FormalPara Key Summary Points

Real-world evidence (RWE) of fixed-combination calcipotriol (Cal) 50 μg/g plus betamethasone dipropionate (BD) 0.5 mg/g foam use in regular clinical practice is important and necessary to fully understand the benefits of this topical therapy for plaque psoriasis across different healthcare settings.

Several non-interventional studies (NIS) have corroborated the beneficial efficacy and safety profiles determined in the randomized clinical trials (RCT) of Cal/BD foam; however, heterogenicity in these NIS prevents the use of a data pooling strategy for comparisons of effectiveness outcomes across different patient populations.

Therefore, a post hoc analysis of effectiveness data consolidated from six prospective NIS was employed to discern any differences in improvement in signs and symptoms of plaque psoriasis attributable to Cal/BD foam treatment across the countries.

The results provide real-world evidence in 1388 patients showing that 4 weeks of Cal/BD foam is an effective and safe treatment option with quick onset of action for patients with plaque psoriasis.

Overall, this post hoc analysis shows that regardless of NIS location, Cal/BD foam remains a well-tolerated, efficacious option for patient care that could be used as a first-line topical therapy for mild-to-severe plaque psoriasis.

Introduction

Plaque psoriasis (hereinafter psoriasis) is a chronic relapsing inflammatory skin disease characterized by red, scaly plaques and pruritus, which often requires long-term therapy. Topical therapies are commonly used to treat psoriasis given their ease of application, effectiveness, and safety profile; notable examples are the vitamin D analogue calcipotriol and the corticosteroid betamethasone dipropionate [1]. Once-daily, fixed-combination calcipotriol 50 μg/g (Cal) plus betamethasone dipropionate 0.5 mg/g (BD) exists as gel, ointment, foam, and cream formulations that are approved as first-line treatments against psoriasis in multiple countries [1, 2]. Treatment of psoriasis with 4 weeks of the aerosol foam formulation of Cal/BD (Enstilar®, LEO Pharma) has been demonstrated to be effective, well tolerated, and associated with high patient satisfaction [2,3,4].

Real-world evidence (RWE) of Cal/BD foam use in regular clinical practice is important and necessary to fully understand the benefits of this topical therapy across different healthcare settings [5,6,7,8]. Since its launch in 2016, there have been robust multicenter non-interventional studies (NIS) throughout the globe focusing on the effectiveness and safety of Cal/BD foam treatment for psoriasis [9,10,11,12,13,14,15,16,17]. However, the heterogenicity in these NIS prevents the use of a data pooling strategy for comparisons of effectiveness outcomes across different patient populations. Therefore, here we aim to (1) describe the different NIS to better discern any differences in improvement in signs and symptoms of psoriasis attributable to Cal/BD foam treatment, and (2) capture the real-world experience of clinicians with Cal/BD foam treatment, factoring in changes in usage since these NIS were performed in their local markets.

Methods

Selection of Cal/BD Foam NIS

A total of 15 NISs with Cal/BD foam from the last 6 years were considered for a post hoc analysis of effectiveness outcomes, as the authors were involved with these NIS and had access to the raw data owned by LEO Pharma (Fig. 1). These 15 studies were filtered on the basis of whether results were published, which decreased the number to 11 studies. We then determined which of these 11 studies had similar designs, factoring in that most Cal/BD foam NIS adapted the design of the original, prospective German NIS [12] and introduced minor protocol adjustments based on local guidelines. Four retrospective studies were omitted [9,10,11, 18], to avoid introducing bias associated with patient selection and timing of treatment response. The retrospectively collected data could not be expected to be available within the same planned timescales as the prospective studies, and the retrospective studies also lacked a rigorous assessment of both inclusion and exclusion criteria compared to the prospective ones. Of the seven remaining prospective studies with data on 4 weeks of Cal/BD foam treatment, one was omitted, as it focused on scalp psoriasis [19], and the endpoints are not comparable to the other six studies. The post hoc analysis reported here included six total phase 4 NIS (five from European countries, one from Asia) of 4 weeks of Cal/BD foam treatment in patients with plaque psoriasis (Table 1): Germany (NIS-1295, completed 03/2017) [12]; Greece (NIS-1438, completed 02/2019) [13]; Austria (NIS-1363, completed 03/2020) [14]; Italy (NIS-1473, completed 11/2020) [15]; France (NIS-1447, completed 11/2020) [16]; and Korea (NIS-1524, completed 07/2021) [17]. Since the six Cal/BD foam studies are NIS, the inclusion and exclusion criteria were per label in each country. All six NIS and this post hoc analysis were sponsored by LEO Pharma and conducted according to the ethical principles derived from the Declaration of Helsinki and Good Clinical Practice guidelines. The six NIS were approved by the local institutional review board or ethics committee of each institution, and all patients provided written informed consent.

