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Received: 30 June 2018    Accepted: 5 February 2019

DOI: 10.1111/jocd.12904

ORIGINAL CONTRIBUTION

A novel triple combination in treatment of melasma: Significant

outcome with far less actives

Erkin Pekmezci MD, MSc

Dermatology Department, Gozde Hospital,

Malatya, Turkey Summary
Background: Melasma is an acquired hyperpigmentation, often involving the face,
Correspondence
Erkin Pekmezci, Dermatology Department, and a source of distress for the affected individuals. Although treatment is challeng‐
Gozde Hospital, Malatya, Turkey. ing and frequently a multimodality approach, topical applications are the mainstay of
Email: [email protected]
therapy.
Objective: Due to the frequent relapses, a therapy both acting rapidly and suitable
for long‐term use, with fewer adverse effects should be administered. In our outpa‐
tient clinic, we treated the melasma patients with a previously unreported triple com‐
bination which was empirically formulated with lesser amount of active components,
regarding the balance between long‐term use and safety.
Methods: Sixty‐eight female patients with melasma who referred to our hospital der‐
matology clinic in the years 2016‐2017 were retrospectively recruited. They all had
completed 6‐month treatment with a prescribed cream mixture comprised of azelaic
acid (4%), hydroquinone (1.6%), methylprednisolone aceponate (0.04%), and salicylic
acid (2%). The outcomes were evaluated both instrumentally (Melanin Index/MI) and
by patients (Patient Self‐Assessment Scale/PSAS).
Results: Adverse effects declared by the patients were transient irritation in three
and mild hypertrichosis in two. Both the MI and PSAS values were found extremely
significant at the end of 6th month, compared with initial values. Approximately 62%
of total decrease in MI was realized in the first 3 months.
Conclusion: The triple combination containing active ingredients with lesser concen‐
trations than proposed, and with the addition of 2% salicylic acid, may be promising
as a quite effective and safe protocol in treatment of melasma for longer durations.

KEYWORDS
melasma, topical agent, treatment

1 |  I NTRO D U C TI O N malar, and mandibular. Although the main pattern in the major‐
ity of the cases is centrofacial, two or three forms may also be
Melasma is an extensively seen and chronic hyperpigmentation seen together. Epidemiological surveys revealed the prevalence
1
of the integumentary system. It most often involves the face and of the disorder in a quite wide range as 1% in general population
therefore is a source of major distress for the affected individu‐ to 50% in high‐risk populations. These ranges may represent dif‐
als. Generally, interpersonal transactions and emotional wellness ferent genetic backgrounds and environmental differences among
2
were influenced unfavorably by this disorder. In clinical practice, discrete geographic conditions. As an acquired dermatosis, me‐
melasma is often encountered in three facial forms; centrofacial, lasma generally sets up in twenties. 3 Approximately 90% of the

J Cosmet Dermatol. 2019;1–5. © 2019 Wiley Periodicals, Inc. |  1

wileyonlinelibrary.com/journal/jocd  
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2       PEKMEZCI

cases are females during the reproductive years.4 Ultraviolet light 2 | M E TH O DS
has been demonstrated to enhance and propagate the disorder.
It has also been found that melasma patients have higher oxida‐ Sixty‐eight nonpregnant female patients with melasma who referred
tive stress markers compared with healthy volunteers. Hormonal to our hospital dermatology clinic in the years 2016‐2017 were
impacts such as pregnancy and oral contraceptive use have been retrospectively recruited. They all had more than 75% epidermal
shown a significant role in the pathogenesis. Melasma has three involvement concluded after Wood's light examination, completed
histologic variants. In the epidermal one, pigment is distributed 6‐month treatment with the prescribed cream mixture, and per‐
abundantly in the layers of epidermis. Melanocytes are enlarged formed the suggested visits in 3rd and 6th months. All of the pa‐
and have increased number of melanosomes. The dermal variant tients had Fitzpatrick skin types II‐IV. The demographic data and
3
is characterized with melanophages widespread in the dermis. In duration since the onset of symptoms are depicted in Table 1.
the mixed type, the hyperpigmentation is the result of both epi‐ The hyperpigmentation value of each patient was measured instru‐
dermal and dermal abnormalities explained above.4 If the pigment mentally by using the melanin probe of Multi Skin Test Center® MC
is epidermal, the hyperpigmentation can be seen darker through 1000 (Courage + Khazaka electronic GmbH, Cologne, Germany) imme‐
3
a Wood's lamp. diately before the beginning, and at the end of 3rd and 6th months of
Due to the psychological and social stress the condition conveys, treatment. So the initial, 3rd and 6th month values were obtained. The
it is mandatory to lecture the melasma patients adequately about measurements were performed on darkest three points clinically ob‐
chronicity of the disorder and the importance of photoprotection. served. The arithmetic mean of the three values was considered as the
Although treatment is frequently a multifaceted approach, topical melanin index (MI) of the patient. The measured points were labeled on
applications are the anchor of therapy for melasma and can be used an anonymous, symbolic sketch of face for each patient, and the subse‐
as single, dual, or triple combinations. Other interventions are often quent measurements were repeated on the same points.
second‐ or third‐line approaches, and mostly, they are the supple‐ Also each patient was asked to fulfill a self‐assessment scale,
1
ments of topical therapy. Hydroquinone (HQ), frequently the main immediately before the beginning of treatment and at the end of
component of pharmaceutical combinations, is utilized with agents 6th month. Patient self‐assessment scale (PSAS) was comprised of
like azelaic acid (AA), retinoic acid, and topical corticosteroids (TCs). five semiquantitative hyperpigmentation values as; 0: Null, 1: Mild,
In addition, mixtures of various other hypomelanizing agents com‐ 2: Moderate, 3: Marked, and 4: Severe hyperpigmentation. The pa‐
posed arbitrarily and generally lacking controlled clinical trials are tients were told to assess the 1‐4 values as approximate 25%‐100%
widely marketed by cosmeceutical companies.4 The most compre‐ quantities of a brown‐black hue.
hensively studied and used pharmaceutical combination is the “triple The cream mixture prescribed for the patients was prepared by
combination” introduced by Kligman and Willis. The original combi‐ private pharmacists by simply mixing the officinal drug products and
nation was composed of 5% HQ, 0.1% tretinoin, and 0.1% dexameth‐ adding salicylic acid, in sterile plastic containers.
asone and was found effective in the treatment of various disorders
with acquired hyperpigmentation, including melasma.5 In time, due
The components of the mixture were: Azelaic acid (20%) 30 g
to the irritation potential of this combination, the original formula cream
has been modified through addition or alteration of one or more
Hydroquinone (4%)
of its components to adapt different skin types. Maximum experi‐ 60 g cream
mentation has been performed with the changes in TC component. Methylprednisolone
Although modified triple combinations were generally shown to aceponate (0.1%) 60 g
be effective in clinical trials, daily use for more than 6 months fre‐ cream
quently associated with TC‐related adverse effects such as atrophy Salicylic acid 3 g
and telangiectasia.4,6 So, the approximate percentages of
In this study, we retrospectively recruited and interpreted our active materials after the dilution effect
in 150 g cream mixture obtained were: Azelaic acid (4%)
outpatient dermatology clinic data of melasma patients treated with
Hydroquinone (1.6%)
a previously unreported triple combination which was empirically
formulated, regarding the safety concerns about the components, to Methylprednisolone
aceponate (0.04%)
have fewer adverse effects with long‐term use.
Salicylic acid (2%)

