Postinflammatory hyperpigmentation (PIH) is a common consequence following cutaneous inflammation in dark-skinned individuals with Fitzpatrick skin phototypes (SPTs) III–VI. The exact pathogenesis of this condition is unknown, but is believed to be an integral part of the normal response of the skin to inflammatory stimuli. PIH can last from months to years and may significantly impair quality of life of affected individuals. The primary treatment of PIH is prevention and treatment of the underlying inflammatory condition. In addition to prevention, there are a variety of medication and procedures used to treat PIH. Although topical skin-depigmenting agents remain the treatment of choice for PIH, lasers and light sources may be an effective adjunctive therapy or alternative for treatment failures. When treating PIH, any treatment options selected should be optimized and utilized carefully because the treatments itself may worsen the PIH.
Postinflammatory hyperpigmentation (PIH) is an acquired condition in which increased pigmentation occurs as a consequence of cutaneous inflammation from a wide range of aetiologies including inflammatory dermatoses, infections, allergic reactions, mechanical injuries, reactions to medications and therapeutic procedures.1–3 PIH can be observed in individuals at any age or gender.3 However, it is commonly seen in darker skinned individuals with Fitzpatrick SPTs III–VI.3–6 Clinically, PIH develops in the same area as the preceding inflammation.3 Colour of a lesion may range from light brown to slate-grey or black depending on the location of melanin deposition, which can be found in the epidermis and the dermis.1,3,4,7,8 Wood’s lamp examination and/or infrared photography are helpful in determining subtle degree of PIH.8,9 Histologically, excess epidermal melanin and dermal pigmentation have been described.1,2 Although PIH usually spontaneously remits, it often fades away slowly, sometimes persisting for years.3 Thus, PIH can cause significant anxiety and lowered self-esteem in affected individuals.
Degree of PIH has been observed to be higher in prolonged and/or recurrent inflammation, when compared with short-term acute inflammation.8 It has been proposed that degree of hyperpigmentation is directly relate to the severity of inflammation or degree of basal layer/dermo–epidermal junction injury, as observed in lichenoid dermotoses such as lichen planus and erythema multiforme.3,4,10 A study of Takiwaki et al.10 in 16 healthy male Japanese with SPT III observed a linear relationship between erythema and melanin indices measured from the skin areas that received ultraviolet B (UVB) irradiation. Moreover, erythema and pigmentation were suppressed significantly by the application of topical anti-inflammatory agents immediately after UVB irradiation. Aforementioned study implies that that the intensity of the inflammation correlated with the degree of PIH, and inflammation had some roles in melanogenesis.
There have been several evidences that may help explain how PIH develops. The inflammation of the epidermis induces production and release of various keratinocyte-derived mediators, including prostaglandins, leukotrienes and many cytokines that affect melanocyte proliferation and melanin production.3,11,12 Previous studies suggested that these reactions may be in response to some stimuli such as ultraviolet radiation and inflammation or inflammatory mediators. Moreover, there are some changes observed in melanocyte, including hyperplasia and hypertrophy.12–19 The inflammatory response of the epidermis may result in an increase in melanin pigment in the epidermis (epidermal hyperpigmentation).3,11 Pigmentary incontinence (Incontinentia pigmenti histologica), or a melanin dropping may cause dermal hyperpigmentation, of which, melanosomes (melanin granules) are found in the macrophages (melanophages) in the dermis.3,20 The evolution of this type of PIH begins with cutaneous inflammation that causes injury to the basal cell layer, such as lichenoid dermatoses.20 Then, the degenerating basal keratinocytes and melanosomes were phagocytized by macrophages, resulting in melanophages accumulation in the upper dermis.3,4,20
It is known that cutaneous manifestations and response to stimuli among races is different, and Asians and other dark-skinned populations are more prone to develop PIH.3–6,21–26 This review focuses on the PIH following acne and aesthetic procedures in Asians.
