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Psoriatic patients treated with secukinumab reach high levels of minimal disease activity: results from the SUPREME study Volume 31, numéro 5, September-October 2021

Illustrations


  • Figure 1

Tableaux

Psoriasis is a systemic, immune-mediated skin disease characterized by a chronic recurrent course and multifactorial aetiopathogenesis, related to the combination of genetic and environmental factors [1-3]. Whilst plaque-type psoriasis is the most commonly occurring form, guttate, flexural, erythrodermic, pustular, palmoplantar, and/or nail manifestations are also recognized.

Dysregulation of the immune system has been widely demonstrated in patients with psoriasis [2, 4]. Interleukin-17A (IL-17A) is overexpressed in psoriatic skin, with levels up to six times higher than normal skin [5]. IL-17 appears to play at least three fundamental roles in psoriatic physiopathology: a role in activation, recruitment and apoptotic inhibition of neutrophils in the psoriatic epidermis; enhancement of dermal angiogenesis; and promotion and release of inflammatory cytokines and chemokines (e.g., tumour necrosis factor [TNF]-alpha, IL-1, IL-6, and CCL20) associated with psoriasis exacerbation [5]. IL-17A is therefore one of the main cytokines that directly promotes the hyperproliferation of keratinocytes, which are also involved in the inflammatory cascade. Higher levels of IL-17A in the skin have also been linked to greater severity of psoriasis [6].

A variety of treatments, including topical agents, phototherapy, systemic, and/or targeted biologic therapies are routinely used for psoriasis [3, 7-10]. Secukinumab is a fully human monoclonal antibody directed against IL-17A with demonstrated long-lasting efficacy and safety in the various domains of psoriatic disease, including the scalp, nails, palms of the hands and soles of the feet, and psoriatic arthritis (PsA) [11-17]. The superiority of secukinumab versus placebo and versus placebo/etanercept was demonstrated in the ERASURE and FIXTURE Phase 3 trials, respectively [15]. Likewise, in the CLEAR head-to-head, double-blind study, secukinumab demonstrated sustained superior efficacy in comparison with ustekinumab in clearing skin up to Week 52, greater improvement in quality of life, and a favourable and comparable safety profile [14]. The SCULPTURE extension study further demonstrated sustained high levels of efficacy with up to five years of secukinumab treatment [13].

The ideal treatment goal for patients with psoriasis is completely clear skin and normalization of health-related quality of life (QoL) over the long term [18]. Nowadays, achieving minimal disease activity (MDA) status should be considered as the most ambitious and sustainable therapeutic goal in psoriasis [19]. MDA defines a satisfactory state of disease activity rather than a change from baseline status, encompassing all aspects of psoriatic disease, and represents a reproducible measure to compare therapies.

However, criteria defining MDA in psoriasis are lacking in the literature. The aim for a treatment target that is useful to drive decisions regarding the continuation, discontinuation, or modification of psoriasis treatment is shared between physicians and patients. Moreover, recent guidelines from the National Psoriasis Foundation recommend a “treat-to-target” strategy for psoriasis management, based on clinicians and patients working together to optimize treatment decisions, diminish disease burden, and improve clinical outcomes [20].

MDA could be identified as a PASI response combined with a QoL measure, such as PASI 90 and Dermatology Life Quality Index (DLQI) <1, or a PASI residual score or residual body surface area (BSA) involvement, such as PASI ≤1 or BSA <3% [19, 21]. In 2019, Gottlieb and colleagues determined the association between the Investigator Global Assessment (IGA) x BSA and two MDA definitions (PASI 90 and DLQI 0/1, or PASI score ≤1 or BSA <3%) through a retrospective, pooled, post hoc analysis of the ERASURE, FIXTURE, FEATURE, and JUNCTURE clinical trials of 691 patients with moderate-to-severe psoriasis randomized to secukinumab 300 mg [22].

In the treat-to-target era, achieving MDA in patients undergoing a specific treatment for psoriasis could be considered as the ultimate goal [19, 22], and the identification of a specific value for MDA represents an emerging unmet medical need.

In this post hoc analysis of the SUPREME study, we aimed to evaluate the effect of secukinumab in achieving MDA at Weeks 16 and 24 in patients with psoriasis and identify clinical factors that may influence MDA at Week 16.

