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 Table of Contents  
Year : 2014  |  Volume : 1  |  Issue : 2  |  Page : 59-69

Postinflammatory hyperpigmentation: Review of pathogenesis, prevention, and treatment

Department of Dermatology, University of Texas Health Science Center at Houston, MD Anderson Cancer Center, Houston, Tx 77030, USA

Date of Web Publication15-Dec-2014

Correspondence Address:
Anisha B Patel
Department of Dermatology, University of Texas Health Science Center at Houston and University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1452, Houston, Tx 77030
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2349-5847.147043

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Postinflammatory hyperpigmentation (PIH) is a common pigmentary disorder that is distressing to patients, particularly those with skin of color, and can be very difficult to treat. Part of this difficulty arises from the dermal melanosis in addition to the epidermal hyperpigmentation. This article reviews the mechanisms that induce the hyperpigmentation including inflammatory mediators such as metabolites of arachidonic acid and reactive oxygen species (ROS) and how these may influence prevention and treatment strategies. Treating the inflammatory cause and sun protecting are crucial to effective therapy. Although common, few studies have been done focusing on prevention and treatment of this disease. Topical therapies are the mainstay of treatment for PIH, but have shown poor efficacy for the dermal hyperpigmentation component. Hydroquinone in combination with topical steroids, retinoids, glycolic acid, and lactic acid have been augmented with numerous emerging natural therapies such as kojic acid, arbutin, ascorbic acid, soy, and niacinamide. Although efficacious for hyperpigmentation, most of the natural therapies have not been studied specifically for PIH. Salicylic acid and glycolic acid chemical peels, as well as the quality-switched (QS) neodymium-doped yttrium aluminum garnet (Nd: YAG), QS Ruby, 1550 nm erbium fiber fractional thermolysis, and 1927 nm fractional thulium fiber lasers have shown good efficacy for the treatment of facial hyperpigmentation.

Keywords: Acne-induced hyperpigmentation, dyschromia, facial hyperpigmentation, pigmentary disorders, postinflammatory hyperpigmentation

How to cite this article:
Patel AB. Postinflammatory hyperpigmentation: Review of pathogenesis, prevention, and treatment. Pigment Int 2014;1:59-69

How to cite this URL:
Patel AB. Postinflammatory hyperpigmentation: Review of pathogenesis, prevention, and treatment. Pigment Int [serial online] 2014 [cited 2023 Feb 5];1:59-69. Available from: https://www.pigmentinternational.com/text.asp?2014/1/2/59/147043

  Introduction Top

Postinflammatory hyperpigmentation (PIH) is extremely common, and can present in patients of all Fitzpatrick skin types. [1] It is, however, particularly noticeable in patients with Fitzpatrick type IV and higher skin types, where the hypermelanosis appears to be more prominent and more persistent. [1],[2] It can be distressing to the patient and just as disfiguring as the inciting inflammatory reaction. [3] The body surface area involved can be significant, particularly in patients with widespread diseases. Arguably, PIH is the most common pigmentary disorder in patients with pigmented skin, yet the literature is sparse compared to melasma and solar lentigines.

Ill-defined hyperpigmented macules and patches that range in color from brown to blue-gray characterize PIH. The lesions occur at the site of a previous inflammatory insult. The brown pigmentation indicates more of an epidermal melanosis, while a blue-gray color indicates dermal melanosis. The differential diagnosis includes primary pigmentary disorders such as lichen planus pigmentosus and erythema dyschromicum perstans, which can be distinguished from PIH by an interface dermatitis seen on biopsy. Dermatomyositis and graft-versus-host-disease can look similar histologically and often present with hyperpigmentation patients with skin of color, but serologies and clinical history would help distinguish these diagnoses. Melasma can be histologically similar to PIH, but the clinical presentation is distinct. With macular amyloidosis, patients will have a history of pruritus, and amyloid deposition can be seen in the dermal papillae on biopsy. Round hyperpigmented lesions such as tinea versicolor or solar lentigines can mimic PIH, but a KOH scraping or biopsy would help clarify the diagnosis. More diffuse hyperpigmentation can be seen with Addison's disease, hemochromatosis, or argyria. Systemic symptoms and work up would identify the first two diseases and the latter diagnosis could be made on biopsy. Furthermore, a diffuse, ill-defined hyperpigmentation would be an unusual presentation of PIH. The differential diagnosis of PIH is wide, however, a key clinical feature to identifying PIH is the history of a preceding inflammatory insult.

