Based on a presentation by Susan Taylor, MD
Watch the video of this Skincare Academy presentation featuring Dr. Taylor at
https://jcad.tv/sca-susan-taylor-topical-approaches-hyperpigmentation/
Dr. Taylor is Bernett L. Johnson Endowed Professor, Department of Dermatology, Perelman University School of Medicine, University of Pennsylvania, Philadelphia; Director, Skin of Color Research Fellowship, and Vice Chair, Equity, Diversity, and Inclusion, University of Pennsylvania; Founder, Skin of Color Society; and President-elect, American Academy of Dermatology (2024).
Post-inflammatory hyperpigmentation (PIH) refers to the clinical presentation of hyperpigmentation that remains after resolution of an inflammatory disorder. Acne is the most common cause of PIH in most of our patients. PIH from acne appears as a tan, brown, violaceous, or black macule or patch. There are long lasting sequelae to PIH. One study from an Asian cohort of over 300 patients from seven Asian countries observed that PIH lasted longer than one year in 65 percent of those patients, and it lasted more than five years in 22 percent. (Abad-Casintahan, et al. J Dermatol. 2016).
PIH is the number one concern among people of color with acne, and it’s more of a concern than the acne lesions themselves. PIH occurs more commonly in individuals with darker skin tones, occurring anywhere between 45 and 87 percent in patients with Fitzpatrick Skin Types IV, V, and VI.
PIH is associated with quite significant decreased quality of life. This can include patients wanting to avoid public places, poor body image, diminished social life, and a perception of more severe disease than what a physician would objectively observe. When we’re differentiating, it’s important to deliver the diagnosis of PIH so as to differentiate it from active acne lesions, which can sometimes be hyperpigmented. The best way to distinguish between an active and an inactive lesion is to palpate the skin. It’s also important to differentiate PIH from exogenous ochronosis.
Exogenous ochronosis is associated with prolonged use of hydroquinone, and it causes a local inhibition of homogentistic acid oxidase, and the homogentistic acid accumulates and polymerizes in the skin, thus producing what we see on histopathology as banana-shaped, yellow-brown ochronotic pigment in the dermis. A very interesting international systematic review (Ishack S. Int J Dermatol. 2022) of exogenous ochronosis found that most cases of hydroquinone-induced ochronosis were in middle aged women, women of African descent or Black races, and those with Fitzpatrick Skin Types V and VI. Unfortunately, 32.5 percent of those women did not know the hydroquinone concentration they were using, and 35.7 percent used hydroquinone with a concentration greater than 4%.
We often think of exogenous ochronosis occurring in our Black patients, but Ishack et al’s systematic review showed that it occurs in our Asian and Latinx or Hispanic patients. Therefore, it is very important to distinguish exogenous ochronosis from PIH. The first step in doing this is to think about exogenous ochronosis and acknowledge that it is not only caused by hydroquinone in high concentrations. Vempuluru et al (Ophthalmic Plastic and Recon Surg. 2023) published an interesting case report of an elderly Caucasian man with chronic lymphocytic leukemia, who was treated with epigallocatechin gallate (EGCG), a polyphenol derived from green tea. Cutaneous and ocular ochronosis followed the prolonged, high-dose supplementation of EGCG in this patient. In cases of atypical presentation of hyperpigmentation, consider inquiring about the use of oral supplements, such as green tea extract, in addition to “skin lightening” or “bleaching” creams that may contain hydroquinone.
The pathogenesis of acne-associated PIH
There are two proposed pathways of PIH secondary to acne lesions. The first is the keratinocyte release of inflammatory cytokines. The second is the release of growth factors by dermal fibroblasts. Both mechanisms can stimulate melanin production. That melanin can drop down into the dermis or it can be engulfed by macrophages that migrate from the epidermis into the dermis, where we see long-lasting dermal pigmentation.
Treatment recommendations for acne-associated hyperpigmentation
A Delphi consensus (Taylor S, et al. J Am Acad Dermatol. 2023) was performed by 10 dermatologists with expertise in PIH in skin of color patients with Fitzpatrick Skin Types IV, V, and VI. They reached consensus about the following key recommendations:
- Avoid excoriations.
- Apply acne mediations to the entire face; in darker skin types, subclinical inflammation may not be as visible, but can still stimulate melanin production.
- Use sun protection, ideally visible-light photoprotection with iron oxide.
- Optimize the role of makeup and tinted sunscreen to camouflage PIH.
In order to treat PIH induced by acne, we need to treat the acne. The medical first-line therapies for acne include topical retinoids and benzoyl peroxide. Topical retinoids are highly effective for the treatment of acne as well as for PIH. In addition, other agents can be used to address acne-induced PIH, including hydroquinone, azelaic acid, and chemical peels.
