Dermatol Ther (Heidelb) (2019) 9:479–496 https://doi.org/10.1007/s13555-019-0301-6 ORIGINAL RESEARCH Economic Impact of Etanercept in Patients with Psoriasis and Psoriatic Arthritis in Spain: A Systematic Review Lluı́s Puig . Lourdes Rodrı́guez Fernández-Freire . Ramón Burgos-Pol . Ismael Gomez . Carmen Peral . Susana Gomez . Francisco José Rebollo Laserna Received: March 21, 2019 / Published online: May 6, 2019 Ó The Author(s) 2019 ABSTRACT inclusion criteria were economic evaluations (total and partial) and dose optimization studies Introduction: Etanercept (ETN), a highly effec- published in English or Spanish on the use of tive biological agent for the treatment of psori- ETN to treat PSO and PsA for ETN in Spain. asis (PSO) and psoriatic arthritis (PsA), is widely Results: A total of 402 publications were iden- used in Spain. However, evidence of its eco- tified, of which 32 were selected for inclusion in nomic impact is limited, indicating the need for the review; of these 32 publications, 81.3% a systematic review of the economic assess- analyzed PSO (14 full economic evaluations, 5 ments conducted on the use of ETN in the partial economic evaluations and 7 dose opti- treatment of both PSO and PsA in Spain. mization studies) and 18.8% analyzed PsA (1 Methods: A systematic review was carried out economic analysis and 5 dose optimization in PubMed, Embase, Cochrane Library, Health studies). The perspective of the Spanish Technology Assessment reports and not National Health Service (NHS) was used in indexed sources up to November 2018. The 90.0% (n = 18) of the full and partial economic evaluations. The time horizons ranged from Enhanced Digital Features To view enhanced digital 12 weeks to 2 years. Reductions in the Psoriasis features for this article go to: https://doi.org/10.6084/ m9.figshare.8040827. Area and Severity Index (PASI) of 50, 75 and 90% (PASI 50, 75 and 90, respectively) were Electronic supplementary material The online most commonly used as efficacy outcomes in version of this article (https://doi.org/10.1007/s13555- 019-0301-6) contains supplementary material, which is the complete evaluations. The economic impact available to authorized users. of ETN ranged from €9110–14,337/PASI 75 at 12 weeks (50 mg/week) to €82,279/PASI 90 at L. Puig 2 years, depending on the health outcome, time Hospital de la Santa Creu i Sant Pau, Barcelona, horizon and ETN dose used. Only one study Spain determined the cost of using ETN for the treat- L. R. Fernández-Freire ment of PSO (€29,430–52,367/QALY for dose Hospital Virgen del Rocı́o, Seville, Spain 2 9 25 mg/week or 50 mg/week, respectively). Only one partial economic evaluation on PSA R. Burgos-Pol (&) Pharmacoeconomics and Outcomes Research Iberia was identified (NHS perspective), resulting in an (PORIB), Madrid, Spain ETN annual cost of €8585/patient-year. e-mail: rburgos@porib.com Conclusion: Consistent evidence on the eco- nomic impact of ETN for the treatment of PSO I. Gomez  C. Peral  S. Gomez  F. J. Rebollo Laserna Pfizer S.L.U., Alcobendas, Madrid, Spain and PSA in Spain is lacking, mainly due to the 480 Dermatol Ther (Heidelb) (2019) 9:479–496 highly heterogeneous methodology used and use in the treatment of these immune-mediated the broad range of outcomes found in the eco- diseases is limited. We have therefore performed nomic evaluations published to date. a critical and systematic review and analysis of Funding: Pfizer S.L.U. the relevant literature in order to draw conclu- sions on the decision-making process regarding Keywords: Economic evaluations; Etanercept; available economic evaluations of the use of Psoriasis; Psoriatic arthritis; Spain; Systematic ETN to treat PSO and PsA in Spain. review METHODS INTRODUCTION Identification Psoriasis (PSO) and psoriatic arthritis (PsA) are autoimmune diseases that are highly relevant We performed a systematic review of citations both clinically and economically. The overall in the PubMed, Medline and Embase Ovid prevalence of PSO ranges from 0.09 to 11.43%, databases up to November 2018. The search and PsA coexists with PSO in 1.3–34.7% of these strategy was structured around recommenda- patients [1]. In Spain, the prevalence of PSO tions for the performance of systematic reviews stands at 2.31%. This figure has increased over in economic evaluations [9], with the key con- the last decade [2] and is higher in men than in cepts taken into account being population (PSO women (2.7% and 1.9%, respectively). It is esti- and PsA patients in Spain), intervention (ETN) mated that 7% of PSO patients in Spain could and outcomes (economic evaluation/burden of develop PsA, which would equate to approxi- disease). Studies with interventions but no mately 0.2% of the PSO patient population [3]. comparator drug were also eligible for inclusion Not only do these pathologies have a signif- in the review. Subsequently, search terms rela- icant impact on the quality of lives of these ted to the objective of the study were used patients, even when only a small area of the (MeSH and free-text, Boolean operators for the body is affected, but they also represent a sig- performance of simple and combined searches). nificant cost to health