¹The George Washington University School of Medicine and Health Sciences, Washington, DC, USA
²Georgetown University School of Medicine, Washington, DC, USA

Conflict of interest:
AJF is a consultant for Aclaris Therapeutics. ECM has no conflicts to declare for this work.

Abstract:
HP40 (Eskata™) is a stabilized, topical solution of 40% hydrogen peroxide (H₂O₂) packaged in an applicator pen that is US FDA-approved to treat seborrheic keratoses (SKs). By harnessing the oxidative capabilities of H₂O₂ , 1-2 treatments with HP40 produced a higher rate of clearance of four SKs per patient compared to vehicle in two phase 3 trials. The clearance rate was higher for the face than the trunk and extremities. Similarly, the risks of pigmentary changes and scarring from HP40 were lower for the face than other locations. Further, based on an ex vivo study, HP40 may be less cytotoxic to melanocytes than cryotherapy, but clinical trials comparing these therapies are needed. Limitations of HP40 are its low efficacy and requirement of multiple treatments, which can result in elevated costs. The application can also be time-consuming, though extenders or even staff members can apply it. Therefore, HP40 may be better reserved for the treatment of facial SKs.

Key Words:
efficacy, Eskata, hydrogen peroxide, safety, seborrheic keratoses, topical therapy

Introduction

Seborrheic keratoses (SKs) are benign epithelial tumors estimated to affect more than 83 million Americans.¹ Existing as at least nine variants, SKs present as round to oval macules or papules with variable surface textures that appear “stuck on” and can occur anywhere on the body, except the palms and soles.^2-4 The incidence and frequency of SKs per person increase with age.⁴ In one study of Korean males, the authors found that 79% of patients had SKs at age 40 (with 5.5 SKs per patient) compared to 94% of patients at age 50 (with 9.9 SKs per patient).⁵

In addition to increasing age, potential risk factors for SKs include ultraviolet light, as they occur with a higher prevalence on sun-exposed skin,^5,6 friction given they commonly occur in intertriginous areas,⁷ and genetic predisposition.^7,8 However, the true etiologic risk factors and pathogenesis of SKs are not fully known. Inhibition of apoptosis may occur in SKs, contributing to their formation.⁴Additionally, mutations in the fibroblast growth factor receptor⁸ and oncogenic phosphoinositide 3-kinase pathway⁹ may impact their development; however, these changes are not present in all SKs so additional genes are likely involved.⁸

While SKs do not require treatment, patients often request removal to relieve symptoms of irritated SKs or for cosmetic reasons.¹⁰ The most common treatment is cryotherapy with liquid nitrogen; surgical therapies are also used including electrodessication, curettage, shave excision, or laser therapy.^7,11

Among other side effects, these invasive methods can cause pain, bleeding, pigmentary changes, and scarring.^7,12-15 The risk of pigmentary changes is especially high in patients with skin of color.⁷ These side effects motivated the pursuit for efficacious topical therapies that minimize long-term adverse effects. Existing keratolytics (ammonium lactate, imiquimod, and tazarotene) and vitamin D analogs were examined to treat SKs, but these agents demonstrated limited efficacy in small clinical trials.^16-19

The first topical therapy to be US FDA-approved for the treatment of raised SKs is HP40 (Eskata™), a stabilized topical solution of 40% hydrogen peroxide (H₂O₂).²⁰ This therapy was approved in December 2017 based on the results of two phase 3 trials.²⁰ An earlier phase 2 dose-ranging trial additionally confirmed that HP40 was more efficacious than 32% H₂O₂ while still having a satisfactory side effect profile.^21, In this review, we will discuss the evidence for and limitations of HP40 based on these clinical trials as well as an ex vivo model of Fitzpatrick Skin Type (FST) V skin that examined HP40’s cytotoxicity.^20,22,23

Application and Mechanism

HP40 is applied by a healthcare professional with a single use pen that includes 0.7 mL of 40% H₂O₂ and can treat about seven SKs.²⁴ According to the manufacturer’s instructions, the tip of the pen is pressed to an SK and the solution is applied in a circular motion for about 20 seconds. This process is repeated up to three additional times per SK with 1 minute between each application. After 3 weeks, the SK can be re-treated if satisfactory clearance was not achieved.

