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Pimecrolimus 1% cream for mild-to-moderate atopic dermatitis: a systematic review and meta-analysis with a focus on children and sensitive skin areas Volume 33, numéro 5, September-October 2023

Illustrations


  • Figure 1.

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  • Figure 3.

Tableaux

A topic dermatitis (AD) is a common, relapsing inflammatory skin disorder characterized by eczematous lesions and persistent pruritus. AD usually appears early in childhood and is often followed by other atopic disorders such as asthma and allergic rhinitis [1, 2]. The prevalence of AD is thought to be up to 20% in children and up to 3% in adults, and is rising [3]. AD flares often occur in sensitive skin areas; such areas are usually the earliest sites of AD lesions in infants [4].

Emollients and topical anti-inflammatory therapy are central to the effective treatment of AD, including the use of topical corticosteroids (TCS) and topical calcineurin inhibitors (TCI) [5]. Many TCS are available with a range of potencies [5]. Two TCI are available: pimecrolimus 1% cream is approved for mild-to-moderate AD in patients aged ≥two years (and infants aged ≥three months in some countries), while tacrolimus ointment is approved for moderate-to-severe AD (0.03% for children aged 2–15 years; 0.1% for patients aged ≥16 years) [5]. The current European guidelines for AD recommend TCS for the first-line treatment of AD when basic therapy with emollients is not effective [6]. However, use of TCS on sensitive skin areas, such as the face and eyelids, can lead to potential local and systemic adverse effects, such as impairment of epidermal barrier function and skin atrophy [7–9]. Unlike TCS, TCI such as tacrolimus and pimecrolimus, do not adversely affect epidermal barrier function or cause skin atrophy [7, 10–12]. The European guidelines for AD recommend pimecrolimus for use in children and the treatment of sensitive skin areas such as facial lesions, and tacrolimus for long-term maintenance [6]. Another topical anti-inflammatory therapy is crisaborole 2% ointment, a benzoxaborole phosphodiesterase-4 inhibitor approved in a limited number of countries for the treatment of mild-to-moderate AD in adults and children (≥three months in the US and Canada) [13, 14].

Multiple clinical trials have shown that pimecrolimus 1% cream is effective with a favourable safety profile for treating mild, moderate and severe AD in infants, children, and adults [15–17]. In particular, pimecrolimus is effective for the treatment of AD in sensitive skin areas, such as the head or neck [18, 19]. However, despite multiple studies reporting the benefits of pimecrolimus for treatment of sensitive skin areas, no systematic reviews have been performed for this indication.

The primary objective of this systematic literature review (SLR) and meta-analysis of randomized controlled trials (RCTs) was to assess the relative efficacy and safety of pimecrolimus 1% cream vs other topical treatments in patients with mild-to-moderate AD, with a focus on children (including infants) and sensitive skin areas. As no head-to-head RCT of pimecrolimus vs crisaborole has been performed, an indirect treatment comparison (ITC) of pimecrolimus and crisaborole was an exploratory objective of the study.

Methods

Systematic literature reviews

Two SLRs were performed using prespecified protocols – one focused on pimecrolimus for the meta-analysis, and one focused on crisaborole for the ITC. Although this review was not registered, best practice guidelines were adhered to when performing the SLRs (PRISMA guidelines [20]; Cochrane Handbook for Systematic Reviews of Interventions, version 5.1.0) [21]. Population, intervention, comparators, outcomes and study design (PICOS) elements [22] were used to build the search strategies and define inclusion and exclusion criteria (supplementary tables 1 and 2); only RCTs were included. The search strategies used for the pimecrolimus and crisaborole SLRs are shown in the supplementary methods. Searches were limited to English language only, with no timeframe limits. Articles were sourced from MEDLINE, Embase and Cochrane Library databases, and supplemented with hand searches from other sources such as clinical trial registries and bibliographies from relevant systematic reviews. Searches for the pimecrolimus and crisaborole SLRs were performed on January 15th, 2020 and October 5th, 2020, respectively.

Study selection

Following deduplication, identified records were exported into the Covidence systematic review management tool [23]. Selected publications had to fulfil all relevant inclusion criteria and none of the exclusion criteria (supplementary tables 1 and 2). Titles and abstracts of all citations were reviewed to determine whether they met the inclusion criteria. Articles that were not excluded were reviewed in full by two independent reviewers in order to assess if they were relevant for inclusion in the report. Other citations were identified through hand searching of conference proceedings, and bibliographies of identified studies and SLRs. A third reviewer was consulted if disagreements were not resolved through discussion.

Data extraction

Data from eligible studies were extracted by one reviewer into data extraction tables. A second independent reviewer checked and validated key outcome data to identify and rectify any errors in data extraction. Information extracted included study design, baseline characteristics, clinical efficacy, quality of life, safety, and patient preferences.

Synthesis of extracted evidence

Meta-analysis

Quantitative synthesis of evidence by meta-analysis was performed based on the studies selected from the pimecrolimus SLR. A feasibility assessment was carried out to assess the possibility of data synthesis for all relevant outcomes, and decisions were taken on choice of outcomes, type of effect size, and patient population, among others. Direct pair-wise meta-analysis was performed to assess the relative effectiveness of pimecrolimus compared with vehicle/tacrolimus/TCS (the eligible comparators identified by the SLR) using fixed-effects and random effects models. Inverse-variance weighting (a method of aggregating two or more random variables where each random variable is weighted in inverse proportion to its variance in order to minimize the variance of the weighted average) was employed for the meta-analysis [24]. Meta-analyses were performed for mild-to-moderate AD in children (including infants), adults, mixed populations (studies including both children and adults), and sensitive skin areas (face, head and neck, intertriginous sites and anogenital areas).

Pimecrolimus vs crisaborole – indirect treatment comparison

No head-to-head trials between crisaborole and pimecrolimus were identified; hence, direct pairwise meta-analysis was not feasible. An ITC premised on the Bucher method [25] was performed using a random-effects model for mild-to-moderate AD in children (≥two years old) and mixed populations (all studies in patients aged ≥two years); no study was identified for crisaborole that included only adults or evaluated crisaborole for use on AD in sensitive skin areas.

Analysis of outcomes

Outcomes analysed for the meta-analysis of pimecrolimus vs vehicle/tacrolimus/TCS included Investigator’s Global Assessment (IGA) up to week 6, adverse events (AEs), quality of life, and acceptability/preference of pimecrolimus vs vehicle/tacrolimus/TCS. Outcomes analysed for the ITC of pimecrolimus and crisaborole were IGA and AEs. IGA outcomes were analysed in terms of relative risk (risk ratio [RR]) of obtaining treatment success defined as the proportion of patients achieving an IGA score of 0 (clear) or 1 (almost clear) at the end of a time period, with RR >1.0 favouring pimecrolimus. AE outcomes were analysed in terms of the proportion of patients experiencing an AE and reported as relative risk, with RR p < 0.050.

Data were managed in Microsoft Excel and the statistical analyses were carried out using the ‘netmeta’, ‘meta’, and ‘metafor’ packages in R software. Forest plots are presented if the number of studies is >1. The choice of presenting the random-effect or fixed-effect model in the forest plot was made based on the heterogeneity statistics: if the I2 statistics were >50%, the random-effect model is presented; if I2 was <50%, the fixed-effect model is presented.

Quality assessment

Quality assessments of the selected studies were carried out using the Cochrane critical appraisal tool [26]. Evaluations were performed on: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other biases. Each domain was judged by the level of risk of bias: high, low or unclear level. Quality assessment was carried out independently by two reviewers and disagreements were resolved by discussion.

Results

Meta-analysis of pimecrolimus vs vehicle/tacrolimus/TCS

Pimecrolimus systematic literature review

A total of 339 records were identified after deduplication. After screening the abstracts/titles, 281 records were excluded and 58 records were reviewed in full for eligibility. Overall, 31 records were deemed relevant for the study and a further eight citations were identified through hand searches. Of the 39 relevant studies identified, only those in which patients with mild-to-moderate AD comprised ≥90% of the study population were included in the meta-analysis. In total, 27 publications were included (supplementary figure 1), which reported relevant outcomes for pimecrolimus vs vehicle or tacrolimus 0.03%/0.1% or TCS. The key characteristics of the studies included in the meta-analysis are presented in supplementary table 3.

The risk of bias assessment for individual studies is shown in supplementary table 4, and a risk of bias summary is shown in supplementary figure 2. Overall, 52% of studies used inadequate randomization but most studies (85%) had a low risk of reporting bias.

Efficacy: IGA 0/1 up to week 6

Pimecrolimus vs vehicle

Results for pimecrolimus vs vehicle are summarized for children and the mixed population (studies including both children and adults); no studies comparing pimecrolimus with vehicle were identified for the adult population. Children treated with pimecrolimus were significantly more likely to achieve IGA 0/1 compared with vehicle up to week 6, with the greatest RR observed at week 1 (RR: 3.0, 95% confidence interval [CI]: 1.94–4.50, p<0.00010; fixed-effect model; figure 1A; supplementary table 5). Among the mixed population, a significantly greater proportion of patients treated with pimecrolimus achieved IGA 0/1 at week 2 compared with vehicle (fixed-effect model; figure 1B; supplementary table 5) and week 1 (fixed-effect model; supplementary table 5). In a mixed-population study in 73 patients, 10% of patients in the pimecrolimus arm achieved treatment success compared with 0% of patients in the vehicle arm at week 6 [27].

Pimecrolimus vs tacrolimus

Among children (figure 2) and adults, no significant differences were found between pimecrolimus and tacrolimus (0.03% for children and 0.1% for adults) in achieving IGA 0/1 up to week 6 (supplementary table 6), with results only numerically favouring tacrolimus.

Pimecrolimus vs TCS

No studies comparing pimecrolimus with TCS were identified for the adult population. One study was identified for infants in which the TCS used were of mild or medium potency depending upon the country label; there was no significant difference in the proportion of patients achieving IGA 0/1 at week 3 or 6 (table 1) [15].

Safety

Pimecrolimus vs vehicle

The frequency of any AE was found to be similar for pimecrolimus and vehicle in both children and the mixed population (table 2). Similarly, for both children and the mixed population, no significant differences were observed between treatment groups in the proportion of patients who experienced irritation, erythema, burning, or treatment-related AEs (table 2).

Pimecrolimus vs tacrolimus

Overall, no significant differences were observed between pimecrolimus and tacrolimus treatment groups in terms of incidence of AEs (table 3). Among children, the incidence of any AE or pruritus was similar for pimecrolimus and tacrolimus 0.03%, whereas the incidence of erythema or burning were non-significantly greater with pimecrolimus (table 3). Among adults, the incidence of any AE, burning or pruritus was non-significantly lower with pimecrolimus than tacrolimus 0.1%, while that of erythema was non-significantly greater with pimecrolimus (table 3).

Pimecrolimus vs TCS

In a five-year study of 2,418 infants and children, no significant difference was observed between the pimecrolimus and TCS groups in the frequency of any AE (RR: 1.0, 95% CI: 0.99–1.03, p=0.31; fixed-effect model) [15].

Sensitive skin areas

Pimecrolimus vs vehicle

In children, a significantly greater proportion of patients treated with pimecrolimus achieved facial IGA 0/1 at week 3 compared with vehicle (figure 3, supplementary table 7). Similarly, the chances of achieving facial IGA 0/1 were significantly greater with pimecrolimus than vehicle up to week 6 in the mixed population (supplementary table 7). In relation to safety in sensitive skin areas, AEs were analysed in a single study of a mixed population (200 children and adults with head and neck AD) [18]. No significant differences were observed between pimecrolimus and vehicle treatment arms for incidence of any AE, irritation, erythema or pruritus (table 4).

Pimecrolimus vs tacrolimus

There was limited evidence for the comparison of pimecrolimus and tacrolimus for use in sensitive skin areas, and IGA outcome data were not available. Among 141 children with moderate AD, the change from baseline in body surface area (BSA) affected by AD for the head and neck region was similar between pimecrolimus and tacrolimus 0.03% arms, although pimecrolimus tended to have a greater, non-significant effect compared with tacrolimus 0.03% (reduction in BSA at week 6: 54% vs 35%, respectively) [28]. In a subgroup analysis of 188 adult patients with moderate AD, the signs and symptoms score for AD in the head and neck region improved significantly for the tacrolimus 0.1% group compared with the pimecrolimus group (69% vs 50%, p=0.050 at week 3; 75% vs 54%, p=0.040 at week 6) [29].

Pimecrolimus vs TCS

Efficacy outcomes for AD in sensitive skin areas were compared between pimecrolimus and TCS (low potency, e.g., hydrocortisone 1%; medium potency, e.g., hydrocortisone butyrate 0.1%; or cream/ointment used according to the country’s label with potency selected by the investigator) in one study in 2,418 infants and children [15]. Pimecrolimus was as effective as TCS in achieving facial IGA 0/1 at week 3 (RR: 0.99, 95% CI: 0.93–1.05, p=0.67; fixed-effect model) and week 6 (RR: 0.97, 95% CI: 0.92–1.02, p=0.26; fixed-effect model). In an intra-individual single-centre study in 20 patients with mild-to-moderate AD of the forehead, a two-week single course of topical treatment with a mildly potent steroid (hydrocortisone 1% cream) resulted in significant transient epidermal thinning (p=0.027), an effect not observed in the pimecrolimus group (p > 0.10 for all time points) [30].

Indirect treatment comparison of pimecrolimus vs crisaborole

Crisaborole systematic literature review

No head-to-head trials between pimecrolimus and crisaborole were identified in the pimecrolimus SLR, hence an additional crisaborole SLR and ITC with pimecrolimus were performed. In the crisaborole SLR, a total of 169 records were identified after deduplication. After screening the abstracts/titles, 118 records were excluded and 51 records were reviewed in full for eligibility. A total of 44 records were deemed relevant, of which nine were suitable for the ITC with pimecrolimus (supplementary figure 3). Overall, seven studies from the pimecrolimus SLR were included in the ITC. The key characteristics of the 16 studies included in the ITC are presented in supplementary table 8.

The risk of bias assessment for individual studies is shown in supplementary table 9, and a risk of bias summary is shown in supplementary figure 4. Random sequence generation and allocation concealment was unclear or inadequate in most studies, whereas reporting bias was not observed in any study.

Efficacy: IGA 0/1 up to week 6

Among children, patients treated with pimecrolimus had a significantly greater chance of achieving IGA 0/1 at weeks 3 and 4 compared with those treated with crisaborole (table 5). Across all studies including patients ≥two years old (mixed population), a significantly greater proportion of patients receiving pimecrolimus achieved IGA 0/1 treatment success at week 3 compared with crisaborole; results were similar between treatment groups for weeks 1, 2, and 4 (table 6).

Safety

AE data were sparsely reported among children for crisaborole; data are reported for completeness (supplementary table 10), but a reliable comparison could not be made as so few studies were available for analysis. In the mixed population, incidence of any AE was similar for both treatment groups (table 7), while the incidence of burning was significantly greater among patients treated with crisaborole compared with pimecrolimus (table 8). There were no significant differences in the frequencies of other AEs between treatment groups (table 8).

Discussion

This SLR and meta-analysis/ITC was performed to assess the efficacy and safety of pimecrolimus 1% cream vs other topical treatments for mild-to-moderate AD. For the first time, results were analysed with a particular focus on children (including infants) and sensitive skin areas.

The SLR and meta-analysis showed that pimecrolimus was more efficacious than vehicle in achieving IGA 0/1 up to week 6 in children and in patients with AD of sensitive skin areas (mixed population only), with a comparable safety profile. These results are in line with previously published SLRs and meta-analysis, which found that pimecrolimus had superior efficacy compared with vehicle up to week 6 in infants, children and adolescents with mild-to-moderate AD, with no significant safety concerns [31–33]. The results also support the European AD guidelines recommendation for use of pimecrolimus for children and facial lesions [6]. An often-overlooked aspect of AD is the effect of treatment on the quality of life of patients, as well as their families. In addition to the superiority of pimecrolimus vs vehicle on efficacy outcomes, we identified one study in children with mild-to-moderate AD that showed pimecrolimus significantly improved the Parent’s Index of Quality of Life in Atopic Dermatitis at six weeks compared with vehicle [34]. Taken together, these results indicate that pimecrolimus has rapid, beneficial effects on both clinical signs/symptoms of AD and quality of life.

Although head-to-head RCTs of pimecrolimus and tacrolimus were limited, the SLR and meta-analysis revealed that the difference between pimecrolimus and tacrolimus (0.03% in children and 0.1% in adults) in achieving IGA 0/1 up to week 6 was non-significant, with results only numerically favouring tacrolimus. These results are supported by a previous SLR and meta-analysis, which found no significant difference in the efficacy of pimecrolimus and tacrolimus 0.03% at week 6 in children with moderate AD [31]. Another SLR and meta-analysis in paediatric patients concluded that tacrolimus was superior to pimecrolimus [32], however, a separate pooled analysis was not performed for patients with mild-to-moderate AD and there were errors in the data reported for Kempers et al. [28] in the meta-analysis (proportion of patients with IGA 0/1 at week 6 incorrectly inputted as n number) [32]. A Cochrane review of 31 clinical trials found no statistically significant difference between pimecrolimus and tacrolimus 0.03% in achieving IGA 0/1 up to week 6, but found pimecrolimus to be significantly less effective than tacrolimus 0.1% at weeks 3 and 6, however, results were not presented separately for mild-to-moderate AD [33]. Compared to this previous Cochrane review, the current study presented here focused on mild-to-moderate AD and included a greater number of trials for this population. In regard to the comparative safety of pimecrolimus and tacrolimus, no significant differences were observed in the incidence of specific AEs, although there were findings of nonsignificantly greater incidence of burning (among children) and erythema (among children and adults) with pimecrolimus vs tacrolimus in the current study.

Very limited evidence was available for the comparison of pimecrolimus and tacrolimus in sensitive skin areas and further studies are warranted. In one study in children, pimecrolimus tended to have a greater effect on the percentage reduction in BSA in sensitive skin areas (head/neck) compared with tacrolimus 0.03% [28]. This study also showed that patients (or their caregivers) preferred the non-greasy cream formulation of pimecrolimus over the ointment formulation of tacrolimus 0.03% [28]. Furthermore, a significantly greater proportion of patients treated with pimecrolimus rated the treatment as ‘very good’ or ‘excellent’ in terms of suitability for use on sensitive facial skin compared with tacrolimus 0.03% [28].

For the comparison of pimecrolimus with TCS, only one study in infants and children was identified [15]. Although this was the only study identified for this population, it was included in this meta-analysis as it met the specified inclusion criteria and allowed for a more comprehensive data set. Based on this study, in which the TCS used were of mild or medium potency, the chance of achieving IGA 0/1 up to week 6 and the frequency of AEs were similar for the pimecrolimus and TCS treatment groups. This study also showed that in paediatric patients, pimecrolimus is as effective as TCS in achieving IGA 0/1 on facial skin areas, as well as on the whole body. These results concur with a previous SLR and meta-analysis that showed no significant difference between pimecrolimus and mild potency TCS in the proportion of children achieving IGA 0/1 [32]. When comparing pimecrolimus to a medium-to-high potency TCS, a Cochrane review found that pimecrolimus was significantly less effective, although outcomes were not presented separately for mild-to-moderate AD [33]. Interestingly, in a study of 20 patients with mild-to-moderate AD, a two-week single course of treatment with a mild potency TCS on the forehead resulted in transient epidermal thinning, which was less pronounced and statistically non-significant in the pimecrolimus group [30]. This supports the suitability of pimecrolimus for treating AD in sensitive skin areas and for repeated application such as long-term maintenance therapy [30].

As no head-to-head RCTs of pimecrolimus vs crisaborole were identified, an ITC was performed to compare the efficacy and safety of these treatments. Among children, results significantly favoured pimecrolimus over crisaborole for IGA 0/1 outcomes at weeks 3 and 4. Specific AE data were sparse for crisaborole in children and therefore a conclusion could not be drawn regarding safety in this patient population. In the mixed population (all studies in patients aged ≥two years), achievement of IGA 0/1 was significantly greater at week 3 for patients treated with pimecrolimus compared with crisaborole. While the incidence of any AE was similar between groups for the mixed population, frequency of burning was significantly lower among patients treated with pimecrolimus. The majority of treatmentrelated AEs reported in the crisaborole Phase III studies were application site pain [35]. However, pain is a relatively new endpoint for AD clinical trials that has not been evaluated for pimecrolimus. Another point of note for the crisaborole Phase III studies is that the ‘vehicle effect’ was greater than that usually observed in AD clinical trials (e.g., 40.6% of patients treated with vehicle had Investigator’s Static Global Assessment [ISGA] 0/1 at day 29) [35]. Overall, the results of the current study suggest that pimecrolimus may have some advantages over crisaborole in patients with mild-to-moderate AD, however, a head-to-head trial is needed to confirm these findings. No study was identified that evaluated crisaborole for treatment of AD in sensitive skin areas and therefore a conclusion could not be drawn about the comparative efficacy/safety of pimecrolimus and crisaborole on sensitive skin. In a recently published network meta-analysis in patients aged ≥two years with mild-to-moderate AD, crisaborole was shown to be superior to pimecrolimus with respect to ISGA 0/1 at 28–42 days [36]. However, the analysis had several limitations, including an absence of some relevant pimecrolimus studies, assumptions made regarding hazard ratios, and the methodology used for baseline risk adjustment [37]. As such, the results of the previously published study should be interpreted with caution [36, 37].