Most lesions are a combination of epidermal and dermal pigment deposition. Without treatment, epidermal pigmentation can take months to years to resolve and dermal pigmentation years to fade. [4] The first challenge for the practitioner is to identify the etiology of the inflammation before the hyperpigmentation can fully be addressed. The sources can be exogenous (allergic or irritant contact dermatitis, dermabrasion, laser therapy, burns), endogenous (primary inflammatory or bullous dermatoses), or infectious (herpes zoster) [Figure 1], [Figure 2] and [Figure 3]. [5] This article will review the pathogenesis of PIH as well as prevention strategies and treatment options.
Figure 1: Postinfl ammatory hyperpigmentation due to herpes zoster

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Figure 2: Postinfl ammatory hyperpigmentation due to graft-versushost-
disease being treated with a triple therapy topical cream
(hydroquinone, retinoic acid, dexamethasone)

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Figure 3: Postinfl ammatory hyperpigmentation due to acne being treated with topical retinoids

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  Etiology and Pathogenesis Top

Clinical PIH is composed of histologic epidermal hypermelanosis and dermal melanophages in varying degrees. [6] Epidermal hypermelanosis is present in different amounts depending on the characteristics of the stimulus. For example, ultraviolet (UV)-induced hyperpigmentation has a different pattern than allergic contact dermatitis-induced PIH [6],[7] and irritant contact dermatitis-induced PIH has an exaggerated melanocytic response compared to allergic contact dermatitis-induced PIH. [8] Further, the allergen and the applied dose of the allergen affect the quantity of dermal melanophages and the increase in epidermal melanocytes stimulated with the inflammation. [9]

In addition to pigment deposition, discoid lupus erythematosus, psoriasis, lichen planus, atopic dermatitis, seborrheic dermatitis, and lichen sclerosus were all shown to have a significant increase in melanocytes per mm 2 in inflamed versus control skin samples. They showed not only hyperplasia of melanocytes, but also hypertrophy. In erythema nodosum, where the primary pathology is in the subcutaneous tissue, there was only a modest increase in melanocytes per mm 2 shown. Interestingly, these findings did not necessarily correlate to clinical hyperpigmentation, which may be a function of the keratinocytic melanin-uptake properties. [8]

Just as important as the stimulus is the patient's tendency to respond with hypermelanosis, which is an inherited trait related to having "weak" or "strong" melanocytes. [2] Furthermore, the degree of hyperpigmentation varies based on an individual's keratinocyte receptiveness. [6] As discussed above in Papa and Kligman study, the "chromatic tendency" may be dependent on keratinocyte properties and their willingness to receive extraneous melanin in inflammatory situations. [8] Keratinocyte growth factor (KGF) release from fibroblasts is stimulated by interleukin (IL)-1 alpha. It binds to receptors on epithelial cells inducing uptake of melanosomes. The KGF receptors vary based on skin type. [10] Predicting the degree of hypermelanosis in PIH is multifactorial, and Lamel et al. advocate for further is quantifying the degree and pattern of melanization of different inflammatory stimuli, as it will help guide our treatment and prevention strategies. [11]

Arachidonic acid is an important mediator in PIH as it stimulates melanogenesis, mainly through its oxidative products. [12],[13] Inflammatory reactions that damage the cell membrane cause release of arachidonic acid, which is oxidized by peroxidase, cyclooxygenase, and 5-lipoxygenase to prostaglandins and leukotrienes. [10],[12] Prostaglandin E2 (PGE2) is increased in inflamed skin of multiple etiologies. [6] Leukotrienes C4 (LTC4) and D4 and thromboxane B2 stimulate melanogenesis by upregulating tyrosinase, increasing melanocyte cell size, and forming new dendritic processes, with LTC4 being the most potent amongst them in increasing tyrosinase activity and melanocyte growth. [13] The elongated dendrites cause an increase in deposition of melanin within the epidermis.

