DOI: 10.1111/jdv.16559 JEADV ORIGINAL ARTICLE Non-invasive clinical and microscopic evaluation of the response to treatment with clobetasol cream vs. calcipotriol/betamethasone dipropionate foam in mild to moderate plaque psoriasis: an investigator-initiated, phase IV, unicentric, open, randomized clinical trial lamos,1,3,4,* O. Ye B. Alejo,1 S. S. Ertekin,1 L. Villa-Crespo,1 S. Zamora-Barquero,1 N. Martinez,1 M. Domınguez,1 P. Iglesias,1 A. Herrero,1 J. Malvehy,2 S. Puig2 1 Dermatology Department, Hospital Clınic, Institut d’Investigacions Biomediques August Pi i Sunyer,Universitat de Barcelona, Barcelona, Spain 2 CIBER de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain 3 Department of Dermatology, Hospital de la Santa Creu i Sant Pau,Universitat Auto noma de Barcelona, Spain 4 Department of Dermatology, Centro Medico Teknon – Quiro nsalud, Barcelona, Spain *Correspondence: O. Yelamos. E-mail: oyelamos@gmail.com Abstract Background Treatment response for psoriasis is typically evaluated using clinical scores. However, patients can relapse after clinical clearance, suggesting persistent inflammation. Dermoscopy, reflectance confocal microscopy (RCM) and optical coherence tomography (OCT) can non-invasively improve treatment response assessment. Objectives To compare the clinical and non-invasive microscopic features in a psoriatic target lesion treated with clo- betasol cream or calcipotriol/betamethasone dipropionate foam (Cal/BD foam). Methods Prospective, unicentric, open, randomized clinical trial comparing clinical data [total clinical score (TCS)] and microscopic data (dermoscopy, RCM and OCT) in psoriasis patients treated with clobetasol or Cal/BD foam. Results We included 36 adult patients (22 men). At week 4, more patients treated with Cal/BD foam achieved TCS ≤1 than with clobetasol (63.2% vs. 18.8%, P = 0.016). Treatment satisfaction was higher with Cal/BD foam (P < 0.03). Microscopically, Cal/BD foam induced more reduction in epidermal thickness at week 4 (P < 0.049). Dilated horizontal blood vessels were more common with clobetasol than with Cal/BD foam at week 8 (69.2% vs. 31.2%, P = 0.159). If epi- dermal hyperplasia was noted at baseline, the response was poorer with clobetasol (P = 0.029). Limitations Small sample size, open study, imaging sampling bias. Conclusion Cal/BD foam is more effective than clobetasol, has better patient satisfaction and induces greater reduc- tion in the hyperkeratosis/acanthosis, regardless of baseline epidermal hyperplasia. Received: 1 March 2020; Accepted: 10 April 2020 Conflicts of interest OY has served as a consultant to Almirall and has received honoraria for this. JM has served as a consultant to Almirall, Amgen, Canfield and Pierre Fabre and has received honoraria for this. PI has served as a consultant to Almirall and has received honoraria for this. SP has served as a consultant to Almirall, Avene, ISDIN, La Roche Posay and Leo Pharma, and has received honoraria for this. The other authors do not have conflicts of interest relevant to the current manuscript. Funding source This research was funded by Leo Pharma. The sponsor did not influence on the study design or planning. Introduction severity index (PASI) or physician global assessment (PGA). The effectiveness of topical treatments for plaque psoriasis is However, sometimes patients relapse short after withdrawing typically evaluated using clinical scores such as psoriasis area their treatments besides showing clinical clearance using these scores, thus suggesting persistence of underlying inflammation IRB: This study was performed under the Hospital Clınic de not visible to the naked eye. In addition, classical topical treat- Barcelona’s Ethics Committee-approved protocol number HC-ENS-2017-01. ments such as potent corticosteroids can lead to side-effects if JEADV 2021, 35, 143–149 © 2020 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. 