Chronic plaque psoriasis is the most common type of psoriasis [1]. The aim of plaque psoriasis treatments should be the decrease or inducing remission of inflammation, scaling, itching, burning, and sky dryness [2]. Topical therapies are usually tried as first line treatments [3]. Evidence based data show that initial management of chronic plaque psoriasis is made mainly with topical corticosteroids, applied most commonly twice daily [4,5]. However there are several adverse effects of corticosteroids including cutaneous atrophy, rebound after discontinuation of treatment and decreasing response to the drug (tachyphylaxis) [6-8]. For these reasons steroid-sparing therapeutic strategies could be important in the treatment approach of chronic plaque psoriasis [9]. In this regards emollient, keratolytic and moisturizer agents can act as an important adjunctive therapy of topical treatments in psoriatic patients [10]. Salicylic acid and high concentration of urea could be used in the initial keratolytic phase, whereas moisturizing products and emollients are especially suitable in the intermediate phase and the chronic/remission phase of psoriasis [11,12]. Concomitant use of keratolytics and emollients with topical corticosteroids has been demonstrated to be efficacious in plaque psoriasis, improving clinical response with a steroid-sparing effect [13]. However, so far, no trials with objective measurement evaluations, i.e. ultrasound assessment of plaque thickness reduction, of the use of keratolytic/emollient treatment with a topical corticosteroid are available.

Study aim

We evaluated using a pilot intra-patient (left vs. right site) randomized, assessor-blinded, 4-week study design, the efficacy of the combination of hydrocortisone valerate 0.1% cream (HVC) once daily with an emollient, keratolytic, keratoplastic and anti-inflammatory cream (EKC) containing urea 20%, salicylic acid 2% and niacinamide 2% (Iralfaris cream, ISDIN, Spain) once daily vs. HVC alone, applied twice daily, for the treatment of plaque psoriasis by means of ultrasound imaging.

Study design

The present study was a mono-centre prospective, intra-patient, randomised (left vs. right), assessor-blinded trial. Randomisation list with a 1:1 ratio and with a block of 4 was generated by the mean of statistical software (G-Power, Los Angeles, US). Study was performed between March 2013 and September 2013.

Subjects

Patients were enrolled in the trial after their written informed consent according to the Declaration of Helsinki [14]. Study protocol was approved by IRB University of Catania. Fifteen patients (12 M, 3 F, age range: 30-76 years) with mild-to-moderate plaque psoriasis were enrolled. For each patient two symmetrical, target lesions were selected and randomized to receive either HVC+EKC, both applied once daily, (HVC applied in the morning and EKC applied in the afternoon, both applied without occlusion) or HVC alone twice daily (one application in the morning and one application in the afternoon, applied without occlusion) for 4 consecutive weeks. Mean daily amount of HVC for application was 3 grams for the twice daily schedule and 1.5 gram of HVC and 1.5 grams for EKC. Exclusion criteria were: age <18 years, no symmetrical psoriatic lesions, localized palmo-plantar psoriasis, pregnancy, lactation, renal or liver diseases. Patients receiving in the previous six months systemic therapy for psoriasis, such as acitretin or methotrexate or biological compounds, were excluded, as were those who had received any form of topical therapy within the preceding 4 weeks. Additionally, enrolment excluded patients with guttate, erythrodermic or pustular psoriasis.

Study outcomes

The primary efficacy parameter was the reduction of skin thickness by ultrasound evaluation, which was made using a 22 MHz B-mode high-resolution system (EasyScan Echo®, Business Enterprise, Trapani, Italy). A secondary endpoint was the clinical evaluation of a Target Lesion Score (TLS) including degree of erythema, scaling, infiltration and itching with a 5-point scale (0=none, 1=mild, 2=moderate, 3=severe, 4=very severe). Both assessments were performed by an investigator unaware of treatment allocation of the patients (operatorblinded fashion).

Statistical analysis

Statistical analyses were done using SPSS (Statistical Package for Social Science) statistical software (version 13.0). Data were expressed as mean (SD). All P values were two-sided. According to the pilot nature of the present trial, a formal sample size calculation was not performed. However we fixed, in an arbitrary manner, in at least 12 evaluable subjects a reasonable sample size for an intra-patient evaluation. Twotailed Mann–Whitney (unpaired) and Wilcoxon (paired) tests were applied to compare treatments and to compare baseline levels with values at the end of study period. Analysis was based on the intentionto- treat principle and involved all randomised patients. A P-value ≤ 0.05 was considered statistically significant. Data are presented as mean ± SD.

