Pigment Cell Melanoma Res - 2021 - Nautiyal - Management of Hyperpigmentation Current Treatments and Emerging Therapies

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INTERNATIONAL FEDERATION OF PIGMENT CELL SOCIETIES · SOCIETY FOR MELANOMA RESEARCH
PIGMENT CELL & MELANOMA

Research
Management of hyperpigmentation: Current
treatments and emerging therapies
Avni Nautiyal | Sarika Wairkar
DOI: 10.1111/pcmr.12986
Volume 34, Issue 6, Pages 1000–1014
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Received: 3 December 2020 Revised: 16 April 2021 Accepted: 10 May 2021
DOI: 10.1111/pcmr.12986
REVIEW
Management of hyperpigmentation: Current treatments and

emerging therapies
Avni Nautiyal | Sarika Wairkar
Shobhaben Pratapbhai Patel School of

Pharmacy & Technology Management, Abstract
SVKMs NMIMS, Mumbai, India Hyperpigmentation of the skin refers to a dermatological condition which alters the
Correspondence color of the skin, making it discolored or darkened. The treatments for hyperpigmen-
Sarika Wairkar, Shobhaben Pratapbhai tation disorders often take very long to show results and have poor patient compli-
Patel School of Pharmacy & Technology
Management, SVKM’s NMIMS, V.L.Mehta ance. The first-line treatment for hyperpigmentation involves topical formulations
Road, Vile Parle (W), Mumbai -400 056, of conventional agents such as hydroquinone, kojic acid, and glycolic acid followed
Maharashtra India.
Email: sarikawairkar@gmail.com by oral formulations of therapeutic agents such as tranexamic acid, melatonin, and
cysteamine hydrochloride. The second-line approaches include chemical peels and
Funding information
This research did not receive any specific laser therapy given under the observation of expert professionals. However, these
grant from funding agencies in the public, therapies pose certain limitations and adverse effects such as erythema, skin peel-
commercial, or not-for-profit sectors.
ing, and drying and require long treatment duration to show visible effects. These
shortcomings of the conventional treatments provided scope for further research
on newer alternatives for managing hyperpigmentation. Some of these therapies in-
clude novel formulations such as solid lipid nanocarriers, liposomes, phytochemicals,
platelet-rich plasma, microneedling. This review focuses on elaborating on several
hyperpigmentation disorders and their mechanisms, the current, novel and emerging
treatment options for management of hyperpigmentation.
KEYWORDS
topical formulations, chemical peels, laser therapy, hyperpigmentation, novel therapies
1 | I NTRO D U C TI O N Hyperpigmentation is an umbrella term that includes various