144 lamos et al. Ye used for long periods of time, which are difficult to anticipate discontinued. At the last visit, patients were also asked to rate when using conventional clinical examination. In this sense, their treatment satisfaction using a Visual Analogic Scale from 0 ancillary tests, ideally non-invasive ones, may help evaluate the to 10, being 0 very dissatisfied and 10 extremely satisfied. treatment response and assess the side-effects. Non-invasive imaging technologies such as dermoscopy, Microscopic evaluation reflectance confocal microscopy (RCM) or optical coherence We obtained dermoscopic pictures using DermLite Foto (3Gen, tomography (OCT) have been extensively used to diagnose skin San Juan Capistrano, CA, USA), handheld RCM images (Vivas- cancers1–6 and to assess skin cancer treatment responses.7–9 Since cope 3000; MAVIG/Caliber ID, Rochester, NY, USA) and these technologies allow the visualization of structures not visi- dynamic OCT image rasters (Vivosight, Michelson Diagnostics, ble with the naked eye and have direct histopathological corre- Maidstone, UK) at the centre of the target lesion. The images lates,10–12 they seem ideal to better define the effective clearance were later evaluated by three investigators (SE, LC and SZ), who and assess the side-effects in psoriatic patients undergoing topi- did not collect the images, and were blinded to the treatment cal treatments. arm. The imaging features evaluated are summarized in Table S3 The current study aims to describe and compare the clinical and included quantitative variables and semiquantitative vari- and non-invasive microscopic features in a psoriatic target lesion ables (0–3). The definition of the features evaluated can be in a prospective cohort of psoriatic patients before, during and found elsewhere.13 after the treatment with two topical treatments for mild to mod- erate psoriasis: clobetasol cream vs. a fixed combination of cal- Sample size calculation and statistical analysis cipotriol/betamethasone dipropionate foam (Cal/BD foam). A sample size of 16 patients in each group was determined in order to detect differences of two units (SD = 2.25) in the Materials and methods reduction of plaque psoriasis descriptors (TCS) between both After approval of the Ethics Committee of Hospital Clınic de groups. We considered a power of 80% and a significance level Barcelona, from March 2018 to March 2019, we prospectively of 0.05. Considering a loss of evaluable individuals (loss of fol- included consecutive patients with mild to moderate plaque pso- low-up, missing data, etc.) of 10%, a total of 18 patients in each riasis who were amenable to be treated with topical treatments group (36 patients in total) were deemed necessary to achieve [total body surface area (BSA) <10%]. Inclusion and exclusion statistically significant results. criteria are found in Tables S1 and S2. Descriptive statistics were used to describe the distribution of After written informed consent, patients were randomized 1:1 clinical and microscopic data. Fisher’s exact test was used to using a predefined randomization table to apply clobetasol cream compare qualitative variables. Mann–Whitney test was used to 0.5 mg/g (Clovateâ; Industrial Farmaceutica Cantabria, San- compare quantitative and qualitative variables that were not tander, Spain) once daily 2–4 weeks according to clinical response normally distributed. Two-sided P values <0.05% were consid- or Cal/BD foam 50 µg/g + 0.5 mg/g (Enstilarâ; LEO Pharma, ered statistically significant. Analyses were performed using SPSS Copenhagen, Denmark) once daily for 4 weeks. The treatment Statistics v. 22 (IBM Corporation, Armonk, NY, USA). arm was not blind since the researchers randomizing and following the patients (OY, NM), and the patients knew the treatment. These Results same researchers decided whether it was necessary to continue or stop the treatment based on clinical response and/or the presence Cohort characteristics of adverse events. Patients were evaluated at baseline, at week 2, at We included 36 patients (22 men, 14 women) with a median age week 4 and at week 8 (1 month without treatment) (Fig. S1). of 47.5 years (range 28–80 years) (Table 1). The median weight, height, abdominal perimeter and body mass index were 75.5 kg Clinical evaluation (range 49–103 kg), 170 cm (range 152–185 cm), 96 cm (range We obtained high-resolution clinical pictures (Canon Powershot 65–117 cm) and 24.94 kg/m2 (range 18.81–38.1 kg/m2), respec- G15, Canon Inc, Tokyo, Japan) of the patient’s most severe pla- tively. Regarding treatments in the previous 4 months, three que at baseline. Later, pictures were obtained at the same