14 Jun 2013 /

The word inflammation comes from the Latin “inflammo”, meaning “I set alight, I ignite”. Inflammation is part of the body’s immune response. Initially, it is beneficial when, for example, your skin experiences damage from trauma, chemicals, or irradiation. Inflammation begins the process of repair, and so is key to survival of all tissues. However, inflammation can sometimes cause further inflammation, in a self-perpetuating cycle. Complications then ensue.

This is BFT’s final installment in our series on cutaneous dyschromias – abnormalities of skin pigmentation. Our first post covered lentigines (singular = lentigo), those pesky and dreaded tan and brown “age spots” that occur on sun exposed surfaces. Our second topic discussed melasma, a commonly seen sex hormone-related hyperpigmentation that affects ten times as many women as men. Today we look at postinflammatory hyperpigmentation, perhaps the worst of the lot because of its potential to cause the most severe and challenging to treat cosmetic consequences. Three words of caution common to all dyschromias, and to all ethnic and racial groups, no matter whether fair or dark skinned: SUNBLOCK. SUNBLOCK. SUNBLOCK.

DISCLAIMER: As always, BFT writes to generally educate, inspire, and entertain. For specific advice or treatment concerning your own skin, see your personal physician.

Postinflammatory hyperpigmentation(“PIH”) is an acquired condition in which excessive melanin deposition occurs at sites of skin inflammation or injury. Although it can be seen in all skin types, it more frequently affects darker Fitzpatrick skin types (IV, V, and VI.) Examples include African Americans, Hispanics/Latinos, Asians, Native Americans, Pacific Islanders, and those of Middle Eastern descent. Within each given group, the incidence is higher among darker skin individuals, suggesting that the degree of pigmentation rather than race/ethnicity per se may be more contributory to PIH development. PIH often has significant psychosocial impact.

Etiology

Many types of inflammatory dermatoses or cutaneous injuries can cause changes in pigmentation. Some in particular, however, show a proclivity to develop PIH rather than hypopigmentation. Examples are fungal and viral infections (chicken pox, measles, etc.), allergic reactions to insect bites or contact dermatitis, psoriasis or lichen planus. PIH may also result from hypersensitivity reactions to medications, cutaneous injury from irritants, burns, or cosmetic procedures. Highly common causes of PIH are acne vulgaris, atopic dermatitis, and impetigo. Among African Americans with pseudofolliculitis barbae (“razor bumps”), the prevalence of PIH is estimated between 45 and 83 percent.

Pathogenesis

PIH results from overproduction of melanin or irregular dispersion of pigment and typically manifests in a pattern of distribution identical to the initial inflammatory process. Melanocyte activity has been

shown to be stimulated by prostanoids, cytokines, chemokines, and other inflammatory mediators as well as reactive oxygen species released during the inflammatory process. The location of the excess pigment within the layers of the skin determine its coloration. When confined to the epidermis, production and transfer of melanin to keratinocytes is increased. Epidermal hypermelanosis will appear tan, brown, or dark brown and may take months to years to resolve without treatment. PIH within the dermis results from inflammation-induced damage to basal keratinocytes, which release large amounts of melanin. The free pigment is then phagocytosed by macrophages, now called melanophages, in the upper dermis. Hyperpigmentation within the dermis has a blue-gray appearance and may either be permanent or resolve over a protracted period of time if left untreated. PIH can worsen with ultraviolet (UV) irradiation or with persistent or recurrent inflammation.

Treatment

The management of PIH begins with addressing the underlying inflammatory condition. Initiating treatment early for PIH may help hasten its resolution and prevent further darkening. It is, however, important to be mindful of the potential the treatment itself has to cause or exacerbate PIH by causing irritation.

Photoprotection is integral to treatment and prevention of PIH. Daily use of broad spectrum sunscreen (SPF of 30) and sun-protective measures, such as avoidance and protective clothing, are mainstays of therapy. This is particularly true for those with higher Fitzpatrick skin types who may not typically normally wear sunscreen or realize the darkening effects UV irradiation has on hyperpigmentation.

Aside from photoprotections (always the first line of defense), there are a variety of medications and procedures that can safely and effectively treat PIH in darker skinned patients. Topical depigmenting agents, such as hydroquinone, azelaic acid, kojic acid, licorice extract, and retinoids, can be effective alone or in combination with other agents, and procedures such as chemical exfoliation and laser therapy can also be incorporated into the management strategy if needed. Topical agents are of use in treating epidermal PIH. Deeper dermal pigmentation does not respond well.

