F or more than 2,000 years, salicylic acid has been used to treat a variety of medical disorders. Originally derived as a component of the extract of willow tree bark (Salix spp.),1-3 salicylic acid (2-hydroxybenzoic acid, orthohydrobenzoic acid) is well-established as a “keratolytic” agent and is beneficial in managing hyperkeratotic skin disorders when used in adequate concentration. Topical salicylic acid is also effective in treating chronic plaque psoriasis, especially when used as adjunctive therapy. This article will offer a review of available data on the clinical use of topical salicylic acid. Also included are reports of observational experience evaluating the efficacy and safety of salicylic acid 6% formulated in a multivesicular emulsion cream used as treatment for chronic plaque psoriasis and localized hyperkeratotic lesions. This article also provides an assessment of the adjunctive benefit of salicylic acid 6% cream when combined with other topical therapies. A Closer Look at Salicylic Acid In 1829 when first derived from willow tree bark, the extract was shown to contain both salicin and salicylic acid. Since then, salicylic acid has also been found in oil of wintergreen and sweet birch. In the mid-1860s, chemists developed methodology to synthesize salicylic acid producing a white, crystalline powder available for several decades for use in compounding of topical products.1-3 Although some have labeled salicylic acid as a beta-hydroxyacid, it is more correctly categorized as a phenolic aromatic acid, which is due to both carboxyl and hydroxyl radicals attached to a benzene ring.4,5 When salicylic acid was first used in dermatology, the agent was suspected to have antibacterial properties. However, limited documentation exists to support this use.1,2 Over time, dermatologists observed that salicylic acid may be used to treat callosities and “corns,” and other disorders associated with hyperkeratosis (ichthyoses, keratoderma, verruca, and other conditions). Salicylic acid proved useful for these applications because of its ability to soften and exfoliate the stratum corneum.1-3,6-8 Although not found to be as potent as tretinoin, salicylic acid exhibits comedolytic activity and has proven applications for treating acne vulgaris, which it has been used for since the 1950s and is still presently used for in some formulations.9 Using salicylic acid as an adjunctive topical therapy for treatment of psoriasis has been well established.2,10 In addition, there is both in vitro and clinical evidence that salicylic acid augments the efficacy of concurrently used topical corticosteroid therapy for treating plaque psoriasis.2,10,11 In a study of patients with psoriasis comparing twice daily application of either monotherapy with fluocinonide 0.05% ointment or the combination of an ointment containing mometasone furoate 0.1% and salicylic acid 5%, the combination regimen proved to be more efficacious.11 Unlike salicylic acid, urea has been shown to cause chemical degradation of some topical corticosteroids, including brand formulations of hydrocortisone valerate, desoximetasone and triamcinolone acetonide.12 Using salicylic acid and calcipotriene concurrently is not recommended because calcipotriene becomes unstable when mixed with salicylic acid, ammonium lactate and some corticosteroids.13,14 Additional applications for which topical salicylic acid may be effective include keratosis pilaris, palmar and plantar keratodermas, plantar hyperkeratosis (for example, keratoderma climactericum), verruca, seborrheic dermatitis, photodamage and hyperpigmentation. Different concentrations, and in some cases vehicle formulations, of salicylic acid are recommended for use in specific entities due to dose-dependent response.1-3,7,15,16 Salicylic acid is commonly used as a component of shampoos for seborrheic dermatitis or psoriasis vulgaris affecting the scalp, and it is found in several “time-honored” combination formulations, such as Whitfield’s ointment, Lassar’s paste and peeling agents (i.e. Jessner’s solution).1,2,7 Mechanisms of Action and Activity of Topical Salicylic Acid Although the mechanism of action of topical salicylic acid is not fully understood, available data suggest that three factors play a significant role. These include reduction in corneocyte adhesion, intercellular cement solubilization and detachment of corneocytes.2,3,17-20 Although salicylic acid has no effect on mitotic activity of epidermal cells, the following have been observed: 1. stratum corneum thinning without loss of human epidermal thickness, 2. decreased keratinocyte hyperplasia in animal models,17,19 3. anti-inflammatory properties.2,7 Although salicylic acid is commonly referred to as “keratolytic,” this terminology is not accurate from a scientific perspective. In fact, the application of salicylic acid does not lead to alteration or breakage of keratin filaments and appears to disrupt at cellular junctions of corneocytes (desmosome structures).3,20,21 As opposed to keratolytic, the term desmolytic has been suggested as a more accurate reflection of the mode of action of topical salicylic acid.3 Recognized study methods using transmission electron microscopy and freeze fracture techniques performed on strippings and human skin biopsies indicate that salicylic acid induces degradation of corneodesmosomal attachments.3,21 Unlike some salicylate derivatives, salicylic acid appears to act uniformly within the overall thickness of the stratum