location patients had only used emollients, two had received photother- using the same camera settings and illumination parameters. Fur- apy, and 30 patients used one or more topical treatments. thermore, based on these images, we determined the Total Clini- The majority of the target lesions were located on the elbows cal Score (TCS), which grades erythema (0–3), induration (0–3) (n = 15) followed by the buttocks/lumbosacral area (n = 8), the and scaling (0–3). The image evaluation was performed at the end abdomen (n = 5), the knees (n = 4), other parts of the legs of the study by three investigators (SE, LC and SZ) who were (n = 3) and the back (n = 1). One patient was withdrawn from blinded to the treatment arm. The study primary end point was the study due to pregnancy, although the patient later delivered to achieve a TCS ≤1 at week 4. Adverse events were also noted, a healthy baby besides incidental application of topical Cal/BD and if they posed a risk to the patient, treatment was foam for less than a week. In eight occasions, patients missed a JEADV 2021, 35, 143–149 © 2020 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology Cal/BD foam vs clobetasol in psoriasis 145 Table 1 Baseline demographics and clinical characteristics of (a) Clobetasol cream each group 6 Cal/BD Median TCS evolution Median Clobetasol Cal/BD foam 4 Age 49.5 years 43 years P <0.022 2 Weight 75.7 kg 73 kg Height 170 cm 171 cm 0 0 2 4 8 Abdominal perimeter 96 cm 93 cm Weeks BMI 24.94 kg/cm2 24.91 kg/cm2 (b) TCS at baseline 4.5 5 Clobetasol cream percentage evolution 0 Cal/BD Median TCS -20 follow-up appointment, and among them, three did not come to -40 the last follow-up appointment and were considered lost to fol- -60 low-up. One patient in the clobetasol arm applied the treatment -80 for 2 weeks due to complete response (TCS = 0) whereas the -100 0 2 4 8 remaining patients applied the treatment for 4 weeks. Weeks Clinical results Figure 1 Line graphs showing the evolution of total clinical score When assessing the lesions at baseline, there were no statistical (TCS) in both treatment groups. Panel (a) shows the median TCS evolution. Panel (b) shows the percentage median TCS evolution. differences in the median TCS before treatment between the clo- betasol group (median 4.5) and the Cal/BD foam group (median 5) (P = 0.235), making the two groups comparable. Compared P = 0.016 Not clear (TCS>1) to the baseline TCS evaluation, at 4 weeks, there was a greater 12.5 Clear/almost clear (TCS ≤1) Number of cases TCS reduction using Cal/BD foam compared to clobetasol (80% 10.0 vs. 43.4% reduction; median TCS 1 vs. 3, P < 0.022) (Fig. 1). At 7.5 week 4, there was a significant difference in the number of 5.0 patients who achieved the study primary end point (TCS ≤ 1): 2.5 63.2% in the Cal/BD foam group vs. 18.8% in the clobetasol 0 group (P = 0.016) (Fig. 2). At week 8, the TCS increased in both am / ea l fo ol cr aso e tri m on ipo groups but remained lower with Cal/BD foam: median TCS with t be as lc lo et Ca C Cal/BD 1.5 vs. median TCS with clobetasol 3 (P = 0.568) am (Fig. 1). No severe adverse events were noted during the study. th be Regarding the adverse events related to the treatment, only itch Treatment arm at the application site was reported in two patients applying Cal/ BD foam and in one applying clobetasol. Four patients in the Figure 2 Graph bar showing cases achieving the study primary’s Cal/BD foam group reported that the treatment was messy to end point (TCS ≤ 1) at W4 (orange bars) in both treatment groups. apply. However, patient satisfaction with the treatment was sig- nificantly higher with Cal/BD foam compared to clobetasol [me- Regarding the microscopic features that were associated with dian 9, mean 9.06 (range 7–10) vs. median 7, mean 6.5 (range 1– sustained response (week 8), we saw that if epidermal hyper- 10), P < 0.03; Fig. S2]. plasia was noted at baseline, the response was poorer with clobe- tasol (P = 0.029), whereas the presence or absence of epidermal Microscopic results hyperplasia did not affect the treatment response at week 8 with Cal/BD foam induced a faster and greater reduction in epider- Cal/BD foam (P = 0.542; Fig. 5). Although it did not achieve mal thickness at weeks 2, and four identified with OCT statistical