Ochronosis

Abstract

Melasma is a chronic and recurrent disorder. It has been underdiagnosed and undertreated due to lack of effective therapies and the perception that it is merely a cosmetic nuisance. Hydroquinone, corticosteroids, licorice extracts and kojic acid have been used as monotherapy to treat melasma. However, the present standard of care in melasma therapy is combination therapy. To date, the most effective treatment is a triple-combination agent that contains hydroquinone 4%, tretinoin 0.05% and fluocinolone acetonide 0.01%. In clinical trials, its use led to complete or near-complete clearing of melasma in 8 weeks. A long-term study demonstrated its continuing efficacy and safety for as long as 360 days. In an examination of quality of life parameters, patients using the triple-combination cream showed significant improvements in self-perception by all 1290 patients. Various combinations of melasma therapy, such as chemical peels, particularly as adjuvants to the triple-combination cream, are discussed.

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Introduction

Melasma is a common acquired hypermelanosis predominantly of the face and neck and, occasionally, the forearms, According to the American Academy of Dermatology, 5-6 million American women have melasma. Melasma is primarily a disease of women of child-bearing age although 10% of cases occur in men (1). It occurs in all skin types but is most common in Fitzpatrick skin types IV-VI, with dark-haired women more susceptible. Its racial distribution is centered among Hispanic, Asian, Indian, African and African-American peoples (2).

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Melasma has largely been underdiagnosed and therefore undertreated in the United States. This is partly attributable to the fact that many physicians consider melasma a "nuisance" rather than a medical problem or one with significant psychosocial impacts. While dermatologists are the specialists most likely to treat melasma, obstetricians and gynecologists (OB/GYNs), family practitioners or internal medicine doctors also see patients with melasma (3). As it frequently develops during pregnancy, many women first present with melasma during visits for prenatal care. Many physicians outside the dermatologic community have not been aware of available treatments and therefore, have typically not addressed the problem unless asked, or have reassured their patients that the hyperpigmentation would fade after delivery. Likewise, many women with melasma do not ask their physicians about their symptoms and do not visit a dermatologist specifically to address the problem. Due to cultural and ethnic misperceptions about skin diseases in general, particularly disorders of pigmentation, affected individuals may not ever seek help for what is a treatable, though chronic, condition.

Melasma has a significant cosmetic impact for many women. However, it also carries a psychosocial burden. It is particularly distressing to women from cultures which favor flawless, evenly pigmented skin. In some Asian cultures, facial pigmentary abnormalities are associated with bad luck. Melasma and other dyspigmentation is also extremely distressing to women in Latin cultures where such stigmata are frequently associated with ill health or poor nutrition. Pigmentary abnormalities are considered disfiguring in Latin cultures where women tend to be especially beauty-conscious. Latina women have the highest prevalence of melasma (2,3).

Melasma Etiology

While the precise etiology of melasma is unknown, multiple factors have been implicated. They include genetic influences, exposure to ultraviolet (UV) and visible light radiation, female hormones in the settings of pregnancy, oral contraception (OC) and post-menopausal hormone replacement therapy (HRT), thyroid autoimmunity, cosmetic ingredients and phototoxic drugs (3). UV radiation and genetic influences have been suggested to be the most important pathogenic factors (4). UV radiation increases melanocyte size, tyrosinase activity and the transfer of melanosomes to keratinocytes. These changes may occur as a consequence of DNA repair.

Melasma is estimated to occur in 50%-70% of pregnancies among US women, usually during the 2nd or 3rd trimester (5). No specific genetic studies have been conducted, but there is a higher incidence in patients with a significant family history (mothers and daughters) as well as in women with skin of color and pigmented races living in areas of high insolation (6).

Among Mexican women, the incidence is estimated to be about 80%, with more than one-third of these patients having the disease for life (7). However, melasma subsequent to OC use typically does not clear and may last up to 5 years following termination of therapy (6). Other evidence regarding hormonal influences includes the finding of significantly increased levels of luteinizing hormone and reduced serum estradiol suggestive of mild ovarian dysfunction (8). Lufti et al found an incidence of thyroid disorders 4 times higher in patients with melasma than in controls. Moreover, there was also a significant association between the development of melasma during pregnancy or subsequent to OC use and thyroid autoimmunity (9).

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Figure 1 depicts the interplay of these three pathogenic factors in the increased pigmentation of melasma. Melanocytes in melasma are hyperactive and increase in number. They form melanosomes which are transferred to the dermis and epidermis leading to the characteristic hyperpigmentation.

