Evidence-Based Treatment for Melasma: Expert Opinion and a Review

Melasma (from the Greek word melas, meaning ‘black’) is a common, acquired, circumscribed hypermelanosis of the sun-exposed skin [1, 2]. It presents as symmetric, hyperpigmented macules having irregular, serrated, and geographic borders. The most common locations are the cheeks, upper lips, the chin, and the forehead, but other sun-exposed areas may also be occasionally involved. Studies indicate the possible role of several risk factors such as genetics, sunlight, age, gender, hormones, pregnancy, thyroid dysfunction, cosmetics, and medications [1]. The objective of the current study was to prepare a treatment consensus and algorithm based on clinical experience and review of the evidence from available literature.

A panel of eminent dermatologists with at least 10 years of clinical experience combined with academic contribution and interest in the subject of melasma was created and their expert opinion was sought to address lacunae in information to arrive at a working algorithm for optimizing outcome in Indian patients.

The process was initiated with a literature search with the keywords as dermatology, hydroquinone, laser, melasma, peels, photoprotection, prevalence, retinoids, safety, topical steroids, and treatment. The databases searched included MEDLINE, COCHRANE LIBRARY, and SCIENCE DIRECT DATABASE.

Literature was searched mainly over the period of the last 2 decades (1990 to August 2013) to include data and latest concepts in melasma epidemiology and therapy. However, a few publications from the 1980s and two from the 1970s have also been included so that valuable foundation concepts as well as evolution of current therapies and past issues with certain drugs are also included.

Articles pertaining to risk and predisposing factors for melasma as well as articles on melasma management, including clinical assessment, investigations, drug therapies, combinations, procedural therapies, and newer emerging therapies, from peer reviewed journals were included. Articles not adequately powered or not randomized with poorly defined methodology and articles with conflicting or non-committal results were excluded.

A total of 115 publications until August 2013 were obtained by electronic database searches of which 52 were randomized controlled trials (1 retrospective) and 42 were review articles (17 were reviews and discussions of specific drug/combination or procedural treatment). The remaining publications included eight articles on prevalence data, five articles of case series, five articles on investigations and histopathology, and three articles on validating scoring and grading systems. The literature search was completed and then followed by three panel discussion sessions, each in the form of a 1-day residential focused program where clinical experiences of each panelist were brought to the table along with the study of the associated literature and publications. All discussions, suggestions, and panel consensus were recorded by a medical writer who was present. In addition, experienced persons from the field of pharmaceuticals also contributed with respect to the pharmacological aspects of the various drug therapies. In between each of these sessions, the outcome and consensus of the previous session were drafted and shared with the panel members for further refining. After all panel discussion sessions were concluded, the final draft of the panel consensus and algorithm was prepared along with the summary of the reviewed literature. This draft was finally refined and accepted by the panelists to come up with a clinically practical, relevant, and acceptable treatment algorithm for melasma. The deployment of this algorithm is expected to act as a basis for guiding and refining therapy in the future.

This article is based on previously conducted studies and the expert opinion of the authors, and does not involve any new studies of human or animal subjects performed by any of the authors.

Melasma commonly occurs in women during their reproductive years. Pregnancy and use of oral contraceptives through estrogen mediated melanocyte stimulation is apparent in the pathogenesis of melasma [2‐4]. Dark-haired persons (Fitzpatrick skin types III–VI) are more susceptible to melasma [5]. Several studies have reported a high incidence of melasma in family members suggesting its genetic predisposition [3, 6‐11].

The ultraviolet (UV) component of sunlight is the major triggering and aggravating factor in melasma causing focal melanocyte hyperplasia and increase in melanosomes [1, 12, 13].

The use of topical cosmetics and fragrances as well as phototoxic drugs can also trigger or aggravate melasma by sensitizing the skin and inducing postinflammatory hyperpigmentation (PIH). Melasma is considered as photocontact dermatitis in a study conducted by Verallo-Rowell [14].

Melasma is classified according to the depth of melanin pigment into epidermal melasma with mixed melasma (a combination of the epidermal and dermal types) having a worse prognosis [1].

The objectives of melasma therapy should be protection from sunlight and depigmentation. Pigment reduction is achieved by using chemicals that interfere with various steps of the melanogenesis pathways via: (i) the retardation of proliferations of melanocytes; (ii) the inhibition of melanosome formation and melanin synthesis; and (iii) the enhancement of melanosome degradation [15]. Table 1 shows the classification of the pigment-reducing agents based on their mechanism of action [16‐18].

First-line therapy usually consists of topical compounds that affect the melanin synthesis pathway, broad-spectrum photoprotection, and camouflage. Chemical peels are often added in second-line therapy. Laser and light therapies represent potentially promising options for patients who are refractory to other modalities, but also carry a significant risk of worsening the disease. A thorough understanding of the risks and benefits of various therapeutic options is crucial in selecting the best treatment.

Traditionally, Wood’s lamp examination is done to identify the location of pigment, but is limited to epidermal melasma and cannot be used reliably in Fitzpatrick skin types V and VI as dark-skin melanin pigmentation obscures the detection of dermal melanin [19]. Melasma is reliably graded on the basis of area and severity parameters [i.e., melasma area and severity index (MASI) score] [20, 21].

India is a country of multiple ethnicity and origin, covering a wide range of skin types. Melasma is found more frequently in Fitzpatrick type III–VI skin [48]. Based on Pigmentary Disorders Academy (PDA) recommendations for melasma treatment for dark-skin types and a thorough review and grading of the literature on evidence-based studies (listed in Table 8) [48, 61] an algorithm is proposed in Fig. 1 to treat Indian melasma patients. All treatments included and their hierarchy in the algorithm is based on the grading of the associated clinical studies according to the US preventive services task force levels of evidence for grading clinical trials [70].