significance, we observed similar results regarding the (P < 0.049, Fig. 3a). Inflammatory cells identified with RCM presence of scale on dermoscopy; when important scaling was increased with Cal/BD foam at week 2 and later decreased, being observed at baseline, the lesions would be less likely to continue lower than clobetasol after week 4 (P < 0.05, Fig. 3b). clear at week 8 with clobetasol (11 not clear vs. 2 clear, Linear blood vessels were identified using dermoscopy in P = 0.489), whereas with Cal/BD foam, more cases with intense 28.6% of clobetasol cases vs. 37.5% of Cal/BD foam cases at scaling on dermoscopy maintained a TCS ≤1 at week 8 (10 not week 8 (P = 0.709). When assessing these vessels with RCM and clear vs. 7 clear, P = 0.211). OCT, we identified dilated horizontal vessels in the upper dermis We did not see significant differences between both treat- (vessels >70 µm) in 69.2% of clobetasol cases vs. 31.2% of Cal/ ments regarding the changes in parakeratosis, spongiosis, irregu- BD foam cases at week 8 (P = 0.159, Fig. 4). lar epidermis or dilated vertical blood vessels. JEADV 2021, 35, 143–149 © 2020 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology 146 lamos et al. Ye (a) formulated in this novel foam compared to the same concentra- median evolution (µm) Clobetasol cream 200 Stratum corneum/ Cal/BD granulosum 160 tions of Cal/BD but formulated as an ointments.15–17 120 Another interesting microscopic finding we identified was P <0.049 related to the presence of dilated horizontal vessels at the end of 80 40 the study. Although our sample size is small and the results did 0 0 2 4 8 not reach statistical significance, our results suggest that clobeta- Weeks sol induces more dilated linear vessels compared to Cal/BD foam (b) Clobetasol cream at week 8 (69.2% of clobetasol cases vs. 31.2% of Cal/BD foam 1.2 Cal/BD cases, P = 0.159). Hence, OCT and RCM allow the visualization inflammatory cells Median change in 1.0 of these dilated vessels better than the naked eye or dermoscopy. 0.8 These vessels indicate the potential iatrogenic effect of corticos- 0.6 0.4 teroids,18,19 thus suggesting non-invasive microscopic methods 0.2 may be necessary to assess the early onset of adverse events 0.0 0 2 4 8 related to treatment. Weeks Interestingly, we have also seen a temporary increase in the numbers of inflammatory cells with RCM when using Cal/BD Figure 3 Line graphs showing the evolution of relevant micro- foam after 2 weeks of treatment (Fig. 3b). An explanation for scopic findings. Panel (a) shows the evolution of the epidermal this finding could be that Cal/BD induces an increase in CD8+ thickness measured with OCT. Panel (b) shows the evolution of lymphocytes, which restores the CD4+ and CD8+ lymphocyte inflammatory cells identified using RCM. epidermal counts thus normalizing the skin microenviron- ment.20 However, to confirm this hypothesis, biopsies may have been needed to perform immunohistochemical studies. Another Discussion possible explanation for this increase may be due to a certain Our results suggest that Cal/BD foam is more effective than clo- degree of irritation related to the vehicle (a foam) or to cal- betasol after 4 weeks of treatment, shown both clinically and cipotriol itself.14 In fact, two patients reported itch at the appli- microscopically, is potentially safer than clobetasol by inducing cation site of Cal/BD foam. Nevertheless, this did not seem less iatrogenic vessels and has higher patient satisfaction. Clini- relevant and did not reduce treatment adherence since patients cally, we have shown that Cal/BD foam induces a faster response continued to apply the treatment and actually reported higher compared to clobetasol cream with a mean reduction of 80% vs. patient satisfaction with Cal/BD foam compared to clobetasol 43.4% (P < 0.022) of the TCS at 4 weeks. Additionally, more (Fig. S2). This increase in inflammatory cells was transient, and patients achieved total or almost total lesion clearance later, the inflammatory cell counts decreased to levels lower than (TCS ≤ 1) at week 4 with Cal/BD foam compared to clobetasol with clobetasol. Hence, probably this early increase in inflamma- (63.2% vs. 18.8%, P = 0.016). Furthermore, more patients tory may correlate with a better treatment