skin discoloration, pigmentation, and darkening-related disorders.
Hyperpigmentation of the skin is a common dermatological condi- Various commonly observed hyperpigmentation disorders include
tion in which the color of the skin generally becomes darker. These melasma, post-inflammatory hyperpigmentation, ephelides, lentig-
changes in skin coloration can be a result of various internal and ines, and many more. Melasma refers to an acquired hypermelano-
external factors including hormonal changes, inflammation, injury, sis skin condition in which irregular patches of light to dark brown
acne, eczema, certain medication, UV exposure, etc. (Pérez-B ernal or gray–brown lesions appear on the sun-exposed parts of the skin
et al., 2000). Skin pigmentation and coloration are governed by (Katsambas & Antoniou, 1995; Victor et al., 2004). It usually af-
the biological processes involving the production of the skin pig- fects the face and the neck regions and predominantly observed
ment called melanin produced by melanocytes in various layers of in women (Handel et al., 2014). Post-inflammatory hyperpigmen-
skin. Thus, alterations in melanocyte production or distribution tation (PIH) refers to another hypermelanosis skin condition in
of melanin result in skin hyperpigmentation disorders (Rossi & which dark patches develop succeeding injury or inflammation of
Perez, 2011). the skin (Kaufman et al., 2018). Solar lentigines is a condition in
© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
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wileyonlinelibrary.com/journal/pcmr Pigment Cell Melanoma Res. 2021;34:1000–1014.
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NAUTIYAL and WAIRKAR 1001
which patches of darkened macular lesions cause hyperpigmenta- various spontaneous enzymatic reactions, also known as the Raper
tion, commonly referred to as “Age spots” or “Sunspots” (Ortonne Mason pathway, as described in Figure 1. The melanogenesis path-
et al., 2006). Another common disorder, Ephelides or Freckles is way occurs within a melanosome leading to the production of black–
darkened, reddish to light brown spots that typically develop on the brown Eumelanin and/or the yellow–red Pheomelanin. L-Tyrosine
facial, neck, and arm areas. They develop during the childhood phase increases melanosome production and L-
Dopachrome increases
and are more prevalent in lighter or fairer skin individuals (Ezzedine tyrosinase activity. Thus, regulating the L-
Tyrosine and L-
DOPA
et al., 2013). Although hyperpigmentation is a common cosmetic levels plays a major role in homeostasis of melanogenic systems
complaint in most skin types, it is prominently found in middle-aged (Yamaguchi & Hearing, 2009).
women and the population with III–VI skin type (Woolery-Lloyd Tyrosinase, a glycoprotein (60–70 kDa), contains copper and acts
& Kammer, 2011). El-Essawi et al reported that skin discoloration as the rate-limiting enzyme of the melanin biosynthesis pathway
and uneven skin tone are common skin problems faced by African and, therefore, considered as a potential target for several therapeu-
Americans, with almost 50% participants facing such concerns tic agents. The tyrosinase, TYRP-1 and TYRP-2, enzymes involved
(Silpa-Archa et al., 2017). Among the Arab Americans, PIH is mainly in melanogenesis are regulated by the master transcription factor
reported by people of darker skin tone originating from Yemen and known as the microphthalmia transcription factor (MITF). The α-
the ones with lighter skin tone from Lebanon and Syria (Kaufman melanocyte-stimulating hormone (α-MSH) and the adrenocortico-
et al., 2018). In another study comprising 3,000 Latinos, the occur- tropic hormone (ACTH) are present in the epidermis and dermis and
rence of melasma and hyperpigmentation was reported to be 7.5% act as major regulators of the melanogenesis pathway.
and 6.0%, respectively (Silpa-Archa et al., 2017). In Asia, Malays and Melanosomes undergo degradation differently in diverse
Indians have a higher incidence of PIH compared with the Chinese skin types during the keratinocyte differentiation process. They
who are lighter skinned. A study conducted in the Netherlands re- either reach the outermost epidermal layers intact, as seen in
ported the occurrence of solar lentigines in 51.4% individuals in darker skin, or form melanin dust like in fairer skin types. The
the face and 83.3% on the back. (Bastiaens et al., 2004) Similarly, vast variations in skin color and complexions seen in humans are
Caucasian patients report incidences of pigmentary disorders, thus a result of these complex processes (D’Mello et al., 2016).
other than vitiligo, which is the seventh most common dermatoses Various factors, intrinsic or extrinsic, can be responsible for dis-
(Callender et al., 2011). rupting the normal melanogenesis process and result in many hy-
Hyperpigmentation is not considered a harmful or lethal disor- perpigmentation disorders. Signals and factors such as UV, cAMP,
der; however, it can affect the quality of life of patients by affecting and IL1 can enhance and regulate the pro-
o piomelanocortin
their emotional and psychological health. Various treatment options (POMC) peptides, which act as precursors of alpha-M SH (Duval
are available for hyperpigmentation. These agents are primarily et al., 2014). Upon UV exposure, melanosomes are distributed to
applied by topical route in the form of creams, gels, or ointments. the surrounding keratinocytes and the upper epidermis for DNA
However, these topical treatments pose various side effects such as photoprotection. It causes the apoptosis of melanin-containing
skin drying, irritation, peeling, or hypopigmentation. The prolonged keratinocytes in the upper epidermis to prevent cell growth with
treatment durations ranging from several months to years may lead unrepaired DNA damage. Keratinocytes further release several
to poor patient compliance and satisfaction. The challenge of effec- growth factors such as alpha-
M SH, Endothelin-
1 (ET-
1), and
tive therapy to treat hyperpigmentation remains unresolved that aid in the UV-induced hyperpigmentation (Eichner et al., 2014;
lays emphasis on the need for novel treatment options. This article Yamaguchi & Hearing, 2009). Various intrinsic factors involved
thus focuses on the therapeutic targets as well the various conven- in hyperpigmentation include signals from fibroblasts, endothe-
tional, novel and emerging therapies being approached for the bet- lial cells, keratinocytes, several hormones, inflammatory cells,
ter, effective, and timely management of hyperpigmentation. and the nervous system. These cells may release ET-1 and NO
(Nitric oxide) which potentiate melanogenesis (Yamaguchi &
Hearing, 2009). Inflammation brings about an increase in the
2 | PATH O PH YS I O LO G Y O F release of arachidonate-r elated chemical mediators such as PGs
H Y PE R PI G M E NTATI O N (PGE2, PGF2a), leukotrienes (LTC4, LTD4), and thromboxanes,
which are known to enhance tyrosinase activity. Additionally,
Melanocytes responsible for the tegument color in skin is pro- muscarinic, and alpha and beta estrogen receptors have been
duced embryonically from neural crest cells. They are melanosome- found to be involved in adenyl cyclase and cAMP production.
producing cells present in the basal layer at the dermal and The elevated estrogen levels in pregnancy can thus contribute to
epidermal junction (Duval et al., 2014). Melanosomes are intracel- hyperpigmentation disorders such as melasma and areolar hyper-
lular, lysosome-like organelles that host the production and stor- pigmentation (Eichner et al., 2014).
age of the skin pigments like melanin. These pigments are further The histopathology of hyperpigmentation can vary with the vari-
distributed to the neighboring keratinocytes, giving skin its color ous pigmentation disorders. The histopathological features of melasma
(Yamaguchi & Hearing, 2009). The amino acid L-Tyrosine acts as the include epidermal thinning and rete ridge flattening. Increased mela-
precursor for melanin biosynthesis and produces melanin through nin content in both the epidermis and dermis and mild perivascular
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1002 NAUTIYAL and WAIRKAR
F I G U R E 1 The melanogenesis
pathway
lymphohistiocytic infiltrate is observed here. Immunohistochemistry 3.1 | Topical treatments