Other keratinocyte-released chemical mediators that stimulate melanocytes include histamine, [14] basic fibroblast growth factor, stem cell factor, and endothelin-1. [15] Mesenchymal mediators are also involved in melanocyte stimulation, [10] and must be taken into consideration in addition to the epithelial mediators when developing therapeutic strategies for PIH.

Regarding the increased dermal melanophages, multiple mechanisms have been proposed. One theory is that intercellular edema prevents melanocytes from reaching keratinocytes with their dendritic processes and the retained melanin then forms melanosome complexes. These complexes are then found within dermal melanophages. [16] Another theory demonstrated by Masu and Seji is that dyskeratotic keratinocytes in vacuolar dermatitides have retained melanin and are phagocytized by epidermal macrophages. These macrophages then return to the dermis, where they are able to break down the bulk of the keratinocyte, except for the melanosomes. [17]

Postinflammatory hyperpigmentation is mediated by a number of different factors, including those endogenous to the patient and external factors based on the etiology and intensity of the inflammation. As we continue to delineate these markers, more options for prevention and treatment will become available to address this difficult to manage the disease.

  Treatment Top

The first issue to be addressed is the cause of the inflammation. Until this process is treated, the pigmentation will continue to worsen. Once the inflammation is controlled, the mainstays of treatment are time and sun protection. Fifty-seven percent of PIH due to acne improved by 40 weeks in one study. [18] In addition to UV-induced pigmentation, it has recently been shown that visible light has been linked to pigmentation changes, [19] making it even more important for patients to wear a sunblock, preferably one with iron oxide. [20] Furthermore, irritants which can worsen the hyperpigmentation, should be avoided. Exposure to UV, medications such as minocycline, infectious agents, and cutaneous injury can all aggravate PIH. [21]

The main categories of intervention include topicals, laser, and chemical peels. Callender et al. included an elegant table of therapies in their 2011 review with an emphasis on studies targeting PIH. [22]

Topical therapies

Topical therapies are the most common and cost-effective treatments.


Hydroquinone (HQ) is the mainstay of these therapies with a complex mechanism of action. Mainly, it inhibits tyrosinase, [23] thereby decreasing the production of melanin. This is seen in the decreased formation of melanosomes. Furthermore, HQ works by altering the melanosome structure and increasing their degradation via destruction of membranous organelles in melanocytes. [24]

The safety of using HQ for longer durations in patients with PIH is often discussed. HQ's most common side effect is irritation, [25] but it can also rarely cause exogenous ochronosis. It was originally reported in South African women who used HQ at high concentrations for years. [26] Based on the decreased incidence of ochronosis in America as compared to Africa, it is thought that resorcinol and hydroethanolic formulations of HQ increase its absorption and side effect profile. [8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27] The duration of use more so than the concentration of the HQ appears to be correlated with ochronosis. Physician-monitoring of HQ use in the US likely contributes to the low incidence of exogenous ochronosis, which is about one in 10 million. [27]

Worry of systemic absorption and carcinogenicity with topical preparations is low and unsubstantiated. [25] HQ is a safe and effective medication that performs a very useful function in treating pigmentary disorders. [27],[28],[29],[30]

Hydroquinone has been studied in combination with many different topicals, with first published reports from Kligman and Willis combining it with retinoic acid and a topical steroid [Figure 2]. [31] Since then, it has been combined with glycolic acid, kojic acid, and other topicals. Few efficacy studies for HQ address PIH alone, and melasma studies are often used as an indicator of efficacy, although the results cannot be directly correlated as PIH can have a much larger dermal component than the melasma.


Retinoids reduce epidermal pigment by blocking the transcription of tyrosinase, inducing desquamation, and dispersing keratinocyte pigment granules. Further, the increased rate of cell turnover decreases the amount of time keratinocytes are in contact with melanocytes, therefore decreasing melanin uptake. [32] Tretinoin, [18] tazarotene, [33] and adapalene [34] have all been shown to significantly reduce epidermal pigmentation as a monotherapy.