Fig. 1
figure 1

Selection of Cal/BD foam NIS for a post hoc analysis of effectiveness outcomes. aGerdes et al. [12]; b Rigopoulos et al. [13]; cZenahlik et al. [14]; dCampanati et al. [15]; eMisery et al. [16]; fJo et al. [17]. gStaubach et al. [19]. Cal/BD calcipotriol/betamethasone dipropionate, N number of studies, NIS non-interventional study

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Table 1 Phase 4 Cal/BD foam NIS included in the post hoc analysis of effectiveness outcomes
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Results

Baseline Characteristics

Baseline characteristics data that were shared between the studies are shown in Table 2 and Fig. 2. The total patient numbers for each NIS varied, with the French study having the lowest (n = 40) [16]. Mean age was approximately 45–55 years old and was similar across all studies, with the French study having the youngest (45.6 years) (Fig. 2a). The proportion of male patients was greater than 50% in all the NIS aside from the French study (37.5%) (Fig. 2b). The disease duration was stable and long-term across the studies, with a mean disease duration of more than 10 years (Fig. 2c). Interestingly, pairwise t tests (α = 0.05) of the baseline characteristics revealed that the German population had a statistically significant higher mean disease duration (15.34 ± 14.22 years) than Greece, Italy, and Korea. There was high variability and heterogeneity from country to country in the proportions of patients who were treatment-naïve prior to initiating Cal/BD foam treatment, and of those who were previously treated with topical corticosteroids (TCS), or systemic therapies (Fig. 2d).

Table 2 Baseline characteristics from six Cal/BD foam NIS
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Fig. 2
figure 2

Baseline characteristics from six Cal/BD foam NIS. a Mean age (years), b percentage of male patients, c mean disease duration (years), d proportion of patients with previous treatment. aDisease duration data were available for 101 Austrian patients. Cal/BD calcipotriol/betamethasone dipropionate, N number of total patients, NIS non-interventional study. *p < 0.05. The comparisons between Germany and Austria/France were not significant

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Improvement in Outcomes Due to Cal/BD Foam Treatment from Six NIS

Cal/BD foam treatment was associated with improvement in effectiveness outcomes (Fig. 3). Mean Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index (DLQI) values showed consistent improvement from baseline to end of treatment (4 weeks) in all the NIS (Fig. 3a, b). Remarkably, in the Italian study, mean PASI improved from 7 at baseline to a clinically meaningful value of 2.70 (Fig. 3a). Notably, mean DLQI score was numerically higher for the Korean population (5.96) than for the other countries at week 4 (Fig. 3b). Improvement after 4 weeks of treatment was also observed in mean values of scaling, redness, itching, and skin dryness across the studies (Fig. 3c–f). While not an unmet need of psoriasis, small improvements in mean itch-related sleep loss were observed in the NIS (data not shown). Across all the countries, no new safety signals, and no local skin reaction linked to the usage of potent corticosteroids such as skin atrophy or telangiectasia, were evident in patients treated with Cal/BD foam, either after treatment for 4 weeks or longer.

Fig. 3
figure 3

Improvements in effectiveness outcomes associated with Cal/BD foam treatment from six NIS. Mean a PASI, b DLQI, c scaling, d redness, e itching, f skin dryness. Error bars represent 95% confidence intervals. Dashed line represents the clinically meaningful threshold for PASI. Cal/BD calcipotriol/betamethasone dipropionate, DLQI Dermatology Life Quality Index, NIS non-interventional study, PASI Psoriasis Area and Severity Index

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Discussion

Six years after its launch, several NIS have provided RWE on the effectiveness, patient satisfaction, and tolerability of 4 weeks of Cal/BD foam treatment for psoriasis [9,10,11,12,13,14,15,16,17]. This post hoc analysis consolidated shared baseline characteristics and effectiveness data from NIS of Cal/BD foam from five European countries and from Korea. Overall, consistent improvement in signs and symptoms of psoriasis was observed in patients on 4 weeks of Cal/BD foam treatment, with alignment between the randomized clinical trials (RCTs) and the RWE included here [12,13,14,15,16,17]. There are differences, however, that are important to consider between the countries and their respective studies that may provide insight and context on how the different patient populations may benefit from this topical therapy. Differences in the type of prescribers and patients, therapy protocols, and guidelines/recommendations are of particular interest to the authors, who were involved with the NIS in their respective countries and provide their clinical experience and perspectives here.