Melasma Treatment

Sun Protection

The goals of melasma therapy are: 1) to retard the proliferation of hyperactive melanocytes, 2) inhibit the formation of melanosomes, 3) promote the degradation of melanosomes and 4) protect the skin from UV radiation (Table 1).

While there is now highly efficacious treatment available for melasma, sun protection is an equally vital component of melasma management. Therefore, patient education is essential to an optimal melasma management regimen. Patients must be counseled that melasma is a chronic, relapsing disease. Sunscreens must be used whenever they are outdoors. In addition, a hat, protective clothing and sunglasses should be worn and overall sun avoidance practiced assiduously. Patients should be aware that even following successful melasma treatment and clearance of lesions, one weekend of sun exposure can lead to a complete recurrence.

Broad-spectrum sunscreens that offer protection against both UVA and UVB light should be used. Sunblocks that combine chemical sunscreens such as Parsol[R] with a physical block such as zinc oxide or titanium dioxide should be used. A physical sunblock is essential, because melasma can be exacerbated by heat. Physical sunblocks reflect light rather than converting it to heat energy within the skin. Many cosmetics now contain sun protection factors, making foundation and powders a good adjunct, but insufficient for sun protection on their own. Novel approaches to sun protection, which can be used as adjuncts, include the use of green tea extracts, topical vitamin C, fish oil, and beta-carotene (10-12).

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Polypodium leucotomos (PL) extracted from a fern is a novel oral sun protection agent that has been found to increase the skin's tolerance to the effects of UV radiation (13). It acts as an antioxidant and prevents actinic erythema. It also acts as an immune modulator by inhibiting UV-induced depletion of epidermal Langerhans cells as well as the inflammatory mediators such as tumor necrosis factor alpha.

Pharmacologic Therapies

A variety of topical agents have been used to treat melasma. They include phenolic hypopigmenting agents such as hydroquinone, mequinol and N-acetyl-4-cysteaminylphenol (NACAP), as well as non-phenolic hypopigmenting agents such as tretinoin, azelaic acid, alpha- and beta-hydroxy acids and topical corticosteroids. In addition, cosmeceutical agents such as kojic acid, arbutin, licorice extracts and mulberry and bear-berry have been used. New compounds include nicotinic acid, niacinamide-Vitamin D3, and 4-n-butylresorcinol which affects melanosome transfer to keratinocytes and is widely used in Japan. Non-selective suppression of melanogenesis can be achieved with indomethacin and systemic corticosteroids.

Figure 2 shows the effects of these molecules at different levels of the pigmentation pathway (14). Glycolic and alpha- and beta-hydroxy acids act at the level of keratinocytes to remove pigment whereas tretinoin inhibits melanosome transfer. Hydroquinone, azelaic acid and kojic acid all act as tyrosinase inhibitors.

Monotherapy for Melasma

While the current trend is toward combination therapy for melasma, a variety of monotherapies have proven useful in its management over the years. Hydroquinone has been the standard of topical therapy of melasma for over 50 years. It blocks melanogenesis by competitive inhibition of tyrosinase which prevents the conversion of dopa to melanin. It may also inhibit DNA and RNA synthesis, degrade melanosomes and destroy melanocytes (3,6,15). In the US, hydroquinone is sold over-the-counter (OTC) in concentrations up to 2%. Prescription-strength hydroquinone is generally 3%-4%, although higher concentrations can be obtained through compounding pharmacies. Typically 4-6 weeks are required before a response is visible. Hydroquinone can be irritating, particularly at higher concentrations. Its most feared side effect is the development of exogenous ochronosis, a chronic, disfiguring sooty pigmentation of the face, characterized by articulated, ripple-like pigmentation of the face. Histologically, collagen and elastin fibers degenerate leading to the characteristic ochronotic deposits in the dermis (3,6).

Although hydroquinone has been used as monotherapy, it is generally combined with other agents for improved efficacy. For example, several products combine hydroquinone with glycolic or salicylic acid, antioxidants such as vitamins C or E and/or sunscreen. The most frequently used formulation is based on a depigmenting formulation proposed by Kligman and Willis in 1975 (16). It combined hydroquinone 5%, tretinoin 0.1% and dexamethasone 0.1%. Other investigators have substituted different corticosteroids and have modified the concentrations of tretinoin and hydroquinone.