Bulengo-Ransby et al. showed an overall reduction in PIH with 40 weeks of tretinoin, where there was a statistically significant decrease in visible pigmentation and epidermal melanin in the treatment group compared to vehicle. However, there was an increase in dermal melanin, likely caused by the retinoid reactions. [18] Tazarotene showed excellent efficacy in a study of mainly Type IV and above patients with acne and PIH. The 0.1% cream was applied once daily in this randomized, double-blinded, vehicle-controlled study with statistically significant improvement in disease severity, intensity of lesions, and the number of lesions. There were no hypopigmentation side effects compared to control. [33] Adapalene has been studied for acne and PIH, and showed improvement with treatment. [34] It has been proven safe and effective in treating acne in pigmented skin, but more trials need to be done regarding PIH. This could be a favorable medication to use in the future as it has a lower side effect profile than its retinoid counterparts [Figure 3]. [35]

Retinoids work synergistically with other depigmenting agents by increasing the absorption of HQ and decreasing the risk of epidermal atrophy from topical steroids. [36] However, dermal pigment was unaffected in a trial of a combination cream of HQ and tretinoin. [37]

Mequinol (4-hydroxyanisole)

Mequinol, a tyrosinase inhibitor, is used at a 2% concentration in Europe in combination with 0.01% tretinoin cream. It is more effective than placebo in treating solar lentigines with 56.3% and 52.6% of patients having clinical success after 24 weeks in two trials. [38] Although mequinol has been shown effective for solar lentigines; no studies with published data have been performed for PIH.

Azelaic acid

Lowe et al. demonstrated that 55% of patients with skin types IV and higher using azelaic acid 20% had improvement of their hyperpigmentation; however, patients with a dermal hyperpigmentation were excluded from the study. [39]

Glycolic acid lotion (15-20%) combined with azelaic acid 20% cream was as effective as HQ 4% cream for the treatment of hyperpigmentation with slightly more irritation in the glycolic acid + azelaic acid group. Most patients in the study had melasma, but eight patients did have PIH. The study had limited patients with skin type higher than III (19/65). [40]

An advantage to using azelaic acid instead of HQ is that HQ lightens hyperpigmented as well as the normal skin and azelaic acid only lightens the hyperpigmented skin. Azelaic acid has a dual mechanism of action where, like HQ, it inhibits tyrosinase, but it also decreases free-radical production, a potent stimulant of PIH. [41]

Natural therapies

Natural therapies provide alternatives for those patients seeking a more organic option; however, little study has been done in PIH, let alone in dark skin.

Kojic acid is derived from fungi such as Acetobacter, Aspergillus, and Penicillium and works by inhibiting the tyrosinase enzyme. It has been proven effective in the melasma therapy, but has not been studied in PIH. The main side effect is irritant or contact dermatitis. [22]

Niacinamide is a form of Vitamin B3 that decreases pro-inflammatory markers, [3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42] many of which are implicated in melanogenesis (PGE2, reactive oxygen species [ROS]). [42] Hakozaki et al. studied niacinamide both in vitro and in vivo and demonstrated that it blocks melanosome transfer to keratinocytes as well. Patients also showed some improvement in the number and intensity of hyperpigmented lesions (solar lentigines and melasma) after 8 weeks of use. [43] Bissett et al. confirmed a decrease in number and intensity of pigmented lesions. [44]

Soy's mechanism of action is to limit keratinocyte phagocytosis of melanosomes by blocking the proteinase activated receptor-2 (PAR-2) pathway, which regulates phagocytosis, with small protein serine protease inhibitors, Bowman-Birk inhibitor, and soybean trypsin inhibitor. [45] One study combining whole soy extract with retinol and salicylic acid in Fitzpatrick type III and above patients demonstrated an improvement in acne-induced PIH. [46]

Arbutin is an oral medication derived from the dried leaves of the bearberry, pear, cranberry, or blueberry plants. It hydrolyzes to free HQ and inhibits tyrosinase activity and melanosome maturation. It has shown improvement with solar lentigines, although it has not been studied in dark skinned patients or in PIH. [22],[45]

Ascorbic acid (Vitamin C) is an antioxidant found in fruits and vegetables. It works by deactivating tyrosinase via a copper ion interaction and reduces dopaquinone, a tyrosinase substrate. It has shown efficacy in the treatment of melasma, solar lentigines, and UV-induced pigmentation. [45]

Other potentially useful natural ingredients include licorice root extract (tyrosinase inhibition), chitin (pro-tyrosinase to tyrosinase inhibition), lignin peroxidase (melanin degradation), and glutathione (tyrosinase inhibition). [45]