corneum, producing a fragmentation of corneodesmosomes and denaturation of membrane-crossing glycoproteins.3 Fragments of peripheral corneosomes are observed on electron microscopy to be attached to corneocytes on opposite sides, which demonstrates a desmolytic effect.3,21 Ultimately, when salicylic acid is topically applied for treatment of disorders characterized by abnormal desquamation with “corneocyte clumping,” the end result is reduced corneocyte adhesion and normalization of epidermal shedding (physiologic exfoliation).2,3 In multiple hyperkeratotic conditions characterized by a dry, fissured and/or thickened stratum corneum, topical salicylic acid may thin and “normalize” corneocyte organization within a few weeks.3,22 The desmolytic effect of salicylic acid is dose-dependent with concentrations of 2% to 3% used for disorders such as xerosis and seborrheic dermatitis, 6% used for more severe xerosis, ichthyosiform disorders, localized hyperkeratosis (for example the palms and soles) and keratosis pilaris, and 17% used for verruca.2,3 Exploring a Novel Cream Formulation of Topical Salicylic Acid: “The Microvesicular Emulsion” A new patented topical delivery system, the multivesicular emulsion (MVE), employs sophisticated formulation technology utilizing concentric layers of emulsified lipids in an aqueous medium.23,24 Thus far in the marketplace, this technology has been applied to specific brand formulations of salicylic acid 6% cream (Salex Cream) and lotion (Salex Lotion). Multivesicular refers to “vesicles within vesicles, within vesicles and so on,” which differs from liposomes. The multivesicular technology allows for active ingredients to be “layered” or “stacked,” including multiple active ingredients if desired. The incorporated ingredients may be water-soluble or oil-soluble. In addition, individual ingredients may be incorporated into the MVE vehicle with different release characteristics over time. A single application of an MVE-based lotion was shown to significantly reduce transepidermal water loss (TEWL), indicating the ability of the emulsion to promote repair of epidermal barrier function.24 Observational Experience In order to evaluate the clinical efficacy and tolerability of a new formulation of salicylic acid 6% multivesicular emulsion cream (Salex Cream), an open observational trial was initiated at two private dermatology offices. Included were patients treated for chronic plaque psoriasis vulgaris, localized hyperkeratosis (palms, soles, heels and/or elbows), and keratosis pilaris (arms and/or thighs). Patient Selection. A total of 70 adult patients (age range 18 to 68 years) were included in an evaluation of treatment with salicylic acid 6% cream applied once daily. To review details regarding the patients who were enrolled in the study, see Table 1 titled “Patient Characteristics at a Glance.” Psoriasis. Patients (n = 15) enrolled with psoriasis vulgaris presented with symmetrically distributed erythematous scaly plaques that in most cases were only partially responsive to mid- or high-potency topical corticosteroid therapy or were refractory despite at least 16 weeks of systemic treatment (for example, etanercept and acitretin). The mean duration of psoriasis was 13 years (range 5 to 22 years). At the start of the trial, all patients were currently utilizing topical corticosteroid therapy with either desoximetasone ointment (n = 8) or mometasone furoate 0.1% ointment (n = 7) once or twice a day at affected sites for at least 8 weeks. Upon enrollment at baseline, patients underwent treatment on one affected side (elbows - 4 patients; knees - 4 patients; legs - 7 patients) with desoximetasone ointment once daily in the evening and a designated moisturizer once daily in the morning. On the other side, the same topical corticosteroid was applied in the evening and salicylic acid 6% cream was applied in the morning. No washout period was used prior to trial initiation in the psoriasis patient group. Patients were followed at 4-week intervals over a duration of 8 weeks. Localized Hyperkeratosis. Patients (n = 35) were enrolled with localized hyperkeratosis; sites included were heels/soles (n = 35), palms/fingers (n = 2) and elbows (n = 2). None of the patients had utilized prescribed therapy for the affected areas of hyperkeratosis. All had tried a variety of over-the-counter moisturizers in the past with little to no benefit, although none had been used for at least 2 weeks prior to study initiation. All patients were instructed to apply salicylic acid 6% cream in the evening and a designated moisturizer in the morning. Keratosis Pilaris. Patients (n = 20) were enrolled with keratosis pilaris; sites included were the posterior-lateral arms (n = 20) and anterior-lateral thighs (n = 6). None of the patients had utilized prescribed therapy for keratosis pilaris. Twelve had tried a variety of over-the-counter moisturizers in the past with little to no benefit, although none had been used for at least 4 weeks prior to study initiation. All patients were instructed to apply salicylic acid 6% cream in the evening and a designated moisturizer in the morning. Investigator Evaluation of Response (Table 2). At each visit, the investigator graded whether the status of the skin disorder under evaluation worsened, was unchanged, was mildly improved, moderately improved, significantly improved (almost clear) or completely improved (completely clear). For psoriasis, the rating was based on assessment of erythema