From systematic literature searches conducted in Medline via PubMed and EMBASE, a total of 49 publications met the inclusion criteria for this review. Furthermore, the reference lists of included publications were scrutinized for additional studies published in January 1983 or later, adding 11 publications to the selection. Thus, a total of 60 publications were reviewed.
Emollients induce an occlusive film that limits evaporation of water from deeper parts of the skin and allows the stratum corneum to rehydrate itself. The application of natural moisturizing factors induces an increase in the water-binding capacity of the stratum corneum . Regular application of emollients improves comfort and reduces scaling, fissuring , and itching in patients with plaque or scalp psoriasis [25, 26]. Additionally, emollients may increase the efficacy of topical corticosteroids by improving the penetration through the skin layers [21, 27, 28]. Guidelines of care for the management of psoriasis and psoriatic arthritis state that when used as a control in topical steroid trials, non-medicated topical moisturizers demonstrated a response rate ranging from 15 to 47% [21, 27]. This broad range may reflect the great variability of their composition; however, in the corresponding guideline dealing with topical therapies, the individual composition of the moisturizers has not been specified . Emollients are usually well tolerated . However, they can cause side effects such as irritant dermatitis, allergic contact dermatitis, fragrance allergy or allergy to other constituents, stinging, cosmetic acne, and pigmentary disorders . In addition, some reports indicate a potential penetration-enhancing effect of the stratum corneum to irritants after long-term use . In clinical and experimental settings it has been shown that some emollients, e.g., oil-in-water emollient enhance the penetration of UVA or UVB when used before irradiation, thus increasing the efficacy of phototherapy [29, 30]. However, in vitro studies and studies in healthy volunteers also demonstrated a blocking effect of other emollients, such as white petrolatum  and the emollient cream Eucerin (Beiersdorf Inc., Wilton, CT, USA), consistent with their thickness .
While 3 small clinical trials including a total of 111 patients provide limited evidence that, compared to baseline, emollients used as a monotherapy may improve skin hydration, barrier function, as well as proliferation and differentiation markers in patients with psoriasis [11, 33, 34], the clinical response showed only a slight symptomatic improvement of psoriasis . Due to inconsistent results from randomized controlled trials, there is limited evidence of a steroid-sparing effect of emollients when used in combination with corticosteroids. In the evaluated studies, only two adverse events of pruritus and folliculitis (each n = 1) were reported (see Table 2) [11, 33–37].
Urea is known to exert proteolytic, keratolytic, hydrating, hygroscopic, penetration-enhancing, epidermis-thinning, and anti-pruritic effects. The moisturizing action of urea in dry and scaly skin conditions has been widely studied and is well accepted [21, 38]. Fluhr et al.  suggested that lipid biosynthesis may be increased by topical application of highly concentrated urea. In vitro and in vivo data showed a reduction of DNA synthesis in the cells of the basal layers (by approximately 45%), a thinning of the epidermis (by approximately 20%), a reduction of the epidermal cells, and a prolongation of the generation time of postmitotic epidermal cells [21, 39]. Therefore, urea has been shown to reduce epidermal hyperproliferation and to induce cell differentiation . As a mechanism of action it has been hypothesized that urea may break hydrogen bonds and interfere with the quaternary structure of keratin thus dispersing and denaturizing keratin without disrupting the epidermal water barrier. Pre-treatment or concomitant treatment with urea may also enhance the efficacy of other topical therapies . Due to its safety, urea-containing preparations represent the standard in the adjuvant therapy of juvenile psoriasis . Only non-systemic side effects have been reported, with mild irritation being the most common, making urea a safe and well-tolerated topical drug .
While a small, older comparative study found no statistical differences on severity parameters such as scaling, erythema, and infiltration compared to the vehicle , in another trial using the same preparation, treatment for 1 week led to a statistically significant improvement of scaling compared to the vehicle (see Table 3) [38, 40–46]. This is in line with two further studies in which severity parameters of psoriasis such as scaling and/or induration were reduced with urea in monotherapy . Of these, in a small randomized, double-blind study, addition of 10% urea to the vehicle was significantly more effective regarding epidermal proliferation, stratum corneum hydration, and epidermal thickness with a 60% reduction of the clinical psoriasis severity score of scaling and a 32% reduction of induration (see Table 3) compared to the vehicle alone . The ointment base also improved psoriasis, but urea was significantly more effective showing a 40% reduction in epidermal proliferation compared to the vehicle . Similar results were demonstrated in a double-blind, placebo-controlled study, in which two urea gel formulations (10% plain urea gel or 5% urea niosomal gel) produced a reduction in erythema, infiltration, and desquamation, as well as in the total psoriasis area and severity index (PASI) score, with the 5% urea niosomal gel being more effective regarding desquamation compared to the plain gel and placebo. However, the percentage of affected area was not influenced . From three small studies, limited evidence is known for an enhanced efficacy of other topical agents such as bifonazole, dithranol or betamethasone dipropionate and calcipotriol leading to a shortened treatment duration (see Table 3) [43–45]. In the evaluated clinical studies, a burning sensation was observed in three patients (see Table 3) [39, 42].