Differing Access to Healthcare Providers and Provider Type May Influence Outcomes

Differences in enrollment in the Cal/BD foam NIS may be attributed to varying access to the patient professionals recognized in each country, such as dermatologists and general practioners (GPs), and to differences in local treatment guidelines and prescription habits. Many patients in Italy have access to dermatologists, which is perceived as quick compared to other countries in Europe. GPs in Italy are also generally aware of Cal/BD foam, and coincidentally, Cal/BD foam has been the first-line choice of topical treatment in Italy since 2018 [20]. Cal/BD foam treatment for 4 weeks is covered by national health insurance with complete reimbursement in Italy; therefore, cost is not a driver, but rather the personal experience and preference of the prescriber. There is strong, increased interest in Cal/BD foam therapy in Italy where objective clinically meaningful improvement in PASI has been observed (i.e., PASI ≤ 3, or no to minimal disease activity) [15]. This improvement after 4 weeks of Cal/BD foam is numerically greater in in the Italian NIS compared to the other countries (Fig. 3a), but the exact reasons for this difference are unclear. The phase 3 PSO-LONG study also supports Cal/BD foam, as long-term proactive management for 52 weeks with twice-weekly maintenance treatment demonstrated superior efficacy with a favorable safety profile vs vehicle foam [4]. Consequently, there are Italian patients that participated in the PSO-LONG study that are still under the twice-weekly maintenance treatment with overall good control of psoriasis [4, 15, 21].

Conversely, France follows the European guidelines of 4 weeks of Cal/BD foam therapy, but there are several challenges in the healthcare system that may have contributed to the low recruitment in the French NIS [16]. In France, private practices were included as enrollment sites, and as such, patients paid for the services of private physicians, which may have limited enrollment. Difficulties from the COVID-19 pandemic also contributed to the poorer recruitment and smaller size of the final analysis set (i.e., number of patients with before and after treatment assessments) in the French NIS [16]. In contrast, the Italian (n ≥ 200) and Korean (n = 218) NIS enrolled their planned number of patients, so dropouts due to the COVID-19 pandemic only decreased the size of their final analysis sets and were not expected to impact the overall results of the studies [15, 17]. Further, it is difficult to schedule an appointment with a dermatologist in France, with wait times of up to 1 year. GPs treat patients with psoriasis in France, but, whether or not they are familiar with Cal/BD foam as an available, effective treatment for psoriasis is unclear. Thus, access to healthcare providers familiar with Cal/BD foam treatment may be a limiting factor in the widespread application of this therapy for patients with psoriasis in different countries.

Evolving Prescription Habits Have Introduced Variation Between Earlier vs Later NIS

Prescription habits pertaining to Cal/BD foam treatment have evolved over time, as patients and their providers become more familiar with its benefits, and as the treatment landscape evolves. The German NIS, for example, included many patients with moderate-to-severe psoriasis at baseline: 55% of patients had a body surface area above 10%, and 36% of patients had a PASI score above 10 [12]. The high proportion of more severely affected patients in the German population may have thus contributed to its higher mean disease duration (15.3 years) compared to the other countries in this post hoc analysis. When the German NIS was completed in 2017, only gel and ointment formulations of Cal/BD—and not the recently launched cream formulation—were available for comparison, and use of gel may not have been prevalent given its lower efficacy and slower onset of action [12]. It is therefore also possible that the German population had a higher mean disease duration since there was minimal experience with Cal/BD foam treatment at the time of the German NIS, and the patients included may not have had their psoriasis adequately managed by previous treatments [12]. This observation is in alignment with the proportions of the treatment-naïve and TCS-experienced German patients in the NIS, which may be different today now that Cal/BD foam has been on the market for several years.

It is important to note that Cal/BD foam treatment is administered earlier now than at the time of the German NIS; topical combination therapies such as Cal/BD foam are now recommended as the first-line options in patients with mild psoriasis in Germany [22]. The treatment landscape, however, continues to evolve, with the addition of systemic therapies like biologics that offer alternative treatment options with differing mechanisms of action and risk–benefit profiles. A recent retrospective study based on German claims data from 2020 showed that real-world systemic treatment of German patients with psoriasis was limited; approximately 15% of patients received systemic treatment, with more than 50% being systemic corticosteroids [23]. These results suggest that systemic treatment may be underused in Germany and a shift towards it is possible.