A total of fifteen patients were enrolled in the study. Twelve subjects were randomised and concluded the trial. Three subjects (2 men and 1 woman) not satisfying inclusion criteria were not randomised in the trial. Trial initiated March 2013 with First Patient First visit and was concluded, last patient last visit, September 2013. Patients’ baseline characteristics are summarized in Table 1. Combination therapy with HVC+EKC was as effective as corticosteroid twice daily treatment with a similar reduction of psoriatic skin thickness at week 4 in comparison with baseline (Figure 1) (combination therapy: from 2.59 ± 0.4 mm at baseline to 2.19 ± 0.4 mm at week 4 (a 16% reduction), p=0.005; monotherapy: from 2.56 ± 0.4 mm to 2.14 ± 0.37 mm, (a 16% reduction), p=0.005). No statistically significant differences were observed between the two treatment regimens at the end of the study period (Figure 2). The efficacy results were paralleled by the TLS decrease observed at the end of the study (from 8.8 ± 2.1 to 5.4 ± 2.3 (representing a 39% reduction) in the combination therapy treated sites and from 8.8 ± 2.1 to 5.5 ± 2.2 (representing a 38% reduction) in the mono-therapy treated sites) with no differences between the two treatment regimens (Figure 3). Trial medications were well tolerated. No serious adverse events were observed during the trial. Glucocorticosteroids remain a cornerstone treatment of chronic plaque psoriasis due to their potent anti-inflammatory and antiproliferative effects [15]. However, the same mechanisms of action responsible for the improvement of dermatologic inflammatory conditions can cause adverse effects [16]. Therefore steroid-sparing therapeutic strategies could be important in the treatment of chronic plaque psoriasis. Emollients or moisturizers might act as an effective adjunctive therapy of topical treatments in psoriatic patients. Use of emollient or keratolytic agents in combination with corticosteroid has been shown to be efficacious in the treatment of plaque psoriasis. In particular, emollients are generally used in a supportive role as an addition to topical treatments, to normalise hyperproliferation, differentiation, and to exert antiinflammatory effects [17]. In addition, keratolytic and some moisturizing agents (e.g. urea) could enhance penetration of topically applied antipsoriatic drugs, representing an additional therapeutic rationale for this combination [18]. Watsky et al. [19] in an open study in 96 psoriatic patients have shown that once daily application of both a topical corticosteroid (betamethasone dipropionate) and either a water-in-oil based cream or lotion was significantly better than once daily application of betamethasone dipropionate cream alone. The conclusion of these authors was that water-in-oil emollients could be useful in the therapy of chronic, plaque-type psoriasis providing also a steroid-sparing effect. In 2009 Seite et al. [20] demonstrated that the use of an emollient can limit relapses after the end of corticosteroid therapy, and maintain the improvement obtained after 1 month corticosteroid therapy at clinical level evaluated through a physician global assessment. However, these trials did not use objective measurement evaluations, i.e. ultrasound assessment of plaque thickness reduction, in assessing the efficacy of this combination therapeutic strategy. High-frequency ultrasound (>20 MHz) is a non-invasive imaging technique that has been used both for diagnosis and therapeutic monitoring in psoriasis as well as in other dermatological conditions [21-24]. In our study we evaluated the clinical efficacy of combination therapy (topical corticosteroid once daily plus an emollient/keratolytic anti-inflammatory cream) in comparison with a twice daily corticosteroid application by means of ultrasound assessment of target psoriatic plaque lesions. The emollient/keratolytic and anti-inflammatory cream evaluated in this study contains urea (20%), salicylic acid (2%) and nicotinamide (2%). Salicylic acid is widely used as a keratolytic agent in the treatment of hyperkeratotic skin conditions, especially psoriasis and it is considered one of the most effective keratolytic compounds [25,26]. Urea is a wellknown moisturizing agent. Urea is also known to exert a proteolytic, keratolytic, hydrating, hygroscopic, and antipruritic effect [27]. In addition urea could exert a penetration-enhancement effect when combined with other active compounds, like corticosteroids [28]. Topical niacinamide shows a potent antioxidant and anti-inflammatory effect on the skin [29]. Furthermore, niacinamide could improve skin barrier functions [30]. Therefore this combination has a strong rationale as adjunctive treatment in plaque psoriasis therapy [31]. The results of this pilot study show that combination of corticosteroid and emollient/keratolytic and anti-inflammatory cream, both applied once daily, has similar effects on the plaque thickness reduction as corticosteroid application twice daily, confirming, in an objective manner, the additional beneficial effect and the steroid-sparing action of this approach. Some limitation of the present study should be taken in account in evaluating the results we obtained. This is pilot trial and therefore the results should be confirmed by a larger sample size trial. However the primary outcome was the ultrasound evolution of target plaque psoriasis which should be considered a sensible and objective tool. We decided to perform an intra-patient trial design improving the power of study size. Finally, outcomes of the study have been evaluated in an assessor-blinded fashion, increasing the internal validity of the results. Another limiting aspect of our trial was treatment duration (4 weeks) not allowing us to evaluate and compare safety and tolerability data of the two regimens used. However the primary outcome of the trial was efficacy and 4 week period is in general the appropriate duration in order to evaluate therapeutic efficacy of a topical regimen in plaque psoriasis.

Figure 1: Clinical and ultrasound evolution of a target lesion: a study case.

Figure 2: Evolution of target plaque thickness evaluated by ultrasound.

Figure 3: Evolution of clinical Target Lesions Score.

Table 1: Patients characteristics at baseline.

Combination therapy (HVC+EKC) was as effective as monotherapy (HVC) twice daily with a similar reduction, objectively evaluated, of skin thickness at week 4 in comparisons with baseline. The efficacy results were paralleled by the clinical evaluation of Target Lesion Score. Our results confirm that the concomitant use of a keratolytic, emollients and anti-inflammatory cream with topical corticosteroid is efficacious in plaque psoriasis, with a steroid-sparing effect.

The present project was partially funded by a grant from ISDIN. The sponsor had no role in the study design and conduct, and was not involved in the collection, analysis, and interpretation of data. Massimo Milani is an employee of ISDIN.