Conflict of interest:
Dr. Emer has been a consultant for Regen Lab and Eclipse.

Abstract
Platelet-rich plasma (PRP) is an autologous serum containing high concentrations of platelets and growth factors. PRP continues to evolve as an important treatment modality with many applications in dermatology, particularly in the areas of hair restoration, skin rejuvenation, acne scars, dermal augmentation, and striae distensae. Furthermore, combining PRP with laser therapies, microneedling, dermal fillers, and autologous fat grafting produces synergistic effects, leading to improved aesthetic results. Future studies should standardize PRP treatment protocols for specific indications. PRP holds considerable promise in dermatology with therapeutic applications continuing to expand.

Key Words:
acne scars, aesthetic, androgenic alopecia, autologous fat grafting, cosmetic, dermal fillers, dermatology, facial rejuvenation, fractional laser resurfacing, hair restoration, microneedling, platelet rich plasma, PRP, rhytids

Introduction

Platelet-rich plasma (PRP) is an ever-expanding treatment modality that continues to demonstrate considerable promise in the field of dermatology. PRP has long been used in the medical fields of cardiac surgery, oral surgery, orthopedics, and facial plastic surgery, and it continues to develop as a versatile therapy in dermatology. PRP is an autologous serum containing high concentrations of platelets and growth factors.¹ Alpha granules within the platelets are responsible for promoting stem cell regeneration and soft tissue remodeling.² Many fundamental growth factors are contained within the PRP alpha granules, such as platelet-derived growth factors (aa, bb, ab), vascular endothelial growth factor, epithelial growth factor, transforming growth factor beta, and insulin-like growth factor.³ Mitogenesis and differentiation of monocytes, fibroblasts, stem cells, keratinocytes, and endothelial cells occur as a result of PRP alpha granule growth factors.² These growth factors are also known to induce cell proliferation, angiogenesis, and chemotaxis, as well as contain serotonin, dopamine, histamine, adenosine, and calcium, which increase membrane permeability.^2-4

The use of PRP results in improved cosmetic dermatologic outcomes through angiogenesis, neocollagenesis, and adipogenesis.² Applications for hair restoration and skin rejuvenation remain the most highly-supported indications for PRP in aesthetic dermatology (Table 1). Moreover, the use of PRP when combined with other treatment modalities, such dermal fillers, lasers, and other devices demonstrates significant improvements in skin appearance, texture, and tone. There is also emerging potential for the use of PRP with augmented fat injections to enhance fat survival (Figure 1). Although few clinical trials have been performed on the numerous above-mentioned therapeutic options, physicians note enhanced results with treatments combined with PRP versus solo treatment. PRP shows promising uses in the field of dermatology, and more studies are needed to test its validity alone or in combinations for enhancing outcomes.

Harvesting Platelet-Rich Plasma

There are many commercially available PRP systems and kits, and protocols vary according to brand name and treatment indication (Table 2). Traditionally accepted preparations involve initial venipuncture to obtain 10 to 22 mL of whole blood, which is combined with an anticoagulant agent. Centrifugation then separates the whole blood sample into three layers: red blood cells (RBCs), platelet-poor plasma (PPP), and the of-interest PRP layer. Subsequent centrifugations isolate and harvest the PRP layer, while discarding the RBCs and PPP. The now concentrated PRP pellet may be treated with calcium chloride or thrombin to activate the platelets (many harvesting systems do not require activation), releasing alpha granules and growth factors. For the most common dermatological uses, activation is not required, as a more viscous substance (once activated) is better suited for wound healing, post-surgical healing, and orthopedic uses. Activation of growth factors occurs within 10 minutes, with nearly 100% activation occurring within 1 hour.⁵ Some cosmeceutical brands have started to create “customized” skin care products that allow patients’ PRP to be added to a base formulation to complete a bespoke growth factor anti-aging skin care product. However, it is not yet known for how long the activated growth factors remain viable. It is thought that changes in pH and temperature may affect the viability of PRP within a few hours after collection. Current US Food and Drug Administration (FDA) guidelines also indicate that platelets should not be used beyond 5 days after collection, due to bacterial contamination during venipuncture. Nevertheless, patient demand for such autologous customized skin care products remains high.

Commercially Available PRP Harvesting Systems

Eclipse PRP® (Eclipse)

Magellan® (Isto Biologics)

PurePRP® (EmCyte)

RegenKit® (Regen Lab)

Selphyl® PRFM (UBS Aesthetics)

Table 2: Commercially available platelet-rich plasma harvesting systems commonly used in dermatology.

Platelet-Rich Plasma Subtype Families

Platelet concentrations vary per harvest protocol; a platelet count of 1 million/mL is widely accepted as the necessary PRP platelet concentration for therapeutic efficacy.⁶ Moreover, PRP contains plasma at concentrations 2 to 8 times greater than unaltered whole blood.² PRP preparations have been classified into four subtypes: pure platelet-rich plasma (P-PRP), leukocyte platelet-rich plasma (L-PRP), pure platelet-rich fibrin matrix (P-PRFM), and Leukocyte and platelet-rich fibrin matrix (L-PRFM). Aesthetic dermatology indications predominantly use the pure PRP preparation with minimal leukocyte collection.³ The P-PRFM preparation has a lower platelet concentration and includes fibrin. The fibrin matrix created in P-PRFM binds and traps growth factors, releasing them more slowly over several days. This preparation may be used for fat grafting procedures, as it allows for sustained, prolonged release of growth factors within the grafted tissues.⁷

Hair Restoration

PRP has demonstrated significant improvements in hair growth when treating androgenic alopecia (AGA) (Figure 2). PRP growth factors promote hair regrowth by stimulating stem cell differentiation of hair follicles, inducing and prolonging the proliferative anagen phase of hair follicles, as well as activating anti-apoptotic pathways and promoting angiogenesis to increase perifollicular vascularization and the survival of dermal papilla fibroblasts.^2,8-10

A wide array of studies indicates that PRP is a promising treatment for thinning hair.² Both male and female pattern hair loss, as well as alopecia areata, can be improved with PRP. Injections of PRP may be combined with progesterone, dalteparin microparticles, or CD34+ cells. PRP administered with progesterone naturally inhibits 5-alpha reductase, the enzyme that converts testosterone to dihydrotestosterone (DHT). DHT damages hair follicles and is culpable in genetic hair loss. Progesterone inhibits 5-alpha reductase and thus DHT, which allows hair growth to recover. PRP with dalteparin induced significant increases in hair diameter and proliferation of collagen fibers and fibroblasts, along with thickened epithelium and hair follicles due to increased angiogenesis.¹¹ Using CD34+ cells with PRP showed significant improvement in hair thickness and overall presentation.¹²

While some studies reveal minimal improvement in hair restoration, it is hypothesized that inadequate treatment protocols have been used. Studies using an insufficient number of treatments lacked substantial improvements.² Multiple continued treatments with PRP is necessary for significant aesthetic improvement of increased hair density. It is thought that three injections per year is the minimum frequency in order to observe any clinically beneficial result. In clinical practice, most physicians commence with a series of monthly injections until improvement is seen, then continuing with maintenance therapies every 2 to 3 months indefinitely. More research is needed nevertheless to determine proper frequency, dosing, and maintenance. Furthermore, combining PRP injections with other hair restoration treatments, such as finasteride (male patients), minoxidil, low-level light therapy, and spironolactone (female patients), may enhance the overall efficacy. PRP injections may also improve the outcome of hair transplantation and may soon be part of the pre-treatment and post-treatment maintenance protocols. In clinical practice, the author (JE) has found substantial improvement with the use of ACell® (naturally-occurring urinary bladder matrix epithelial basement membrane; MicroMatrix®) and/or human exosomes (placental mesenchymal stem cell and amniotic fluid derived; Kimera Labs, Inc.) combined with PRP in patients with less than substantial improvement with PRP injections alone. Combined with hair transplantation, injectable regenerative therapies have shown improved outcomes in the author’s experience.