Tretinoin has been found to be effective as monotherapy. Like glycolic acid and topical steroids, it accelerates cell turnover in the epidermis, thereby reducing the amount of time cells have to acquire pigment (16). In a small series, Kimborough-Green and co-workers found that 73% of African Americans with melasma were improved or much improved following 40-weeks of treatment with 0.1% tretinoin versus 46% of controls. Statistically significant lightening was first noted at 24 weeks and side effects were minimal (17). However, use of tretinoin monotherapy at concentrations of 0.05% and 0.1% is frequently associated with dermatitis and post-inflammatory hyperpigmentation (PIH). An additional advantage of tretinoin in a depigmenting regimen is its beneficial effect on photodamage.

Topical corticosteroids are usually not used as monotherapy to treat melasma although they do have their own skin bleaching action (18). They likely act by suppressing secretory metabolic products from melanocytes without causing their destruction. When used with caution, topical corticosteroids can be useful to reduce irritation in Hispanic and Asian patients whose skin is especially sensitive. Drawbacks to their use as monotherapy for melasma include the typical adverse events associated with topical corticosteroids on the face including the development of telangiectasia, acneiform eruptions, and skin atrophy. Patients receiving topical corticosteroids should be monitored for the development of side effects every 2-4 weeks. If adverse events are encountered, the steroid concentration should be decreased.

Other monotherapies that have been used with some success in melasma include azelaic acid, a naturally occurring dicarboxylic acid synthesized by the yeast Malassezia furfur from lipids in the skin. It has been used widely in the treatment of acne. It is a weak competitive inhibitor of tyrosinase in vitro with antiproliferative and cytotoxic effects on melanocytes. In a study of dark-skinned patients with facial hyperpigmentation, azelaic acid 15% and 20% combined with glycolic acid was as effective as 4% hydroquinone (19). The patients receiving azelaic acid had a slightly higher rate of local irritation. Azelaic acid is currently being used sequentially with super-potent topical steroids. A review of recent studies of the use of azelaic acid in melasma showed good-to-excellent clinical responses in 73%-65% of patients who were treated for 6 months (20).

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Kojic acid is derived from the fungus, aspergillus oryzae. It inactivates tyrosinase by chelation of copper. Melanocytes treated with kojic acid become nondendritic and melanin content decreases. Although it is effective at concentrations of 1%-4%, it has a high sensitizing potential and can cause irritant contact dermatitis (6,21).

Combination Therapy for Melasma

The original combination therapy for melasma was that developed by Kligman and Willis in 1975 (16). It consisted of 5% hydroquinone. 0.1% tretinoin and 0.1% dexamethasone in a hydrophilic ointment. Other similar formulations were developed using different concentrations of tretinoin or different corticosteroids. However, these combinations, made at compounding pharmacies were not standardized, unstable and prone to oxidation. The first triple-combination topical therapy to receive FDA approval for the treatment of melasma (Tri-Luma[R] Cream) contains hydroquinone 4%, tretinoin 0.05% and fluocinolone acetonide 0.01%. The latter is a low potency Class VI fluorinated steroid.

This triple-combination takes advantage of the additive and synergistic effects of the three components first noted by Kligman and Willis (16). Tretinoin-induced irritation may facilitate the penetration of hydroquinone and also overrides the atrophy-promoting and anti-mitotic effects of the corticosteroid component while the corticosteroid appears to antagonize stratum corneum thinning and to reduce retinoid-induced irritation, thus improving tolerability. Figures 3A-C and 4A-C show the results obtainable in a Hispanic and an Asian patient with the triple-combination therapy beginning with baseline and up to 8 weeks of therapy.

In two multicenter studies that enrolled 641 patients with mild-to-moderate facial melasma, 28% achieved complete clearing in 8 weeks while 78% achieved complete or near-complete clearing in 8 weeks (22). The triple-combination cream was also compared with dyads consisting of two of its constituent components. Table 2 shows the rates of complete clearing at 8 weeks for each of the treatment dyads versus those that were obtained with the triple-combination cream.

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The triple-combination cream was well tolerated. Treatment-related adverse events at week 8 consisted largely of erythema, desquamation, burning, dryness and pruritus. The incidence of possible steroid-related adverse events was also relatively low. Only one patient (in the hydroquinone+fluocinolone acetonide group) developed skin atrophy. Most instances of telangiectasias were mild and occurred in patients who had them before enrolling in the trial (Table 3).

A 12-month, open-label continuation study was conducted to assess the long-term safety of the triple combination formulation, but investigator and patient assessments of efficacy were also collected (23). A total of 797 patients were enrolled, including 569 patients who continued from the initial 8-week controlled clinical trial. Those who continued were patients who had achieved complete or near-complete clearing of their melasma or those who had not achieved satisfactory clearing. The latter group received once-daily treatment with the triple-combination cream and were followed at monthly intervals until they had achieved a satisfactory response or lack of response was demonstrated and treatment was terminated. They were followed every two months while off treatment. The patients who had achieved a complete or near-complete response in the initial trial were followed every two months and retreated as necessary when melasma reappeared. All patients used a broad-spectrum sunscreen with SPF 30 during the trial whether on or off treatment.

The triple combination cream was used for an average of 6.8 months. There were 415 patients who were treated for at least 180 days and 92 who were treated for 360 days. The majority of the patients received two or more treatment courses. Some were retreated as early as one month. As in the original clinical trial, application-site erythema and desquamation were the most commonly reported adverse events. Most of the treatment-related adverse events were mild and transient and did not lead to study discontinuation. The incidence of treatment-related side effects was very low. The incidence of telangiectasia was 4% in the 92 patients with at least 360 days of treatment. All cases of telangiectasia were mild, and 15 of 23 had improved or resolved by study end while 8 were unchanged. The incidence of skin atrophy and acne were 0.6% and 8%, respectively in all 797 patients in the long-term study.

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The triple-combination cream produced a highly significant reduction in MASI (Melasma Area and Severity Index) scores. This effect was consistent across all study groups for overall scores, darkness scores and homogeneity scores. Figure 5 shows the long-term efficacy results obtained in this study. At month 1, 73% of the patients were cleared or nearly-cleared. At 6 months, 79% were cleared or nearly cleared while at month 12, 81% had achieved complete- or near-complete clearing. The response time was more rapid with each retreatment so that patients who were retreated required less time to achieve the desired result.

An open-label, community-based phase IV study examined the efficacy and safety, as well as changes in quality of life parameters of 1400 patients with moderate to severe facial melasma (2). Assessments of melasma severity were made at baseline and at weeks 4 and 8. The overall mean MASI score by race/ethnicity showed a highly significant 75% reduction from 14.68 at baseline to 7.38 at week 4, and 3.64 at week 8 (P<0.0001) (Figure 6). The reduction was greater among Caucasians (-78%) and less among Asians (-67%). Improvements in darkness (Figure 7) and homogeneity (Figure 8) scores were similarly dramatic across all study groups. On Global Assessment, 30% of all patients were clear or almost clear by week 8.

The triple-combination cream [Tri-Luma[R] Cream] demonstrated a favorable safety profile in the intent-to-treat population of 1290 patients. The most common adverse events were erythema and desquamation and >99% were mild or moderate in severity. Of the possible corticosteroid-related adverse events, atrophy did not occur in any patient. The incidence of telangiectasia was <2%, and, in some cases, these lesions were preexisting (Table 4) (22).

All subjects showed significant improvements in self-perception categories including "embarrassment," "cosmetic use," "feeling older," and "feeling unattractive" (Figure 9). Melasma's impact on quality of life has traditionally been under-appreciated by the medical profession yet it has been significant to many melasma patients, especially those from cultures where beauty and flawless skin are highly important.

Procedural Therapy

Chemical peels act in melasma by removing melanin. There are numerous options for chemical peels. Including 30%-35% trichloracetic acid (TCA) peels + hydroquinone, 20%-70% glycolic acid, 48% free glycolic acid + 30% TCA, modified Jessner's solution with hydroquinone + kojic acid--the so-called "Miami peel," and 20%-30% salicylic acid peels. It is important to note that while higher concentrations can be used in white skin, Hispanics, blacks and Asians require lower concentrations. Mild glycolic acid or salicylic acid peels will give good results in these patients while avoiding the risk of causing PIH.

Peels can be used as adjuvants or for enhancement as well as in recalcitrant cases. For example, in one study, 40 Indian patients with epidermal melasma received either a modified Kligman's formula (5% hydroquinone, 0.05% tretinoin and hydrocortisone acetate 1% in a cream base) plus serial glycolic acid peels or the modified Kligman's formula alone (24). While both groups showed significant decreases in MASI scores from baseline to 21 weeks, the group receiving the combination treatments showed a statistically significant trend towards greater and more rapid improvement (P<.001).

Lasers act in melasma by disrupting melanin granules. While there are several types of lasers which can treat pigmentary abnormalities, their use in melasma is associated with equivocal or negative results, and their use remains controversial. In a study of 10 patients with melasma that was refractory to bleaching creams and chemical peels, full face laser resurfacing was performed using an erbium YAG laser using a fluence of 5.1-7.6 J/[cm.sup.2] (25). There was an initial marked improvement in MASI scores and melanin reflectance spectrometry. However, between weeks 4 and 6 postoperatively, all 10 patients developed PIH which was worse than the initial melasma. All improved following biweekly glycolic acid peels, topical azelaic acid cream and sunscreens. However, the authors warned that the development of PIH necessitates prompt and persistent intervention to reverse it. They note that the use of this laser therapy should be reserved only for recalcitrant melasma.

Nouri and co-workers conducted a comparison study of the combination of pulsed C[O.sub.2] laser at 300 mJ/[cm.sup.2] versus pulsed C[O.sub.2] followed by another pass with the Q-switched alexandrite pigmented dye laser (26). All 4 patients in the combination therapy group showed complete resolution of melasma within the treatment area. In the C[O.sub.2] only group, 2 of 4 patients developed peripheral hyperpigmentation. The authors suggest that this may be due to lower energy at the edges leading to PIH in areas with intact melanocytes. However, in both treatment arms, all patients showed complete resolution of melasma within the treatment area.

Therapeutic Approach in Melasma

The choice of treatment for melasma depends upon the area of involvement and the intensity of pigmentation. The new trend is the use of combination topical therapies as well as the combination of topical therapies plus procedures such as peels. Figure 10 presents a treatment algorithim for the management of melasma according to its severity. Mild melasma can be treated with hydroquinone with or without glycolic acid or with azelaic acid. Moderate melasma can be treated with hydroquinone plus tretinoin or another retinoid such as adapalene [Differin[R]]. Severe melasma requires treatment with the triple-combination cream [Tri-Luma[R] Cream]. Chemical peels or microdermabrasion may be helpful in some cases with the caveat that darker complexions should receive relatively gentle chemical peels. In most cases, lasers do not add benefits to treatment and may result in the development of PIH.

Essential for all treatment regimens is maintenance therapy to prevent repigmentation of treated areas. The use of retinoids or azelaic acid in combination with kojic acid, which can be used long-term as a skin bleaching agent plus sunscreens appears to be effective.

Summary

Melasma is generally under-diagnosed and under-treated. Nevertheless, it is a distressing problem for some 5-6 million American women. Currently, there is no standard treatment for melasma so therapy should be individualized according to severity and Fitzpatrick skin type. Epidermal melasma responds to virtually all treatments whereas dermal melasma is more recalcitrant. Until recently, monotherapy was most often used to treat melasma. Bleaching and keratolytic creams have proven to be effective over years of use, but may be irritating. Moreover, there is often a long latency until results are visible. Combination therapy has proven to produce more rapid and significant results, often with fewer side effects. New combination compounds consisting of a retinoid or azelaic acid in combination with a skin bleaching agent such as hydroquinone or kojic acid plus a corticosteroid have a synergistic effect and are the current standard of care for melasma. The only triple-combination treatment [Tri-Luma[R] Cream] currently approved for use is based on the original Kligman and Willis formulation. It contains hydroquinone 4%, tretinoin 0.05% and fluocinolone acetonide 0.01% in a cream base. The use of lasers should be reserved only for refractory cases. Because melasma is a chronic relapsing condition, sunscreens are critical to long-term success and maintenance of results.

References

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18. Kanwar AJ, Dhar S, Kaur S. Treatment of melasma with potent topical corticosteroids. Dermatology. 1994;188:170.

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MARTA I. RENDON, MD

DERMATOLOGY & AESTHETICS CENTER, BOCA RATON, FL

ADDRESS FOR CORRESPONDENCE:

Marta Rendon, MD

Dermatology & Aesthetics Center

880 NW 13th Street

Boca Raton, FL 33486

phone: (561) 750-0544

fax: (561) 750-9873

email: skincareresearch@cs.com

AUTHOR DISCLOSURES/CONFLICT OF INTEREST:

Dr. Marta Rendon receives research support, consultant fees, and/or honorarium from the following companies: Galderma Laboratories, L.P. Dr. Rendon has no stock ownership.

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