Alpha-Hydroxy Acids and Poly-Hydroxy Acids
Alpha-hydroxy acids (AHAs), most notably glycolic acid and lactic acid, are used in chemical-peel solutions to exfoliate thickened skin in hyperkeratotic conditions. However, their use in the treatment of psoriasis has only recently been advocated and, thus, they are not mentioned as keratolytic agents in relevant psoriasis guidelines [7, 17]. AHAs penetrate the epidermis, inducing an increase in stratum corneum turnover and cause desquamation of the outermost layer without impairing barrier function . They reduce intercorneocyte bonds by increasing the distance between corneocytes due to increased stratum corneum water content, by reducing the charges on the surface of cells, by inhibiting enzymes involved in the cohesion between corneocytes, and by breaking desmosomes as they diminish the pH of the medium. This reduction can also degrade keratinocytes directly, thus promoting cell proliferation. In the dermis, AHAs can stimulate the biosynthesis of glycosaminoglycans, collagen, and other substances, which cause thickening of the skin . Poly-hydroxy acids (PHAs) also aid in dermal expansion and can provide the components for glycosaminoglycans. PHAs have anti-oxidant and moisturizing properties and may provide protection of psoriatic skin with a disrupted skin barrier. When used in combination with topical corticosteroids, AHAs or PHAs exert a synergistic effect and reduce steroid-induced skin atrophy .
For AHAs and PHAs, results from 3 small clinical studies including 57 patients in total are available. One of these trials, a small, controlled study, demonstrated that glycolic acid in monotherapy may lead to significant reduction in hyperkeratosis and erythema as compared to baseline, which was comparable to that achieved with 0.05% betamethasone valerate (see Table 4) [3, 47, 48]. In a small, short-term study, AHA/PHA and salicylic acid exhibited similar efficacy with regard to the reduction of scaling when compared to baseline (see Table 4) . The third small study found a synergistic effect of 10% glycolic acid in combination with topical corticosteroids leading to reduced treatment duration and an increased healing rate (see Table 4) . In the evaluated studies, no treatment-related adverse events were reported (see Table 4).
Salicylic acid is the most commonly used and most thoroughly studied of the currently known keratolytic compounds . In concentrations of 5% and above, it exerts an increasingly potent, rapid, and deep keratolytic effect on the stratum corneum which leads to descaling . As a mechanism of action, it is suggested that salicylic acid reduces intercellular cohesion between corneocytes by dissolving the intercellular cement material and reducing the pH of the stratum corneum, thereby increasing hydration and softening [3, 7, 31]. Topical salicylates also reduce pruritus  and, at concentrations of ≥0.3%, they possess bacteriostatic and bactericidal activity against yeast and Gram-negative and Gram-positive bacteria . In their clinical guide, Naldi and Rzany  state that there is consensus that salicylic acid is an effective initial and adjunctive treatment in chronic plaque psoriasis. It is most beneficial in extremely thick or scaly psoriatic plaques . According to current guidelines, salicylic acid promotes skin availability of other topical therapies including topical corticosteroids due to its keratolytic and penetration-enhancing effect [1, 7, 14, 20, 49]. This leads to improved efficacy of other topical treatments. While salicylic acid is commonly applied and effective when used as a pre-treatment before phototherapy [15, 16], topically administered salicylic acid, in concentrations ≥0.1%, is photoprotective . Thus, application of salicylic acid before UVB phototherapy is not recommended [15, 16, 22, 32, 50, 51]. According to the evaluated reviews, topical use of salicylic acid is limited by the risk of chronic or acute systemic intoxication [2, 7] with symptoms such as oral pain, headache, central nervous system symptoms, dizziness, metabolic acidosis, tinnitus, nausea, vomiting, and gastric symptoms, as well as hyperventilation [2, 3, 52]. These symptoms may occur after prolonged topical treatment of large body surfaces (i.e., >20%) [6, 7, 25], especially in children under 12 years of age and in patients with significant renal or hepatic impairment [2, 3, 7, 22, 25]. Local irritation such as stinging, burning, dry skin, peeling, scaling, or contact dermatitis was also reported [1, 9, 53]. Temporary shedding of telogen hair has been observed when used in the treatment of scalp psoriasis . Concomitant use of other drugs, which may contribute to elevated serum salicylate levels, should be avoided . There is an increased risk for developing toxicity to other topically applied agents used concurrently, as salicylic acid may increase their skin penetration . In addition, topical use of salicylic acid can reduce the efficacy of calcipotriol .