Skin Rejuvenation

Several reports demonstrate improvements in traumatic scars and acne scars with PRP treatment. Increases in collagen density and dermal elastic fibers are notable benefits when using PRP in aesthetic dermatology. When PRP is used in combination with other therapies, such as laser treatments, microneedling, and hyaluronic acid fillers, further improvements in skin appearance are achieved (Figure 3). Autologous fat grafting combined with PRP to enhance long-term fat survival has preliminarily shown positive results. Furthermore, cosmetic improvements in striae distensae have been noted when combining radiofrequency, laser, and ultrasound therapies with PRP.

Acne Scars & Traumatic Scars

Multiple studies indicate significant improvement in appearance of acne scars, as well as traumatic scars, when using PRP^13,14 (Figure 4). Cutaneous injuries may result in scar tissue, presenting aesthetic and functional issues. Optical coherence tomography revealed improved acne scar depth when PRP was used with fractional laser therapy, compared to laser alone.³

A decrease in erythema and edema is observed when treating acne scars with PRP. Improved skin elasticity and increased collagen and fibroblasts are also noted when treating scars.¹⁵

Combination Therapies: Lasers & Microneedling

The use of PRP in conjunction with laser therapies and microneedling is increasingly popular in aesthetic dermatology. Fractional laser resurfacing and microneedling treatments create small holes in the skin, which act to enhance uptake and delivery of PRP.² Combining PRP with laser therapies and microneedling procedures improves wound healing and shortens recovery times, as well as reduces erythema and melanin index of treated areas.^14,16,20 Transepidermal water loss (TEWL) and inflammatory hyperpigmentation are also found to be significantly lower when combining PRP with device treatments. Patients treated with PRP after CO₂ or erbium fractional resurfacing have improved skin elasticity, increased fibroblasts, and notably thicker collagen bundles when compared to laser treated sites without added PRP.²⁰ Furthermore, there is anecdotal evidence of improved healing times with PRP combined with laser therapy, as well as earlier granulation, decreased erythema, and improved outcomes.

Dermal Augmentation

Combining PRP with hyaluronic acid-based fillers has been popular and widespread in cosmetic dermatology for several years. The “Vampire Facelift” was coined after combining PRP and dermal fillers; this technique has become well-known via social media. The numerous growth factors in PRP are thought to rejuvenate the skin, improving texture and smoothness, while also decreasing rhytids.^22,23 Hyaluronic acid fillers or other dermal augmentation agents serve as a scaffold to which PRP can bind and enhance skin rejuvenation, as well as enhance soft tissue augmentation² (Figure 5). Lasting cosmetic improvements are seen when treating nasolabial folds, horizontal neck bands, skin homogeneity and tonicity, and facial rhytids with dermal fillers combined with PRP. Studies have also indicated significant improvements in rhytids and skin tone in the infraorbital region.²⁴

Augmented Fat Injections

Combining PRP with autologous fat grafting is thought to bolster survival of the injected fat. Autologous fat injections have gained popularity for facial rejuvenation and dermal augmentation, as the fat grafts are deemed safe and free from potentially transmissible blood-borne pathogens due to the autologous origin of the fat. Pure PRP preparations with a fibrin matrix (P-PRFM) binds and traps growth factors contained within PRP, releasing them more slowly, ensuring prolonged survival of injected fat.⁷ Reports have indicated considerable potential for the use of PRP with augmented fat injections, while some investigations indicate no significant improvement was observed. Patients with HIV-associated facial fat atrophy treated with PRP fat grafting did not experience a significant difference in cosmetic appearance when compared to fat injections alone.¹⁷ However, results from other studies indicate PRP enhances volume retention of injected fat, maintains volume overtime, and reduces revision rates.^7,18,19 In the author’s opinion (JE) there is a substantial improvement in fat viability and retention with the use of PRP in a high enough ratio of PRP to fat; although that “ratio” is not defined based on the current studies in the literature and in practice at least 4-8:1 (fat to PRP) is utilized for a noticeably improved long-term outcome.

Striae Distensae

Continuous stretching of the skin often leads to atrophic dermal scars, known as striae distensae. Reports indicate beneficial cosmetic outcomes when combining intradermal radiofrequency and ultrasound devices with PRP.^21,25 Ultrasound therapies often follow radiofrequency treatments, as ultrasound assists in transepidermal penetration of PRP. Abdominal biopsies posttreatment have indicated increases in collagen density and elastic fibers, and the majority of patients report good or very good improvements in cosmetic appearance of their striae distensae.²¹

Conclusion

PRP continues to evolve as a consequential therapeutic tool in dermatology. Numerous growth factors contained within PRP promote neocollagenesis, angiogenesis, and overall proliferation of stem cells and soft tissue remodeling. PRP is easily harvested from patients’ own whole blood using numerous commercially available systems, making it a safe, in-office procedure. Top evidence-based dermatologic indications for PRP include hair restoration and skin rejuvenation, as well as improvements in acne scars. Moreover, combining PRP with other treatment modalities, such as laser therapies, microneedling, dermal fillers, and autologous fat injections has demonstrated synergistic effects, enhancing overall cosmetic outcomes. The dermatologic community stresses that more studies are needed to further standardize and define PRP protocols beyond anecdotal experience for specific indications.

Acknowledgement

The author gratefully acknowledges the editorial support from Bradford Ferrick in preparing this manuscript.

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¹Rush University Medical Center, Chicago, Il, USA
²Florida International University, Herbert Wertheim College of Medicine, Miami, FL, USA
³Spalding Drive Plastic Surgery and Cosmetic Dermatology, Beverly Hills, CA, USA

Conflict of interest: None Reported.

ABSTRACT
Dyschromia is a leading cause for cosmetic consultation, especially in those with diverse skin types (mixture of ethnicities) and with the rise of non-core and untrained physicians performing cosmetic procedures. Melasma and post-inflammatory hyperpigmentation (PIH) account for the majority of cases and are characterized by pigmented macules and patches distributed symmetrically in sun-exposed areas of the forehead, cheeks, and chin in melasma, and irregularly in areas of inflammation or an inciting traumatic event with PIH. Treatment is challenging and focused on a variety of mechanisms to stop, hinder, and/or prevent steps in the pigment production (melanocytic hyperactivity) process, breaking down deposited pigment for internal removal or external release, exfoliating cells to enhance turnover, and decreasing inflammation. Topical lightening therapy in combination with sun protection is essential for potential improvement. The most commonly prescribed and researched topical lightening agents are hydroquinone (HQ), azelaic acid (AzA), and retinoids – although only HQ and a triple combination cream (Tri-Luma®; fluocinolone acetonide 0.01%, HQ 4%, tretinoin 0.05%) are US FDA-approved for “bleaching of hyperpigmented skin” (HQ) and “melasma” (Tri-Luma®). Numerous non-HQ brightening/lightening agents, including antioxidant and botanical cosmeceuticals, have recently flooded the market with improvements that claim less irritant potential, as well as avoiding the stigmata associated with HQ agents such as carcinogenesis and cutaneous ochronosis. Combining topical therapy with procedures such as chemical peels, intense pulsed light (IPL), fractional non-ablative lasers or radiofrequency, pigment lasers (microsecond, picosecond, Q-switched), and microneedling, enhances results. With proper treatment, melasma can be controlled, improved, and maintained; alternatively, PIH can be cured in most cases. Herein, we review treatments for both conditions and provide an opinion on proper management for enhanced results.