A post-hoc analysis of a pooled, 12-week, randomized, double-blind, vehicle-controlled, Phase III study by Bhatia et al (J Drugs Dermatol. 2020) looked at tazarotene 0.045% lotion for the treatment of PIH and acne. Of the sub-group of the patients in the study (N=1,614), 62 were of African descent and 352 were of Hispanic ethnicity. The researchers found that after 12 weeks, there was significant decrease in hyperpigmentation with the use of this lotion in this sub-group of patients. Other studies have demonstrated improvement of PIH with tretinoin. Additionally, it is important to remember that patients with acne and PIH who are being treated with topical retinoids and perhaps benzoyl peroxide might be experience skin dryness and irritation, which can lead to further hyperpigmentation. Therefore, we want to make sure that we use ceramide-containing moisturizers and very gentle, nonexfoliating cleansers.
Photoprotection for the treatment of hyperpigmentation
Photoprotection, unfortunately, is a topic we bring up with our patients as we are walking out the door. Instead, we need to lead the conversation with photoprotection, because we know that protection from ultraviolet A and B can significantly improve hyperpigmentation. Additionally, we have recently learned more about the role of visible light (VL) and UVA1 in the production of hyperpigmentation. High energy VL and ultraviolet A1 lead to the production of reactive oxygen and nitrogen species with a notable effect on patients with darker skin tones. This stimulates the production of melanin, leading to dyspigmentation, melasma, photoaging, and clinical erythema. The mechanism of VL damage can be attributed to melanin and OPSIN3. VL light exposure in patients with Fitzpatrick Skin Types III, IV, V, and VI leads to the activation of OPSIN3, a key sensor in melanocytes. This initiates a cascade of reactions resulting in increases in tyrosinase and dopachrome tautomerase (DCT). The induced tyrosinase DCT complex results in hyperpigmentation in patients with darker skin tones.
Considering this, it is critically important that we protect the skin from visible light in addition to ultraviolet A and B. We do this by recommending a sunscreen that contains iron oxide. Iron oxide is a mix of yellow, red, and black hues that are mixed together to achieve a tinted sunscreen. I tell patients to look for a sunscreen that says “tinted” on the front of the bottle. Another method for preventing VL damage and resultant pigmentation is to use a sunscreen that contains antioxidants, particularly vitamins E, C, and licochalcone.
Cosmeceuticals for hyperpigmentation
Many of our cosmeceuticals for hyperpigmentation inhibit tyrosinase, including azelaic acid, kojic acid, resorcinol, arbutin, and vitamin C. Agents such as ellagic acid work through tyrosinase copper chelation. For preventing the transfer of melanosomes from the melanocyte into the keratinocyte, we can use niacinamide. Therefore, when we select cosmeceuticals, we want them to contain multiple agents to attack the various cascades, along with the production of melanin. Tranexamic acid (TA) for the treatment of hyperpigmentation has gotten a lot of attention recently. TA reduces plasmin and ultimately results in less melanogenesis.
A study by Desai et al (J Drugs Dermatol. 2019) evaluated a cosmeceutical containing 4% TA, kojic acid, and 5% niacinamide. The 55 Brazilian women with a multitude of skin tones included in this 12-week clinical trial showed significant improvement in their hyperpigmentation with this cosmeceutical. Not only is it important to carefully select the agents in your cosmeceuticals, but it is also vital to consider the ideal formulation for optimized efficacy. Research is showing that the formulation of these cosmeceuticals is advancing. An in-vitro study by Chevala et al (J Cosmet Dermatol. 2022) evaluated 2% TA formulations using a hydrophilic polymeric cross-linked system loaded with an active moiety, creating a film-forming gel that allowed for greater stability and sustained drug release over a period of 48 hours. We can combine our cosmeceuticals with procedures, such as chemical peels and microneedling, for better results. A study by Saleh et al (J Egypt Womens Dermatol Soc. 2019) evaluated microneedling with or without topical TA in 42 women with melasma. The treatment group applied topical TA repeatedly throughout the entire procedure while the control group received microneedling without TA. The TA+microneedling group showed a greater mean reduction in MASI score versus the microneedling only group. Cysteamine as a cosmeceutical has shown greater performance compared to hydroquinone, making it another very effective agent for treating hyperpigmentation. Chemical peels are another topical therapy that can be effective for our patients with PIH.
In Summary
In summary, individuals with skin of color are at increased risk of hyperpigmentation. We want to treat the underlying inflammatory condition, such as acne, while avoiding or minimizing irritant ingredients. These patients must apply tinted sunscreens that are broad spectrum and protect from visible light via iron oxides with additional antioxidants. A myriad of cosmeceuticals are available to help hyperpigmentation, in addition to some procedures, such as chemical peels and microdermabrasion.