analysis suggests enlarged melanocytes with prominent dendrites, a
larger number of dermal melanophages, and their melanin deposition. Topical agents are widely used for the treatment or management
Electron microscopy studies reported increased melanosomes in the of site-specific skin hyperpigmentation and were formulated into
melanocytes and keratinocytes. In PIH mainly, increased epidermal topical dosage forms such as creams and gels. Hydroquinone, a gold
melanin content is observed in the lymphocytes surrounding blood standard for hyperpigmentation treatment, has been in topical use
vessels in dermal papilla and dermal melanophages. Perifollicular, peri- since the 1960s that acts by inhibiting tyrosinase to interfere with
vascular lymphocytic infiltration, and dermal fibrosis can also be ob- the melanin synthesis. The strength of the available products ranges
served with increased expression of several markers such as [CD]-68, up to 4% (Haddad et al., 2003). Another agent, Arbutin, is a deriva-
c-kit, and MMP-2 emphasizing the role of skin inflammation. Two his- tive of hydroquinone, but with much lesser melano-toxic effects. Its
topathological patterns of PIH can be distinguished as epidermal type depigmenting activity is due to its tyrosinase inhibition along with
and dermal type. In prior, increased melanogenesis, melanin deposition melanosome maturation inhibition activity. The anti-
t yrosinase
in the epidermis is observed, whereas the latter is characterized by en- activity of arbutin is dose dependent; however, the use of higher
hanced pigment deposition in the dermis in spite of enhanced melano- concentrations should be monitored as it may cause paradoxical hy-
genic activity in the epidermis (Nicolaidou and Katsambas, 2014; Kang perpigmentation (Piamphongsant, 1998).
et al., 2002; Silpa-Archa et al., 2017; Isedeh et al., 2016). Glycolic acid is a white crystalline alpha hydroxy acid extracted
from sugarcane (Van Scott et al., 1996). The effect of glycolic acid is
concentration dependent. It works by causing desquamation of ke-
3 | CU R R E NT TR E ATM E NT S FO R ratinocytes at lower concentrations and by producing epidermolysis
H Y PE R PI G M E NTATI O N at higher concentrations (Fischer et al., 2010). Kojic acid is commonly
used for hyperpigmentation disorders owing to its various mecha-
The potential targets for the depigmenting and hyperpigmentation nisms including tyrosinase inhibition. It acts mainly by inhibiting the
control agents include various cell receptor antagonists, inhibitors catecholase activity of tyrosinase. Another study suggested that its
of melanocyte stimulation, tyrosinase enzyme inhibitors, inhibitors depigmenting and anti-melanogenesis effect is due to the forma-
of melanosome transfer, and degraders of formed melanin in ke- tion of interleukin-6 protein by kojic acid in keratinocytes (Cabanes
ratinocytes as described in Figure 2. The widely targeted approach et al., 1994; Choi et al., 2012). However, various clinical studies have
includes the inhibition of tyrosinase, most important rate-limiting suggested contact dermatitis as a common side effect of kojic acid
enzyme of the melanogenesis pathway. therapy (Nakagawa et al., 1995).
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F I G U R E 2 Process of hyperpigmentation, potential targets and agents for control of hyperpigmentation
Retinoids comprise of Vitamin A or Retinol and its structural and pathway between melanocytes and keratinocytes as suggested by
functional derivatives. They have multiple mechanisms that lead to various in vitro studies. It, however, does not inhibit tyrosinase activ-
depigmentation including effects on cell proliferation, differentia- ity or cell proliferation to affect melanogenesis (Matts et al., 2002).
tion, and inflammation (Jacyk, 2001). Retinoids inhibit the induction The melanin synthesis pathway is a complex, multistep process;
of melanogenesis process by the melanocyte-stimulating hormone therefore, several topical agents can be employed together to act
(MSH) or L-t yrosine, but do not affect the growth and morphology upon different steps of the pathway suggesting a rationale for combi-
of the melanocytes, tyrosinase enzyme, or dopachrome tautomer- nations of topical agents for synergistic effects, or could sometimes
ase (Ebanks et al., 2009). Tretinoin, a first-generation retinoid, is a alleviate the undesirable side effects of the other. Hence, several top-
natural derivative of retinol and has been suggested to be effective ical combinations have been studied and even marketed by various
against hyperpigmentation due to photoaging (Bhawan, 1998; Weiss pharmaceutical companies. Hydroquinone is the most widely used
et al.,1988) Formulating lower concentrations of tretinoin (up to component for combinations with several agents such as kojic acid,
1%) in creams or gels can help in reducing its side effects (Embil & glycolic acid, azelaic acid, or corticosteroids. These combinations
Nacht, 1996). Certain third-generation synthetic retinoids such as have shown to be therapeutically more effective than hydroquinone
adapalene (0.1 to 0.3%) and tazarotene (0.05 to 1%) creams and gels alone (Ferreira Cestari et al., 2007). The “Triple combination” of 5%
have also been found to be safe and effective in treating PIH (Grimes hydroquinone with 0.1% tretinoin and 0.1% dexamethasone was sug-
& Callender, 2006; Jacyk, 2001). gested to be effective in treatment of PIH, melasma, and ephelides.
Azelaic acid inhibits tyrosinase and produces a direct anti- Tretinoin was found to prevent the oxidation of hydroquinone and
proliferative effect on the melanogenesis pathway (Bergman & also enhance its epidermal penetration and the corticosteroid re-
Luke, 2017). It does not affect the normal melanocytes and does not duced skin irritation and side effects (Kligman & Willis, 1975). This
lead to ochronosis on prolonged use as seen in 4% hydroquinone combination, however, possessed the side effect of skin irritation due
(Baliña & Graupe, 1991). Niacinamide is the physiologically active to high tretinoin concentration, and thus instead, the combination
analog of Vitamin B3, which inhibits the transfer of melanosomes to of 4% hydroquinone with 0.05% tretinoin and 0.01% fluocinolone
the surrounding keratinocytes and also to disrupt the cell-signaling acetonide was studied and found to be effective (Torok et al., 2005).
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Various clinical studies performed on these topical agents to eluci- Tretinoin peels have been explored due to their capability of caus-
date their efficacy have been described in Table 1. ing similar therapeutic and histological effects as topical Tretinoin,
but in a reduced span of 2.5 weeks instead of 4–6 months (Cucé
et al., 2001). A study suggested that increasing the concentration
3.2 | Oral treatments of Tretinoin peel from 1% to 10% decreased the time for skin con-
tact from 4 to 8 hr to just 1 hr, while still maintaining the same effi-
Oral drugs are considered as second-line treatment for hyperpig- cacy (Ghersetich et al., 2010). Similarly, glycolic acid peels have been
mentation, and Tranexamic acid is one of them. Studies in guinea pig found to be beneficial in hyperpigmentation disorders like melasma
skin suggested that it reduces tyrosinase enzyme activity by inhibit- and post-inflammatory hyperpigmentation (Fischer et al., 2010).
ing UV-induced plasmin activity which in turn leads to reduction in Salicylic acid peels (20%–30%) cause peeling of the superficial
both arachidonic acid and prostaglandins, eventually affecting ty- skin layer, however, have shown mixed results. In a randomized,
rosinase (Cho et al., 2013; Kato et al., 2011). double-blind study conducted by Ejaz et al., 2008, salicylic acid peel