Key Words:
melasma, post-inflammatory hyperpigmentation, dyschromia, hydroquinone, azelaic acid, Q-switched lasers, picosecond lasers, microneedling, management, chemical peels, fractional laser, skin bleaching

Introduction

Dyschromia is a frequent complaint in the cosmetic consultation as it is psychologically distressing and may be a signal of systemic changes (e.g., hormones, sun sensitivity/autoimmune, medications).¹ Although dyschromia is more commonly reported in those with darker or diverse skin types, there is an increasing number of patients of all skin types seen in practice presenting with irregular macules and patches of hyper and hypopigmentation from improperly performed cosmetic procedures by non-core or untrained physicians inducing color changes (Figures 1a and 1b). Given the degree of importance patients place on a clear complexion with regards to color and tone, we set forth to describe updated treatment options for melasma and post-inflammatory hyperpigmentation (PIH) to guide proper management.

Melasma is an acquired disorder of pigmentation that is characterized by symmetrically distributed pigmented macules and patches in sun-exposed areas of the face such as the forehead, cheeks and chin. Although the pathogenesis is not completely understood, hyperactive melanocytes stimulated by ultraviolet (UV) light exposure is the most widely accepted cause. UV exposure stimulates an increase in tyrosinemediated melanogenesis and melanosome transfer to epidermal keratinocytes, which is reflective of what we see clinically with worsening of pigmented patches after sun exposure or burn. Other causes such as genetics, photosensitizing medications, and hormones/endocrinopathies also play a role and may contribute to UV sensitivity.² Estrogen, associated with pregnancy or oral contraceptive pills, induces the release of melanocyte-stimulating hormone (MSH), stimulating tyrosinase; a reason the majority of cases are seen in females versus males.³

In lesional skin of patients with melasma, there is upregulation of vascular endothelial growth factor (VEGF), stem cell factor (kit-ligand), Wnt (Wingless-related integration site) signaling modulating genes, and reactive oxygen species, all of which are byproducts of UV induced dermal inflammation that in turn promote vascularization and stimulate melanocyte hyperactivity.⁴ This local inflammatory milieu is also seen in PIH.³

PIH represents another form of reactive hypermelanosis that occurs following an inciting event, which causes cutaneous inflammation such as inflammatory skin conditions (e.g., psoriasis, eczema, acne), trauma (e.g., picking, burns), or cosmetic procedures (Figure 2).⁵ The majority of cases are irregularly placed and not symmetrical or necessarily in sunexposed areas, as seen in melasma. Patients with darker or diverse skin types are more prone to PIH due to higher basal amounts of epidermal melanin. PIH is gender neutral, conversely, melasma is much more common in females due to hormonal influences.⁵ Histologically, there is no difference between either entity and clinical correlation is essential. Epidermal and dermal pigmentation may be differentiated on biopsy or with Wood’s lamp examination to dictate the nature of treatments offered at the onset.

Treatment of disorders of pigmentation can be challenging. For PIH, the key component guiding all other treatment remains prevention. PIH may be prevented or minimized by using pre-procedural topical lightening/bleaching agents, antiinflammatories, and/or retinoids. In contrast, melasma prevention is quite difficult. Patients with a family history of melasma or a diverse or ethnic skin type, who are pregnant, on hormonal therapy, or taking a photosensitizing medication, should be counseled on appropriate skin care with photoprotection, antioxidants, and lightening agents. While PIH may resolve spontaneously without treatment, melasma has no cure and needs continuous topical therapy focused on protection from UV damage in addition to targeted lightening/bleaching. This paper will review the common topical and procedural treatments for melasma and PIH.

Discussion

The treatment of melasma is frustrating due to its relapsing nature, few therapies offering a cure, and a struggle for successful preventative options. Alternatively, PIH can be prevented and often clears spontaneously on its own despite therapies that are available. Photoprotection and topical medical treatments are critical to the management of both entities in order to suppress melanogenesis (Table 1). In addition, medical treatments (both topical and procedural) work to aid in the removal of excess melanin that is already deposited.

Photoprotection

Photoprotection underscores all treatment modalities for disorders of pigmentation, particularly melasma. Without photoprotection, minimal benefit will be seen with any other therapeutic option. UVB (290-315 nm), UVA (315-400 nm), and even visible light (400-700 nm) all stimulate melanocytes to produce melanin and in some instances can overproduce observable pigmentation.⁶ While the lower wavelength UVB has the highest energy of this group and is the most erythemogenic, both UVA and visible light have a greater impact on stimulating melanogenesis and creating more chronic pigmentation.⁷ Broadspectrum sun protection against both UVA and UVB is critical, with physical blockers such as those with zinc or titanium dioxide the most recommended; however, sunscreens with the addition of chemical photosensitizers such as avobenzone (Parsol® 1789), octocrylene (Milestab™ 3039), oxybenzone (Helioplex®), and ecamsule (Mexoryl™) can increase the spectrum of protection by decreasing the production of free radicals while remaining photostable and absorbative. Many broad-spectrum sunscreens do not fully protect against the visible light spectrum that may contribute to pigmentary exacerbation; this is why compounds such as Tinosorb® M (not available in the United States) are added. Tinosorb® M increases the stability of other UV filters (like octinoxate, Eusolex®/Uvinul®) and has an inherent ability to reflect and scatter most wavelengths (with the majority being UVA and UVB). Additional benefit has been seen in sunscreens tinted with compounds such as iron oxide that also protect against visible light.⁸ Sun-protective clothing and broad rimmed hats are also key components to a comprehensive photoprotection strategy. Additionally, Polypodium leucotomos (fern extract, Heliocare®) is an oral antioxidant that has shown photoprotective effects and is recommended by the authors for all patients with pigmentary concerns or those undergoing any laser therapy.^9-10

Topical Therapies

Hydroquinone and Combination Therapy

The best-studied and most widely used topical depigmenting agent is hydroquinone (HQ), a structural analog of melanin precursors that inhibits the conversion of L-3,4-dihydroxyphenylalanine (L-DOPA) to melanin by tyrosinase. Adverse cutaneous effects include irritation, allergic contact dermatitis, and rarely ochronosis. Multiple studies have shown that the depigmenting effect is augmented when combined with a retinoid and a corticosteroid.^3,11-13 A triple combination cream of HQ 4%, fluocinolone acetonide 0.01%, and tretinoin 0.05%(Tri-Luma®) is the most widely used, although many compounded variants are used in clinical practice today. To prevent long-term sequela such as ochronosis from HQ products, it is suggested that practitioners limit treatment to 3-6 months continuously and then take a HQ “holiday.”¹⁴ However, shortterm continuous therapy with long-term “weekend only” or “3 times weekly” maintenance therapy has substantial benefit for treating both melasma and PIH with very few complications. Concerns over cutaneous carcinogenesis have not been confirmed in clinical practice and are not a concern to these authors when topical HQ products are used as described above (Figure 3).

Retinoids interfere with melanosome transfer to keratinocytes, accelerate pigment loss by increasing epidermal turnover, and directly inhibit tyrosinase.¹⁵ The use of retinoids as monotherapy is not recommended as an irritant reaction may cause inflammation that induces paradoxical hyperpigmentation; a similar concern exists over the use of HQ as monotherapy at very high concentrations (i.e., 8-20%). The addition of a low potency topical corticosteroid (see Tri-Luma® above) helps limit irritation, improves epidermal penetration, and prevents oxidation of HQ, thereby giving a synergistic improvement over HQ alone.¹⁶

A 2010 open-label study of 70 patients with moderate to severe melasma showed that 67.7% of patients achieved results of “clear” or “mild” disease as evaluated by the study researchers after 12 weeks of daily treatment with triple therapy.¹² Another study of 242 patients showed twice weekly maintenance treatment kept 53% of patients symptom free for 6 months.¹⁷

Non-Hydroquinone Alternatives

A number of HQ alternative (tyrosinase inhibition) products have flooded the market due to a demand for ingredients with less irritation and less stigma (i.e., ochronosis and carcinogenesis) than HQ. AzA, tranexamic acid, resorcinol, mequinol, and kojic acid are common constituents, often as part of a combination of agents used for lightening.18-22 AzA has intrinsic antityrosinase activity, but also acts as an anti-inflammatory agent.¹⁵ Tranexamic acid is a plasmin and prostaglandin inhibitor that leads to reduced tyrosinase activity.²³ Kojic acid, a naturally derived fungal metabolite, is a potent antioxidant and has been used in combination therapy with good success given its ability to enhance epidermal penetration of other medications through improved cell turnover.