The mechanism by which HP40 destroys keratinocytes is not fully elucidated, but is thought to involve H₂O₂‘s oxidizing power²¹ as both a direct oxidant and indirect oxidant through the formation of hydroxyl radicals.²⁵ When this oxidative stress overwhelms the antioxidant properties of the skin, H₂O₂ can lead to cellular destruction by damaging proteins, lipids, and nucleic acids.²⁵ Applied at a supra-physiologic concentration, a portion of the HP40 dose likely diffuses through the stratum corneum (SC) and into the epidermis.^20,21 Free radicals generated by H₂O₂ can then induce apoptosis or necrosis of seborrheic keratinocytes among other cell types (Figure 1). Given this mechanism, HP40 should not be applied to open or infected SKs; without an intact SC to act as a barrier, high concentration H₂O₂ can cause rapid death of adjacent cells (Figure 1).²⁶ Additionally, HP40 should not be applied within the orbital rim where contact with H₂O₂ can cause corneal injury.²⁴

Efficacy of HP40

In two phase 3 trials with a total of 937 patients, four raised SKs per patient were treated with either HP40 or vehicle using the previously described method (Application and Mechanism).²⁰ Three weeks later, residual SKs were re-treated. Pedunculated SKs or SKs in intertriginous areas, hair-bearing areas, or within 5 mm of the orbital rim were excluded. The therapeutic efficacy was assessed with a 4-point scale, Physician’s Lesion Assessment (PLA), developed by the manufacturer where 0 is clear, 1 is nearly clear, 2 is a thin SK with a depth of 1 mm or less, and 3 is a thick SK with a depth greater than 1 mm. The primary endpoint was complete clearance (0 on PLA) of all four SKs.²⁰

The treatment and control groups had similar demographic characteristics, with an average age of 68.7 years, and the completion rate was nearly 100% for each trial (99%, 98% per trial). At the end of the study (day 106), HP40 resulted in a significantly higher rate of complete clearance of all four SKs than vehicle; however, the rate of clearance of all four SKs with HP40 was low overall (4%, 8% per study for HP40 versus 0% for both studies for vehicle). Post hoc, the authors also calculated the mean per-patient percentage of clear/nearly clear SKs, which was higher for HP40 than vehicle (47%, 54% versus 10%, 5%, respectively).²⁰

To examine the efficacy of HP40 by location, the percentage of clear/nearly clear SKs at day 106 for each anatomic site was calculated in another study.²² A total of 1,868 SKs were treated in the HP40 group and 1,880 SKs were treated in the vehicle group; 59% of SKs were on the trunk, 30% on the face, and 11% on the extremities. The highest rate of clearance/near-clearance with HP40 treatment was observed for the face (65%), followed by the trunk (46%), and then the extremities (38%). The authors theorized that these efficacy differences may be due to variations in skin topography, such as varying water or lipid content or SC thickness. For instance, the thin SC of the face may allow enhanced penetration of HP40 compared to other anatomical sites. Another explanation proposed by the authors was that the high exposure of the face to ultraviolet radiation may impair its ability to respond to H₂O₂-induced oxidative stress.²²

Adverse Effects of HP40

In the phase 3 trials, 21% of the HP40 group and 19% of the vehicle group reported adverse effects; most were mild to moderate and all were limited to local skin reactions.²⁰ Three events related to HP40 were considered severe: application site pain, a burn from treatment, and a burning sensation. Ten minutes after HP40 application, erythema was observed in 91% of SKs and edema in 75% of SKs. By day 106, the percentage of HP40-treated SKs with erythema decreased to 10.1% and no SKs exhibited edema. Other symptoms at day 106 included scaling (8.0%), hyperpigmentation (7.8%), crusting (5.4%), hypopigmentation (3.0%), scarring (<1%), and erosion (<1%).²⁰ Examining skin reactions by anatomic location, Smith et al. found that SKs on the face showed the lowest rates of hyperpigmentation (2.3% versus 10.8% trunk, 6.9% extremities), hypopigmentation (1.9% versus 3.5% trunk, 3% extremities), and scarring (0% versus 0.6% trunk, 1% extremities).²²