Materials and methods

Study design and patients

This is a post-hoc analysis from the SUPREME study (NCT02394561). The SUPREME study was a 24-week, Phase 3b, multicentre, prospective study conducted across 50 centres in Italy, with a variable extension period up to 48 weeks [23, 24]. The study aimed to evaluate the efficacy and safety of secukinumab 300 mg in HLA-Cw6-positive (Cw6-POS) and HLA-Cw6-negative (Cw6-NEG) patients with moderate-to-severe chronic plaque-type psoriasis. Patients enrolled in the SUPREME study were aged ≥18 years with a diagnosis of moderate-to-severe chronic plaque-type psoriasis (defined at enrolment as a PASI score ≥10 or PASI score >5 but <10, and DLQI ≥10) for at least six months, and included patients with concomitant nail or scalp manifestations, or with PsA, according to the Classification Criteria for Psoriatic Arthritis (CASPAR) [25]. In the core phase, 433 patients received subcutaneous secukinumab at 300 mg/week for five weeks followed by 300 mg every four weeks (q4w) until Week 24; patients entering the extension phase self-administered secukinumab at 300 mg q4w for a variable period up to Week 72. Written informed consent was obtained from all patients before their enrolment in the study, and the study protocol was approved by the Institutional Review Board of each participating centre. The trial was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice, and in compliance with all federal, local, and regional requirements.

Assessments

The severity of psoriasis can be measured using different instruments [26, 27]. The most widely used is the PASI score, which combines the assessment of skin lesion severity and the extent of the involved area into a single score ranging from 0 (no disease) to 72 (maximal disease) [28]. Although typically used in clinical trials, PASI score is not pragmatic for routine clinical use in daily practice.

The 5-point IGA score provides a subjective evaluation of the overall severity of psoriasis and ranges from 0 (clear), 1 (almost clear), 2 (mild), 3 (moderate) to 4 (severe) [29].

The estimation of involved BSA is incorporated in many assessments of psoriasis severity. BSA can be estimated by the number of handprints that fit within affected areas, assuming one “handprint” reflects approximately 1% of BSA, or by the “rule of nines”, with the head and neck, each arm, anterior and posterior leg, and four trunk quadrants each representing 9% coverage, plus 1% for the genitalia [30-35].

The effect of psoriasis on a patient's QoL was assessed with the 10-item DLQI questionnaire, yielding a total possible score of 0–30; a higher score reflects a greater effect of disease on QoL [36].

Symptoms of anxiety and depression were assessed using the Hospital Anxiety and Depression Scale (HADS) [37]. HADS consists of 14 items, seven items each for anxiety (HADS-A) and depression (HADS-D) subscales, and is focused mainly on symptoms of generalized anxiety disorder and anhedonia, respectively.

Study endpoints

The primary endpoint of this post hoc analysis was the effect of secukinumab in achieving MDA after 16 and 24 weeks of treatment. MDA was assessed following the established criteria: PASI 90 and DLQI 0/1 (MDA-1), PASI score ≤1 or BSA <3% (MDA-2), or IGA x BSA (MDA-1a and MDA-2a), for which two different cut-off values were considered, representative of reaching MDA and extrapolated through the backward analysis of IGA x BSA values obtained in patients who had reached MDA-1 and MDA-2 [19, 22].

The secondary endpoint was to evaluate determining clinical factors that influence reaching MDA at Week 16.

Statistical analysis

The safety set included all enrolled patients who were given at least one dose of secukinumab at 300 mg with available baseline PASI assessment.

The percentage of patients reaching MDA-1 was calculated at Weeks 16 and 24, as the DLQI was collected at baseline, Week 16, and Week 24 only; MDA-2 was calculated at each study visit (i.e. every week until Week 4 and q4w thereafter). Demographic and clinical determinants that influence achieving MDA, defined in both modalities, were analysed to observe intra- and inter-group differences.

For the calculation of IGA x BSA (MDA-1a and MDA-2a), several cut-offs to evaluate MDA have been proposed in the literature, but no established and unique cut-off is available [19, 22]. Therefore, to identify the cut-off value for IGA x BSA for each of the two MDA definitions in this post hoc analysis, a Receiver Operating Characteristic (ROC) curve analysis was performed and the optimal cut-off was determined using Youden's index, calculated as sensitivity + specificity–1) [38].

Absolute and relative frequency were calculated for categorical data. Mean, standard deviation (SD) and median values were calculated for continuous variables.

