Agents Used for Treatment of Hyperkeratosis

Verruca, Molluscum, and Callosities

Salicylic acid is present in a wide variety of wart and callus topical treatments and is often compounded with other keratolytic agents such as lactic acid. Salicylic acid, 2% to 20%, is available in collodion-based paints and gels, which dry and form a film from which salicylic acid is absorbed into the skin. In higher concentrations (10%–50%), salicylic acid is used as a plaster that can be cut to fit a wart, corn, or callus. A 2006 Cochrane review suggests that salicylic acid in combination with other agents have the most evidence for first-line use in treatment of warts, but as of the time of writing there has been no study comparing salicylic acid, cryotherapy. and placebo. A cream containing 5% imiquimod and 15% salicylic acid applied five times per week was more effective than cryotherapy in treating plantar warts, and equally efficacious in treating common and plane warts in children at 3 months, with the former treatment generally better tolerated because of no postprocedural pain. A meta-analysis strongly suggested that salicylic acid was particularly efficacious when compounded with 0.5% 5-fluorouracil (5-FU) and was found to be superior to salicylic acid by itself. A modified combination of 2.5% 5-FU and 17% salicylic acid is available in the United States from a compounding pharmacy (WartPeel).

A 2017 Cochrane Systematic Review analyzing interventions for molluscum contagiosum found that salicylic acid may be a useful adjunctive treatment, although overall quality of the studies found was low. A compounded preparation of 10% povidone–iodine and 50% salicylic acid was shown to be effective for all 20 patients with molluscum treated over the course of 26 days.

Scalp Psoriasis and Seborrheic Dermatitis

Many shampoos contain 2% salicylic acid, often with tar and sulfur (see Chapter 51 ) These shampoos are useful in treating psoriasis, seborrheic dermatitis, and ‘cradle cap’ of the scalp. Salicylic acid in ointments and oils, which are usually applied under occlusion, is a useful treatment for thick plaques of scalp psoriasis. A Cochrane review recently published studying efficacy of various treatments of scalp psoriasis found there was insufficient data to adequately assess the role of salicylic acid in the treatment of scalp psoriasis. One study that was included in the Cochrane review suggested that topical corticosteroid (TCS) plus salicylic acid was no more efficacious than TCS monotherapy, but the combination tended to lead to complete clearance of psoriatic scalp plaques more often.

Ichthyosis and Related Conditions

A proprietary compound (Keralyt gel), 6% salicylic acid, 60% propylene glycol, and 20% ethanol, formulated as a gel, is useful in removing thick scales of ichthyosis vulgaris, X-linked ichthyosis, lamellar ichthyosis, and epidermolytic hyperkeratosis, especially when used under occlusion. This gel is also useful in various forms of keratoderma, hyperkeratosis palmaris and plantaris of Unna, pityriasis rubra pilaris, and psoriasis.

Dermatophyte Infections

The keratolytic effect of the above gel (Keralyt) has been credited with clearing three patients with Trichophyton rubrum infection of the sole. Whitfield’s ointment, a time-honored remedy for treatment of tinea infection, contains 6% salicylic acid and 12% benzoic acid in wool fat and petrolatum. The concentrations of salicylic and benzoic acids can be used at half-strength to reduce irritation. Whitfield’s ointment has been largely replaced by more effective and elegant preparations. A 3% salicylic acid preparation that also includes benzoic acid is available as Bensal HP in the United States. A compound of 10% salicylic acid and 20% urea has been useful as a means of avulsing toenails nonsurgically.

Acne

Salicylic acid is believed to have a mild comedolytic effect and is used in acne preparations, including creams, liquid cleansers, astringents, medicated pads, and bar soaps. A meta-analysis of 12 randomized controlled trials demonstrated that salicylic acid, when used as a chemical peel in varying concentrations (10%–30%) as a treatment for acne, was comparable in efficacy and tolerability to trichloroacetic acid, glycolic acid, and additional α-hydroxy acids/fruit acids. Two studies suggest that glycolic acid is more effective for comedonal acne than Jessner’s solution (14% salicylic acid, 14% resorcinol, and 14% lactic acid in ethanol), with potentially improved tolerability.

Psoriasis (Nonscalp)

Salicylic acid is added into topical preparations containing anthralin to prevent its oxidation. The original Lassar’s paste contained 2% salicylic acid, 24% zinc oxide, 24% starch, and 50% white soft paraffin. Compounds duplicating the formulation of the original Lassar’s paste should always be freshly prepared because on standing the ingredients combine to form zinc salicylate. Modern formulations of Lassar’s paste do not contain salicylic acid because of the interaction of salicylic acid and zinc oxide.

Salicylic acid cannot be incorporated into vanishing creams because salicylic acid ‘cracks’ the cream by decomposing the soap needed to form the appropriate emulsion. Although in vitro data suggest that salicylic acid enhances absorption of TCS, this was not confirmed by in vivo studies in animals and human subjects. However, a study comparing the efficacy of mometasone furoate 0.1% combined with salicylic acid 5% in an ointment, versus a stronger corticosteroid (CS) fluocinonide 0.05% ointment, in the treatment of psoriasis showed that the mometasone furoate–salicylic acid combination was more effective. Because of reports of the instability of calcipotriene when mixed with salicylic acid, the compounding of calcipotriene with salicylic acid should be avoided.

Use in Sunscreens

Salicylic acid and related salicylates can be used as sunscreen ingredients (see Chapter 50 ). Salicylates maximally absorb ultraviolet B (UVB) in the range 300 to 310 nm. Topical salicylic acid, which is frequently used in psoriasis, can interfere with UVB phototherapy for psoriasis. Octyl salicylate (2-ethyl hexyl salicylate) and homomenthyl salicylate are used as sunscreen agents in many cosmetic products.