response, suggesting maintained a TCS ≤1 at week 8 (1 month without treatment) in that microscopic data may not only improve the detection of the Cal/BD foam arm, although it did not reach statistical signif- early adverse events, but can better grade the treatment icance (P = 0.568). response. Regarding the microscopic findings, we identified a faster Non-invasive microscopic assessment using tools such as der- reduction in the scaling observed with dermoscopy when using moscopy, RCM or OCT has been used extensively in the fields of Cal/BD foam, as well as a faster reduction in the hyperkeratosis/ dermato-oncology and more recently to diagnose inflammatory acanthosis in OCT with Cal/BD foam. This correlates well with dermatoses21–24 and to grade treatment response.13,25 The another of our findings which shows that if more epidermal advantage of these technologies is that they allow a fast assess- hyperplasia was noted with OCT at baseline, the lesions would ment without the need of being invasive. Dermoscopy uses a be less likely to respond with clobetasol. This suggests that clobe- magnifying lens (commonly 109) which allows the visualization tasol cream may not penetrate deep enough in the psoriatic pla- of structures not visible to the naked eye but not reaching the que if this is thick, whereas Cal/BD foam can be still effective cellular level.12 RCM uses a near-infrared light laser which allows regardless of the plaque thickness, even though the vehicle is a the visualization of en face images with cellular resolution;26,27 foam. The reason for this increased effectivity may be that the however, because of this high resolution, RCM can only image current formulation of Cal/BD foam is a novel aerosol foam up to ~250 µm (superficial dermis). OCT uses also a laser light which when sprayed does not crystalize and allows the rapid source which allows a deeper penetration, up to 1 cm, but at the evaporation of propellants thus leaving a supersaturated layer of cost of a worse resolution. OCT can assess the architecture and Cal/BD on the skin.14 In fact, previous studies have shown that in some devices the visualization of blood vessels (dynamic Cal/BD penetrates deeper and exerts a more intense action when OCT).6,28,29 JEADV 2021, 35, 143–149 © 2020 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology Cal/BD foam vs clobetasol in psoriasis 147 Figure 4 Clinical, dermoscopic, RCM and OCT images at week 8 in a case treated with clobetasol (panel a) and in a case treated with Cal/BD foam (panel b). (a) Clobetasol case at week 8 showing TCS 2, linear vessels (arrows) and scale (arrowheads) on dermoscopy, and parakeratosis (arrowheads) and dilated horizontal blood vessels (arrows) on RCM and OCT. (b) Cal/BD foam case at week 8 showing TCS 1, linear (arrows) and dotted vessels (arrowheads) on dermoscopy, increased numbers of vertical dilated blood vessels (arrowheads) and slightly dilated horizontal blood vessels (arrows) on RCM and OCT. JEADV 2021, 35, 143–149 © 2020 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology 148 lamos et al. Ye Epidermal hyperplasia Another limitation of our study is that the patients and investiga- at baseline (OCT) No tors acquiring the images were not blind to the treatment and that Yes although the analysis of the images was performed by three evalu- (a) Clobetasol (b) Cal/BD ators who were blind to the treatment arm, subjective interpreta- cream 12 8 tion of the images may have impacted the results. 10 Regarding the last point, efforts have been made to provide 6 objective, automated or semi-automated image assessment using 8 P = 0.029 P = 0.542 Count (n) Count (n) 6 4 artificial intelligence (AI). Currently, different AI algorithms 4 have shown to have high diagnostic accuracy to diagnose multi- 2 ple dermatoses, at the same level or superior to dermatolo- 2 0 0 gists.30,31 Thus, it seems intuitive that AI algorithms may allow Not clear Clear/almost Not clear Clear/almost (TCS>1) clear (TCS≤1) (TCS>1) clear (TCS≤1) an objective accurate objective evaluation in psoriasis. Several TCS ≤1 at week 8 TCS ≤1 at week 8 studies have attempted to do so by using colour calibration,32 and in fact semi-automated and automated PASI calculation algorithms have been developed using calibrated images Figure 5 Graph