Medical therapy

Hydroquinone (HQ), a phenolic compound that blocks the conversion of dihydroxyphenylalanine (DOPA) to melanin by inhibiting tyrosinase, remains the mainstay of treatment for PIH. A recognized complication of HQ is paradoxical hyopigmentation, especially around the area of treatment. HQ is commonly used at concentrations from 2 to 4% but can be prescribed in strengths up to 10% and is available over the counter (OTC) at 2% in the United States. More recently, HQ has been formulated with other agents, such as retinoids, antioxidants, glycolic acid, sunscreens, and corticosteroids, to increase efficacy. Irritant reactions can result from long-term daily use of 4% or higher HQ, particularly when used in combination with other agents that can be irritating, such as retinoids. However, concomitant use of a topical corticosteroid can reduce irritation, thereby decreasing the risk of further hyperpigmentation.

Interestingly, a small number of patients exposed to chronic higher doses of hydroquinone may develop a difficult to treat paradoxical hyperpigmentation of the dermis termed exogenous ochronosis. It occurs most commonly in persons who have used higher-dosed preparations of hydroquinone, often unregulated formulations sold in ethnic markets.

In 2006, the United States Food and Drug Administration (FDA) released a statement proposing a ban on all OTC HQ agents based on rodent studies, which suggested that oral HQ may be a carcinogen. However, there have been no reports of skin cancers or internal malignancies associated with topical HQ use. To date, a final ruling by the FDA is still pending.

Mequinolis a derivative and alternative to hydroquinone. Although the two agents are related, mequinol is thought to be less irritating to the skin than HQ. The drug is available by prescription in a

2% concentration and is typically formulated with 0.01% tretinoin, a retinoic acid and penetration enhancer. The mechanism by which mequinol causes depigmentation may involve a competitive inhibition of tyrosinase. Several clinical studies have shown that mequinol effectively treats solar lentigines in all patients including ethnic populations

Retinoids are structural and functional analogues of vitamin A, and are effective alone or in combination with other agents for the treatment of PIH in ethnic patients. Retinoids exert multiple biological effects that result in skin lightening including the modulation of cell proliferation, differentiation, and cohesiveness; induction of apoptosis; and expression of anti-inflammatory properties.

Third-generation retinoids, adapalene and tazarotene, are synthetic topical agents that are also effective in the treatment of PIH. Adapalene is formulated in creams or gels in 0.1 to 0.3% concentrations; whereas, formulations of tazarotene include 0.05 and 0.1% creams or gels. Both agents have been shown in clinical studies to safely and effectively treat PIH, particularly acne-induced PIH, in darker skinned individuals.

Azelaic acid is a naturally occurring dicarboxylic acid isolated from the organism responsible for Pityriasis versicolor that has been shown to be effective in the treatment of PIH. Azeleic acid has several mechanisms by which it depigments the skin including tyrosinase inhibition as well as selective cytotoxic and antiproliferative effects toward abnormal melanocytes through the inhibition of DNA synthesis and mitochondrial enzymes.

Kojic acid is a fungal metabolite of certain species of Acetobacter, Aspergillus, and Penicillium. Its depigmenting ability originates from a potent inhibition of tyrosinase by chelating copper at the active site of the enzyme.

Arbutinis extracted from the dried leaves of the bearberry shrub or pear, cranberry, or blueberry plants. Arbutin is another derivative of HQ, but without the melanotoxic effects. Arbutin causes depigmentation by inhibiting not only tyrosinase activity but also melanosome maturation. Although its efficacy is dose-dependent, higher concentrations of arbutin can lead to a paradoxical hyperpigmentation. Synthetic forms of arbutin, alpha-arbutin and deoxyarbutin, exhibit greater ability to reversibly block melnagenesis.

Niacinamide is the physiologically active derivative of vitamin B3 or niacin. In-vitrostudies show that niacinamide significantly decreases melanosome transfer to keratinocytes without inhibiting tyrosinase activity or cell proliferation, and niacinamide may also interfere with the cell-signaling pathway between keratinocytes and melanocytes to decrease melanogenesis.

N-acetyl glucosamine (NAG) is an amino sugar that is a precursor to hyaluronic acid and is found throughout nature and human tissues. Its depigmenting ability originates from the inhibition of tyrosinase glycosylation, a step necessary in the production of melanin.

Ascorbic acid or vitamin C is a naturally occurring antioxidant obtained from certain fruits and vegetables. It causes skin lightening by interacting with copper ions at the tyrosinase active site and by reducing oxidized dopaquinone, a substrate in the melanin synthetic pathway. In addition to skin lightening, other advantages of AA include not only antioxidant effects but some studies also demonstrate anti-inflammatory and photoprotective properties.