Pruritus and Pain

Salicylic acid is used in antipruritic formulations at a concentration of 1% to 2%. Choline salicylate is used as a topical anesthetic for aphthous ulcers. Methyl salicylate (found in oil of wintergreen) is used for topical musculoskeletal symptomatic pain relief likely to being a counter irritant.

Photoaging—Chemical Peels

Salicylic acid has been used as a peeling agent. Jessner’s solution (14% salicylic acid, 14% resorcinol, and 14% lactic acid in ethanol) is a frequently used superficial peeling agent. Salicylic acid in concentrations of 20% to 30% in a hydroethanolic vehicle (5% water) has gained popularity as a superficial chemical peeling agent for the treatment of acne, photodamage, and hyperpigmentation. The effect of salicylic acid in chemical peeling procedures is thought to be largely related to epidermal injury, which may be similar to injury caused by other chemical peeling agents, and perhaps even lasers and other ablative techniques.

A study involving hairless mice showed that a loss of cornified cells was the only morphologic alteration with salicylic acid (7.5%–30%) peeling, followed by activation of the epidermal basal cells and underlying fibroblasts. The authors concluded that following salicylic acid-induced damage to the cornified layer, biochemical and physiologic changes may occur throughout the whole epidermis and in the superficial dermis. These actions may result in a regenerative effect, especially in more photoaged skin.

A 50% salicylic acid ointment has been used to treat severely photodamaged hands and forearms. At lower concentrations of 1% to 2%, salicylic acid is used as an exfoliant to increase corneocyte shedding and improve the appearance of aged skin. In a controlled study, a 1.5% to 2% salicylic acid proprietary formulation in a moisturizing vehicle resulted in greater improved facial skin appearance, exfoliation of follicular contents, and increased stratum corneum turnover compared with a bland moisturizer and glycolic acid formulations.

Salicylic acid has been shown to be safe and effective to use in Fitzpatrick type IV to V skin for postinflammatory hyperpigmentation, whereas more aggressive treatments may aggravate this condition. When combined with tretinoin 0.1% cream, salicylic acid peel serves as an even more effective method of treating hyperpigmentation in Fitzpatrick types II to IV without significantly worse tolerability.

Actinic Keratoses

Q55.3 Salicylic acid 10% may be combined with 0.5% 5-FU in the treatment of diffuse actinic keratoses. This combination is thought to enhance the penetration of 5-FU attributed to the keratolytic properties of salicylic acid. The tolerability and efficacy of such a regimen has been established in a large patient cohort of over 1000 patients, with 70% overall clearance of actinic keratoses on the head and neck. The efficacy of such a regimen has also been established in anatomic areas where actinic keratoses tend to be more refractory to treatment, such as the arms. This study of 649 patients (treated with the above combination) demonstrated a clearance rate of 92% for actinic keratoses on the upper extremities. The use of this combination has also been applied in a randomized controlled study that included hyperkeratotic actinic keratoses, which, because they are difficult to treat, are not usually included in the clinical trials for field therapy using other agents such as imiquimod 3.75% or ingenol mebutate 0.5%.

Hyperkeratosis

A delivery system for salicylic acid (multivesicular emulsion) was previously available in the united states as a proprietary product called Salex, which used concentric layers of emulsified liquids in an aqueous medium. The multivesicular emulsion is reported to allow for active ingredients to be ‘layered’ or ‘stacked’, and differs from liposomes. In an open observational uncontrolled trial, the multivesicular emulsion salicylic acid 6% cream applied once in the morning, in combination with desoximetasone or mometasone ointment applied in the evening, was reported to improve psoriasis. The same authors also reported that localized hyperkeratosis (i.e., heels/soles, palms/fingers, and elbows) and keratosis pilaris improved when the multivesicular emulsion 6% salicylic acid cream was applied once in the evening in combination with a morning application of a designated moisturizer. As this study was not controlled, the addition of this salicylic acid preparation to provide extra benefit beyond using CS or moisturizers alone for these conditions is not conclusively proven.

Hyperhidrosis

Salicylic acid at a concentration of 2% added to a gel containing 15% aluminum chloride hexahydrate (Hydrosal) was reported to be efficacious and less irritating for the treatment of hyperhidrosis than preparations that contained aluminum chloride hexahydrate without salicylic acid.

Systemic Absorption—Salicylism

Q55.4 When applied topically to the skin, salicylic acid is readily absorbed. If salicylic acid is applied to erythrodermic skin, it can be detected in the urine within 24 hours. Percutaneous absorption of salicylic acid is enhanced by incorporation into hydrophilic ointment, tape stripping of the stratum corneum, or application under occlusion.

Systemic toxicity because of percutaneous absorption of salicylic acid is a rare but potentially serious event ( Box 55.3 ). Salicylates in high concentrations are toxic to the central nervous system. Clinical manifestations of salicylate toxicity include nausea, vomiting, confusion, dizziness, delirium, psychosis, stupor, coma, and death. Tinnitus because of salicylate toxicity is caused by increased labyrinthine pressure and effects on cochlear hair cells, perhaps secondary to vasoconstriction in the auditory microvasculature. With salicylate toxicity, there is stimulation of the medullary respiratory center that causes marked hyperventilation and respiratory alkalosis; in infants and children, metabolic acidosis may also occur. Signs of salicylate toxicity generally occur when blood concentrations exceed 35 mg/dL.