Botanicals and Cosmeceuticals

Botanically derived antioxidants and natural extracts are frequently used for skin lightening due to their skin brightening and anti-inflammatory effects (Table 2). Silymarin, arbutin, resveratrol, Aloe vera, pycnogenol, Boswellia, aloesin, niacinamide, ascorbic acid, and extracts of coffeeberry, soy, green tea, orchids, grape seed, marine algae, and licorice are some of the more common agents seen in cosmeceutical products.^3,24 Arbutin, a derivative of hydroquinone derived from plants, inhibits melanosome maturation and tyrosinase activity and is one of the most widely used skin-lightening agents worldwide.¹⁶ Niacinamide (vitamin B3) interferes with the interaction between keratinocytes and melanocytes by modulating the proteaseactivated receptor (PAR-2) that is involved in melanosome transfer.²⁵ Ascorbic acid is a natural antioxidant that interacts with copper ions in the tyrosinase active site and acts as a reducing agent in various steps of melanogenesis to inhibit pigment formation.¹⁶ Coffeeberry is another antioxidant whose effects of depigmentation have not yet been adequately studied but has been found to be helpful as an alternative treatment of melasma.¹⁶ Soy’s skin lightening effects are mediated by PAR-2 and DOPA oxidase inhibition.

SkinCeuticals® Advanced Pigment Corrector, composed of a proprietary combination of a synthetic tyrosinase inhibitor (hydroxyphenoxy propionic acid), a flavonoid antioxidant (0.5% ellagic acid), 5% yeast extract, and 0.3% salicylic acid, showed similar results in terms of skin tone, spot intensity, spot size, and hyperpigmentation in a 12 week study compared to combination 4% HQ and 0.025% tretinoin cream.²⁶ The SkinCeuticals® formulation had significantly less adverse effects such as irritability.

SkinMedica® Lytera® Skin Brightening Complex is a combination of tetrahexyldecyl ascorbate (vitamin C), niacinamide (vitamin B3), ethyl linoleate (essential fatty acid) and squalene (lipid), retinol, Dunaliella salina extract (carotenoids of phytoene and phytofluene extracted from unicellular algae), hexylresorcinol, tetrapeptide-30 (skin brightening peptide), 4-ethoxybenzaldehyde, and Glycyrrhiza glabra (licorice) root extract (rich in glabridin, an antioxidant). This unique proprietary combination of ingredients work together to brighten and even skin tone and texture, improve luminosity, and reduce the appearance of dark spots through inhibition of tyrosinase, increasing keratinocyte turnover, improving the natural skin barrier (lipid), and decreasing inflammation (antioxidants). A split face study of 68 Caucasian women with moderate to severe facial hyperpigmentation with different dose formulations of Lytera® Skin Brightening Complex versus 4% hydroquinone showed the highest patient satisfaction with Lytera® and the lowest with 4% hydroquinone. All subjects achieved a significant reduction in overall hyperpigmentation.²⁷

Elure® Advanced Skin Brightening Technology has a natural enzyme formulation Melanozyme® that is mushroom-derived (ligninase) and a natural inhibitor of tyrosinase. In a randomized, double-blind, placebo-controlled, split-face, single-center study of 51 patients, twice daily application of this enzyme on one-half of the face led to a mean 7.6% improvement in pigmentation as measured by Mexameter® (to asses melanin and erythema values) after 31 days. The other half of the face was randomized to receive either 2% hydroquinone or placebo and did not result in a statistically significant lightening effect.²⁸

Melaplex® is a patented combination of disodium glycerophosphate, L-leucine, phenylethyl resorcinol, and undecylenoyl phenylalanine. Both the biosynthesis of melanin (tyrosinase inhibition) as well as the transfer of melanosomes to keratinocytes is inhibited (by decreasing the supply of L-tyrosine).^29-30

Chemical Peels

Chemical peels are frequently reported in the literature as effective for the treatment of hyperpigmentation such as melasma.^3,31 Superficial peels such as salicylic acid, Jessner’s solution (salicylic acid and lactic acid with resorcinol) and glycolic acid are reported to provide improvement with the least risk of complications. Stronger peeling agents such as multiple pass Jessners, Jessner’s/trichloroacetic acid (TCA) combination, TCA 35% or phenol, induce much more inflammation and the potential to significantly worsen pigmentation. It is the author’s preference (JE) to limit chemical peeling agents for the treatment of hyperpigmentation with the exception of salicylic acid (or lowdose combination peels, see below) due to the intrinsic ability for this agent to decrease inflammation, which is a reason it functions well as a peeling agent in other skin conditions like rosacea.

More recently, combination peeling agents such as the Vi Peel® (TCA, retinoic acid, salicylic acid, phenol, and vitamin C) group of peels, have the ability to address a range of skin complaints such as pigmentation, scarring, wrinkles, pores and acne in all skin types due to the low-strength combination of multiple agents that work while inducing little inflammation. The Vi Peel® with Precision Plus is a booster peel with the ingredients listed above plus the addition of HQ, kojic acid, and hydrocortisone, yielding improved treatment of melasma and PIH.

Intense Pulsed Light

Intense pulsed light (IPL) is not considered a first-line treatment for melasma or PIH.¹ Initial studies for the treatment of melasma showed improvement compared to control, but results were rarely sustained and, in some instances, showed the condition worsening.³² Results were improved if topical triple therapy was combined with IPL treatments, as compared with triple therapy alone.^33-34 Although there are some studies documenting improvement in PIH with IPL, it is not a standard therapy as one of the more common complications from IPL treatment, even when well performed, is post-inflammatory dyschromia.³⁵ Moreover, IPL is not ideal for Fitzpatrick skin types 4 to 6, comprising the more common population of patients with melasma and PIH. IPL for pigmentation should be considered as a last resort therapy employing very conservative treatment parameters, and administered through a series of sessions combined with an appropriate lightening skin care regimen and sun protection.

Lasers

Although lasers are reported in many studies to be helpful for the treatment of melasma (and in some instances PIH), in reality, there is a significant limitation to laser-based devices for pigmentation given the risk of rebound pigmentation or worsening, even with conservative treatment.^3,11 Theoretically, selective photothermolysis of melanosomes should induce destruction of excessive pigmentation, but any irritation or inflammation has the ability to induce reactive melanocytosis and, thus, worsen pigmentation.³⁶ In addition, post-procedural photosensitivity (along with hormonal induced photosensitivity seen in melasma) poses a major problem for long-term maintenance of results without an intensive brightening, anti-inflammatory, and sun-protective skin care regimen. Fitzpatrick skin types 4 to 6 can rarely be treated with energy-based devices due to the risk of PIH. Shortening the pulse duration (less than the 50 to 500 nanosecond thermal relaxation time of melanosomes) allows for more specific pigment targeting with less thermal byproduct.^2,3 By quickly pulsing the energy, you can obtain a high peak power and generate high local temperature gradients between melanosomes and the surrounding structures. Further shortening (to picosecond and beyond) adds a high-pressure photoacoustic effect that decreases the thermal consequence on surrounding structures and increases pigment removal through physical disruption of the involved melanosomes.^11,37-38

Common theory is that longer wavelengths (e.g., 1064 nm, Q-switched neodymium-doped yttrium aluminum garnet [Nd:YAG]) penetrate deeper but also spare the epidermis (normal melanin), making it safer to treat darker skin types and deep dermal pigmentation. Q-switched ruby (694 nm) lasers, although beneficial for pigmentation due to their high reactivity on melanin, can induce permanent hypopigmentation if conservative settings on patients with the appropriate skin type are not followed. Studies have shown improvement in a variety of pigmented conditions treated with longer-wavelength lasers such as ephelides, nevus of Ota, and tattoos.³⁹ As with any laser, dyspigmentation, acneiform eruptions, petechiae and herpes simplex re-activation are risks. Combination treatment with topical brightening agents (e.g., hydroquinone, triple cream, arbutin, vitamin C, and AzA) and other cosmetic procedures described above (e.g., chemical peels) may enhance outcomes.^11,40