Licorice root extract (Glycyrrhiza glabra, Glycyrrhiza uralensis) is a common ingredient found in many skin-lightening cosmeceuticals, and is also used in the treatment of a wide variety of diseases even outside the scope of dermatology due to its anti-inflammatory, antiviral, antimicrobial, and anticarcinogenic properties. Some of the active ingredients in licorice root extract include glabridin, which inhibits tyrosinase and possesses anti-inflammatory effects, and liquiritin, which does not inhibit tyrosinase but causes depigmentation by melanin dispersion and removal.

Soy. The activation of protease-activated receptor 2 (PAR-2) cell receptors found on keratinocytes mediates the transfer of melanosomes from melanocytes to surrounding keratinocytes. Soy proteins, such as soybean trypsin inhibitor (STI) and Bowman-Birk inhibitor (BBI), inhibit the activation of these cell receptors, and as a result, phagocytosis of melanosomes into keratinocytes is reduced leading to reversible depigmentation.

Destructive therapies

Destructive therapies are based on the principle that damage or trauma to the skin’s surface results in a healing or restorative response. In theory, and usually in practice, this can result in a diminution of hyperpigmentation. The problem is that they also typically cause another round of inflammation. Individuals who are prone to a hyperpigmentary response to inflammation in the first place could see a return, or even a worsening, of ther condition they are trying to treat.

Chemical peels. In 2008, chemical peeling was the fourth most common nonsurgical cosmetic procedure performed in the United States, and dyschromias, such as PIH, are one of the most common indications for this procedure in skin of color.

For darker skinned individuals, superficial chemical peels, which penetrate into the papillary dermis, are generally well tolerated with good clinical results. However, care should be taken in selecting and using the specific chemical peel to avoid irritation, which can worsen PIH and lead to other complications, such as new areas of dyspigmentation, keloid formation, and hypertrophic scarring.

A detailed history, including other dermatological conditions, current oral and topical medications, history of herpes simplex virus (HSV) infection, past reactions to other cosmetic procedures, and a skin examination should be obtained prior to the procedure.

Glycolic acid (GA), found in sugarcane, is a naturally occurring alpha-hydroxy acid (AHA) that induces epidermolysis, disperses basal layer melanin, and increases dermal collagen synthesis.

Salicylic acid (SA), derived from willow tree bark, is a beta-hydroxy acid that induces keratolysis by disrupting intercellular lipid linkages between epithelioid cells.

Other complications include hypopigmentation, hypertrophic scarring, and keloid formation. Patients should also be educated on the importance of photoprotection to prevent or avoid worsening PIH after chemical peeling.

Laser and light-based therapies . Although topical skin-lightening agents remain the treatment of choice for PIH, lasers and light sources may be an effective adjunct to therapy or alternative for treatment failures. Typically, energy from short wavelength lasers is more efficiently absorbed by epidermal melanin while longer wavelengths penetrate deeper with more selective absorption by dermal targets making them safer to use for darker-skinned patients. There have been case reports of the successful treatment of PIH with blue light photodynamic therapy, neodymium-doped yttrium aluminum garnet (Nd:YAG) laser, and fractional photothermolysis in darker skin types

Cosmetic camouflage may be useful to conceal pigmentary disorders, vascular lesions, scars, and chronic skin conditions that are not amenable to medical or surgical treatments. These coverage techniques can help alleviate the patient’s distress regarding their appearance and significantly improve quality of life.

Camouflage can be particularly useful in darker skinned individuals where pigmentary changes may be more noticeable and when highly visible parts of the body are affected by the disease, such as the face, neck, and hands. Cosmetic covers can be applied for subtle coverage up to full concealment.

Topical Application of Anti-inflammatory (stem cell derived) Cytokines

Melanocyte responses to trauma and inflammation are incompletely understood and highly complex. Hence, melanocytes can respond with normal, increased, or decreased production of melanin.

In PIH, production is increased. It is thought that both hyperpigmentation and hypopigmentation result from cytokines and inflammatory mediators from keratinocytes, melanocytes, and inflammatory cells that are released in an inflammatory process in the skin. These include leukotriene (LT), prostaglandins (PG), and thromboxane (TXB).

PGE1 and PGE2 increase melanogenesis strongly while PGA1 and PGD2 represent strong inhibitors Leukotrienes such as LTC4 and LTD4, are metabolites of the lipoxygenase pathway and are able to induce the proliferation of melanocytes in vitro. Histamine, another inflammatory agent, may activate melanogenesis via proteinase A activation.

DrJohn has written extensively on cytokine patterns elsewhere on BFT, explaining that bone marrow derived mesenchymal stem cultures produce predominantly anti-inflammatory patterns of cytokines. BFT is aware of at least one PIH subject who has experienced substantial improvement in her appearance following eight weeks of twice daily application of a product containing such a pattern of anti-inflammatory cytokines. The photos she provided to speak for themselves.