Regarding monotherapy, three studies on salicylic acid including 65 patients were evaluated [54–56]. Of these, an open-label, pilot study demonstrated that 6% salicylic acid used as a monotherapy was highly effective, well tolerated, and acceptable in 10 patients with scalp psoriasis . All psoriasis severity parameters as well as the percentage of affected area were reduced with a significant decrease in Psoriasis Scalp Severity Index score from 15.3 to 3.0 after 4 weeks of monotherapy when compared to baseline (P < 0.001). A total of 60% of patients were either “completely cleared” or “almost cleared” (see Table 5) . In a randomized, double-blind study in 25 patients investigating 6% salicylic acid vs. 20% AHA/PHA cream (see also Table 4), both topical agents resulted in significant improvement of scaling, erythema, and induration, as well as investigator global assessment, at the end of week 1 and 2 and exhibited similar efficacy in reducing scaling. However, the extent of affected area was not investigated in this study (see Table 5) . Similar results were obtained in an earlier, randomized controlled trial reporting successful treatment of moderate or severe scalp psoriasis with 6% salicylic acid in 30 patients, including 10 in-patients and 20 out-patients . In-patients were treated for 3 weeks with daily applications of 6% salicylic acid removed with a shampoo 24 h later. Out-patients were treated for 6 weeks with salicylic acid applied once daily and removed 12 h later. If progress was slow, a shampoo containing 3% coal tar solution was substituted for the shampoo. As a result, 90% of in-patients and 65% of out-patients improved with salicylic acid regarding scaling and percentage of affected area and in one patient, the scalp cleared completely. Scaling scores for out-patients improved from baseline 7.0 to 4.5 at 6 weeks (n = 20; P < 0.01) and the scores for in-patients improved from baseline 7.7 to a score of 3.7 at 3 weeks (n = 10; P < 0.001). Eight of the out-patients, but none of the in-patients used the coal tar shampoo. Out-patients used less salicylic acid (27 g weekly) than in-patients (72 g weekly; see Table 5) .
Concerning combination therapy with the super-potent or potent corticosteroids betamethasone dipropionate and mometasonefuroate, 5 randomized controlled trials in a total of 1,248 patients were identified. Patients with psoriasis were treated for up to 3 weeks with a combination of 2% salicylic acid and 0.05% betamethasone dipropionate (2 studies; n = 72) or 5% salicylic acid and 0.1% mometasonefuroate (3 studies; n = 519). The respective control groups received the corresponding corticosteroid only. In one study, a more rapid onset of action and a more rapid clearing of scaling, pruritus, and inflammation was demonstrated with the combination ; whereas in another trial, the combination was statistically more effective than the respective corticosteroid alone in terms of mean total disease sign scores beginning at day 8 (P = 0.05) and continuing through days 15 and 22 (P < 0.01) . This is also reflected in the individual sign scores: the combination was significantly more effective than the corticosteroid alone for scaling starting on day 8 (P = 0.01), erythema (P < 0.02), and pruritus on day 14 (P < 0.01) as well as induration on day 15 (P = 0.03), with P ≤ 0.01 for all three signs of psoriasis (erythema, induration and scaling) at day 22 [46, 57]. According to the investigators’ global evaluation of overall clinical response, patients treated with the combination showed a better progress than those treated with the corticosteroid alone (P < 0.01) . After 7 days of treatment, a significantly greater reduction of the Psoriasis Area Severity Index score was observed compared to the corticosteroid alone (P = 0.0017). Regarding the items of the Dermatology Life Quality Index (DLQI) questionnaire, data showed significant differences in the ‘symptoms and feelings’ (P = 0.0464) and the ‘personal relationships’ items (P = 0.0378) . On the self-assessment questionnaire, patients preferred the combination over the corticosteroid alone for overall improvement of general appearance and overall improvement of psoriasis (both P = 0.03; see Table 5) . In the evaluated studies, no systemic toxicity was observed and absorption of salicylate was negligible after application of 6% to the scalp . Yet application-site reactions such as dryness, irritation, burning, pruritus, and skin atrophy were reported (see Table 5) [46, 55, 58, 59].