One author’s go-to standard treatment is low-energy, low-density 1440 nm fractional diode laser (Clear + Brilliant® Laser System) as it can treat pigmentation with little downtime or risk of PIH due to the low energy/density settings and improvements occurring slowly over time (Figure 4). Additionally, there are several studies that have shown benefit of the 1927 nm thulium fiber laser of the Fraxel® re:store Dual, FDA approved in 2009 for the treatment of melasma and pigmented lesions.41-43 Previously, this author utilized the 1927 nm thulium fiber laser (Fraxel® re:store Dual) for melasma due to its shallow penetration (200 µm depth as compared to 400-1500 µm depth of the 1550 nm erbium (Er):YAG). However, after having frequent cases of worsening or rebound, he switched to utilizing low-fluence, lowdensity treatments alone or in combination with salicylic acid peels, microneedling, or spot liquid nitrogen treatment, which ultimately gave much better initial and long-term outcomes. Additionally, melasma, and sometimes PIH (although seen more with poikiloderma than PIH), has a vascular component that needs treatment with either a pulsed dye laser (585 nm) or potassium titanyl phosphate (KTP) laser (532 nm) to improve the overall texture and tone. More studies are needed on combination treatments for melasma and PIH, as in clinical practice multiple modalities with strict topical skin care regimens are being used to give the best results with long-term outcomes (Table 3).

Lastly, although reported in the literature as effective, ablative lasers (Er:YAG 2940 nm or carbon dioxide [CO2] 10600 nm) should never be used for melasma or PIH due to the very high potential of worsening hyperpigmentation.

Radiofrequency

Radiofrequencey (RF) technology has more recently become widely used in cosmetic medicine as a result of its efficacy and safety in a variety of aesthetic conditions including melasma. RF devices produce electrical current using electromagnetic radiation in the frequency range of 3 kHz to 300 MHz.44 When the current is applied to tissue, the resistance (impedance) produces heat that induces dermal neocollagenesis. Fractional RF devices produce low-density ablation with deep penetrating energy, giving these devices the ability to improve texture, tone and color in all skin types, while also improving wrinkles, acne scars, and laxity. Since melanin is not a target of the device, there is little to no risk of hyperpigmentation unless multiple pass treatments are used with fractional devices, thereby inducing too high levels of ablation (Figure 5).

One study using a monopolar RF device (Endosit NIR®) for 6 weekly sessions to facilitate drug delivery (phytocomplex of 1% kojic acid) showed mean Melasma Area and Severity Index (MASI) score improvement from 21.3 at baseline to 15.7 after 1 month of treatment. Improvements were maintained after 6 months of no therapy (mean MASI 16.9).⁴⁴ Future studies will be investigating the use of RF devices in the treatment of melasma and PIH. One idea being researched is a combination of microneedling with fractional RF for a synergistic approach to treating melasma or PIH.⁴⁵

Conclusion

Melasma and PIH are cosmetically disturbing to patients and frustrating to physicians performing procedures, as there is currently no best single therapy that gives significant short and long-term results. Combination therapies have the potential to improve results, but long-term maintenance treatments are needed for optimal outcomes. Future direction of studies are focusing on “color blind” technologies that can treat all skin types and multiple cutaneous concerns. It is important that physicians be knowledgeable about the most current therapies such as picosecond lasers, low-fluence/low-density non-ablative lasers, fractional radiofrequency, and microneedling in order to enhance patient results and limit complications.

Figure 1a. Dyschromia from IPL on a patient with skin type 4 who was not an appropriate candidate for this treatment. Notice the broad areas of hyper and hypopigmentation.

Figure 1b. Melasma. Hyperpigmented patches in the classicdistribution of the face of a female with worsening skin complaints despite topical hydroquinone and sunscreen.