A t-test or Wilcoxon test was used based on data distribution to evaluate differences between patients reaching or not reaching MDA. The Chi-square test was used for frequencies. No multiple corrections were performed and all p values were considered as nominal.

Univariate and multivariate logistic regression models on patients who achieved MDA at Week 16 versus those who did not achieve MDA were used to evaluate the determinant of response. The following covariates were considered: Cw6 status, HADS anxiety and depression score (i.e., HADS-A: i.e., positive vs negative), complement C3, complement C4, and high-sensitivity C-reactive protein (hs-CRP) at baseline.

All analyses were performed with SAS® release 9.4 (64-bit) or later (SAS Institute Inc., Cary NC, USA).

Results

In total, 433 patients enrolled in the safety set of the SUPREME study were considered in this analysis, among them 184 (43%) were Cw6-POS and 246 (57%) were Cw6-NEG; HLA-Cw6 assessment was not performed for three patients. Among the patient series, 384 were evaluable for MDA-1 at 16 weeks and 408 at 24 weeks and 409 for MDA-2

MDA-1 (defined as PASI 90 and DLQI 0/1) and MDA-2 (defined as PASI ≤1 or BSA <3%)

After 16 weeks of secukinumab, 65% of the evaluable population (251/384 patients) reached MDA-1 (figure 1). When stratified according to Cw6 expression, 66% of Cw6-POS patients and 65% of Cw6-NEG patients reached MDA-1 after 16 weeks. At 24 weeks, MDA-1 was achieved by 70% (286/408 patients) of the evaluable population (figure 1), and by 73% and 68% of Cw6-POS patients and Cw6-NEG patients, respectively.

In contrast, a higher proportion of the evaluable population reached MDA-2 after 16 weeks of secukinumab (76%, 310/409 patients) (figure 1), with 79% of Cw6-POS patients and 74% of Cw6-NEG patients achieving MDA-2 when results were stratified according to Cw6 status. Similarly, the proportion of patients who achieved MDA-2 at 24 weeks was higher for the evaluable population (83%, 339/409 patients) (figure 1), and when stratified according to Cw6 status (84% of Cw6-POS patients and 82% of Cw6-NEG patients), than those who achieved MDA-1.

A comparison of the demographic and anthropometric baseline profile of patients stratified according to reaching MDA-1 (PASI 90 and DLQI 0/1) and MDA-2 (PASI ≤1 or BSA <3%) at Week 16 is shown in table 1. For MDA-1 and MDA-2 non-responders, patients were significantly older (p = 0.0001 and p < 0.0001, respectively), and had significantly more weight (p = 0.0011 and p < 0.0001, respectively), a higher BMI (p = 0.0002 and p < 0.0001, respectively) and a larger waist circumference (p = 0.0004 and p < 0.0001, respectively) compared with MDA-1 and MDA-2 responders. A significantly higher percentage of patients with BMI ≥25 were present amongst the cohort of patients who failed to reach MDA-1 and MDA-2 than those who responded (p = 0.0105 and p = 0.0068, respectively).

A significantly higher proportion of patients aged ≥65 years failed to achieve MDA-1 compared with MDA-1 achievers (p = 0.0119), whereas age ≥65 years was not a determinant for reaching MDA-2 (table 1).

Surprisingly, the MDA-2 non-responders included a lower percentage of smokers than those who reached MDA-2 (42.42% vs 48.06%); smoking status was not a determinant for reaching of MDA-1 (table 1).

There were no statistically significant differences in gender, race, height, or geographical area (south vs central vs north Italy) for achieving both MDA-1 and MDA-2 (table 1).

With regards to the disease profile at baseline, patients who failed to reach either MDA-1 or MDA-2 were significantly older at diagnosis (p = 0.0045 and p = 0.0071, respectively) and had a significantly higher prevalence of metabolic syndrome (p = 0.0065 and p = 0.0002, respectively) compared with patients who responded (table 2). The presence of PsA at diagnosis did not affect reaching MDA-2 at Week 16, whereas a significantly greater prevalence of concomitant PsA was identified amongst MDA-1 non-responders versus responders (29.3% vs 14.3%, p = 0.0004). Significantly more MDA-2 non-responders had higher PASI scores at diagnosis (p = 0.0020) and higher IGA scores at diagnosis (59.60% vs 36.77%, p = 0.0003) than responders.