TA B L E 1   The demographic data and duration of the symptoms The patients were cautioned to use the preparation in the eve‐
ning and not to wash till morning. In case of irritation, they were
Age Duration of symptoms (y)
informed to use the mixture every other day in the first 2 weeks.
Mean ± SD: 31.88 ± 7.83 Mean ± SD: 3.75 ± 2.09
Also all patients were strictly lectured to use a 50+ SPF sunproof
Median: 32 Median: 4 three times during daylight throughout the therapy period. The pa‐
SD: standard deviation. tients were advised to keep the cream mixture in the door shelf of a
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refrigerator in order to achieve longer durability. Nevertheless, the TA B L E 3   The comparative P values of the MI and PSAS
same prescription was repeated in the 3rd month visit of each pa‐ evaluations
tient. Also each patient was photographed immediately before the 3rd month vs 6th month
beginning of the treatment and at the end of 6th month.   initial 6th vs 3rd month vs initial
Student's t test was used for statistical analysis.
MI =0.0013 =0.0141 <0.0001
PSAS NA NA <0.0001

MI: Melanin Index; NA: Not Applicable; PSAS: Patient Self‐Assessment

3 | R E S U LT S
Scale.

The adverse effects declared by the patients were mild irritation in

three (4.4%) and mild hypertrichosis in two (2.9%). The irritations in the treatment of melasma is to take the advantage of the effects
were expressed to occur at the beginning of treatment and disap‐ of different agents on different steps of this enzymatic reaction.
peared in 2 weeks of every other day application. Hypertrichosis Also besides this potential synergy, an active material in the combi‐
was hardly visible in both of the patients and denoted to commence nation may abort undesirable effects of another one.4
in the 6th month of therapy. A hydroxyphenolic compound and also a tyrosinase inhibitor,
The mean and standard deviation values of MI and PSAS evalua‐ HQ is the most often used topical bleaching agent in melasma.
tions are presented in Table 2. A gradual decrease in the mean values Pigment lightening by HQ becomes evident after the first month,
of MI can be seen during the time course. The comparative P values and the treatment is recommended to be kept on at least 3 months.
of the evaluations are shown in Table 3. As it can be seen in the table, 2%‐4% HQ is prominently used as mono‐therapy.6 HQ may have
the significancy of MI P value in the first 3 months (3rd month vs additional actions in melanocytes, such as derogation of membra‐
initial) is greater compared with second 3 months (6th vs 3rd month). neous structures, inhibition of nucleic acid synthesis, and apoptosis.
Both the MI and PSAS values are found extremely significant at the Adverse effects like irritation, pruritus, colloid milium, and transient
end of the 6th month, compared with initial values. hypochromia have been reported in previous studies. Exogenous
It is also formed an improvement curve (Figure 1) by taking the ochronosis is a rare adverse effect seen in higher concentrations
decreases in MI means in the 3rd and 6th months from the initial and darker skin types. 2,4 Although controversial, regulatory author‐
mean, which are depicted in Table 2. Although this is a 6‐month ities in Japan, Europe, and the USA, brought up the safety concerns
treatment, as it can be seen in the improvement curve, approximately about HQ to the agenda, and it has been prohibited in cosmeceutical
62% of total decrease in MI was realized in the first half of total pe‐ preparations in quite a few countries.4
riod. The significancy of this ratio may also be confirmed by the lower AA, is a nonphenolic dicarboxylic acid that exerts its bleaching
P value in the first half compared with the second half of the therapy effect by competitive inhibition of tyrosinase. It also inhibits nucleic
period (Table 3). In the second half, the hypopigmentation process acid synthesis and some mitochondrial enzymes causing anti‐pro‐
continued, though in a lower extent than the first half. In Figure 2, liferative and cytotoxic effects on abnormal melanocytes. Being an
various degrees of clinical improvement at the end of 6th month are anti‐acne agent at the same time, it has no hypopigmentation effect
demonstrated as before (A, C, E, G) and after (B, D, F, H) photographs. on nonhyperpigmented skin. AA has a good safety profile but may
rarely cause pruritus, mild erythema, and stinging.4,6 AA also acts by
decreasing the production of free radicals which are thought to en‐
4 | D I S CU S S I O N hance hyperpigmentation. It has shown that the efficacy of 20% AA
is approximately the same with 4% HQ in the treatment of melasma,
Production of melanin is realized in melanosome, an organelle lo‐ though with less adverse effects.6
cated in the cytoplasm of melanocyte. This is a multi‐step reaction How do the TCs bleach skin is still not understood well. As the
in which tyrosinase is the main and rate‐limiting enzyme. After the melanocytes interact with a diverse range of mediators, the anti‐in‐
completion of melanogenesis, melanin laden melanosomes are trans‐ flammatory effects of TCs may explain their efficacy on hyperpig‐
ferred to the keratinocytes via dendrites of melanocytes, to com‐ mentation to a certain extent.4 TCs are used in combination products
pose visible color of the skin. The rationale of utilizing combinations for their contribution to synergy, for the attenuation of irritation
from other products in the combination and to mitigate their own
potential adverse effects. Nevertheless, a careful watch for adverse
TA B L E 2   The mean and SD values of the MI and PSAS
effects of TCs must be performed because of frequent confronta‐
evaluations
tion with telangiectasia, acne‐like dermatitis, atrophy, and hyper‐
  Initial 3rd month 6th month trichosis.4,6 It is reported that mometasone or fluticasone containing
MI 31.29 ± 2.56 (SD) 29.93 ± 2.13 (SD) 29.09 ± 1.90 (SD) combinations should be totally discouraged.6 Methylprednisolone
PSAS 2.79 ± 0.68 (SD) NA 2.15 ± 0.55 (SD) aceponate (MPA), a nonhalogenated TC with a methyl group at C6,
confers higher intrinsic activity. As a fourth generation TC, MPA
MI: Melanin Index; NA: Not Applicable; PSAS: Patient Self‐Assessment
Scale; SD: standard deviation. is included in the potent group. Several clinical studies supporting
 4       | PEKMEZCI

Time in Months
0
Inial 3rd Month 6th Month
-0,5
Decrease in Means

-1

-1,36
-1,5

-2
-2,2 F I G U R E 1   Improvement curve.
-2,5 The line shows the improvement in
Melanin Index in the 3rd and 6th months,
Improvement Curve compared with initial value

(A) (B)

(C) (D)

(E) (F)

(G) (H)

F I G U R E 2   Various degrees of clinical

improvement at the end of 6th month.
Before (A, C, E, G) and after (B, D, F, H)
photographs

the use of 0.1% MPA with minimal local or systemic adverse effects salicylate, SA also has anti‐inflammatory and anesthetic properties.
7
have been reported. Compared with traditional TCs, MPA has an Its anti‐inflammatory activity is most notable between 0.5% and 5%
enhanced therapeutic index.8,9 concentrations.12
Salicylic acid (SA) is a lipid‐soluble compound which is de‐ These retrospective data are interesting in two points. First,
scribed as both a beta‐hydroxy acid and a phenolic aromatic acid this combination for melasma treatment has not been reported so
by different authors.10,11 It is an agent widely used for a number of far, and second, it can be seen that a good outcome may be ob‐
dermato‐cosmetic problems, including melasma. It weakens the ad‐ tained with lesser amounts of active ingredients than reported in
hesion of corneocytes and leads to their detachment. It is therefore the literature. AA was preferred in the combination because rela‐
known to improve the penetration of other topical agents. As it is a tive high irritation rates and patient complaints were observed in
PEKMEZCI |
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CONFLICT OF INTEREST
How to cite this article: Pekmezci E. A novel triple
None. combination in treatment of melasma: Significant outcome
with far less actives. J Cosmet Dermatol. 2019;00:1–5. https://
doi.org/10.1111/jocd.12904
ORCID

Erkin Pekmezci  https://orcid.org/0000-0003-1469-2557