References

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3. Sarkar R, Arora P, Garg VK, et al. Melasma update. Indian Dermatol Online J. 2014 Oct;5(4):426-35.
4. Kang HY, Suzuki I, Lee DJ, et al. Transcriptional profiling shows altered expression of wnt pathway- and lipid metabolism-related genes as well as melanogenesisrelated genes in melasma. J Invest Dermatol. 2011 Aug;131(8):1692-700.
5. Cestari TF, Dantas LP, Boza JC. Acquired hyperpigmentations. An Bras Dermatol. 2014 Jan-Feb;89(1):11-25.
6. Mahmoud BH, Ruvolo E, Hexsel CL, et al. Impact of long-wavelength UVA andvisible light on melanocompetent skin. J Invest Dermatol. 2010 Aug;130(8):2092-7.
7. Duteil L, Cardot-Leccia N, Queille-Roussel C, et al. Differences in visible lightinduced pigmentation according to wavelengths: a clinical and histological study in comparison with UVB exposure. Pigment Cell Melanoma Res. 2014 Sep;27(5):822-6.
8. Boukari F, Jourdan E, Fontas E, et al. Prevention of melasma relapses with sunscreen combining protection against UV and short wavelengths of visible light: a prospective randomized comparative trial. J Am Acad Dermatol. 2015 Jan;72(1):189-90 e1.
9. Bhatia N. Polypodium leucotomos: a potential new photoprotective agent. Am J Clin Dermatol. 2015 Apr;16(2):73-9.
10. El-Haj N, Goldstein N. Sun protection in a pill: the photoprotective properties of Polypodium leucotomos extract. Int J Dermatol. 2015 Mar;54(3):362-6.
11. Kauvar AN. The evolution of melasma therapy: targeting melanosomes using low-fluence Q-switched neodymium-doped yttrium aluminium garnet lasers. Semin Cutan Med Surg. 2012 Jun;31(2):126-32.
12. Grimes PE, Bhawan J, Guevara IL, et al. Continuous therapy followed by a maintenance therapy regimen with a triple combination cream for melasma. J Am Acad Dermatol. 2010 Jun;62(6):962-7.
13. Taylor SC, Torok H, Jones T, et al. Efficacy and safety of a new triple-combination agent for the treatment of facial melasma. Cutis. 2003 Jul;72(1):67-72.
14. Woolery-Lloyd H, Kammer JN. Treatment of hyperpigmentation. Semin Cutan Med Surg. 2011 Sep;30(3):171-5.
15. Levy LL, Zeichner JA. Management of acne scarring, part II: a comparative review of non-laser-based, minimally invasive approaches. Am J Clin Dermatol. 2012 Oct 1;13(5):331-40.
16. Sarkar R, Arora P, Garg KV. Cosmeceuticals for hyperpigmentation: what is available? J Cutan Aesthet Surg. 2013 Jan;6(1):4-11.
17. Arellano I, Cestari T, Ocampo-Candiani J, et al. Preventing melasma recurrence: prescribing a maintenance regimen with an effective triple combination cream based on long-standing clinical severity. J Eur Acad Dermatol Venereol. 2012 May;26(5):611-8.
18. Wu S, Shi H, Wu H, et al. Treatment of melasma with oral administration of tranexamic acid. Aesthetic Plast Surg. 2012 Aug;36(4):964-70.
19. Kanechorn Na Ayuthaya P, Niumphradit N, Manosroi A, et al. Topical 5% tranexamic acid for the treatment of melasma in Asians: a double-blind randomized controlled clinical trial. J Cosmet Laser Ther. 2012 Jun;14(3):150-4.
20. Lee JH, Park JG, Lim SH, et al. Localized intradermal microinjection of tranexamic acid for treatment of melasma in Asian patients: a preliminary clinical trial. Dermatol Surg. 2006 May;32(5):626-31.
21. Khemis A, Kaiafa A, Queille-Roussel C, et al. Evaluation of efficacy and safety of rucinol serum in patients with melasma: a randomized controlled trial. Br J Dermatol. 2007 May;156(5):997-1004.
22. Huh SY, Shin JW, Na JI, et al. Efficacy and safety of liposome-encapsulated 4-n-butylresorcinol 0.1% cream for the treatment of melasma: a randomized controlled split-face trial. J Dermatol. 2010 Apr;37(4):311-5.
23. Budamakuntla L, Loganathan E, Suresh DH, et al. A randomised, open-label, comparative study of tranexamic acid microinjections and tranexamic acid with microneedling in patients with melasma. J Cutan Aesthet Surg. 2013 Jul; 6(3):139-43.
24. Sundaram H, Emer J. Natural therapies for hyperpigmentation. J Drugs Dermatol. 2011 Sep 1;10(9):s15-20.
25. Hakozaki T, Minwalla L, Zhuang J, et al. The effect of niacinamide on reducing cutaneous pigmentation and suppression of melanosome transfer. Br J Dermatol. 2002 Jul;147(1):20-31.
26. Draelos Z, Dahl A, Yatskayer M, et al. Dyspigmentation, skin physiology, and a novel approach to skin lightening. J Cosmet Dermatol. 2013 Dec;12(4):247-53.
27. Makino ET, Mehta RC, Garruto J, et al. Clinical efficacy and safety of a multimodality skin brightener composition compared with 4% hydroquinone. J Drugs Dermatol. 2013 Mar;12(3):s21-6.
28. Mauricio T, Karmon Y, Khaiat A. A randomized and placebo-controlled study to compare the skin-lightening efficacy and safety of lignin peroxidase cream vs. 2% hydroquinone cream. J Cosmet Dermatol. 2011 Dec;10(4):253-9.
29. Dreher F, Draelos ZD, Gold MH, et al. Efficacy of hydroquinone-free skin-lightening cream for photoaging. J Cosmet Dermatol. 2013 Mar;12(1):12-7.
30. Gold MH, Biron J. Efficacy of a novel hydroquinone-free skin-brightening cream in patients with melasma. J Cosmet Dermatol. 2011 Sep;10(3):189-96.
31. Moubasher AE, Youssef EM, Abou-Taleb DA. Q-switched Nd: YAG laser versus trichloroacetic acid peeling in the treatment of melasma among Egyptian patients. Dermatol Surg. 2014 Aug;40(8):874-82.
32. Wang CC, Hui CY, Sue YM, et al. Intense pulsed light for the treatment of refractory melasma in Asian persons. Dermatol Surg. 2004 Sep;30(9):1196-200.
33. Goldman MP, Gold MH, Palm MD, et al. Sequential treatment with triple combination cream and intense pulsed light is more efficacious than sequential treatment with an inactive (control) cream and intense pulsed light in patients with moderate to severe melasma. Dermatol Surg. 2011 Feb;37(2):224-33.
34. Figueiredo Souza L, Trancoso Souza S. Single-session intense pulsed light combined with stable fixed-dose triple combination topical therapy for the treatment of refractory melasma. Dermatol Ther. 2012 Sep-Oct;25(5):477-80.
35. Ho WS, Chan HH, Ying SY, et al. Prospective study on the treatment of postburn hyperpigmentation by intense pulsed light. Lasers Surg Med. 2003 32(1):42-5.
36. Lee DB, Suh HS, Choi YS. A comparative study of low-fluence 1064-nm Q-switched Nd:YAG laser with or without chemical peeling using Jessner’s solution in melasma patients. J Dermatolog Treat. 2014 Dec;25(6):523-8.
37. Kauvar AN. Successful treatment of melasma using a combination of microdermabrasion and Q-switched Nd:YAG lasers. Lasers Surg Med. 2012 Feb;44(2):117-24.
38. Luebberding S, Alexiades-Armenakas M. New tattoo approaches in dermatology. Dermatol Clin. 2014 Jan;32(1):91-6.
39. Fabi SG, Metelitsa AI. Future directions in cutaneous laser surgery. Dermatol Clin. 2014 Jan;32(1):61-9.
40. Lee MC, Chang CS, Huang YL, et al. Treatment of melasma with mixed parameters of 1,064-nm Q-switched Nd:YAG laser toning and an enhanced effect of ultrasonic application of vitamin C: a split-face study. Lasers Med Sci. 2015 Jan;30(1):159-63.
41. Polder KD, Harrison A, Eubanks LE, et al. 1,927-nm fractional thulium fiber laser for the treatment of nonfacial photodamage: a pilot study. Dermatol Surg. 2011 Mar;37(3):342-8.
42. Niwa Massaki AB, Eimpunth S, Fabi SG, et al. Treatment of melasma with the 1,927-nm fractional thulium fiber laser: a retrospective analysis of 20 cases with long-term follow-up. Lasers Surg Med. 2013 Feb;45(2):95-101.
43. Lee HM, Haw S, Kim JK, et al. Split-face study using a 1,927-nm thulium fiber fractional laser to treat photoaging and melasma in Asian skin. Dermatol Surg. 2013 Jun;39(6):879-88.
44. Cameli N, Abril E, Mariano M, et al. Combined use of monopolar radiofrequency and transdermal drug delivery in the treatment of melasma. Dermatol Surg. 2014 Jul;40(7):748-55.
45. Chandrashekar BS, Sriram R, Mysore R, et al. Evaluation of microneedling fractional radiofrequency device for treatment of acne scars. J Cutan Aesthet Surg. 2014 Apr;7(2):93-7.

The Mount Sinai School of Medicine, Department of Dermatology, New York, NY, US A

Conflict of interest: No conflicts of interest
ABSTRACT

Topical corticosteroids (TCS) and topical calcineurin inhibitors (TCIs) are very effective treatments in inflammatory dermatoses, but carry risks with long-term use. TCS are associated with cutaneous atrophy and tachyphylaxis and TCIs can be irritating and contain a black box warning of an increased risk of cancers including lymphoma and non-melanomatous skin cancers. Nevertheless, they are appropriate treatments for inflammatory conditions such as psoriasis and atopic dermatitis (AD) and should be used more often with disease flares and less as maintenance therapy. Given the associated risks of long-term continuous use with these pharmacologic agents, alternatives are needed with similar anti-inflammatory and barrier repair properties that can be used indefinitely without risk. Some over-the-counter (OTC) ingredients such as colloidal oatmeal and petrolatum, as well as anti-inflammatory prescription moisturizers (medical device creams), have demonstrated efficacy with little complications in skin barrier repair and symptom relief in steroid-responsive conditions. With regimented application, these non-drug options are safe and effective and can limit the long-term continuous use of TCS or TCIs.

Key Words:
atopic dermatitis, emollients, eczema, skin barrier repair, moisturizers, topical corticosteroids, topical calcineurin inhibitors

Introduction

Topical corticosteroids (TCS) are the cornerstone of treatment for inflammatory dermatoses, particularly for the swift resolution of acute flares, as TCS can calm inflamed and irritated skin due to rapid absorption and action.¹ A wide range of potencies and vehicles enables tailoring of therapy to be site-specific and considerate of patient preference. Long-term continuous therapy with TCS can lead to localized side effects such as cutaneous atrophy, telangiectasias, acne and rosacea exacerbation, and tachyphylaxis, as well as systemic absorption if used on large surface areas causing hypothalamic-pituitary-adrenal (HPA) axis suppression, growth retardation in children, and cataract and glaucoma formation in adults.^2-6 Thus, intermittent therapy should be supplemented with alternative treatments that can help limit localized side effects and provide epidermal barrier dysfunction improvement.⁷

Topical calcineurin inhibitors (TCIs; tacrolimus ointment/ Protopic®; pimecrolimus cream/Elidel®) represent secondline therapies for the short-term and non-continuous chronic treatment of moderate-to-severe atopic dermatitis (AD) in non-immunocompromised adults and children who have failed to respond adequately to or are not suitable for other topical prescription AD treatments.^8,9 TCIs inhibit calcineurin in T-cells, reducing the production of interleukin (IL)-2 and related proinflammatory cytokines. Clinical studies have demonstrated longterm efficacy, minimal systemic absorption, and few transient side effects, such as localized irritation, with the use of these agents.^10-12 TCIs do not induce skin atrophy or inhibit collagen synthesis, enabling their use on the face, neck and intertriginous areas.¹³ In 2006 the United States Food and Drug Administration (USFDA) placed a black box warning on TCIs based on safety concerns over the possible risk of systemic absorption and on data from transplantation research reporting systemic immune suppression with oral calcineurin inhibitors (tacrolimus and cyclosporine) is associated with an increased cancer risk.¹⁴ To date, this risk remains theoretical and is based mainly on the drug’s mechanism of action, data from animal studies and a few single case reports of lymphoma and skin cancer in patients treated with TCIs.