Melatonin, a hormone secreted by the pineal gland, possesses was found to be as effective in melasma patients as that of Jessners's
free radical scavenging and antioxidant properties and stimulates solution (Ejaz et al., 2008). Another randomized study suggested no
various antioxidant enzymes like glutathione peroxidase, and in- significant improvement in the pigmentation of patients with post-
hibits the α-MSH receptor. According to a study, topical melatonin inflammatory hyperpigmentation treated with salicylic acid peel
alone, as well as combined with 4% hydroquinone and oral mela- (Joshi et al., 2009). In the same way, lactic acid peels study revealed
tonin, was shown to significantly decrease the pigmentation in all its safety and efficacy in reducing the hyperpigmentation in dark-
melasma patients. It also caused an increase in glutathione levels and skinned patients with melasma by decreasing MASI scores to 56%
a decrease in malondialdehyde levels, showing alleviation in oxida- (Monheit, 2005). Trichloroacetic acid is known to penetrate between
tive stress (Hamadi, 2009). Cysteamine hydrochloride occurs natu- superficial papillary and mid-reticular dermis and cause medium-
rally in the body as the degradation product of the L-cysteine amino depth chemical peeling on the skin (Otley & Roenigk, 1996). The
acid. A randomized, double-blind study showed that 5% cysteam- use of higher concentration of trichloroacetic acid (10%–65%) as a
ine significantly improved pigmentation in melasma patients than deeper peel poses a risk of causing post-inflammatory hyperpigmen-
placebo owing to its hydroxy radicals scavenging activity (Besouw tation in patients with darker skin (Chun et al., 2004).
et al., 2013). Glutathione, a tripeptide produced in the body, acts as Although peels are effective in various hyperpigmentation dis-
a strong antioxidant. It has skin-lightening activity via various mech- orders, their high concentrations and related side effects are often
anisms like tyrosinase enzyme inhibition and the ability to switch concerning.
production of eumelanin to pheomelanin (Sonthalia et al., 2016).
In a clinical study, 50 mg glutathione lozenge was shown to mod-
erately lighten or reduce hyperpigmentation in 90% of the subjects 3.4 | Laser therapy
(Handog et al., 2016). Another randomized, double-blind clinical
study suggested that both oral and topical glutathione significantly Light amplification by stimulated emission of radiation (Lasers) is a
reduced the melanin index in patients with melasma (Hashizume & source of high-intensity monochromatic coherent light. The intro-
Chan, 2014). duction of laser therapy transfigured the treatment options for many
skin disorders, especially hyperpigmentation. The safety and effi-
cacy of lasers remains debatable; however, many hyperpigmentation
3.3 | Chemical peels disorders have reported good results with this therapy.
Intense pulsed light (IPL) has shown promising improvements in
Chemical peels are a prevalent option for several hyperpigmenta- the treatment of hyperpigmentation. It involves the use of a xenon-
tion disorders, second to topical ones. Chemical peels work by caus- chloride lamp that emits light with a wide spectrum. Due to possible
ing desquamation and remove the superficial topmost layers of the alterations in parameters such as wavelength and fluence, it is fre-
stratum corneum. They further enhance the penetration if and when quently used for melanocytic lesions, hair removal, vascular lesions,
used in combination with other topical agents. and melasma (Sarkar et al., 2012). Another widely used option for
Jessner's solution is a chemical peel consisting of 14% salicylic hyperpigmentation is Q-Switched neodymium-doped yttrium alumi-
acid, 14% lactic acid, and 14% resorcinol in alcohol solution. It has num garnet (QS Nd:YAG) laser. This laser is highly selective, having a
been widely used for several years, with good safety and efficacy longer wavelength and hence does not damage the epidermis but is
as a medium depth chemical peel, de-keratinizing agent, and even very well absorbed by melanin cells at low doses. (Lee, 2003). Pulsed-
as a penetration enhancer. Amer and Metwalli, 2000 studied the dye laser or PDL is believed to reduce melanocyte stimulation by
effect of Jessner's solution chemical peel on 60 Asian melasma targeting the vascular components in lesions (Plonka et al., 2009).
patients in a randomized study. After 12 weeks of treatment, the Furthermore, Q-switched ruby laser or QSRL has been widely stud-
melasma area severity index (MASI) scores were significantly de- ied for hyperpigmentation; however, its efficacy remains question-
creased from the initial 6.5 ± 3.84 to 2.9 ± 3.03. (Ejaz et al., 2008). able although its mechanism is similar to QS Nd:YAG laser. Since the
NAUTIYAL and WAIRKAR
TA B L E 1 Clinical studies on topical agents for hyperpigmentation
Topical agent Study group Study type Outcome/s References
Hydroquinone (4%) 30 melasma patients with skin types A double-blind, randomized, prospective Improvement in hyperpigmentation in (Haddad et al., 2003)
III-V study 76.9% patients treated with 4% topical
hydroquinone as compared to placebo,
adverse effects such as itching and
eruptions reported in 25% of patients
Arbutin (3%) 50 Caucasian and dark-skinned patients A paired comparison, vehicle-controlled, Effective in treating solar lentigines in (Boissy et al., 2005)
with solar lentigines double-blind study patients with lighter skin but failed to
show therapeutic response in darker-
skinned individuals
Tretinoin (0.1%) 40 Caucasian patients A randomized, double-blind, vehicle- More effective against photoaging- (Weiss et al., 1988)
controlled study related hyperpigmentation in dark-
skinned patients as compared to vehicle
but reported retinoid dermatitis as a
side effect
Azelaic Acid (20%) 155 patients of Indo-Malay and A randomized double-blind study 20% azelaic acid cream found to be more (Verallo-Rowell et al.,1989).
Hispanic origin effective than 2% hydroquinone cream
against hyperpigmentation
Azelaic Acid (20%) 329 female patients A randomized double-blind study 20% azelaic acid cream found to be (Baliña & Graupe, 1991)
equally effective as 4% hydroquinone
cream against hyperpigmentation
Niacinamide (5%) 18 Japanese women with multiple types A randomized split-face double-blind Significant decrease in facial (Hakozaki et al., 2002)
of brown pigmentation paired design study hyperpigmentation spots in the patients
as compared to vehicle
Fluocinolone acetonide (0.01%), 228 patients with facial melasma A long-term, multicenter, open-label, Melasma either completely or mostly (Torok et al., 2005)
Hydroquinone (4%), Tretinoin 12-month study cleared in more than 90% patients, no
(0.05%) notable safety concerns
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QSRL has a wavelength of 694 nm, it was thought to be highly se- in skin with the CUR-SLN gel (82.32% ± 0.39%) after 24 hr, than plain
lective toward melanosomes compared with QS Nd:YAG laser with CUR gel (28% ± 0.24%). Skin irritation tests showed no erythema or ir-
a wavelength of 1,064 nm (Sarkar et al., 2012). The erbium:YAG is a ritation with the CUR-SLN gel, marking it safe for topical use (Shrotriya
laser having wavelength of 2,940 nm which ablates skin with least et al., 2018). Wu et al., 2017 formulated hydroquinone-NLC wherein
thermal damage and thus, reduces the risk of post-inflammatory hy- the rate of tyrosinase inhibition by hydroquinone-NLC was found to be
perpigmentation. (Manaloto & Alster, 1999). Several clinical studies 42.39%% ± 0.63% as compared to 28.40%% ± 1.12% of hydroquinone
have been carried out for laser therapies suggesting varied results solution, suggesting improved light stability of hydroquinone by NLC
