Speaker: Marta Sar-Pomian

Post-inflammatory hyperpigmentation (PIH) is an acquired form of hypermelanosis characterized by hyperpigmented macules or patches in areas previously affected by inflammatory skin conditions. The condition varies significantly among skin phototypes, with an incidence of 65% in African Americans, 48% in Hispanics, and 25% in Caucasians. It can occur in any gender and age. The primary causes of PIH include acne, impetigo, and atopic dermatitis, although any inflammatory skin condition can lead to its development. Other contributing factors include skin infections, contact dermatitis, and cosmetic procedures such as chemical peels, laser treatments, skin burns, skin injuries and insect bites. In lighter-skinned individuals (phototypes I and II), PIH appears as light brown macules. In darker-skinned individuals, it is more pronounced due to a higher concentration of melanin and increased melanocyte activity. The pathogenesis of PIH involves the release of cytokines and leukotrienes by inflammatory cells, which affect melanocyte activity. Sun exposure is also a significant factor in exacerbating PIH.

Two types of PIH can be distinguished: epidermal and dermal. Epidermal PIH involves melanin deposits in the epidermis with minimal dermal involvement, while dermal PIH is characterized by increased melanin deposits in the dermis and perivascular lymphocytic infiltrates. Two main hypotheses explain the presence of melanin in the dermis: (1) melanin may pass through gaps in the basement membrane due to disruption of the dermal-epidermal junction, and (2) melanophages phagocytize melanin and migrate into the dermis, transporting the pigment intracellularly. Wood's Lamp can differentiate between the two types, with epidermal PIH showing a more pronounced contrast between lesions and surrounding skin. PIH lesions typically appear on the cheeks and forehead and are chronic, lasting months or years, with a higher probability of prolonged courses in individuals with darker skin. Women with dark skin affected by acne often prioritize the elimination of PIH, which significantly impacts their self-consciousness and socialization compared to those without PIH. It is also important to assess whether patients may inadvertently provoke inflammatory lesions during the course of their acne. Investigation into skin picking disorder is warranted due to its potential to exacerbate PIH. 

The treatment approaches for PIH can be categorized into pharmacological methods, which include both medications and cosmeceuticals, as well as energy-based devices, chemical peels, and sun protection. It is crucial to address the underlying condition promptly to mitigate the development of PIH. Several therapeutic targets exist for managing PIH. Direct destruction of melanocytes is inadvisable, as it may lead to further hyperpigmentation. Strategies include blocking the transfer of melanosomes to keratinocytes, inhibiting the activity of tyrosinase—an essential enzyme in melanogenesis, and managing sun exposure and inflammation.

Among the pharmacological options, hydroquinone is often considered the first-line treatment, frequently referenced in the literature due to its ability to reversibly inhibit tyrosinase. However, its safety profile raises concerns regarding potential carcinogenicity observed in animal studies, although such effects have not been confirmed in humans. Side effects may include irritation, contact dermatitis, and ochronosis. to minimize irritation it is commonly combined with glucocorticosteroids. Formulations such as the original and modified Kligman formulas have demonstrated significant efficacy in reducing pigmentation. Arbutin, a plant-derived compound similar to hydroquinone, also inhibits tyrosinase but without the melanotoxic effects associated with hydroquinone. While synthetic forms of arbutin serve as stronger tyrosinase inhibitors, high concentrations can paradoxically induce hyperpigmentation. Thiamidol, a hydroquinone derivative, is recognized for its fewer adverse reactions and has been identified as a potent inhibitor of human tyrosinase. Studies indicate that thiamidol effectively reduces PIH, with improvements noted in suction blister-induced PIH after two weeks and in observational studies over a span of 12 weeks.

Azelaic acid (5%-20%), with its depigmenting properties, is particularly beneficial for patients with acne-induced PIH, as it also reduces oxidative tissue damage. Clinical studies have shown complete clearance in one-third of patients using a 15% azelaic acid gel twice daily over 16 weeks. Kojic acid (1%-4%), available in various formulations, works by inhibiting tyrosinase activity but may cause contact dermatitis in some individuals. Additionally, cysteamine exhibits efficacy comparable to hydroquinone while being non-melanocytotoxic and non-mutagenic, making it a safer alternative. Tranexamic acid can be administered topically, intradermally, or orally, with oral dosages typically ranging from 650 mg to 1,500 mg daily. Its mechanism of action likely involves plasmin inhibition, and preliminary evidence suggests it may also function as a tyrosinase inhibitor. some studies have indicated its potential prophylactic use for PIH in patients with darker skin types. Before initiating procedures with inherent risks, it is advisable to consider pre-treatment with tranexamic acid, particularly for patients experiencing PIH. 