Acne-induced and aesthetic procedure-related postinflammatory hyperpigmentation
Postinflammatory hyperpigmentation is a common consequence of acne, especially in dark-skinned individuals.19,27 According to a population-based study by Perkins et al.,28 PIH was found in African American and Hispanic more than Caucasian, Asian and Continental Indian women. PIH is clinically apparent at a certain period of time after the erythema from acne subsides (Fig. 1).4,29 Most of the time, PIH occurred can remit spontaneously, however, very slowly in some cases.4
Interestingly, in dark-skinned patients, PIH from acne disturbs some patients, psychologically, more than the active lesions itself.25,30,31 Thus, for acne treatment, particularly when dealing with dark-skinned patients, the treatment of PIH should be incorporated in their acne treatment regimen.19,32,33 As the hyperpigmentation is a result of the inflammation, effective and adequate control of the inflammation is crucial to prevent and to minimize the severity and the course of PIH.4
An occurrence of PIH following aesthetic procedures and light-based treatments is not uncommon, especially in darker skinned patients such as Asians, African American and Hispani (Fig. 2). In essence, darkening of the skin may occur after any aesthetic, and laser and light procedures causing inflammation to the skin. PIH can last from months to years after the procedure has been performed (Fig. 3). An incidence of PIH following ablative fractional CO2 laser resurfacing in Thai patients with SPT IV can be as high as 92% (Fig. 4),34 whereas an incidence of 23% observed in a study in SPTs I–III patients using a similar type of ablative fractional CO2 laser.35Table 1 illustrates studies of aesthetic and laser procedures performed in Asians that were complicated with PIH.
Table 1. Studies related to postinflammatory hyperpigmentation (PIH) after aesthetic and laser procedures in Asians
25 Females with complex dyspigmentation of the face
All patients were initially treated with IPL, followed by QS ruby laser, either on the same session or within 1 week after IPL treatment. Patients received an average of 2.88 and 1.52 treatments with IPL and QS ruby laser respectively
Three of 25 (12%) patients were complicated with mild-to-moderate PIH in the areas treated with QS ruby laser
13 Thai women with acquired bilateral nevus of Ota-like macules (ABNOMs)
Of all patients, one side of their lesion was randomly treated with QS ruby laser only, whereas the other side was treated with a CO2 laser resurfacing, followed by QS ruby laser.
At 1-month follow-up, 54% (7/13 patients) and 46% (6/13) of the patients had pigmentary changes (hypo- and hyperpigmentation) on the side treated with QS ruby laser alone and the side treated with CO2 + QS ruby lasers respectively.
All patients got two treatments of a low-fluence, VSP Er:YAG laser 1 month apart. Twelve patients were randomly treated with a pulse duration of 0.3 ms and the rest were treated with a pulse duration of 250 ms.
PIH occurred in 13% (6 of 46) of the total treatment sessions.
24 Chinese patients with acne scars, SPTs III–IV Total 92 treatments
Up to five treatments
PIH developed in four patients in 6 of the total 92 treatment sessions (6.5%) and most lesions faded within 2 months
Treatment of PIH
There are several important aspects worth noting in treating PIH. First, the primary treatment of PIH is to prevent and control the ongoing inflammatory condition that may cause further PIH. Second, the prompt initiation of PIH treatment helps hasten its resolution and prevent further darkening of PIH lesions. Lastly, in many circumstances, PIH can develop as a consequence of either the skin conditions themselves, or from cutaneous irritation caused from the treatment of the active lesions or PIH.3,4,29,36 Therefore, any treatments considered should be able to aggressively and adequately control the pigmentation and the inflammation of primary lesion, while being gentle enough to the skin. Sun avoidance and non-comedogenic sunscreen should be advised and included in the treatment regimen because sun exposure may prolong the resolution of PIH.4,33 In addition, patents should be instructed to avoid any physical trauma, such as scratching or rubbing to the skin that may worsen the degree of PIH. Any concurrent medications that may make PIH worse, such as tetracycline, should also be taken into account.