While the risks of pigmentary changes and scarring at day 106 were low, especially for facial SKs, 98.8% of the study sample were FST I-IV, with only 7.3% having FST IV, so the effects on patients with FST IV or higher could not be adequately assessed.²⁰ A study by Kao et al. used an ex vivo model of human FST V skin to explore the toxicity of HP40 (1 and 2 μL) compared to cryotherapy (5- and 10-second cycles).²³ A colorimetric MTT assay was used to measure overall cytotoxicity and S100 stained-melanocytes were quantified to assess melanocyte toxicity. The authors found that HP40 was less cytotoxic overall and to melanocytes compared with cryotherapy, meaning that HP40 may cause less pigmentary changes in patients with dark skin.²³ However, clinical trials comparing the adverse effects of HP40 and cryotherapy are needed before conclusions can be drawn. Given hyperpigmentation was seen in 8% of HP40-treated SKs²⁰ and patients with darker skin are more prone to pigmentary changes,⁷ HP40 should be used cautiously in FST IV-VI patients until further research is done.

Limitations and Future Directions

HP40 was found to be superior to vehicle for the treatment of raised SKs, but its efficacy is limited overall, producing complete clearance of all four SKs in only 4% and 8% of patients per study.²⁰ As Bauman et al. discussed, patient satisfaction was not evaluated in the trials, and considering patients determine therapeutic success based on their appearances in the mirror rather than on physician-completed scales, superior results may have been observed with self-assessments.²⁰ Regardless, patients still often require repeat treatments to produce adequate SK clearance (97% of the trial participants required second treatments), which can be cost prohibitive and time intensive for patients.²⁰ HP40 is not covered by insurance and costs about $131 (US dollars) per treatment (as reported by The Medical Letter on Drugs and Therapeutics²⁴).

HP40 is also time consuming to apply for the dermatology clinic. In the clinical trials, treatment of four SKs took about 5 minutes and 20 seconds,²⁰ and this time would be almost doubled for the average of seven SKs that can be treated with each HP40 pen.²⁴ With four 20-second treatment cycles recommended per SK, this therapy is more time intensive than cryotherapy, which requires only 5 to 10 seconds of freezing for thin lesions.¹² Thicker SKs may require an additional freeze-thaw cycle with cryotherapy,¹² but this is still a shorter process than HP40 application. However, trained non-physician staff can also administer HP40, so practices can develop protocols to maximize application efficiency.

Patient Selection

When choosing a strategy for SK removal, it is important to consider the SK’s location as well as the patient’s skin type and treatment expectations. Based on the finding that HP40 is most efficacious for SKs on the face compared to the trunk and extremities, HP40 may be a good therapy to discuss with patients seeking treatment for SKs in cosmetically-sensitive areas like the face. While additional clinical studies are needed to explore this assertion, HP40 may destroy fewer melanocytes than cryotherapy, meaning that HP40 may be a potentially beneficial therapy for patients with dark skin who are susceptible to pigmentary changes with cryotherapy.⁷ On the contrary, because of the high cost of HP40 and need for repeat treatments, it is likely less useful for symptomatic SKs in non-cosmetically sensitive locations where patients desire rapid relief without as much concern about the cosmetic outcomes.