Combination therapies

Kligman and Willis first proved that HQ works better in a combination therapy as HQ 5% + tretinoin 0.1% + dexamethasone 0.1% in 1975. [31] Since, then there have been multiple studies using combination therapy for melasma and a few for PIH. Yoshimura et al. proposed that high concentrations of retinoic acid in an aqueous gel could be used safely, and that concomitant steroid therapy could be avoided. The study used all-trans retinoic acid (atRA) 0.1% in aqueous gel versus ointment in combination with HQ 4% and lactic acid (LA) 7%. Treatment times were variable based on patient's response, which is not clear in the study how an adequate response was determined. However, at this time point, atRA was stopped, and the HQ-LA combination was continued with the addition of dexamethasone 0.12% until erythema was reduced. The results showed similar efficacy and tolerance to the hydrophilic ointment vehicle, however, the treatment time was significantly faster. [47] In a study of women with Fitzpatrick type IV and above skin with PIH due to acne, HQ 4%, glycolic acid 10%, Vitamin C, Vitamin E, and sunscreen were combined and compared to untreated skin. Objective measurements showed statistically significant improvement from baseline and compared to the untreated skin. [48] Taylor et al. compared the use of HQ 4% + tretinoin 0.05% + fluocinolone acetonide 0.01% with HQ + tretinoin, HQ + fluocinolone, and tretinoin + fluocinolone for melasma. Triple therapy was significantly more efficacious than HQ + tretinoin or tretinoin + fluocinolone therapies. [49]

Two similar studies using a microencapsulated HQ 4% and retinol 0.15% were evaluated for efficacy against hyperpigmentation (melasma and PIH) in mainly Fitzpatrick type IV and above patients. [2],[3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43],[44],[45],[46],[47],[48],[49],[50],[51] Notably, one study excluded patients with dermal melasma or PIH based on Wood's lamp examination and limited the treatment areas to face only, [51] whereas patients with dermal pigmentation and lesions on the body were included in the former study. [52] Both showed statistically significant improvement in all categories of evaluation, and propose that the microencapsulated HQ + retinol formulation is efficacious and well-tolerated without the additional steroid. [2],[3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43],[44],[45],[46],[47],[48],[49],[50],[51] A head-to-head study with a triple cream would be helpful as well.

A review of studies with retinaldehyde 0.1% and glycolic acid 6% shows statistically significant improvement compared to vehicle in animal studies, [53] and showed similar efficacy in acne treatment and decreased erythema and hyperpigmentation at the 3 month follow-up on human skin samples. [54] This is being proposed as a less irritating alternative to retinoic acid, although the two have not been studied head-to-head in humans.

The above studies demonstrate that combination therapies are well-tolerated and efficacious, and in many cases, they are more efficacious than the single ingredients. The goal with these therapies is to provide long-term therapy with minimal side effects without reducing the effect of the medicine. With the discovery and use of new depigmenting agents, these possibilities are limitless.

Chemical peels

Salicylic acid peels have already been proven safe and efficacious in treating acne; even in dark-skinned patients. [55] It has also been shown in a group of Korean patients that there is a statistically significant improvement in PIH as well. These patients were not using any other acne treatments in addition to the 30% salicylic acid peels applied every 2 weeks for 3 months. [56]

Glycolic acid is useful for epidermal melasma, [57] but was not shown to be helpful for dermal melasma. [58] Burns et al. showed improvement in PIH with six serial high-concentration (maximum 68%) glycolic acid peels applied in combination with 2% HQ + 10% glycolic acid gel twice daily and 0.05% tretinoin cream at night. The control group applied the topical therapy only. All patients were Fitzpatrick skin type IV or above. [59]

Although trichloroacetic acid (TCA) peels could potentially reach superficial dermal pigmentation, there was significantly less improvement in mixed melasma compared to epidermal melasma, with one study of Indian females treated with TCA 10-20% peels having greater downtime after the peel compared to glycolic acid. Both peels had similar efficacies. [60]

Commercially-available blended peels containing kojic acid 2% with and without HQ 2% are available, however, there is no literature regarding their efficacy in pigmentary disorders.