Topical treatment is an effective treatment modality and should be considered as the first-line treatment for PIH.4 Topical hydroquinone (HQ), a gold standard treatment of PIH, can be used safely for up to 6 months and can be introduced either early in the acne treatment programme or later when the acne is improved.29 Topical retinoids can be applied for both acne and PIH treatment.19,37,38 The efficacy of tretinoin on the treatment of PIH has been demonstrated.2,19 Topical tazarotene 0.1% cream has proven effective for treatment of acne, dyspigmentation in photoaging and PIH.38 A combined topical retinaldehyde 0.1% and glycolic acid (GA) 6% preparation also provided some benefit in acne and PIH treatment.39 Azelaic acid is another effective agent for both acne and PIH treatment.40 Topical medications such as kojic acid and licorice extract are also effective treatment of choice for PIH.2,33 Agents that have been studied and reported to provide beneficial response in the treatment of PIH from acne are listed in Table 2. In general, combination treatment is favoured because it enhances the treatment efficacy while minimizing side-effects that may occur with monotherapy.4 From topical acne treatment, iatrogenic PIH may occur as a result of irritation, irritant contact dermatitis. Therefore, topical treatment regimen should be tailored carefully to minimize irritation that may occur. This can be achieved by using the lowest concentration and least irritating products possible. Moreover, moisturizers might be incorporated in the regimen, either by means of choosing product with moisturizing vehicles or adding moisturizer as a part of the regimen.41,42
Table 2. Studies related to the treatment of postinflammatory hyperpigmentation (PIH) from acne in Asians
40 Korean patients with PIH and mild-to-moderate acne, SPTs IV–V
Two groups (20 each) 5 weekly treatments of Group 1: Full-face low-fluence 1064 nm QS Nd:YAG laser with comedone extraction and intralesional injections for severe inflammatory papules and topical 4% benzoyl peroxide gel twice daily Group 2: Only comedone extraction and intralesional injections for severe inflammatory papules and topical 4% benzoyl peroxide gel twice daily
Low-fluence 1064 nm QS Nd:YAG laser treatment was effective for PIH
33 Patients with mild-to-moderate facial acne and PIH, SPTs IV–VI
Two groups 1. A topical gel containing 1.2% clindamycin phosphate and 0.025% tretinoin 2. Placebo Duration: 12 weeks
Acne: A combined 1.2% clindamycin and 0.025% tretinoin gel provided better result compared with the placebo PIH: Slight improvement in PIH was found from the combined clindamycin/tretinoin gel, and it was superior to the placebo
Triple combination of 2% hydroquinone, 0.05% tretinoin and 0.01% fluocinolone acetonide cream with three glycolic acid peels at 2-week interval
After treatments, 12 patients had more than 50% improvement in PIH and three patients showed more than 75% improvement.
Single topical agent can be used as monotherapy for PIH. However, combination therapy is preferred because with combination treatment, the clinical outcome will be enhanced.3,4 The most commonly used combination preparation for PIH is the formula containing HQ, retinoic acid (RA) and corticosteroids. In this formula, the irritation might occur from HQ and RA and may worsen the hyperpigmentation.4,8 Other topical agents that can be considered for PIH treatment include kojic acid, licorice, arbutin, ascorbic acid, soy, N-acetyl glucosamine and niacinamide.43
Chemical peelings and laser treatment are considered as second-line therapy for treating recalcitrant PIH. Importantly, these second-line therapies have a higher risk of worsening the PIH condition compared with that of topical depigmenting agents. The role of chemical peelings and laser treatment in treatment of PIH may be primarily for pigmented lesions that remain refractory after several months of topical therapy. A retrospective study on acne PIH noted an optimal clearing of PIH by 3 months after using topical lightening agents.4 This period may be an appropriate timing to start using second-line treatments to further optimize the therapeutic outcome. Superficial chemical peels with either GA or salicylic acid (SA) can be used in dark-skinned acne patients.33 Grimes44 performed a study using five treatments of 2-week interval SA peels for melasma, oily rough skin, acne and PIH in SPTs V–VI patients, and reported that 100% of PIH patients had moderate to significant improvement. Garg et al.45 compared 35% GA vs. 20% salicylic–10% mandelic acid combination peels (SMPs) for active acne, acne scars and hyperpigmentation in 44 Indian patients and found that both agents were effective, but SMPs gave superior results for both active acne lesions and hyperpigmentation.