In terms of pregnancy and lactation risk, topical H₂O₂ is not systemically absorbed. Therefore, application of HP40 during pregnancy or while lactating should not result in exposure of the fetus or breastfeeding infant.²⁴

Conclusion

Given our current options for the treatment of SKs include only more invasive, non-topical therapies, HP40 fills a void in our therapeutic repertoire as the first FDA-approved topical therapy for SKs. However, this therapy has limited efficacy with 1-2 treatments, producing only about 50% clearance per patient.²⁰ Further, HP40 is expensive and can be time-intensive to apply. Nevertheless, considering HP40 produces higher clearance of SKs on the face than other anatomic locations²² and that it may be less cytotoxic to melanocytes than cryotherapy,²³ HP40 may be useful for the treatment of facial SKs. Given 92% of the phase 3 trial participants were FST I-III, further research is needed to explore the risk of pigmentary changes with HP40 in patients of FST IV or higher.

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¹Department of Dermatology, McGovern Medical School at The University of Texas Health Sciences Center at Houston, Houston, TX, USA
²Center for Clinical Studies, Houston, TX, USA

Conflict of interest:
The authors have no conflicts to declare for this work.

Abstract:
The ichthyoses, also termed the disorders of keratinization, are a heterogenous group of skin diseases in which a distinctive horny layer arises secondary to excessive transepidermal water loss. Although occasionally acquired, the majority of ichthyoses are inherited and can be pinpointed to characteristic genetic mutations. Management depends on disease severity and includes topical agents and lifestyle modifications with or without oral retinoids. Genetic counseling is also an important consideration. This review aims to highlight advances in our understanding of disease pathogenesis as well as the holistic approach necessary to adequately manage ichthyosis patients.

Key Words:
ichthyosis, keratinization, lifestyle, management, pathogenesis, treatment

Introduction

Ichthyoses are an inherited group of skin disorders in which cornified layer accumulation leads to characteristic phenotypic features including xerosis, hyperkeratosis, excessive scaling, keratosis pilaris, and palmar and plantar hyperlinearity.¹ The common manifestations of this heterogeneous group of diseases arise due to abnormal skin barrier function that causes increased transepidermal water loss and a resultant compensatory hyperproliferation.² The clinical symptoms of ichthyosis typically present at birth or within the first few years of life.² With limited treatment regimens and no current cure, it is important to acknowledge the associated impaired quality of life that patients with lifelong ichthyosis experience.³ A recent study demonstrated that adults affected with this disorder report diminished quality of life regarding their physical health (impaired appearance of skin and mobility), daily life (cost of disease), and relationships with others and oneself (negative reaction of others to disease).³ In the following brief review, we aim to update advances in understanding the pathophysiology and management of ichthyosis.

Pathogenesis

As previously mentioned, the ichthyoses, or disorders of keratinization, are characterized by hyperproliferation triggered by increased transepidermal water loss.² The distinctive horny layer can be localized or diffuse and may be complicated by hypohidrosis, erythema, and infection. Although occasionally acquired, ichthyosis is largely an inherited condition with over 50 genes implicated in its pathogenesis. These genes influence a variety of cellular functions from DNA repair to adhesion, with the end result being a dysfunctional epidermal barrier.² The common ichthyoses are ichthyosis vulgaris and X-linked recessive ichthyosis, both of which are caused by well-characterized genetic mutations.^2,4 Ichthyosis vulgaris occurs due to autosomal dominant mutations in the filaggrin gene (FLG), and X-linked recessive ichthyosis results from alterations in the STS gene, which encodes steroid sulfatase.^2,4 Harlequin ichthyosis, lamellar ichthyosis, and congenital ichthyosiform erythroderma all result from autosomal recessive mutations.² Harlequin ichthyosis is associated with homozygous loss of function mutations in ABCA12, which encodes an ATP-binding cassette transporter.² Lamellar ichthyosis, congenital ichthyosiform erythroderma, and others exist on a spectrum of autosomal recessive congenital ichthyoses characterized by mutations in TGM1, NIPAL4/ ICHTHYIN, ALOX12B, ALOXE3, CYP4F22, ABCA12, PNPLA1, CERS3, LIPN, SDR9C7, and SULT2B1.^2,5-7 Understanding the impact of genetics in the pathogenesis of the ichthyoses gives perspective as to why these diseases often present in infancy or childhood, why they are lifelong burdens to those affected, and why finding a cure presents a challenge.