Recently, medical device creams (Table 1), which are nonsteroidal agents with emollient, anti-inflammatory and antipruritic properties, have entered the marketplace for the treatment of inflammatory dermatoses to help treat epidermal barrier dysfunction as well as limit potential long-term use of TCS and TCIs. Atopiclair® is a hydrolipidic cream containing Butyrospermum parkii (shea tree), glycyrrhetinic acid (licorice), Vitis vinifera (grapevine) extract, bisabolol (German chamomile), hyaluronic acid and tocopheryl acetate (vitamin E), and is thought to have moisturizing, anti-inflammatory and antioxidant properties.¹⁵ It also contains telmesteine, which inhibits elastase, collagenase and matrix metalloproteinases, helping to prevent epidermal breakdown. MimyX™ contains lipid components that mimic the normal skin barrier (triglycerides, phospholipids, and squalene) along with the anti-inflammatory cannabinoid N-palmitoylethanolamine (N-PEA), an endogenous fatty acid amide thought to target the peroxisome proliferator-activated receptor-alpha (PPAR-α).¹⁶ Other added ingredients such as purified water, olive oil, glycerin, pentylene glycol, vegetable oil, and hydrogenated lecithin have humectant and emollient effects. EpiCeram® is a microencapsulation system emulsion of ceramide, conjugated linoleic acid, cholesterol and palmitic acid formulated with Euphorbia cerifera (candelilla) wax, corn syrup solids, squalene, glycerin, petrolatum, and dimethicone.^17,18 Eletone® has a high lipid content dispersed in an outer aqueous phase (Hydrolipid Technology™) in petrolatum, purified water, and mineral oil.¹⁹ Hylatopic Plus® is an emollient cream and foam containing Theobroma grandiflorum seed butter (a skin conditioning butter made from the fruit of a the Cupuaçu tree that is native to Brazil), hyaluronic acid, glycerin, dimethicone, petrolatum, and tocopheryl acetate (vitamin E).²⁰ All of the medical device creams are indicated for the treatment of various dermatoses such as AD, allergic contact dermatitis, and radiation dermatitis, which are associated with symptoms of itching, burning, and pain.

Epidermal Barrier Dysfunction

Defects in skin barrier function and stratum corneum hydration have been identified in a variety of inflammatory dermatoses.²¹ A functioning stratum corneum consists of corneocytes surrounded by ceramides, cholesterol, and free fatty acids – the so-called “bricks and mortar” model.²² Topical balms containing lipids and lipid-like substances have been shown to restore the barrier function of an impaired stratum corneum by replacing the deficient lipids, thereby improving skin hydration through decreasing transepidermal water loss (TEWL).²³ Further, epidermal barrier disruption results in greater density of epidermal Langerhans cells (antigen-presenting immune cells), enhanced inflammatory responses by increased foreign antigen presentation, and decreased anti-microbial proteins (AMPs), which play a role in innate skin defense (first-line skin protection).²⁴

In AD, the disturbed epidermal barrier is explained by nonsense mutations in the gene encoding filaggrin (FLG) and subsequent affect on the pro-inflammatory cascade, such as abnormal elevation in IL-1 cytokine profile in the stratum corneum.^25,26 FLG is a structural protein essential in the cornified envelope and is expressed as pro-FLG, which functions to secure keratinocytes together in the stratum corneum. Dysfunction or loss of FLG heavily influences keratinocyte adhesion, enhances TEWL, and causes dysregulation of skin pH, resulting in increased skin permeability.²⁷ Overall, this can induce persistent, recalcitrant and/or severe disease, increase the risk of cutaneous infections caused by microbes such as herpesvirus (eczema herpeticum) and Staphylococcus aureus, as well as increase the risk of sensitization to allergens and asthma.²⁸ Thus, the importance of an uncompromised skin barrier in improving inflammatory conditions cannot be over-emphasized and should be a major consideration in the treatment of acute flares as well as in longterm disease management.

It is important to note that despite the acknowledged contributions of a defective epidermal permeability barrier [i.e., FLG mutations, decreased AMPs such as human tissue kallikreins and cathelicidins (LL-37)] and dryness of eczematous skin, immunologic abnormalities such as T-helper type 2 (Th2) cytokines [i.e., IL-4 and IL-13 that influence immunoglobulin E (IgE) synthesis and adhesion molecule expression] also contribute to the pathogenesis of AD.²⁹ This suggests the development of inflammatory disorders is likely due to underlying immune dysregulation as the primary cause and epidermal dysfunction may be a secondary consequence.

Over-The-Counter Options and Clinical Studies

Petrolatum

Petrolatum – a mixture of long-chain hydrocarbons that is pale yellow in color, translucent, odorless, and hydrophobic – has been used for over 100 years as a healing ointment. Originally thought to be an occlusive moisturizer that forms a hydrophobic layer on the skin surface, petrolatum can penetrate and restore the stratum corneum by filling the spaces between desquamating corneocytes. This can reduce the appearance of fine lines and impart a soft, silky feel to the skin. Increased skin hydration is a consequence of epidermal lipogenesis and production of free sterols, sphingolipids, and free fatty acids.^30-32 Occlusives are generally not appealing to patients, due to their greasy feel, but can be very beneficial directly as a moisturizer and indirectly by reducing TEWL. A recently published study demonstrated the clinical efficacy and cost-effectiveness of a petrolatum-based moisturizer (Aquaphor® Healing) in treating mild-to-moderate AD as compared to two commonly prescribed medical device creams; one glycyrrhetinic acid-containing barrier repair cream (Atopiclair™) and another a ceramide-dominant barrier repair cream (EpiCeram®).³³ Some barrier repair creams contain petrolatum as their primary ingredient (Eletone®) and one study demonstrated comparable efficacy to a TCI (i.e., Elidel®) in the treatment of AD.³⁴

Dimethicone

Dimethicone – a mixture of polydimethylsiloxanes and silicon dioxide sometimes called simethicone – is another occlusive (insoluble in water) used in many OTC moisturizers and found to be safe and effective at skin moisturizing, though it is not as effective as petrolatum at reducing TEWL.^35,36 Dimethicone is the first ingredient in a foam formulated for the relief of irritation from inflammatory dermatoses such as AD and allergic contact dermatitis (Neosalus™). A combination of cyclomethicone (a cyclic higher-viscosity silicone) and dimethicone are used in barrier creams designed to prevent skin sensitization to allergens and can be useful in patients with itching and burning associated with contact dermatitis (Tetrix™).^37,38 Additionally, a recent study showed significant reduction in the incidence of incontinenceassociated dermatitis in patients using dimethicone-impregnated clothes.³⁹