bars comparing TCS clearance status at the end of the study (week 8) based on the presence or absence of epider- acquired in order to provide more objective disease quantifica- mal hyperplasia at baseline. Panel (a) shows the results for the tion than manual PASI or PGA calculations performed by physi- patients treated with clobetasol cream, and panel (b) shows the cians.33–35 Hence, such methods could also be applied in other results for the patients treated with Cal/BD foam. fields of dermatological imaging in order to improve disease quantification and to better determine response and manage- As stated in the previous paragraph, the use of these imaging ment of side-effects.36,37 technologies has some limitations; although we used different imaging technologies to maximize the information obtained, Conclusion some degree of sampling error may have occurred, since psori- To sum up, we have shown that Cal/BD foam is more effective atic plaques are typically in the range of centimetres, much larger than clobetasol cream after 4 weeks of treatment, has better than the field of view of the technologies used. Nevertheless, we patient satisfaction than clobetasol and induces a faster and tried to minimize this issue by imaging the centre of the target greater reduction in the hyperkeratosis/acanthosis, regardless of lesion, although sometimes identifying the same exact area was the initial epidermal hyperplasia status. Our results also suggest hard since the morphology of psoriatic plaques may change that clobetasol may induce more iatrogenic telangiectasias com- throughout the treatment process. pared to Cal/BD foam. However, our sample was small and lacks Another challenge we encountered was the assessment of ves- automated measurements. Hence, future studies using AI and sels using dynamic OCT. Vessel quantification in OCT needs to multimodal imaging methods are necessary to obtain objective be done in the different planes and can vary depending on data regarding treatment response and prediction of early anatomical factors, vasodilation due to exogenous factors (tem- adverse events in psoriatic patients treated with topical perature, elevation of the area imaged, irritation), among others. treatments. In addition, the software does not provide an objective measure- ment of the quantity of vessels, which makes its assessment diffi- Acknowledgements cult. Because of this, we started the development of an We would like to thank all the physicians at the dermatology informatics algorithm to automatically quantify the vessel den- department at Hospital Clınic, as well as family physicians at sity. However, this is not an easy endeavour since vessels in CAP Casanova for contributing patients to the study. dynamic OCT need to be adjusted by the blood flow in healthy skin, which can also change depending on the anatomic area. References Additionally, dynamic OCT induces a ‘shadow’ artefact in which 1 Alarcon I, Carrera C, Palou J et al. Impact of in vivo reflectance confocal under a given vessel the device cannot assess correctly the blood microscopy on the number needed to treat melanoma in doubtful lesions. flow. Another aspect to take into consideration is that vessels need Br J Dermatol 2014; 170: 802–808. 2 Borsari S, Pampena R, Lallas A et al. Clinical indications for use of reflec- to be measured at the same vertical plane to be compared, but tance confocal microscopy for skin cancer diagnosis. JAMA Dermatol since psoriatic plaques changed their thickness, comparison over 2016; 152: 1093. time was challenging. 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Dermatology 2014; 229: 215–221. this study. 23 Ardigo M, Maliszewski I, Cota C et al. Preliminary evaluation of in vivo Figure S1. Scheme of the treatment visits. reflectance confocal microscopy features of Discoid lupus erythematosus. Figure S2. Box plot comparing patient satisfaction with clobeta- Br J Dermatol 2007; 156: 1196–1203. sol vs. calcipotriol/betamethasone dipropionate foam, showing 24 Astner S, Gonzalez E, Cheung A, Rius-Diaz F, Gonzalez S. Pilot study on the sensitivity and specificity of in vivo reflectance confocal microscopy an overall higher satisfaction with the latter. JEADV 2021, 35, 143–149 © 2020 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology