for melasma along with treinoin and hydroquinone. Adding a steroid reduces the irritant effects of hypopigmented agents and inhibits melanin synthesis. Maximum duration for which topical steroids can be continued for melasma is 8-12 weeks . Side effects of steroid include hirsutism, atrophy, telengiectasia and rosacea like dermatosis.
Kojic Acid:
Kojic acid is a molecule produced by Aspergilline oryzae and Penicillium spp. It acts as a tyrosinase inhibitor that works by chelating copper at the enzyme’s active site. This agent is usually available over the counter in a 2% concentration.
Azelaic Acid:
Azelaic acid is a 9-carbon dicarboxylic acid derived from Pityrosporum ovale that acts as a weak reversible competitive inhibitor of tyrosinase. The most commonly reported side effects of preparations containing azelaic acid include pruritus, mild erythema, scaling, and burning. It has been shown to be safe for use in combination with retinoids. 20% azelaic acid has been shown to have greater efficacy than 2% hydroquinone in a 6-month study and to be equally as efficacious as 4% hydroquinone in a 24-week double blind trial
Glycolic Acid:
It is alpha hydoxy acid and has been studied in the combination with other agents. Available in concentration of 5-12 %. It decreases pigment by many mechanisms including thinning of stratum corneum, enhancing epidermolysis, dispersing melanin in the basal layer of epidermis and increasing collagen synthesis.
Miscellaneous agents
Soy, licorice extract, ellagic acid, glucosamine, niacinamide, vitamin C, n butyl resorcinol, vitamin E, phytosterol, glycyrrhetinic acid, rucinol and pidobenzone 4%, are other therapies with efficacy. Many of these agents are added to cosmetic products for skin lightening, and may be combined, as they act on different steps of melanogenesis.
Whats new in melasma
TRANEXEMIC ACID
Tranexamic acid TXA (trans-4-aminomethyl cyclohexane carboxylic acid) is used as a haemostatic agent due to its antifibrolytic action.7 It is a synthetic derivative of the amino acid lysine used to treat and prevent excessive bleeding. TXA inhibits melanin synthesis in epidermal melanocytes and also exhibits tyrosinase activity by blocking the interaction of melanocytes and keratinocytes by inhibition of plasminogen/plasmin system. TXA acts by attaching to the lysine-binding sites of plasmin and plasminogen and also prevents ultraviolet rays induced pigmentation.
Histological evaluation following oral and topical TXA for melasma was done which concluded that TXA decreases epidermal pigmentation associated with melasma and also reverses melasma-related dermal changes, such as vessel number and increased numbers of mast cells.8Use of oral TXA for melasma in similar dose have been tried in Chinese population and authors recommend TXA to be an effective and safe therapy for the treatment of melasma.9 Dose of oral TXA used in melasma is far less than that prescribed for its haemostatic action. Venous thromboembolism, myocardial infarction, cerebrovascular accidents and pulmonary embolism are some reported complications in haemostatic dose of TXA. It is contraindicated for patients having acquired defective color vision, an active intravascular clotting condition, and hypersensitivity to TXA. Hence, proper patient selection ruling out any risk factor resulting in hypercoagulability is of pivotal importance prior to the start of therapy.
Recomended Dose of oral tranexamic acid is 250mg twice a day for 3-6 months.
Intralesional Tranexamic acid 4mg/ml weekly for 12 weeks caused significant decrease in MASI score. 10 But further data and randomised controlled trials are necessary.
PYCNOGENOL
It is a plant extract obtained from bark of French maritime pine .Pycnogenol has antioxidant and antiinflammatary properties. A Clinical study on efficacy of pycnogenol with 75mg daily orally thrice a day showed decrease in pigmentary intensity of melasma patients. 11
PROANTHROCYANIDIN
In a randomised double blind placebo controlled trial in 60 phillipino females with bilateral epidermal melasma a combination of oral proanthrocyanidin plus vitamin A, C and E taken twice daily for 8 weeks were compared with placebo intake by mexametric and MASI scores.There was significant reduction in MASI scores and pigmentation with mexametryin malar regions. This combination was found to be safe. 12
Chemical Peels
Glycolic acid may be the most efficacious peeling agent for melasma, but it should be used cautiously. Glycolic acid peels should be used in conjunction with a depigmenting agent for maximal benefit and to minimize the risk of postinflammatory hyperpigmentation. 6 Salicylic-mandelic peel is as effective as glycolic peels (35%) and more superior to combination phytic acid in the reduction of the pigmentation in melasma in dark-skinned patients. 13
LASER AND LIGHT THERAPIES
Intense pulsed light therapy may provide modest benefit as an adjunctive therapy for refractory patients. Copper bromide lasers may be of benefit for melasma, especially in patients with a visible vascular component, but require further study. 6
Q-switched ruby lasers and erbium: yttrium aluminum- garnet lasers have been shown to worsen melasma. The combination of carbon dioxide laser with Q-switched Alexandrite laser is not beneficial for melasma and carries a significant risk of worsening hyperpigmentation in dark-skinned patients. Fractional resurfacing is approved by the FDA for the treatment of melasma and has been shown to have some benefit; however, additional controlled trials are needed to evaluate its efficacy for melasma.
Conclusion
Melasma is known to be chronic and recalcitrant. Treatment requires a multimodality approach. Sunscreen and hydroquinone have been the mainstay of treatment for years. Newer treatments are promising and are a cause of optimism in treatment of melasma.
References
References are available on request
Whats new in the treatment of Melasma.
Melasma is a common disorder of hyperpigmentation affecting millions of people worldwide. It is thought to be triggered or exacerbated by sun exposure and hormones, but much remains to be understood about its pathogenesis.
Melasma is an acquired disorder of symmetrical hyperpigmentation appearing as light brown to dark, light brown to dark macules and patches on the face, especially the forehead, malar areas, and chin. It is sometimes referred to as chloasma or the mask of pregnancy. 1
Several clinical patterns of melasma have been described, but many patients have a mixture of these patterns.2 The centrofacial pattern is the most common and consists of lesions on the forehead, cheeks, nose, upper lip, or chin. The malar pattern describes lesions located primarily on the cheeks and nose. The mandibular pattern consists of lesions on the ramus of the mandible.
Although melasma of the forearms has been described, this entity is not always present in patients3 with facial melasma and has not been well characterized. Melasma can be further classified based on a Wood’s lamp examination to help identify the location of the pigment.
ETIOPATHOGENESIS
- UV light, sun exposure is a common exacerbating factor
- Hormones
- Genetics
- Pregnancy
- Drugs like OC pills, Hormone replacement drugs, Phenytoin.
The Melasma Area and Severity Index
The Melasma Area and Severity Index (MASI) was created by Kimbrough-Green et al 4 in an attempt to standardize the subjective evaluation of melasma. It is calculated by dividing the face into four areas: the forehead, right malar area, left malar area, and chin. Each area is weighted such that the forehead, right malar area, and left malar area are 30% each, and the chin is 10%. Scoring for darkness (D) of pigment when compared with normal skin and homogeneity (H) of the pigment in the specified area (A) is then performed. A numerical value for area of involvement, ranging from 1 (\10% of the area involved) to 6 (90-100% of the area involved) is assigned. The total score is calculated as follows:
MASI= 0.3 A(D+H) forehead +0.3A(D+H) right malar +0.3 A(D+H) left malar + 0.1 chin (D +H) The range of scores is 0 to 48. The MASI score is the most commonly used measurement technique.
Differential Diagnosis
- Acanthosis Nigricans
- Hori’s Nevus
- Frictional Melanosis
- Actinic Lichen Planus
- Nevus of Ota
TREATMENT OPTIONS FOR MELASMA
The treatment of melasma includes topical formulations, chemical peels, lasers and light sources. While no single therapy has proven to be of benefit to all patients hence combinations of modalities can be used to optimize management in difficult cases.
SUNSCREENS
A broadspectrum UVA- and UVB-protective sunscreen with an SPF of at least 30 along with a physical block, such as titanium dioxide or zinc oxide, should be used by patients with melasma and should be reapplied every 2 to 3 hourly . Patients should also be instructed to wear protective hats and clothing when outdoors and to practice sun avoidance .