and details are described in Table 2. and thus showed better tyrosinase inhibition assay (Wu et al., 2017).
Among multiple hyperpigmentation treatments, 4% hydroqui- Such promising results of SLN and NLC could be taken ahead for in-
none topical formulations was a gold standard, but US-FDA pro- depth study and its use in managing hyperpigmentation Figure 3.
posed a ban overall OTC preparations of hydroquinone in 2006 due
to its potential carcinogenicity. After its ban, many topical drugs
such as azelaic acid, tretinoin, and kojic acid have entered the mar- 4.1.2 | Liposomes/Nanosomes
ket. Although these drugs are effective, they have long treatment
durations, poor stratum corneum penetration, and poor epidermal Liposomes are microscopic, spherical vesicles made up of a concen-
targeting. Oral treatments, which are still newer and under assess- tric phospholipid and cholesterol bilayer and can incorporate the hy-
ment, compared with the traditional topical medications. Oral drugs drophobic and the hydrophilic drug. They can easily merge with the
have also been reported to cause lesser adverse effects such as cell membrane and alter membrane fluidity to effectively deliver the
spot-specific skin irritation, burning, and erythema than the topical drug and enhance stratum corneum penetration. Arbutin liposomes
treatments, however, are not very widely marketed as standalone displayed slower skin permeation and higher skin deposition than
treatment. Later, chemical peels were employed as they cause the arbutin solution in in vitro study that finally results in reduced sys-
complete removal of the damaged skin, allowing regeneration of the temic absorption of the drug (Wen et al., 2006). Liposomal serum
skin cells. Yet, they have a risk of inflammation, scarring and changes contaṇining a combination of azelaic acid, 4-n-butylresorcinol, and
in natural skin color. A wide variety of lasers too can be employed retinol was studied in patients with melasma. After treatment, the
in the treatment of hyperpigmentation along with drugs; however, MASI score was enhanced from 41.7% to 85%, and melasma severity
the safety aspect of using lasers remains questionable. Considering scale (MSS) improved from “moderate” to “mild.” Microneedling was
all the conventional therapies, there is an underlying need for safe, suggested to enhance the effects of liposomal serum (Kusumawardani
more evolved therapeutics for hyperpigmentation. et al., 2019). Similar observations were reported by Ghafarzadeh and
Eatemadi, 2017 in a double-blinded, randomized clinical study on
the efficacy of topical liposome-encapsulated aloe vera on melasma
4 | N OV E L TH E R A PI E S FO R patients with 32% improvement in the MASI score (Ghafarzadeh &
H Y PE R PI G M E NTATI O N Eatemadi, 2017).
Nanosomes are very similar to liposomes but have only a single-
4.1 | Novel formulations lipid monolayer. A single-blind clinical study evaluated the safety and
efficacy of topical vitamin C nanosome with iontophoresis and com-
4.1.1 | Solid lipid nanoparticles (SLN)/ pared it with 70% glycolic acid peel for the melasma patients. The re-
Nanostructured lipid carriers (NLC) sults were evaluated using baseline comparison and photographs, and
the nanosome was found to be better than glycolic acid peel in improv-
Solid lipid nanoparticles and NLC were explored as attractive choices ing hyperpigmentation. Also, vitamin C nanosomes reported fewer and
for topical delivery as they form an occlusive layer on the skin surface more transient adverse effects such as burning, irritation, and dryness
leading to hydration of the stratum corneum and enhanced drug pen- of the skin (Sobhi & Sobhi, 2012). Therefore, liposomes and nanosomes
etration. Also, they have many advantages such as high drug loading, formulations can be used clinically in future for hyperpigmentation.
improved stability, and bioavailability. Therefore, several agents for
hyperpigmentation, especially tyrosinase inhibitors have been formu-
lated as lipid nanocarriers. Ghanbarzadeh et al., 2015 prepared hyd- 4.1.3 | Nano/Micro emulsions
roquinone SLNs gel that showed greater hydroquinone deposition in
skin epidermis (46.5% ± 2.6%) than hydroquinone gel (15.1% ± 1.8%) Nanoemulsions and microemulsions are nanocarriers having two im-
and thus, improved drug localization and better skin targeting miscible phases—the aqueous phase mixed with an oil phase with
(Ghanbarzadeh et al., 2015). Kojic acid SLNs reported for controlled the help of surfactants. These carriers are potential vehicles in cos-
release and higher tyrosinase inhibition activity than conventional kojic meceuticals and for topical administration of drugs due to their size,
acid (Khezri et al., 2020). A popular phytoconstituent, curcumin, was solubility enhancement of both hydrophilic and lipophilic drugs etc.
formulated into solid lipid nanoparticles (CUR-SLNs) for skin pigmenta- The microemulsion of hydroquinone was studied for me-
tion. Drug deposition studies further indicated greater drug retention lasma and hyperpigmentation. The in vitro drug release, 87.405%
TA B L E 2 Laser Therapies for Hyperpigmentation
Wavelength of
Type of laser therapy laser Study group Study type Outcome/s References
NAUTIYAL and WAIRKAR
Intense Pulsed Light (IPL) 500–1200 nm 33 Taiwanese women A prospective, case–control IPL with 4% hydroquinone cream reported an (Wang et al., 2004)
laser with melasma clinical study improvement of 39.8% in relative melanin index
as compared to 11.6% improvement by 4%
hydroquinone alone. Complete resolution of
melasma in 35% patients seen in the IPL group.
56 Patients with A split-face, randomized, 57% of melasma patients treated with IPL (Goldman et al., 2011)
symmetrical melasma evaluator blinded, open-label combined with Triple combination cream showed
lesions, with skin study clear to almost clear skin as compared to 23%
types I-IV of patients treated with IPL combined with a
placebo cream.
Q-Switched Neodymium- 1,064 nm 22 Thai Melasma A split-face, randomized study QS Nd: YAG laser with 2% hydroquinone showed (Wattanakrai et al., 2010)
Doped Yttrium Aluminum patients with skin an improvement of 92.5% in the relative lightness
Garnet (QS Nd: YAG) Laser types III-V index compared to 19.7% in control. The laser
group reported improvement of 75.9% in
modified MASI scores.
50 Chinese Melasma An open-labeled, prospective QS Nd: YAG laser showed an improvement (Xi et al., 2011)
Patients study of 35.8% from the baseline in patients with
melasma. Concluding that results of laser therapy
depend on the severity of the disease at baseline.
Pulsed-Dye Laser (PDL) 585 nm 17 Melasma patients A prospective, randomized, PDL with triple combination therapy reported (Passeron et al., 2011)
with skin types II-IV single-blind, split-face study a decrease in the MASI score from 6.20 to
2.79 as compared to 6.76 to 4.35 seen in triple
combination therapy alone.
Q-Switched Ruby Laser 694 nm 20 patients with benign A prospective, randomized Treatment response better with QSRL in the (García García, 2010)
(QSRL) pigmented lesions study removal of pigmented lesions with lesser bleeding
than the 1,064 QS Nd: YAG laser.
4 patients with - Treatment with QSRL pulses of 694 nm, at (TAYLOR & ANDERSON, 1994)
refractory melasma fluences 1.5–7.5 was ineffective in treating
and 4 with post- patients with melasma and post-inflammatory
inflammatory hyperpigmentation.
hyperpigmentation
Erbium: YAG Laser 2,940 nm 10 female melasma - Marked improvement in the hyperpigmentation in (Manaloto & Alster, 1999)
patients with skin melasma patients immediately on treatment
types II-V
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F I G U R E 3 Novel therapies for