Univariate logistic regression modelling revealed that the absence of depression (p = 0.0015) and anxiety (p = 0.0078), younger age (p = 0.0002), less weight (p = 0.0013), lower BMI (p = 0.0003), and decreased complement C3 serum levels (p = 0.0113) were related to successfully reaching MDA-1 response (table 3). The multivariate regression model showed age and presence of depression as factors influencing the MDA-1 response: younger patients (p = 0.0108) and those without depression (p = 0.0078) had a greater probability of reaching MDA-1.

Factors associated with a greater probability of reaching MDA-2 were identified by univariate logistic regression modelling as younger age (p < 0.0001), less weight (p < 0.0001), lower BMI (p < 0.0001), and lower serum levels of hs-CRP (p = 0.0077) and complement C3 (p < 0.0001) (T=table 3). The multivariate regression model showed age and BMI as factors influencing the MDA-2 response; younger patients (p = 0.0058) and a lower BMI (p = 0.0002) were associated with a greater probability of reaching MDA-2.

MDA as IGA x BSA

Youden's index was defined for all points of a ROC curve (data not shown), and the maximum value of the index was used as a criterion for selecting the optimum cut-off point. The optimal IGA x BSA cut-off values to calculate MDA-1a and MDA-2a determined using Youden's index are shown in table 4.

Considering the cut-off of 0.5 at Week 16 and 0 at Week 24 for MDA-1a, the percentage of patients reaching MDA-1a was 64% and 70%, respectively (figure 1).

Using the cut-off of 2.8 for Week 16 and Week 24 for MDA-2a, the percentage of patients reaching MDA-2a was 74% and 81%, respectively (figure 1).

Discussion

This post hoc analysis of the SUPREME study showed that 70% of the evaluable population achieved MDA-1, defined as a PASI 90 response and DLQI 0/1, and that 83% of the evaluable population achieved MDA-2, defined as PASI ≤1 or BSA <3%, after 24 weeks of treatment with 300 mg secukinumab.

Several factors appear to influence the probability of achieving MDA, regardless of the method used for its calculation; age and age at psoriasis diagnosis, with younger patients and younger patients at diagnosis of psoriasis having higher probabilities to be MDA responders; weight, BMI, and waist circumference, with thinner patients more likely to achieve MDA. These results are not surprising, as it has been widely demonstrated in the literature that psoriasis is a systemic disease characterized by an inflammatory background [39]. Thus, it is reasonable that any condition which worsens inflammation, such as older age or obesity, could negatively influence reaching MDA [40].

The presence of PsA, metabolic syndrome, anxiety, and depression negatively affects MDA response when MDA is set to PASI 90 and DLQI 0/1, whereas, if MDA is set to PASI ≤1 or BSA <3%, a higher PASI score and IGA at baseline are the most adversely influencing factors. High complement C3 serum levels affect the ability to reach MDA, regardless of the method used to calculate MDA, and high serum levels of hs-CRP, in particular, are affected if MDA is defined by PASI ≤1 or BSA <3%.

In a clinical setting, PASI calculation and regular utilization of QoL questionnaires can be somewhat unpractical, thus it seems potentially easier to evaluate MDA through the simple calculation of IGA x BSA, which encompasses two simple measures regularly used in clinical practice. It is therefore crucial to establish specific cut-off values to define MDA calculated through this method. In our post hoc analysis, MDA was also recalculated as IGA x BSA considering two different cut-off values representative of reaching MDA, which were extrapolated through the backward analysis of IGA x BSA values obtained in patients who had reached MDA-1 and MDA-2 [19] and designated, respectively, as MDA-1a and MDA-2a.

After 24 weeks of treatment with secukinumab, there was a clear correlation to PASI 90 response and normalization of QoL in the case of MDA-1a, and low residual skin involvement with PASI

In particular, MDA-1a appears to be more than a generic clinical instrument; it provides useful information on the clinical status of patients that includes not only the residual involvement of the skin but also the impact of the residual disease on patients’ QoL, exceeding the need for DLQI and PASI calculation.