Topical treatments:
Phenolic Compounds
Hydroquinone: It is the mainstay and gold standard drug in the treatment of melasma .Available as 2 % and 4 %. It can be used alone or in combination with tretinoin and fluocinolone (Kligmans formula consisting of 5% hydroquinone, 0.1% tretinoin, and 0.1% dexamethasone, Modified kligmans regime consists of 2% hydroquinone ,1% hydrocortisone and 0.05 % tretinoin ) . Hydroquinone is thought to act by inhibition of tyrosinase, by binding to the enzyme or by interaction with copper molecules at the enzyme’s active site. This leads to altered melanosome formation and increased melanosome destruction, and even the inhibition of DNA and RNA synthesis. In a nonrandomized trial, 4% hydroquinone and broad-spectrum sunscreen was also shown to be efficacious in the treatment of melasma, with 89.5% of subjects showing a good to excellent response. 5 Some patients may develop hypersensitivity to hydroquinone6 .
Other side effects of hydroquinone are burning ,pruritus , itching , ochronosis , occupational vitiligo.
Mequinol:
Mequinol (4-hydroxyanisole) is a phenolic agent that is thought to act as a competitive inhibitor of tyrosinase without damaging melanocytes. It is available in concentration of 2% .It has lesser side effects compared to hydroquinone.
Arbutin:
Arbutin is a beta-D glucopyranoside derivative of hydroquinone that is derived from Uva ursi folium (the bearberry plant) and can also be found in cranberry and blueberry leaves. Its mechanism of action is inhibition of tyrosinase and 5,6-hydroxyindole-2-carboxylic acid (DHICA) polymerase and inhibition of melanosome maturation. Deoxyarbutin is a recently developed derivative of arbutin
Retinoids
Synthetic retinoid such as tretinoin is thought to have inhibitory effect on tyrosinase by inhibiting the enzyme’s transcription as well as on dopachrome conversion factor with a resulting interruption of melanin synthesis and also acts through induction of desquamation. Concentration of retinoid ranges from 0.025 to 00.1%.Associated side effects are erythema and peeling and post inflammatory hyperpigmentation.
Topical steroid Fluocinolone acetonide 0.01 % is used mainly as a triple combination for melasma along with treinoin and hydroquinone. Adding a steroid reduces the irritant effects of hypopigmented agents and inhibits melanin synthesis. Maximum duration for which topical steroids can be continued for melasma is 8-12 weeks . Side effects of steroid include hirsutism, atrophy, telengiectasia and rosacea like dermatosis.
Kojic Acid:
Kojic acid is a molecule produced by Aspergilline oryzae and Penicillium spp. It acts as a tyrosinase inhibitor that works by chelating copper at the enzyme’s active site. This agent is usually available over the counter in a 2% concentration.
Azelaic Acid:
Azelaic acid is a 9-carbon dicarboxylic acid derived from Pityrosporum ovale that acts as a weak reversible competitive inhibitor of tyrosinase. The most commonly reported side effects of preparations containing azelaic acid include pruritus, mild erythema, scaling, and burning. It has been shown to be safe for use in combination with retinoids. 20% azelaic acid has been shown to have greater efficacy than 2% hydroquinone in a 6-month study and to be equally as efficacious as 4% hydroquinone in a 24-week double blind trial
Glycolic Acid:
It is alpha hydoxy acid and has been studied in the combination with other agents. Available in concentration of 5-12 %. It decreases pigment by many mechanisms including thinning of stratum corneum, enhancing epidermolysis, dispersing melanin in the basal layer of epidermis and increasing collagen synthesis.
Miscellaneous agents
Soy, licorice extract, ellagic acid, glucosamine, niacinamide, vitamin C, n butyl resorcinol, vitamin E, phytosterol, glycyrrhetinic acid, rucinol and pidobenzone 4%, are other therapies with efficacy. Many of these agents are added to cosmetic products for skin lightening, and may be combined, as they act on different steps of melanogenesis.
Whats new in melasma
TRANEXEMIC ACID
Tranexamic acid TXA (trans-4-aminomethyl cyclohexane carboxylic acid) is used as a haemostatic agent due to its antifibrolytic action.7 It is a synthetic derivative of the amino acid lysine used to treat and prevent excessive bleeding. TXA inhibits melanin synthesis in epidermal melanocytes and also exhibits tyrosinase activity by blocking the interaction of melanocytes and keratinocytes by inhibition of plasminogen/plasmin system. TXA acts by attaching to the lysine-binding sites of plasmin and plasminogen and also prevents ultraviolet rays induced pigmentation.
Histological evaluation following oral and topical TXA for melasma was done which concluded that TXA decreases epidermal pigmentation associated with melasma and also reverses melasma-related dermal changes, such as vessel number and increased numbers of mast cells.8Use of oral TXA for melasma in similar dose have been tried in Chinese population and authors recommend TXA to be an effective and safe therapy for the treatment of melasma.9 Dose of oral TXA used in melasma is far less than that prescribed for its haemostatic action. Venous thromboembolism, myocardial infarction, cerebrovascular accidents and pulmonary embolism are some reported complications in haemostatic dose of TXA. It is contraindicated for patients having acquired defective color vision, an active intravascular clotting condition, and hypersensitivity to TXA. Hence, proper patient selection ruling out any risk factor resulting in hypercoagulability is of pivotal importance prior to the start of therapy.
Recomended Dose of oral tranexamic acid is 250mg twice a day for 3-6 months.
Intralesional Tranexamic acid 4mg/ml weekly for 12 weeks caused significant decrease in MASI score. 10 But further data and randomised controlled trials are necessary.
PYCNOGENOL
It is a plant extract obtained from bark of French maritime pine .Pycnogenol has antioxidant and antiinflammatary properties. A Clinical study on efficacy of pycnogenol with 75mg daily orally thrice a day showed decrease in pigmentary intensity of melasma patients. 11
PROANTHROCYANIDIN
In a randomised double blind placebo controlled trial in 60 phillipino females with bilateral epidermal melasma a combination of oral proanthrocyanidin plus vitamin A, C and E taken twice daily for 8 weeks were compared with placebo intake by mexametric and MASI scores.There was significant reduction in MASI scores and pigmentation with mexametryin malar regions. This combination was found to be safe. 12
Chemical Peels
Glycolic acid may be the most efficacious peeling agent for melasma, but it should be used cautiously. Glycolic acid peels should be used in conjunction with a depigmenting agent for maximal benefit and to minimize the risk of postinflammatory hyperpigmentation. 6 Salicylic-mandelic peel is as effective as glycolic peels (35%) and more superior to combination phytic acid in the reduction of the pigmentation in melasma in dark-skinned patients. 13
LASER AND LIGHT THERAPIES
Intense pulsed light therapy may provide modest benefit as an adjunctive therapy for refractory patients. Copper bromide lasers may be of benefit for melasma, especially in patients with a visible vascular component, but require further study. 6
Q-switched ruby lasers and erbium: yttrium aluminum- garnet lasers have been shown to worsen melasma. The combination of carbon dioxide laser with Q-switched Alexandrite laser is not beneficial for melasma and carries a significant risk of worsening hyperpigmentation in dark-skinned patients. Fractional resurfacing is approved by the FDA for the treatment of melasma and has been shown to have some benefit; however, additional controlled trials are needed to evaluate its efficacy for melasma.
Conclusion
Melasma is known to be chronic and recalcitrant. Treatment requires a multimodality approach. Sunscreen and hydroquinone have been the mainstay of treatment for years. Newer treatments are promising and are a cause of optimism in treatment of melasma.
References
- Sheth V, Pandya A. Melasma: A Comprehensive update Part 1 Journal of Am Acad Dermatol 2011oct 65(4)689-97
- Sanchez NP, Pathak MA, Sato S. Melasma: a clinical, light microscopic, ultrastructural, and immunofluorescence study.J Am Acad Dermatol 1981;4:698-709
- O’Brien TJ, Dyall-Smith D, Hall AP. Melasma of the forearms. Australas J Dermatol 1997;38:35-7.
- Kimbrough-Green CK, Griffiths CEM, Finkel LJ, Hamilton TA, Bulengo-Ransby SM, Ellis CN, et al. Topical retinoic acid (tretinoin) for melasma in black patients. Arch Dermatol 1994;130:727-33.
- Amer M, Metwalli M. Topical hydroquinone in the treatment of some hyperpigmentary disorders. Int J Dermatol 1998;37:449-50.
References are available on request