Lasers4,46–51 and pulsed light source52 have been used to treat PIH with variable success. Vascular laser, such as the 595-nm long-pulsed dye laser (LPDL), can be used in the treatment regimen of acne-induced PIH. It works by treating the vascular component of the inflammation; thus, shortens and lessens the inflammatory process, and, as a result, reduces the PIH risk. Another mechanism of action of LPDL may due, partly, to its ability in treating pigmentary lesion, when used with compression.4 Pigment-specific laser, such as 1064-nm Q-switched (QS) Nd:yttrium aluminum garnet (YAG) laser can be used in PIH treatment when using at a low-fluence setting.47 Kim and Cho46 demonstrated effective treatment by low-fluence QS Nd:YAG laser of acne PIH in SPTs IV–VI patients. As anticipated, PIH can also be developed as a side-effect from this treatment technique for PIH.4
‘Laser toning’ using low fluence, large spot size, multiple passed QS 1064-nm Nd:YAG laser for skin rejuvenation, melasma and treatment of PIH has recently gained much popularity, especially in Asian countries however, there are still very few evidence-based data supporting this approach in the treatment of PIH and melasma.46,47,53,54 In laser toning, multiple passes of low-fluence laser (e.g. 1.6–3.5 J/cm2) are delivered through a large spot size (e.g. 6–8 mm) to optimize energy delivery and to achieve mild erythema as the clinical endpoint. Some physicians have proposed the daily usage of laser toning for skin rejuvenation, while others offer treatments at weekly, 2-weekly, or monthly intervals with a wide variation in the total number of treatment.55
Confetti-like or spotty hypopigmented macules or punctate leucoderma55,56 and rebound hyperpigmentation are common side-effects associated with low-fluence QS 1064-nm Nd:YAG laser for skin rejuvenation and melasma.57 Recently, Chan et al.55 assessed a case series of 14 Chinese patients with laser toning-associated facial depigmentation with cross-polarized and ultraviolet (UV) photographic images. Of all 14 patients, nine received laser toning for non-ablative skin rejuvenation and the other five for melasma. Treatment protocols received by these patients were highly variable. The total number of treatments received ranged from 6 to 50 (mean 22). In all cases, UV photographic images demonstrated facial mottled depigmentation. Laser toning failed to significantly improve melasma in all five patients.
Non-ablative fractional resurfacing (NAFR) has shown inconsistent results for treatment of PIH.49–51 A previous study demonstrated transepidermal elimination of dermal component through incorporation into microscopic epidermal necrotic debris. The expulsion of dermal pigment in conjunction with the affected microthermal zones (MTZs) is the most likely mechanism of action when treating dermal pigmentary disorders including melasma, drug-induced hyperpigmentation and PIH.58 However, PIH itself is the most common adverse effect following NAFR59–61 and ablative fractional resurfacing (AFR)34,62 in Asian individuals. Graber et al.60 retrospectively studied 961 treatments with the 1550-nm erbium-doped fibre laser and found that PIH occurred more frequently in darker skin types (incidence of 2.6%, 11.6% and 33% for skin type III, IV and V respectively), appeared later posttreatment and lasted longer than other complications.
Previous studies investigating the use of NAFR61,63and AFR35 indicated that treatment density, rather than energy, was a stronger determining factor in the development of PIH in predisposed patients. Therefore, to reduce the risk of PIH associated with NAFR and AFR when treating Asian patients, the total treatment density (MTZ/cm2) should be reduced. However, on the other hand, the total number of treatment sessions should be increased to maintain the clinical efficacy.