Retinoids play a crucial role in managing PIH, especially in cases induced by acne, due to their efficacy in promoting skin health. Among the retinoids, adapalene is often favored for its accessibility, although tazarotene has also been cited in relevant studies. It is essential to inform patients that retinoids require time to yield visible results. Retinoids enhance keratinocyte turnover, reduce melanosome transfer from melanocytes to keratinocytes, and inhibit tyrosinase transcription. While data on the efficacy of natural retinoids, bakuchiol remain scarce, they are believed to be beneficial for PIH resulting from trichloroacteic acid (TCA) use. Vitamin C is another key ingredient, valued for its safety and pleasant application experience for patients. Its antioxidant properties are beneficial, it interacts with copper ions at the active site of tyrosinase and possesses anti-inflammatory and photoprotective effects. Formulations such as ascorbyl palmitate and magnesium ascorbyl phosphate are commonly utilized for their effectiveness.

Niacinamide, also known as nicotinamide, is another promising agent, as it inhibits the transfer of melanosomes from melanocytes to keratinocytes and is well-tolerated by patients. A study has demonstrated positive outcomes when combining niacinamide with tranexamic acid, leading to significant pigmentation reduction within eight weeks. Licorice extract, derived from the Glycyrrhiza glabra plant, contains two active compounds—glabridin and liquiritin—that exhibit depigmenting properties. Glabridin serves as a tyrosinase inhibitor with anti-inflammatory benefits, while liquiritin facilitates melanin dispersion and removal; however, clinical studies specifically targeting PIH are lacking, necessitating extrapolation from research on melasma.

Chemical peels are another effective treatment modality for PIH, as they enhance epidermal turnover and decrease melanin levels within the epidermis. A systematic review has noted partial responses in approximately one-third of patients undergoing chemical peels. However, there is a lack of robust data, and more extensive studies are needed for a comprehensive meta-analysis. It is essential to note that monotherapy with chemical peels is often insufficient for treating PIH, and they should be incorporated into a broader therapeutic approach. Glycolic and salicylic acids are commonly used in these peels; salicylic acid, in particular, is beneficial for patients with acne-induced PIH due to its anti-inflammatory properties, mitigating inflammation that may arise during procedures. The modified Jessner's solution, which typically contains lactic and citric acids alongside salicylic acid, has demonstrated depigmenting effects. Caution is advised with TCA peels, as they can pose risks, including the potential exacerbation of PIH. 

Laser treatments, with a wide spectrum of melanin absorption of 250-1200nm in PIH, require careful consideration due to the risk of worsening pigmentation, especially in individuals with darker skin tones. Short impulse durations and low thermal energy are recommended to minimize tissue damage. It is crucial to avoid ruby and Alexandrite lasers in dark-skinned patients. For those presenting with dermal hyperpigmentation, lasers with longer wavelengths are preferred for deeper penetration. Literature predominantly supports the use of Q-switched Nd:YAG lasers for managing PIH. According to a systematic review on the efficacy of laser treatments for PIH, complete responses were observed in approximately 30% of patients treated with laser therapy in monotherapy. Notably, this response rate improved significantly when patients also used sunscreen. In clinical practice, it is challenging to envision patients not utilizing sunscreens, especially those with PIH following any procedure. Non-ablative fractionated resurfacing has a similar risk profile as it may exacerbate PIH, necessitating caution in its application. The systematic review noted a high rate of partial response in patients treated with intense pulsed light (IPL), although this should be considered a supplementary method rather than a first-line treatment.

Broad photoprotection is crucial in managing PIH. A noteworthy study indicated that patients with PIH experienced improvements when they solely used sunscreen, highlighting its role not only in prevention but potentially also in treatment. For practitioners looking to develop a strategy for managing PIH, a suggested algorithm from a 2017 article can provide tailored approaches based on the availability of treatment modalities in different regions.

In conclusion, sun protection through the consistent use of sunscreen must be prioritized, along with patient education. Research indicates that compliance with photoprotection measures is often lacking, particularly among patients with darker skin types. Early intervention targeting the underlying causes of PIH is essential to prevent its development. The first-line treatment for PIH is typically topical, with combination therapies showing greater efficacy than monotherapy based on systematic review findings.

33, European Academy of Dermatology and Venereology Congress, 25-28 September 2024, Amsterdam.