This SLR and meta-analysis/ITC were based on RCTs only. A six-month, open-label study to evaluate the safety and efficacy of pimecrolimus in clinical practice showed that pimecrolimus improved AD, particularly on the face, and was most effective in children with mild or moderate AD, in addition to being well tolerated [17].

In addition to drug efficacy and safety, patient adherence is an important contributing factor to treatment outcomes. Although drug adherence was not assessed in this study, previous studies have reported low adherence to TCS in patients with AD, with one study finding that only 32% of patients followed medical advice [38]. Poor adherence to TCS may be due to TCS phobia, defined as negative feelings and beliefs related to TCS experienced by patients and patients’ caregivers [39–41]. Adherence to pimecrolimus and tacrolimus has not been widely studied, but a study on secondary medical adherence to topical tacrolimus among 129 Korean patients with localized AD found that only 21% of patients used the correct amount of tacrolimus: 67% under-used the treatment and 12% over-used the treatment [42].

A large observational study on patient satisfaction of 3,200 patients found that more than twice as many patients reported that pimecrolimus was easy to apply compared with TCS, and that 81% patients felt that their disease was well-controlled with pimecrolimus, vs around one-quarter of patients with TCS [43]. While patient preference is not equivalent to adherence, it may be indicative of likelihood of adherence [44, 45].

Limitations

Several limitations must be acknowledged when evaluating the results of the current study. Firstly, the evidence for pimecrolimus vs tacrolimus and TCS is based on a limited number of RCTs and should be interpreted with caution. In addition, although the SLR and meta-analysis focused on mild-to-moderate AD, some trials identified also included patients with severe AD to allow for a robust analysis; most of these studies were vehicle-controlled and would not have impacted the findings of the review. Head-to-head trials of pimecrolimus vs crisaborole were not identified, hence the need for an ITC to be performed to provide evidence for this comparison. The analysis of pimecrolimus vs crisaborole was based on an unadjusted indirect comparison. Although baseline response was different in the pimecrolimus and crisaborole trials, adjustments for this were not attempted as only a few studies were available for the two treatments and patient-level data were not available for either pimecrolimus or crisaborole trials.

Conclusion

This study has established pimecrolimus 1% cream as an effective topical treatment for mild-to-moderate AD. Pimecrolimus was found to have similar efficacy to other topical treatments such as tacrolimus, mild-medium potency TCS and crisaborole, with a favourable safety profile. Based on the results of this study, pimecrolimus can be considered as a first-line treatment option for mild-to-moderate AD, particularly in children and for AD of sensitive skin areas. A head-to-head trial is warranted to establish the true differences in efficacy and safety between pimecrolimus and crisaborole. ■

Funding:

this study and the writing/editorial support were funded by Meda Pharma S.p.A., a Viatris company.

Conflict of interest:

TL has received consulting fees and honoraria from, and participated in an advisory board by Meda Pharma S.p.A. (a Viatris company). C-YC reports receiving grants from Sanofi, consulting fees, honoraria from and participated in an advisory board by AbbVie, Janssen, Lilly, Novartis, Pfizer, Roche, Sanofi and United Biopharma, honoraria from, and participated in an advisory board by Viatris, support for attending meetings from Novartis and Sanofi, and holds a leadership role with the Taiwanese Dermatological Association. AE and ZZ report they have nothing to disclose. SBBKI has received honoraria from Mylan, and reports a leadership role with The Dermatological Society of Malaysia. NM reports grants from Amryt Pharma, Eli Lilly, and Pfizer, grants and personal fees from Janssen and Novartis, and personal fees from AbbVie, Bayer, Galderma, Pierre Fabre, LEO Pharma. SR is an employee of SmartAnalyst India Pvt. Ltd., an Ashfield Advisory company, which received funding from Meda Pharma S.p.A., a Viatris company to conduct the study.

Data availability statement:

the study protocol and data that support the findings of this study are available from the corresponding author upon reasonable request.

Acknowledgments:

the authors thank Prof. Ashraf Reda for reviewing the manuscript. Medical writing support for the development of this manuscript, under the direction of the authors, was provided by Jane Murphy (PhD), Andrew Briggs (BA) and Eleanor Thomas (BSc) of Ashfield MedComms, an Inizio company, and funded by Meda Pharma S.p.A., a Viatris company.

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