The key considerations in developing the algorithm are: the Fitzpatrick skin types susceptible to melasma in the Indian population, the severity of melasma, the sensitivity of patients to active ingredients of medication, the patient treatment history, any existing skin condition (besides melasma), possible therapy-related AEs such as PIH, exogenous ochronosis, blotchy depigmentation, irritation, erythema; and the probability of pigment recurrence after stopping treatment, i.e., prognosis indicators. The darker skin types tend to be highly sensitive to treatment agents, for example, ochronosis on HQ treatment, sensitization to KA, and skin irritation reactions to peeling agents like GA. In addition, darker skin types are more prone to PIH post-treatment and have a greater chance of relapse [71]. With these considerations in mind, darker skin types, which are commoner among Indian people, are recommended longer treatment periods, with lower concentrations of those treatment agents that can induce PIH or irritation, followed by longer maintenance periods to prevent recurrence of pigmentation and melasma. We have found that treatments like laser therapy, although described for all skin types in literature, are in fact not suitable for Indian skin as PIH and relapse occurs frequently once treatment is stopped in spite of maintenance therapy. However, light therapy does have some value in Indian patients.

In the opinion of the authors, broad-spectrum sunscreen use during and post-treatment is mandatory, along with protective clothing and hats. Experts recommend the fixed triple combination as the first-line therapy for all melasma types and degrees of severity, and dual combinations or single agents should be considered only when it is unavailable or patients have sensitivity to the ingredients [48]. In such cases, we suggest dual-combination therapy (e.g., HQ + GA) or monotherapy (e.g., 4% HQ, 0.1% retinoic acid, or 20% AA). For moderate or severe melasma which does not respond to first-line treatment, options for second-line therapy include peels either alone or in combination with topical therapy.

In the opinion of the authors, some patients will require therapy to maintain remission status and a combination of topical therapies should be considered. A minimum of four sessions of a given peel are suggested before changing to an alternative therapy. It is to be noted that for Indian skin types, especially Fitzpatrick types IV–VI, the concentration of certain agents should be reduced; 5% HQ should be avoided for Indian patients as PIH and irritation are more likely at higher concentrations. Because of the risk of prolonged hyperpigmentation, medium-depth peels like ≥35% TCA should be conducted with caution in patients with dark-skin types; deep peels should not be used in these patients. Furthermore, chemical peels are generally used to treat only the epidermal and mixed forms of melasma, as an attempt to treat with deep peels often leads to unwanted complications like hypertrophic scarring and permanent depigmentation. There are ample studies on the effect of GA peels on ethnic skin [55] (Table 9) and hence make for a recommended choice of treatment. In most of these studies, there was a moderate improvement achieved in almost one-half of the patients [58, 59, 72, 73].

Lasers should rarely be used in the treatment of melasma and, if applied, it is important to consider skin type. The mode-toning laser treatment is generally recommended in all skin types and its major advantage is that it destroys melanin without cell damage. Both QS low fluence and IPL are effective for recalcitrant melasma, when patients are non-responsive to other treatments, or when patients are intolerant of other treatment medications. The combination of IPL with QS laser gives a rapid resolution of mixed-type melasma with possible long-term benefits [67‐69]. Fractional non-ablative lasers can be considered only if all other modalities fail. Ablative lasers should not be considered.

Patient consent and a photograph of the condition must be obtained prior to therapy. As important as actual therapy is proper patient counseling, and an understanding of the psychosocial impact on the patient and of his/her condition leading to low quality of life [74, 75]. This is likely to lead to a better patient compliance and an adherence to the regimen. It has been reported in Indian patients that overuse of certain treatment modalities such as mometasone-based therapies leads to undesirable fallouts [47, 49].

The recommendation is to use an alternative triple-combination cream, better suited for Indian patients, i.e., 2% HQ, 0.05% tretinoin, and 0.01% of the mild steroid fluocinolone acetonide cream. Another option is to replace the mometasone-based triple combination after 4–8 weeks, with a fluocinolone or a hydrocortisone-based one for a further 3- to 6-month period. As discussed earlier, this cream is safe and effective based on extensive clinical studies. The gradual withdrawal of the therapeutic agent is also a consideration and is achieved by decreasing doses of the active agent. The proposed algorithm for Indian patients is presented in Fig. 1.

There are several conditions that determine the outcome of treatment in melasma since its etiology is multifactorial. Several factors predict potential failure of treatment (listed in Table 10). Moin et al. [3] found a statistically significant relationship between melasma and ethnicity, and phototype and grade of parity. Exogenous ochronosis has also been reported to be being misdiagnosed as a melisma treatment failure [76]. However, these prognostic factors lack sufficient scientific evidence.

Here, the Indian dermatologists panel has graded the results of safety and efficacy of various melasma therapies from clinical trials conducted worldwide (Table 7) applying the quality and level of evidence based on the US preventive services task force on health care (Table 8). Focus on the efficacy as well as AEs particular to the major skin types of Indian population, using evidence from clinical trials and physicians’ experience in the clinic, has directed the selection process for each recommended therapy. Using these guidelines, a much needed algorithm specific to melasma in India has been evolved and will assist physician’s decision on melasma treatment, disease management, and optimal outcome. We have also brought to attention some practices in treatment of melasma, for example, prolonged use of mometasone-based triple combination and prognosis indicators that have negative connotations. The key therapy recommended is fluorinated steroid containing 2–4% HQ-based triple combination for first-line therapy, with additional selective peels if required in second-line therapy. Lasers are a last resort.