Similar to Germany, when the Austrian NIS was completed in March 2020, Cal/BD formulations were not of common usage in primary care [14]. GPs in Austria are now familiar with managing their patients with psoriasis using Cal/BD foam, which is also prescribed per the European guidelines and reimbursed by health insurance. Topical combination therapies such as Cal/BD foam are also now recommended as first-line options in patients with mild psoriasis [24]. If topical therapies do not succeed sufficiently, ultraviolet therapy is added before initiation of systemic therapy. Austrian public health insurance demands that healthcare providers first consider synthetic disease-modifying antirheumatic drugs, such as methotrexate or fumaric acid esters, before introducing biological therapies [24]. Interestingly, in France, both patients and dermatologists tend to not favor systemic treatment, leading to the perception of therapeutic inertia, or the lack of initiation or intensifying of therapy [25, 26]. These different attitudes toward the stepwise shift from topical therapies to systemic biologics will continue to evolve as more RWE of their use becomes available, impacting the varied treatment history profiles reported here.

Local Geography and Cultural Considerations May Impact Treatment Decisions

In addition to NIS being influenced by differences in healthcare/payor systems country-to-country, inherent differences due to geography and patient disposition may lead to variation in treatment priorities and therefore NIS differences. In Greece, as a result of the weather and sun exposure, psoriatic lesions which are exposed to the sun tend to clear during the summer period. As such, Greek patients with mild psoriasis tend to self-manage their disease during the summer and only consult their healthcare providers upon exacerbation of their symptoms. A similar consideration cannot be easily made for Italy, on the other hand, as it is a larger country with differences in weather and climate (e.g., northern Italy is similar to the rest of Central Europe, while Southern Italy is similar to Greece). Some countries also have greater within-country diversity; France is a notable example with heterogenicity in patient demographics between South and North France and in age groups. Young French adults that were enrolled are experiencing the disease and its signs and symptoms with a different perspective, thus they are more difficult to satisfy. In Korea like in many Asian countries, cultural norms and social stigma about physical appearance add to the burden psoriasis has on patients’ mental health and quality of life, particularly psoriasis-related stress, depression, and perceived severity of psoriasis [27, 28]. Accordingly, the mean DLQI of the Korean population was higher than that of the other countries in this study [17]. A multinational dermatologist and patient survey also reported that Korean patients had the highest mean DLQI compared to eight other countries, supporting this post hoc analysis [29]. To better understand the effects of Cal/BD foam treatment in different populations, further research areas could consider effects of geography and culture, as well as include the investigation of the localization of lesions, influence of body mass index, and age on the perceived disease burden in terms of signs and symptoms.

Limitations

Notable limitations of this post hoc analysis are (1) whether the data are representative for the patients in the individual countries for each NIS and (2) whether any differences between countries are due to differences in the patients, or other factors. The authors acknowledge that the data and perspectives reported here are representative of their clinical experience. The NIS from which this post hoc analysis draws from are observational in nature, so the exact reasons for any differences between countries can not be readily identified. The results observed in each NIS may have been influenced by the way they were captured, or how the questions were asked at the sites. For instance, it is possible that for some questions, patients were asked if they were previously on a treatment with a specific name, and if the patient did not know or remember the name, then it would not have been captured appropriately. Local protocols were made after adjusting the German protocol, as previously mentioned, which could also have contributed to any differences in capturing previous therapy. In the 6 years since Enstilar’s launch, patient profiles and prescribing habits may have evolved, which could have also impacted the results on previous therapy, particularly regarding the proportions of patients who were TCS-experienced. Furthermore, BMI, localization of lesions, and the age differences between the countries may have contributed to the differences seen in signs and symptoms of psoriasis.

Conclusion

Patient satisfaction and improvement of quality of life are priorities for psoriasis management; the common objective is to prescribe the best treatment option to achieve lesion clearance and maintain the patient out of flare. The RWE highlighted here from 1388 patients in six Cal/BD foam NIS is consistent with and strengthens the results of the Cal/BD foam RCTs, supporting the use of 4 weeks of Cal/BD foam as a treatment option in daily clinical practice in multiple countries [12,13,14,15,16,17]. It is important to note that there may still be inherent differences that may have influenced the results of the Cal/BD foam NIS in each local market, such as access to healthcare providers/provider types, prescription habits, and geography/cultural considerations. Overall, this post hoc analysis shows that regardless of NIS location, Cal/BD foam remains a well-tolerated, efficacious option for patient care that could be used as a first-line topical therapy for mild-to-severe psoriasis, as first suggested by the German treatment pathway [22].