Laser therapy

As with topical and chemical peel therapies, most of the current literature focuses on melasma and solar lentigines, with few studies specifically targeting PIH. Particularly for lasers, where the depth of the targeted chromophore has implications for the type of laser, settings, and potential side effects, the differences between treating melasma and PIH can be significant. The 1064 nm quality-switched (QS) neodymium-doped yttrium aluminum garnet (Nd: YAG), QS Ruby, and 1550 nm Erbium fiber fractional thermolysis lasers are the most frequently used in studies. The QS Ruby had poor results in PIH refractory to topical therapy. [61] It did well, however, in studies for melasma [3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43],[44],[45],[46],[47],[48],[49],[50],[51],[52],[53],[54],[55],[56],[57],[58],[59],[60],[61],[62] and postsclerotherapy hyperpigmentation, although the Fitzpatrick types of the patients were not noted in this case. [63] Case reports of PIH being treated with multiple sessions of Erbium fiber fractional photothermolysis have been successful. [7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43],[44],[45],[46],[47],[48],[49],[50],[51],[52],[53],[54],[55],[56],[57],[58],[59],[60],[61],[62],[63],[64],[65] A case series of three patients with PIH treated with a QS Nd: YAG 1064 nm laser showed good results after five sessions with prolonged improvement at 2 months. [66]

The 1927 nm fractional thulium fiber laser is recently reported effective in melasma treatment, [67],[68],[69] and one case of PIH was successfully treated as well. [70] The long wavelength allows deeper penetration while still targeting melanin as the chromophore. This decreases the chances of surface burns and PIH.

Wang et al. discussed the efficacy of intense pulsed light (IPL) when used with a long wavelength filter and long pulse delays in melasma. Treatments were successful for epidermal pigmentation. [71] Studies using IPL for PIH remain to be seen.

One should emphasize that the use of sunscreen before and after treatment as well as pre- and post-treatments with topical lightening agents and steroids can be helpful. Before and after care are important to the success of these treatments. [5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43],[44],[45],[46],[47],[48],[49],[50],[51],[52],[53],[54],[55],[56],[57],[58],[59],[60],[61],[62],[63],[64],[65],[66],[67],[68],[69],[70],[71],[72],[73],[74]

Emerging therapies

Patients are always interested in dietary solutions to their cutaneous diseases. Polypodium leucotomos is a tropical fern from Central and South America. It has proven to be a safe drug that increases repigmentation with narrow band-UVB-treated vitiligo and helps decrease melasma area severity index in combination with sunscreen faster than sunscreen alone. [75] There are no clinical trials for P. leucotomos in PIH, however, it has shown beneficial properties against the harmful effects of UV on the skin, [8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43],[44],[45],[46],[47],[48],[49],[50],[51],[52],[53],[54],[55],[56],[57],[58],[59],[60],[61],[62],[63],[64],[65],[66],[67],[68],[69],[70],[71],[72],[73],[74],[75],[76],[77] including pigmentation. [78] Furthermore, it has demonstrated in vitro properties of neutralizing ROS [79] and inhibiting COX-2 expression, [80] thereby decreasing arachidonic acid oxidization. These mechanisms address two key mediators in melanogenesis.

By this theory, oral and topical non-steroidal anti-inflammatory drugs (NSAIDs) should decrease PIH as well. An in vitro study showed the inhibition of mushroom tyrosinase enzyme with the use of NSAIDs, [81] but no in vivo studies of oral or topical NSAID use have been undertaken to assess the effect on PIH.

Epithelial growth factor (EGF) was shown to decrease inflammation-induced melanogenesis in vitro[82] and decrease inflammation via arachidonic acid mediation. [83] Yun et al. went one step further, showing that human melanocytes express the EGF receptor (EGFR) and hypothesized that this interaction affects inflammatory mediators responsible for PIH. [82] In vitro studies of an EGFR small molecule inhibitor showed inhibition against mushroom tyrosinase as well as scavenging of nitric oxide, with overall inhibition of UV-induced melanogenesis in vivo (murine model). [84]

A case report showed a dramatic improvement of acne and PIH with oral isotretinoin in a patient with type III skin. [85] This advocates for the aggressive treatment of acne in patients with severe PIH.