intensity, degree of scaling, and plaque thickness. For localized hyperkeratosis and keratosis pilaris, grading of improvement was based on a combination of visible and tactile assessment; both parameters would need to achieve a given degree of improvement to be rated at that level. If both these two parameters were not met, then the next lower rating of improvement was reported. Also recorded was the presence of adverse skin reactions such as increased erythema, dryness or scaling. Photos 1A and 1B and photos 2A and 2B depict effective treatment of localized hyperkeratosis of the heels in an adult female and elbows in an adult male, respectively. See the table titled “Investigators’ Assessment of Clinical Outcomes” for specific results based on investigator observation. Patient Evaluation of Response (Table 3). At each visit, patients independently rated whether their skin conditions were unchanged, were mildly improved, moderately improved, significantly improved (almost clear) or completely improved (completely clear). Patients were instructed to make their determination based on their own feeling regarding overall level of visible and tactile improvement. Any adverse reactions, such as stinging, burning, pruritus or dryness, were documented. All study participants were asked about their perception of the cosmetic acceptability of the salicylic acid 6% cream. See the table titled “Patients’ Assessment of Clinical Outcomes” for specific results based on patient observation. How Is Salicylic Acid 6% Cream Cosmetically Accepted? All participants were questioned at study endpoint regarding the cosmetic acceptability of the salicylic acid 6% cream. Parameters evaluated were as follows: 1. ease of spreadability 2. “feel” on the skin after application 3. lack of residue 4. lack of odor 5. lack of stickiness 6. lack of dryness 7. willingness to continue use. Parameters one through six were rated as “excellent,” “very good,” “good,” “fair” or “poor,” and parameter 7 was recorded as a “yes” or “no” response. All study participants (70/70) reported that the salicylic acid 6% cream was a product that they would continue to use. Every patient (70/70) rated ease of spreadability (“feel” on the skin after application and lack of residue) as excellent or very good; no patients detected an odor (excellent rating). Three patients detected a mild stickiness and five patients detected a sense of mild skin dryness after use; the remainder rated lack of stickiness (67/70) and lack of dryness (65/70) as excellent or very good. The overall tolerability of salicylic acid 6% cream was highly favorable. With regard to adverse events related to skin tolerability, two patients noted a stinging sensation within the first few minutes of application of salicylic acid 6% cream. Both patients exhibited superficial skin fissures (one patient each with hyperkeratosis involving the fingers and heels). In both cases, the stinging reactions dissipated after approximately 10 to 15 minutes and eventually stopped occurring after the first week of use. No patients discontinued treatment, and there were no systemic adverse reactions reported during the observational study period. Points to Remember As discussed, salicylic acid has many treatment applications and advantages. Some of the highlights mentioned in this article are as follows: • Salicylic acid is a well-established topical agent that efficaciously treats a variety of dermatoses associated with hyperkeratosis, including chronic plaque psoriasis, ichthyosis, localized hyperkeratosis (for example on the hands, feet and elbows) and keratosis pilaris. • This report of observational experience supports that salicylic acid 6% cream applied once daily is an effective, well-tolerated and cosmetically acceptable option for the treatment of psoriasis vulgaris, localized hyperkeratosis and keratosis pilaris. Specifically, some of the findings included the following: • For plaque psoriasis, the addition of salicylic acid 6% cream to topical corticosteroid therapy resulted in 66.6% (10/15) of patients being graded as at least “significantly improved” by investigator evaluation at 8 weeks. • For localized hyperkeratosis (predominantly of plantar surfaces and heels), 69.2% (27/39) and 82% (32/39) of treated sites were rated by investigators to be at least “significantly improved” after 4 and 8 weeks, respectively. • For keratosis pilaris, the investigator graded treated sites to be at least “significantly improved” for 61.5% (16/26) and 69.2% (18/26) of sites at weeks 4 and 8, respectively. Patient ratings indicating at least “moderately improved” at weeks 4 and 8 were 80.7% (21/26) and 96.2% (25/26) of treated sites, respectively. • Patient assessments were very similar to investigator evaluations at weeks 4 and 8 for all three disease entities. • 100% of patients reported that they would continue use of salicylic acid 6% cream. Cosmetic acceptability parameters were rated predominantly as “excellent” or “very good.” Favorable safety and local skin tolerability were observed throughout the trial. • A major mechanism of action of topical salicylic acid is reduction of corneocyte adhesion through disruption of corneodesmosomes (“desmolytic effect”). Salicylic acid does not induce alteration of keratin filaments. • The microvesicular emulsion technology used to formulate a specific brand of salicylic acid 6% cream provides a novel and cosmetically acceptable delivery system, which contributes to epidermal barrier repair.