Management

Topical Agents

Ichthyosis management should incorporate hydration and lubrication with the addition of keratolytics and modulators of keratinocyte differentiation depending on scale severity.⁸ Hydration can be accomplished with creams and ointments containing low concentrations of salt, urea, or glycerol. Such topical therapies are employed to increase the water-binding capacity of the stratum corneum. Hydrophobic ointments such as petroleum jelly are effective for adequate lubrication. Of note, evidence does not support the use of skin-lipid-containing creams over the aforementioned plain creams and ointments in ichthyosis. When disease is characterized by markedly thickened stratum corneum, topical keratolytics such as alpha-hydroxy acids (lactic acid, glycolic acid), salicylic acid, N-acetylcysteine, propylene glycol, and high-dose urea allow for desquamation while keratinocyte differentiation modulators such as the retinoids (tretinoin, adapalene, tazarotene) and calcipotriol limit epidermal proliferation.⁸

Oral Medications

Although generally not necessary in the management of the common ichthyoses (ichthyosis vulgaris and X-linked recessive ichthyosis), oral retinoids are a mainstay in the systemic management of severe disease.⁸ Patients suffering from lamellar ichthyosis, epidermolytic hyperkeratosis, or congenital ichthyosiform erythroderma can benefit from retinoids as the drug’s keratolytic effects allow shedding and prevent further hyperproliferation. It is recommended that these agents be administered in low, effective doses as their use could be lifelong in ichthyosis patients.⁸ Additionally, retinoids are well-known teratogens.⁹ Retinoic acid plays a significant role in transcription regulation by binding retinoic acid response elements (RAREs) that are located proximally to numerous genes. RAREs have been found to inhibit Fgf8, homeobox genes, and other genes integral to neuron and organ development, thereby causing major craniofacial, thymic, cardiac, and central nervous system malformations in addition to spontaneous abortion.^9,10 In an effort to increase awareness and reduce birth defects associated with isotretinoin use, US-based physicians prescribing isotretinoin should be certified in and patients taking the medication should be registered with the iPLEDGE Program.¹¹ For female patients of child-bearing potential, this program mandates regular pregnancy tests and requires two forms of contraception.¹¹ Providers and patients in other countries should adhere strictly to local pregnancy avoidance programs and policies. In a patient considering pregnancy, isotretinoin may actually be preferred to acitretin due to its shorter half-life and resultant shorter washout period.⁸ At this time, data suggest oral retinoids are safe to use in reproductively active men.¹²

While retinoids share many features, some agents may be more effective than others situationally.⁸ For example, isotretinoin and aromatic retinoids (such as etretinate, acitretin) appear equally efficacious in the treatment of lamellar ichthyosis, whereas the propensity of acitretin to act on volar skin makes it the preferred therapy in palmoplantar hyperkeratosis.⁸

Lifestyle Considerations

The majority of ichthyosis therapies aim to improve the barrier function of the skin. Important aspects of an ichthyosis patient’s daily routine include bathing and proper application of the bland creams and ointments discussed previously.¹³ Daily bathing with water or mild cleanser and the application of plain emollients directly after bathing, as well as frequently throughout the day, help to seal in moisture.¹⁴ It is thought that bathing aids to hydrate and promote shedding of the stratum corneum, therefore reducing the thickness of scaling and improving overall skin appearance.¹³ Many emollients are not covered by insurance; in addition, patients self-report applying topical agents as time-consuming.³ Thus, it is important to be aware of the possible financial and lifestyle stresses with which these therapies may burden the ichthyosis patient population.

In addition, patients diagnosed with ichthyosis should be aware of the lifelong course of this group of disorders, as there is currently no cure. Patients who are carriers of the FLG gene mutation may be at increased risk of developing atopic disorders, such as atopic dermatitis and asthma.¹ To decrease potential risks for the development of atopic disorders, individuals diagnosed with ichthyosis vulgaris should be advised to avoid certain environmental risk factors including professions involving wet work or excessive metal and contact irritant exposure.¹ Smoking tobacco should also be discouraged as an interaction between FLG mutations and tobacco smoking has been shown to favor the development of asthma in patients with ichthyosis vulgaris.^1,15

Finally, it is important to acknowledge lifestyle factors that commonly influence the quality of life in ichthyoses patients. Patients self-report suffering from altered skin and eye appearance, including pain, pruritus, and “smelly” skin, that worsen in relation to environmental and psychological changes.³ To accommodate these changes, most patients refrain from activities that risk exacerbating their condition by avoiding hot atmospheres and activities in which they cannot hide their skin.³ As affected patients consistently express dissatisfaction with their medical care, it is prudent for physicians to advocate for the development of strategies and therapeutic programs targeted at improving the care and quality of life of these individuals.³

Genetic Counseling

Gene therapy is not yet a reality in ichthyosis therapy; however, genetic counseling remains an integral aspect of disease management. As mentioned previously, the most common forms of ichthyosis are ichthyosis vulgaris and X-linked recessive ichthyosis, which are inherited in autosomal (pseudo-) dominant and X-linked recessive patterns, respectively, via well-characterized genetic mutations. Although the diagnosis of ichthyosis vulgaris in particular may be evident from biopsy alone, the diagnosis of X-linked recessive ichthyosis requires polymerase chain reaction analysis, Southern blot, or fluorescent in situ hybridization analysis.^4,8 A positive male-only family history of scaly skin, the detection of low estriol on the prenatal triple screen, and/or low estrogen and nonhydrolyzed sulfated steroids in maternal urine can point toward a diagnosis of X-linked recessive ichthyosis, thus prompting analysis of chorionic villi or amniotic fluid using the aforementioned techniques.⁴ Additionally, a recent case report suggests that a rare and extreme form of fetal ichthyosis, harlequin ichthyosis, can be detected on ultrasonography as early as the second trimester with subsequent genetic screening to elucidate mutations in ABCA12.^2,16 A referral to a genetic counselor can serve to answer questions and alleviate anxiety regarding the diagnosis of a congenital ichthyosis as well as assist parents in consideration of future pregnancies.

Future Considerations

Topical therapy is necessary in the management of ichthyosis; thus, consideration should be given to the cosmetic appeal and fragrance of treatment creams and ointments. A recent case report found preliminary success utilizing carbocysteine cream in the treatment of ichthyosis.¹⁷ Carbocysteine is a molecule similar to N-acetylcysteine except that it contains a bound sulfhydryl group rather than a free one.¹⁷ As the sulfhydryl group cannot be liberated, this cream lacks the rancid egg smell of N-acetylcysteine cream, a major barrier to treatment compliance.¹⁷ Further research dedicated to such creams, ointments, and even cosmetic products has the potential to improve the quality of life in patients suffering physical discomfort and social stigmata due to their condition. In addition, development of gene therapy has tremendous potential in treating patients with these disorders and should be explored further.

Conclusion

The ichthyoses are typically inherited conditions exhibiting disordered keratinization secondary to excessive transepidermal water loss, with the most common variants being ichthyosis vulgaris and X-linked recessive ichthyosis. Ichthyosis management requires a multimodal approach, including topical and oral agents in addition to lifestyle modifications. Topical creams and ointments are the mainstays of treatment utilized to achieve adequate hydration and, when applicable, keratolysis, while more severe phenotypes benefit from the use of oral retinoids. Patients should also be educated regarding bathing practices and avoidance of topical irritants and tobacco, as well as be actively supported by their clinician, as ichthyosis patients often report decreased quality of life.

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Methotrexate for SC injection

Trifarotene cream 50 mcg/g

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Lidocaine + tetracaine (7%/7%) local anesthetic cream

Maralixibat oral solution

Cetirizine hydrochloride for IV injection

Minocycline foam 4%

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Articles are indexed by drug names, trade names and disease terms. Bold entries refer to major references.

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