Prevention of postinflammatory hyperpigmentation
Various attempts have been made to reduce the occurrence of PIH after laser treatment in Asian skin. These include sun avoidance, the use of preoperative and postoperative treatment regimens, treatment using conservative energy setting and epidermal protection.
Sun exposure before and after laser treatment has been shown to interfere with skin pigmentation by increasing epidermal melanin pigmentation and epidermal thickness leading to a change in the optical property of the skin.64–66 In our practice, several recommendations to minimize the effects of UV light have been suggested. From a practical standpoint, it is not easy to avoid sun exposure when living in tropical countries. Most laser treatments are elective surgeries. Thus, surgery may be postponed during summer months. Topical sunscreens protecting against both UVA and UVB – usually zinc oxide based – should be applied regularly at least 6 weeks prior to the treatment to obtain the optimal outcome. Patients should not visit tanning booths or go sunbathing, although the influence of acquired pigmentation compared with constitutional pigmentation for the development of adverse effects remains unidentified.
The advantage of preoperative treatment regimens with various topical bleaching agents remains controversial. A randomized, controlled study in 100 consecutive CO2 laser resurfacing patients (SPTs I–III) has not showed the difference in the incidence of PIH after laser treatment between subjects who received pretreatment with either topical GA cream or combination tretinoin/HQ cream, and those who received no pretreatment regimens.67 In practice, we often observe that PIH occurred even with careful preoperative treatment with topical depigmenting agents, and this complication resolved spontaneously without using any topical preparations other than a broad-spectrum sunscreen and sun avoidance.
The application of conservative energy setting is another technique used to reduce the risk of PIH. A recent study on the treatment of lentigines in Japanese patients using 532-nm, QS Nd:YAG and QS ruby lasers suggested that the use of lower energy setting (using slight immediate whitening as an endpoint) did not decrease the treatment efficacy and had a significant lower incidence of PIH, when compared with that of high-energy setting (using very obvious immediate whitening of the pigmented lesion as a treatment endpoint).68
Tranexamic acid (TA), a plasmin inhibitor, has been found to prevent UV-induced hyperpigmentation in guinea pigs.69 The mechanism of pigmentary inhibition of TA is unknown. A previous study suggested that TA inhibits melanin synthesis in melanocytes by interfering with the interaction between melanocyte and keratinocyte through inhibition of the plasminogen/plasmin system.69 Localized intradermal microinjection of TA has demonstrated a promising result in melasma treatment.70 However, oral TA given postoperatively failed to prevent PIH after QS ruby laser treatment for senile lentigines in Japanese patients.71 Short-term use of prophylactic systemic prednisolone has been anecdotally used to reduce the risk of posttherapy inflammatory reactions and related pigmentary alterations in Asian individuals.72 Corticosteroids are believed to suppress general activity of cell, leading to the inhibitory effect on melanin synthesis.14 However, use of corticosteroids postoperatively is controversial as it may interfere with the normal wound-healing process and may increase the risk of infection. Recently, Ortiz et al. reported two cases of patients having bacterial infection after the application of a high-potency topical corticosteroid following ablative laser resurfacing. It is uncertain whether a short application of potent topical corticosteroids can predispose the patients to infection. However, a previous animal study has not found an increase in infection rate in steroid-treated burn wounds.73
Lowering the temperature of the skin’s surfaces is a method for selectively controlling the depth at which heat is produced in the skin by lasers or light sources. The effect of epidermal cooling has been shown to enhance clinical efficacy and minimize epidermal damage caused by the laser treatment process.74 Although epidermal cooling is supposed to reduce patient’s discomfort during laser treatment and to minimize the risk of PIH, it may also induce PIH.75,76
Management of PIH remains a challenge, especially in dark-skinned individuals. The primary treatment of PIH is prevention and treatment of the underlying inflammatory condition. Although many treatment options available for PIH, it yet takes months for PIH to resolve, even with an adequate therapy. Thorough patient counselling regarding the natural course of PIH and its management plan is a helpful tool to get the patients through the psychological stress of this condition.