hyperpigmentation
hydroquinone was released from microemulsion after 24 hr. as com- melanin synthesis inhibition by hesperidin through dose-dependent
pared to 30% release from hydroquinone cream. This microemulsion tyrosinase enzyme inhibition (Zhu & Gao, 2008). In contrast, Usach
did not contribute to any skin irritation or disruption of epidermal et al reported that hesperidin was found to rather induce melano-
layers as confirmed in histopathology (Üstündağ Okur et al., 2019). genesis in human melanocyte cells by enhancing tyrosinase activity
Kojic monooleate, a tyrosinase inhibitor, was formulated into na- in a dose-dependent manner (Usach et al., 2015). Hence, there is a
noemulsion (KMO) indicated 54.76% survival rate of 3T3 cells need for further evaluation and in-depth study of the depigmenta-
(Afifah et al., 2018). Likewise, azelaic acid and hyaluronic acid nation property of hesperidin.
noemulsion was studied for tyrosinase inhibition along with in- Ellagic acid, a polyphenol, reported to possess inhibition of ty-
creased drug retention. The in vitro mushroom tyrosinase inhibition rosinase and melanogenesis. In a study involving 30 female melasma
assay showed that the formulation significantly reduced tyrosinase patients, ellagic acid was stated to significantly reduce the melanin
activity and also exhibited good skin permeation in vitro (Jacobus production (Ertam et al., 2008). Pycnogenol, a procyanidin, is the
Berlitz et al., 2019). Thus, nanoemulsions and microemulsions could bark extract of the French maritime pine which has been found to
be explored for the treatment of melasma and hyperpigmentation. act by protecting the skin against UV-induced erythema by inhib-
Lipid based carriers exhibited high stratum corneum penetration iting the nuclear factor (NF)-B-dependent gene expression (Saliou
and drug bioavailability and, hence, have been widely studied over et al., 2001). Polypodium leucotomos is extracted from fern species
the course of time. Yet, the ultimate aim was to improve efficacy and and acts as an anti-inflammatory, antioxidant, and photoprotective
reduce toxicity of treatment to satisfy the patient. agent. A clinical study showed that oral Polypodium leucotomos de-
creased the cutaneous pigmentation response in patients who were
earlier exposed to PUVA (Middelkamp-Hup et al., 2004). In another
4.2 | Phytochemicals study, the effect of oral polypodium leucotomos extracts on visible
light-induced pigmentation in 22 patients with Fitzpatrick skin type
Phytochemicals are natural compounds extracted or derived from IV-VI was studied with a daily dose of 480 mg for 28 days. The spec-
plants and have been reported for skin hyperpigmentation treatment troscopic analysis suggested a significant decrease in persistent pig-
owing to various mechanisms inhibiting melanogenesis. Aloesin, a ment darkening and delayed tanning, post-polypodium leucotomos
glycoprotein extracted from aloe vera, was reported to show anti- extract administration, and a decrease in markers for cellular damage
tyrosinase activity in a dose-dependent way. It works by inhibiting was also observed in immunohistochemistry results. (Mohammad
L-DOPA oxidation and has shown better affinity than kojic acid, ar- et al., 2019). Likewise, flavonoids silymarin and resveratrol exhibit
butin etc. However, it has poor stratum corneum penetration due photoprotective properties through various mechanisms like sup-
to its hydrophilicity and high molecular weight, suggesting the need pression of UV-induced oxidative stress, DNA damage, apoptosis, and
for novel delivery systems to be more effective (Choi et al., 2002). anti-inflammatory properties (Choo et al., 2009; Kasai et al., 2006).
Hesperidin is a flavonoid obtained from various citrus fruits and pos- Similar activities were reported for isoimperatorin and imperatorin
sesses anti-t yrosinase, anti-inflammatory, photoprotective, and anti- (Lin et al., 2008), glabridin, and liquirtin (Amer & Metwalli, 2000;
oxidant properties. Studies on human melanocyte cells showed the Yokota et al., 1998), alpha-bisabolol (Lee et al., 2010).
|
Thus, further studies on phytochemicals could explore their po- 5 | O U TCO M E M E A S U R E S A N D
tential integrated with the standard therapies for effective manage- E VA LUATI O N M O D E L S FO R
ment of hyperpigmentation. It is also important to note that natural H Y PE R PI G M E NTATI O N
agents often pose several risks of allergic and phototoxic reactions
and are sometimes adulterated with corticosteroids. Various studies have been conducted to measure the effectiveness
of treatment options for pigmentation disorders. However, most
of these methods or scales are non-validated and sometimes do
4.3 | Fractional photothermolysis not give a clear indication of the satisfactory results of the study.
Validated outcome measures can act as standards for evaluating
It is a newer type of laser therapy which forms several microscopic treatments, such as the Psoriasis Area and Severity Index (PASI)
thermal damage zones on skin, leaving most of it intact which then used for Psoriasis. Hence, similar methods and tools for hyperpig-
acts as a reservoir for healing. The thermal damage zones are also mentation disorders are employed to improve the evaluation and
called microthermal treatment zones (MTZ) and are responsible for comparison of the treatments being studied.
extruding out the microscopic epidermal necrotic debris (MENDs) Colorimetry is standard measurement tool used to evaluate the out-
which contains the pigmentation in the basal layer. The movement of comes in patients with facial and axillary hyperpigmentation, melasma,
MENDs is then facilitated by the keratinocytes at the wound corners vitiligo, etc. Tristimulus colorimetry employing a chromameter CR 200
(Katz et al., 2010). A randomized study reported that fractional pho- (Minolta) employs a specific combination of three stimuli—green, blue,
tothermolysis was equally effective in improving the MASI scores as and red lights for the in vivo quantitative evaluation of hyperpigmen-
5% trichloroacetic acid in patients with melasma. About one-third tation. Three parameters are taken into account: L* representing color
of the patients exhibited post-
inflammatory hyperpigmentation, brightness, a* parameter expressing changes from red to green surface
which got resolved by the end of the treatment duration (Hong and, b* parameter representing changes from yellow to a blue surface.
et al., 2012). Another study evaluated fractional photothermolysis The mean value of three chromameter measurement readings is eluci-
in ten female patients of melasma with 4–6 sessions at an interval of dated for skin pigmentation determination. In a randomized, double-blind