A recent review of new therapies discusses 4-n-butylresorcinol, a tyrosinase inhibitor, for solar lentigines [86] and melasma. [87] It showed improvement compared to vehicle, but has yet to be compared to HQ or studied for PIH. [7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43],[44],[45],[46],[47],[48],[49],[50],[51],[52],[53],[54],[55],[56],[57],[58],[59],[60],[61],[62],[63],[64],[65],[66],[67],[68],[69],[70],[71],[72],[73],[74],[75],[76],[77],[78],[79],[80],[81],[82],[83],[84],[85],[86]

Decapeptide-12, a synthetic oligopeptide that inhibits tyrosinase, has been shown effective in melasma [88] and when topical therapy is combined with a dermal infusion, it showed improvement with PIH in a case report. [89]

Emerging oral agents include grape seed extract and pycnogenol and emerging topical agents include ellagic acid, resveratrol, linoleic acid, aloesin, green tea extracts, and paper mulberry tree extracts. [3] These have anecdotal benefits, but remain to be studied in controlled trials.

A summary of PIH-specific studies and case reports is detailed in [Figure 4] and [Table 1].
Figure 4: Treatment algorithm

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Table 1: Summary of studies for the treatment of PIH

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Most important is aggressively treating the inflammatory stimulus, and avoiding medications that cause increased pigmentation or worsening of hyperpigmentation, such as minocycline.

Sunscreen and avoiding sunlight and wind are critical to decreasing the incidence of hyperpigmentation. [18] Manipulation of the lesions can increase inflammation and cause pigmentation as well. Twenty-six patients underwent ablative fractional resurfacing in Thailand, in a split-face study where the only intervention was sunscreen. After 1 week, there was significantly less PIH on the intervention side (which was near baseline) compared to the control side. [90]

Takiwaki et al. showed that using oral and topical anti-inflammatories decreases the prostaglandins in the epidermis during inflammation and correlates to a decrease in PIH. He even suggests that measuring the change in pigmentation is an indication of the anti-inflammatory properties of the intervention. [91]

Laser therapy can be a cause for PIH as well as a treatment. Employing effective preventative strategies including correct laser settings and pre-treatments can have a significant effect on the presence of PIH. Asian patients with laser treatment have the lowest risk for PIH with IPL, followed by long-pulsed long wavelength lasers, and then QS long wavelength lasers. [92] QS lasers have many photomechanical side effects, including hemoglobin destruction, that makes them high-risk for inducing PIH. Using the hand piece to provide compression with the laser or light source empties vessels and decreases hemoglobin destruction. [93] With fractional resurfacing, using low-fluencies, increased intervals between treatments, [94] and decreased density [95] reduces PIH. Furthermore ensuring that there is contact cooling when using other lasers helps control PIH. [94]

Prepping the skin with sun avoidance at least 2 weeks before the procedure with physical blocker sunscreen as well as with a lightening regimen such as a mid-potency topical steroid combined with tretinoin, HQ, kojic acid, azelaic acid, or glycolic acid 2 weeks before and 4 weeks after procedure has been used as well. Chan reduced use of retinoic acid because of irritation and phototoxicity, and prefers a topical steroid and azelaic acid combination. An additional mild glycolic acid peel alternating with microdermabrasion every other week if PIH persists beyond 6 weeks has been effective. For melasma, because the melanocytes are more active, Chan recommends treatment for 3 months prior to laser therapy with HQ. [94] In a different study, post treatment with topical steroids was advocated. Patients showed a decreased tendency toward PIH after laser treatment with the 1064 nm QS Nd: YAG with post-treatment use of topical steroids for 2 weeks, although this result was not statistically significant, the sample size was small, and the follow up was limited to 4 weeks. [96]

  Conclusion Top

Prevention is critical for PIH. Identifying the inflammatory stimulus and aggressively treating it is the first step. Furthermore, the use of sun avoidance and sun protection in dark-skinned patients should be emphasized. There is, however, massive opportunity for improvement of targeted prevention for PIH. Topical or systemic blockade of melanogenic mediators are emerging, and although studied in melasma or solar lentigines, need to have separate trials for PIH, which can differ histologically by having a significant dermal component. This is a very real problem and is experienced by almost every patient to some degree with skin type IV or above, and the literature does not reflect the prevalence and quality of life impact that this disease has.

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

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