Colloidal Oatmeal

Colloidal oatmeal has a long-standing history of benefit in dermatologic conditions associated with itch and irritation because of the ability to soothe and protect inflamed skin.⁴⁰ It contains a variety of active components including polysaccharides, proteins, lipids, saponins, enzymes, flavonoids, vitamins and avenanthramides (polyphenol).⁴¹ In 2003, colloidal oatmeal became an approved OTC monograph ingredient.⁴⁰ Current, ready-to-use oatmeal preparations are the concentrated starch-protein fraction of the oat grain mixed with emollient. Fine particles disperse on the skin and form a protective, occlusive barrier that retards water loss and moisturizes to improve the epidermal barrier. Further, oatmeal saponins help to solubilize dirt, oil and sebaceous secretions, which may normalize the skin pH.⁴² Oats have important antioxidant, ultraviolet (UV) absorbent and anti-inflammatory properties attributed to the ferulic, caffeic and coumaric acids, as well as flavonoids and α-tocopherol (vitamin E) components.^43,44 Recent research has identified avenanthramides (phenolic compounds) as a minor component of oat grains and in vitro work has demonstrated anti-inflammatory and anti-pruritic properties by decreased production of Nuclear Factor-kappaB (NF-κB) in keratinocytes and reduced pro-inflammatory cytokine (such as IL-8) production.⁴⁵ Avenanthramides have also been reported to inhibit prostaglandin synthesis.⁴⁶ As a result, many studies have substantiated the anti-inflammatory, hydrating and anti-pruritic properties of colloidal oatmeal and their use in the management of common inflammatory dermatoses.

Ceramides

As discussed previously the ceramides – which are a family of lipid molecules composed of sphingosine and a fatty acid, and found in high concentrations within the membrane of cells in the stratum corneum – are an essential component of the normal stratum corneum and function to help maintain the integrity of the skin barrier.⁴⁷ They serve as important water-holding molecules in the extracellular space, linking corneocytes and creating a waterproof barrier. In ceraminde-deficient skin there is enhanced TEWL, dryness, and increased permeability to environmental irritants and allergens. A recent study found that the mechanisms of ceramide changes in atopic skin are due to both Th1 (accentuate) and Th2 (attenuate) cytokines, as both IL-4 and IL-6, as well as interferon (IFN)-γ and tumor necrosis factor (TNF)-α influenced ceramide content in the stratum corneum.⁴⁸ This further solidifies that immune dysregulation in AD has a multitude of pathophysiological effects on the skin.

Newer moisturizers/topical skin care products (Table 2) targeted to improve epidermal barrier dysfunction by replenishing the amount of ceramides in the skin – with ceramide and pseudoceramide products mimicking the natural physiological skin barrier – are a mainstay of adjunctive therapy for patients with AD. Although evidence on their efficacy compared to older, less expensive traditional therapies, such as occlusives and humectants, remains to be validated.⁴⁹ It is known that proper moisture therapy can reduce the frequency of flares and limit the need for TCS or TCIs, likely a result of barrier recovery, including restoration of proper permeability function and increased levels of AMPs. In one study, a ceramide-hyaluronic acid emollient foam (Hylatopic Plus®) and pimecrolimus both showed equivalent improvement in the signs and symptoms of AD.⁵⁰ In another study, a ceramide-dominant, physiologic lipid-based, barrier repair emollient (TriCeram®) showed improvement when substituted for other OTC moisturizers in 24 children also receiving standard therapy (TCS or TCIs) for recalcitrant AD, thereby demonstrating the use of a ceramide-dominant moisturizer as compared to traditional agents can elicit significant improvement in symptoms of AD.⁵¹ TriCeram® has been discontinued by the manufacturer and is no longer available on the market.

EpiCeram® (a prescription device) consists of a specific combination of ceramides, cholesterol and fatty acids (in the ratio of 3:1:1) that mimics those naturally found in the skin and is reported to have similar efficacy to a mid-potency topical corticosteroid.^1,52,53 It contains capric acid, cholesterol, conjugated linolenic acid, candelilla and petrolatum. In a fivecenter, investigator-blinded, randomized trial, EpiCeram® was compared to fluticasone (Cutivate®) cream in 121 patients with moderate-to-severe AD and showed reduced clinical disease severity, decreased pruritus and improved sleep habits at both 14 and 28 days after initiation of therapy. The fluticasone group improved faster – greater improvement by day 14 – but by day 28, both interventions showed equal efficacy.¹⁷ A more recent study established improvement in clinical dryness scores and skin hydration and reduction in TEWL with the use of a new moisturizer (Cetaphil® Restoraderm® Body Moisturzier; CRM) containing FLG breakdown products [natural moisturizing factor (NMF)], a ceramide precursor pseudoceramide 5 or N-(2-hydroxyhexadecanoyl) sphinganine and niacinamide (vitamin B3), at week 4 as compared to the untreated areas.⁵⁴ A significantly higher level of ceramide and a trend toward increased water content were observed in the stratum corneum of CRM-treated skin when compared to the control.

Additional Ingredients

Additional ingredients such as glycerin or glycerol, urea, hydroxy acids and propylene glycol are common humectants added to OTC ingredients to help increase the ability of the skin to absorb water; although they are typically combined with an occlusive to prevent upward migration of water from the dermis and inadvertent increased TEWL. Glycerol or glycerin are the most effective as they have the ability to activate transglutaminase activity in the stratum corneum, accelerating the maturation of corneocytes as well as increasing water channels called aquaporins (particularly aquaporin-3) in diseased skin, which ultimately increases cutaneous hydration and reduces TEWL.^55,56

Clinical Studies

Several studies have directly examined the steroid-sparing potential of OTC emollients in patients with AD. Daily hydrocortisone 2.5% cream in the morning combined with a once daily water-in-oil emollient cream in the evening (Eucerin® Creme) was equally efficacious as twice daily hydrocortisone 2.5% cream in children.⁵⁷ Similarly, once daily betamethasone diproprionate cream with Eucerin® Creme was equally efficacious as twice daily betamethasone diproprionate cream in patients with plaque psoriasis.⁵⁸ As well, in infants under 12 months of age with AD, the addition of an emollient containing water, petrolatum, shea butter, evening primrose oil, glycerin, paraffin oil, niacinamide, butylene glycol, benzoic acid, carbomer and also specific active Rhealba® oat extracts (flavonoids and saponins) (Exomega® Emolient Lotion) significantly reduced the use of topical corticosteroids (desonide 0.1% cream).⁵⁹

Prescription Alternatives: Medical Device Creams

Prescription medical device creams are not classified as drugs, but rather as medical devices that have received 510(k) FDA clearance based on a demonstrated reduction in TEWL, which is a less extensive regulatory process that focuses on safety and less on efficacy. Each device cream has ingredients with proposed moisturizing, anti-inflammatory and anti-pruritic properties that may be useful as adjunctive or maintenance therapy in inflammatory dermatoses and, thereby, may help to limit the use of TCS or TCIs. Whether these device creams are equivalent in efficacy and long-term maintenance as compared to their OTC counterparts remains to be seen. Financial burden and supply limitation (insurance approval required in the US) may create difficulty in initiating and continuing therapy, especially in cases of severe disease.

Conclusion

Epidermal barrier dysfunction is a consequence of a combination of genetic factors influenced by immune dysregulation and abnormal structural proteins. Inflammatory dermatoses require treatment with TCS and/or TCIs to control acute flares, but also necessate appropriate and adequate moisturization to mitigate structural dysfunction and insufficient skin hydration. High predisposition to recurrent and recalcitrant disease, as well as infections and sensitization to allergens, makes long-term management with the goal to prolong periods of remission and reduce the severity of flares of utmost importance. As TCS can induce long-term complications and some patients are concerned with the black box warning of TCIs, non-drug options such as OTC and/or prescription medical device creams containing active ingredients known to have moisturizing, anti-inflammatory and anti-pruritic properties, are important therapeutic adjuncts that can be used daily without the risks associated with pharmacologics. Further studies are needed to determine the long-term efficacy of these products in treating chronic inflammatory dermatoses and validate their role through the development of management guidelines.

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