1–2 weeks and results reported that 75%–100% lightening in original study on niacinamide and desonide, the improvement in facial axillary
pigmentation was observed in 60% of the patients and less than 25% pigmentation was evaluated using chromameter. Improvement was indi-
improvement was recorded in only 30% of the patients. (Rokhsar & cated by an increase in the L* value, depicting lightening of the skin pig-
Fitzpatrick, 2005). mentation. The DermaSpectrometer consists of diodes that emit light at
specific wavelengths of 568 nm-green and 655 nm-red. It also involves
a photodetector for measuring the light reflected by skin. The absorbed
4.4 | Microneedling and reflected light at different wavelengths is measured by the meter,
green for hemoglobin, and red for melanin. The absorbed and reflected
Microneedling is a process in which an instrument studded with mi- light intensities project the melanin index and erythema index at 568 and
croneedles is rolled over the skin to penetrate the epidermis and reach 655 nm, respectively. Mexameter works on a similar principle involving 16
the upper dermis (0.5 mm) to induce a wound-healing response. It was diodes that emit light at three different wavelengths of 568 nm—green,
studied as a means to augment trans-epidermal delivery of various 660 nm—red, and 880 nm—infrared, arranged circularly. The intensities
agents for the treatment of hyperpigmentation disorders. In a clini- of the absorbed and the reflected light at 660 and 880 nm give the mela-
cal study, a Rucinol and sophora-alpha serum was evaluated with and nin index, whereas the erythema index is obtained from the light intensi-
without microneedling. The microneedle combination group showed ties at 568 and 660 nm. On comparison of the sensitivity performances,
a significant decrease in MASI score as compared to the serum alone it is observed that all the three colorimetric methods detect minor quan-
(Fabbrocini et al., 2011). Similar results were stated using a combi- titative differences in skin pigmentation effectively. The mexameter,
nation of microneedling with triple combination cream containing however, showed lesser sensitivity in melanin index, and the strongest
0.05% tretinoin, 4% hydroquinone, and 1% fluocinolone acetonide sensibility for the erythema index was shown by the DermaSpectrometer
(Lima 2015). In a randomized study, treatment with microinjections (Castanedo-Cazares et al., 2013; Clarys et al., 2000).
of tranexamic acid combined with microneedling showed greater im- Spectrophotometric inputs from the skin have been analyzed using
provement in the hyperpigmentation in melasma patients than control complex algorithms to give back high-resolution data about the total
group. (Budamakuntla et al., 2013). Assessment of microneedling ther- melanin content of the epidermis. Spectrophotometric intracutaneous
apy for the improvement of acne pigmentation scars was done in 39 analysis (SIA) produces eight narrow band spectrally filtered images of
patients with dark skin. The results showed substantial improvement the skin over an area of 24 × 24 mm with radiation ranging from 400 to
from baseline scores after microneedling treatment when reviewed 1,000 nm. Certain highly replicable features such as the collagen holes
after 2 and 4 weeks subsequently. (Al Qarqaz & Al-Yousef, 2018). and dermal melanin identified by this technique are specific when stud-
Thus, microneedling could be explored as an effective and promising ied using receiver operator characteristic curves with dermatoscopy.
augmenting therapy for deeper and more uniform penetration of the This method provides valuable and credible information which can be
depigmenting agents for treatment of hyperpigmentation disorders. utilized in diagnosing pigmented skin lesions (Moncrieff et al., 2002).
|
In image analysis, digital camera mounted on a microscope is to acne lesions, as they are more uniform in pigment intensity and
employed to scan the epidermis and dermis and tissue images are size. However, it is also observed that the TCA-
induced lesions
captured under high magnification. The camera is connected to a and the acne-induced PIH are clinically, histologically, and spectro-
computer, and the images captured can be processed using Image J scopically indistinguishable after 28 days, suggesting that the TCA-
v 1.44 software. Further, the captured epidermal images are treated induced PIH model could be a reproducible and reliable alternative
by deconvolution and binary processing to quantify the melanin con- for the assessment of acne-induced PIH. (Isedeh et al., 2016; Lyons
tent. The area of pigmentation involved can also be estimated and et al., 2020). Another model focuses on inducing PIH by employing
expressed as % per mm2 (Castanedo-C azares et al., 2013). repeated hapten application of 2,4-dinitrofluorobenzene in hairless
Hyperpigmentation area and severity index (HASI) or melasma transgenic mice (hk14-SCF Tg/HRM) having human-t ype epidermis
area and severity index (MASI) were developed by Kimbrough- containing melanin. Its histopathological analysis revealed epidermal
Green et al. It is an objective scoring system commonly used for ac- hyperplasia, infiltrated inflammatory cells, and melanin-containing
curate quantification of facial hyperpigmentation and its treatments. cells in the dermis. Increased melanin without spongiosis and in-
It depicts the severity of hyperpigmentation, and thus, the higher creased dermal melanophages are observed which are similar char-
the HASI score, the more severe or worse is the pigmentation. While acteristics detected in PIH. Hence, suggesting that this mouse model
using HASI evaluation, the face is divided into four zones: the fore- replicates the human PIH characteristics and could be employed to
head (F), right malar region (MR), left malar region (ML), and the chin assess novel treatments targeting PIH (Nakano et al., 2021).
(C). A (area of involvement), D (darkness), and H (homogeneity) are
the main factors assessed. MASI is then calculated by the adding
severity ratings of darkness and homogeneity factors, multiplied by 6 | FU T U R E PE R S PEC TI V E
the area involved for all four areas.
MASI total score = 0.3A(f)[D(f)+H(f)] + 0.3A(lm) [D(lm) + H(lm)] + The need and demand for newer, safer, and more effective treat-
0.3A(rm) [D(rm) + H(rm)] + 0.1A(c) [D(c) + H(c)]. ments for various hyperpigmentation disorders have paved the way
The range of the MASI score can be from 0 to 48. The study for researchers to explore treatment options continuously. Various
conducted by Pandya et al assessed the reliability and validity of compounds and combinations are currently being tested and have