Furthermore, MDA-2a seems to be an even more intriguing index than MDA-1a. It is as easily calculated as MDA-1a, but additionally shows a direct and linear correlation both with hs-CRP and complement C3 serum levels, thus providing indirect information on the improvement of the inflammatory status of the patients. C3 complement fragment is strategically positioned in the complement cascade: it serves as a central ‘hub’ that transduces initiating signals into downstream activation of effectors and rapid amplification of complement responses on cell surfaces, mediating a plethora of pro-inflammatory interactions in inflammatory and immune-mediated skin diseases [41, 42]. It has already been demonstrated that sera and plasma from psoriasis patients showed elevated levels of complement components, including C3. Moreover C3 complement serum levels have been suggested as a potential proteomic biomarker for psoriasis and psoriatic arthritis, which correlates with overall disease activity in psoriatic arthritis [43-45].

Evaluation of MDA using IGA x BSA values, based on the proposed cut-offs, provides indirect information on the ability of patients to reach very relevant treatment goals such as PASI 90 and DLQI 0/1 (MDA-1a) and PASI ≤1 or BSA <3% (MDA-2a), without the need for time-consuming PASI calculations for clinicians, and annoying elaborations of DLQI questionnaires for patients.

MDA (IGA x BSA) indirectly reflects the inflammatory status of treated patients, and provides further information of clinical benefits of on-going therapy, in full accordance with the contemporary vision of psoriasis as a systemic disease with several repercussions on metabolism and the cardiovascular axis [46, 47].

Therefore, in psoriatic patients treated with targeted biologic drugs, the evaluation of MDA (IGA x BSA) could be considered a therapeutic goal, and its use as a standard assessment of therapeutic response should be strongly encouraged in routine clinical practice.

Following these considerations, it seems reasonable to argue that treatment with secukinumab may significantly reduce or limit the inflammatory status of patients, based on the high percentage of patients with psoriasis who achieve MDA after 24 weeks of treatment. This evidence could have significant clinical repercussions in preventing several steps occurring during the so-called “psoriatic march” [48, 49], and positive repercussion on the prioritization of resource allocation between medical fields and within dermatological subspecialties.

This study is limited by the nature of the analysis in that it was a post hoc analysis of data from the SUPREME study and was therefore not pre-specified in the study protocol. It is also unknown whether patients received other systemic therapies before secukinumab as this may have affected the outcome. Notably, patients who failed response to other systemic therapies (i.e. cyclosporine, methotrexate, and PUVA) or with an anti-TNFα were included in the SUPREME study, however, patients were excluded if they had received cyclosporine or methotrexate therapy within four weeks before study start or anti-TNFα therapy within timelines depending on drug half-life [22]. It would also be of interest to validate the findings of this study in data sets from other studies.

In conclusion, patients treated with secukinumab achieved high levels of MDA at Week 16 and Week 24, regardless of the method used to calculate MDA. MDA provides a reliable assessment of disease activity in patients initiating treatment with secukinumab and our findings support the use of MDA to guide treatment decisions during routine clinical care. However, it is important to note that some patients may take longer than six months to achieve MDA. For patients who tolerate therapy and are showing signs of improvement, but have not yet achieved MDA, it may be appropriate to continue treatment for more than six months before switching treatment.

Acknowledgments

Medical writing assistance was provided by Melanie Gatt (PhD), an independent medical writer, on behalf of Springer Healthcare Communications. Medical writing assistance was funded by Novartis Farma SpA.

The patients in this manuscript have given written informed consent to publication of their case details.

Conflicts of interest

The authors have the following conflicts of interest to disclose. Prof. Anna Campanati has received honoraria as speaker, scientific board member, and consultant from: Abbvie, Pfizer, Eli Lilly, Sanofi, Novartis, Leo-Pharma, and UCB, Galderma. Prof. A. Offidani has received honoraria as speaker, scientific board member, and consultant from: Abbvie, Pfizer, Eli Lilly, Sanofi, Novartis, Leo-Pharma, UCB, and Galderma. Dr. Federico Diotallevi has received honoraria as speaker from Novartis and Leo-pharma. Dr. Giulia Radi has received honoraria as speaker from Novartis. Dr. Tommaso Bianchelli has received honoraria as speaker from Sanofi. Dr. Elisa Molinelli has received honoraria as speaker from Abbvie. Dr. Emanuela Martina, Dr. Valerio Brisigotti and Dr. Matteo Paolinelli have no conflicts of interest to disclose. Dr. Cristiano Covi and Dr. Marta Bartezaghi are Novartis employees.