this MASI scoring method (Pandya et al., 2011; Sarkar et al., 2017). shown promising results in the initial phases of clinical trials and are
Similarly, investigators at the Henry Ford Hospital, Detroit, USA, de- currently being considered for further evaluation.
veloped a six-point IGA scale for the determination of hyperpigmen- Established anti-diabetic drug metformin tested topically in an-
tation and erythema (Isedeh et al., 2016). imals that show whitening of tails and exhibited anti-melanogenic
Post-acne hyperpigmentation index (PAHPI) involves three main effects when evaluated on human skin biopsies and reconstituted
important characteristics of PIH: the size, number, and intensity of human skin (Lehraiki et al., 2014). Methimazole topical cream was
the lesions. A focus group of PIH patients ranks these factors in evaluated for its depigmenting efficacy in melasma patients showing
order of importance. These factors are weighted based on focus hydroquinone-resistance and was found to be effective in reduc-
group feedback and the PAHPI score is calculated as the total of the ing the hyperpigmentation through inhibition of melanin synthe-
weighted variables, ranging between 6 and 22. A study conducted by sis (Malek et al., 2013). These candidates, though found to be safe
Savory et al on 15 PIH patients employed four raters who were asked and well-tolerated, require more studies to establish their efficacy.
to independently rank the photographs of PIH-affected patients and Topical serums can be explored for treating hyperpigmentation dis-
assign them a PAHPI score according to the severity. Excellent inter- orders. A topical serum of 2.0% (w/w) cetyl tranexamate mesylate, a
rater and intra-rater reliability was observed and hence produced tranexamic acid derivative, evaluated for its depigmenting and anti-
encouraging preliminary results (Savory et al., 2014). inflammatory activity in patients revealed improved skin tone and re-
Several models of pigmentation have been developed for assess- duction in pigmentation spots and redness (Silva Souza et al., 2020).
ment of agents for their inhibitory effects on the hyperpigmenta- A similar observation was shown by 0.3% rucinol serum in melasma
tion processes. In vitro cell-line studies are very commonly used for patients (Khemis et al., 2007).
the evaluation of tyrosinase inhibitors in reducing melanin content.
Other more complex assays using melanocytes, three-dimensional
skin equivalent cultures, or reconstructed skin which may contain 7 | CO N C LU S I O N
both dermal and epidermal cells such as the fibroblasts, keratino-
cytes, and melanocytes can be similarly performed in multiwell Although topical agents are considered as the first-line treatment for
plates (Ortonne and Bissett, 2008). In human models, the trichlo- hyperpigmentation, they also cause adverse effects such as skin irri-
roacetic acid (TCA)-induced PIH model has been extensively stud- tation and peeling with higher concentrations. Chemical peels come
ied for clinical, histological, and spectroscopic characteristics. next as second-line treatment, which have shown good efficacy
Here, studies comparing TCA-induced PIH with acne-induced PIH but poses a greater risk of side effects and is more expensive. Oral
in human patients have suggested that a better comparison among therapies have usually demonstrated mixed results and more relapse
the sites is possible with the TCA-induced PIH lesions as compared rate. Laser and microneedling therapies are approached as third-line
|
treatment options due to limited data and usage history and high L. D. (2013). A randomised, open-label, comparative study of
tranexamic acid microinjections and tranexamic acid with mi-
risks of side effects. Additionally, prevention or maintenance
croneedling in patients with melasma. Journal of Cutaneous
therapy with sunscreens for sun/UV protection remains crucial. and Aesthetic Surgery, 6(3), 139. https://doi.org/10.4103/097
Unfortunately, existing treatments demonstrate limited safety and 4-2 077.118403
efficacy, with prolonged treatment durations. Thus, several newer Cabanes, J., Chazarra, S., & Garcia-C armona, F. (1994). Kojic Acid,
a Cosmetic Skin Whitening Agent, is a Slow- binding Inhibitor
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of Catecholase Activity of Tyrosinase. Journal of Pharmacy
under development for timely management of hyperpigmentation and Pharmacology, 46(12), 982– 985. https://doi.org/10.1111/
with short duration and reduced adverse effects. However, a guar- j.2042-7158.1994.tb03253.x
anteed therapy is still a dream for researchers relentlessly working Çağlar, E. Ş., Pekcan, A. N., Okur, M. E., Ayla, Ş., & Üstündağ okur, N.
on the clinical therapeutics of hyperpigmentation. (2019). Preparation, optimization and in vivo anti- inflammatory
evaluation of hydroquinone loaded microemulsion formulations for
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C O N FL I C T O F I N T E R E S T https://doi.org/10.12991/jrp.2019.174
None. Callender, V. D., Surin-Lord, S. S., Davis, E. C., & Maclin, M. (2011).
Postinflammatory hyperpigmentation. American Journal of Clinical
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AU T H O R C O N T R I B U T I O N
000000 000-0 0000
Avni Nautiyal has contributed to acquisition, interpretation of data, Castanedo- C azares, J. P., Lárraga- Piñones, G., Ehnis- Pérez, A.,
and drafting of the manuscript. Sarika Wairkar has contributed to Fuentes-A humada, C., Oros-O valle, C., Smoller, B. R., & Torres-
the conception and design of the review and approved final draft of Álvarez, B. (2013). Topical Niacinamide 4% and Desonide 0.05% for
Treatment of Axillary Hyperpigmentation: A Randomized, double-
the manuscript.
blind, placebo-controlled Study. Clinical, Cosmetic and Investigational
Dermatology, 6, 29.
ORCID Cho, H. H., Choi, M., Cho, S., & Lee, J. H. (2013). Role of oral tranexamic
Sarika Wairkar https://orcid.org/0000-0002-0124-1741 acid in melasma patients treated with IPL and low fluence QS Nd:YAG
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Management of hyperpigmentation: Current treatments and

Shobhaben Pratapbhai Patel School of

topical formulations, chemical peels, laser therapy, hyperpigmentation, novel therapies

1 | I NTRO D U C TI O N Hyperpigmentation is an umbrella term that includes various

lymphohistiocytic infiltrate is observed here. Immunohistochemistry 3.1 | Topical treatments

F I G U R E 2 Process of hyperpigmentation, potential targets and agents for control of hyperpigmentation

TA B L E 1 Clinical studies on topical agents for hyperpigmentation

Topical agent Study group Study type Outcome/s References

F I G U R E 3 Novel therapies for

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