services [1]. In Europe in No restrictions were applied for the year of particular, the annualized cost of PSO and PsA publication, type of study or language. may reach international USD 13,132 and USD In order to identify the maximum number of 17,050, respectively (USD-purchasing power references possible, the search was extended to parity [PPP] 2015, hypothetical currency that the Cochrane Library, MEDES databases in makes it possible to compare the purchasing Spanish, National Health Technology Assess- power of different currencies; in this case, the ment Agencies and journals of interest. A Euro with the USD) [4]. manual search was also conducted on abstracts Biological therapies (BT) are a well-estab- and posters in communications presented to lished alternative for the treatment of immune- national and international congresses related to mediated skin diseases [5]. The biological agent the area of interest that had been published etanercept (ETN) is indicated in patients with between 2010 and 2018, namely, the American PSO for whom another systemic therapy is Academy of Dermatology (AAD), the Spanish contraindicated and for those who have not Academy of Dermatology and Venereology responded to or do not tolerate another sys- (AEDV), the American College of Rheumatology temic therapy, as well as in patients with active (ACR), the European Academy of Dermatology and progressive PsA, when the response to a and Venereology (EADV), the Spanish Health previous disease-modifying antirheumatic drug Economics Association (AES), the European treatment was inadequate [6]. Association of Hospital Pharmacists (EAHP), the Although ETN is frequently used in the European League Against Rheumatism (EULAR), clinical setting in Spain to treat PSO and PsA the International Society for Pharmacoeco- [7, 8], evidence of the economic impact of its nomics and Outcomes Research (ISPOR), the Dermatol Ther (Heidelb) (2019) 9:479–496 481 Spanish Society of Rheumatology (SER) and the Compliance with Ethics Guidelines Spanish Society of Hospital Pharmacy (SEFH). This article is based on previously conducted Study Selection studies and does not contain any studies with human participants or animals performed by Inclusion criteria were applied to language any of the authors. (publications in English and Spanish only), the country where the analysis was performed (Spain only), pathologies (PSO and PsA) and the RESULTS type of study (economic evaluations). Publica- A total of 402 publications were identified, of tions that were not related to ETN or to the which 32 were selected for data extraction (26 on pathologies defined by the study, those that PSO and 6 on PsA); of these latter 32 publications, were not developed and conducted in Spain and 53.1% (n = 17) were communications to con- those that were not economic evaluations (e.g. gresses. Of the publications selected, 14 were cost-effectiveness, cost-benefit, cost analysis, classified as complete economic evaluations cost-consequence and cost-minimization stud- (cost-effectiveness or cost-benefit analysis) in ies) were excluded from the analysis. If there patients with moderate–severe PSO, 18.8% (5 on were two publications on the same study, both PSO and 1 on PsA) were classified as partial eco- were selected, and they were jointly presented nomic evaluations (cost and cost-minimization in the analysis of outcomes obtained. analyses) and 37.5% (6 on PSO and 5 on PsA) were PRISMA declaration criteria were applied to classified as dose-optimization studies (Fig. 1). the identification process for duplicated, rejec- ted and selected references [10]. Study Characteristics Data Extraction Complete Economic Evaluations Decision tree modeling was applied in 50% A tool was designed to facilitate the process of (n = 7) of the complete economic evaluations, extracting data exclusively pertaining to ETN for with a time horizon of between 12 weeks and all references published, with the following 2 years [11–17]. With the exception of a solitary parameters: pathology, author–year, type of pub- publication which included evaluations of the lication, type of economic evaluation, study char- direct non-healthcare costs and the indirect costs acteristics, perspective, time horizon, type of costs, owing to productivity loss [18], the Spanish measures of effectiveness used and outcomes. National Health Service’s (NHS) was the per- Each complete economic evaluation grouped spective mainly used. The main measures of studies evaluating at least two different alterna- effectiveness used were the percentage of tives and containing incremental cost data patients obtaining a 50, 75 or 90% improvement relating to a pre-determined effectiveness vari- with respect to the baseline PASI score (PASI 50, able (e.g. responding patient PASI 75 [75% 75 and 90, respectively), quality-adjusted life reduction in the Psoriasis Area and Severity years (QALY) [19], the percentage of patients who Index] at 12 weeks). Each partial economic eval- were successfully treated (ETN maintained from uation included studies containing cost data for the start) after 1 year [13] or the number needed ETN, but the increase in costs was not assessed to treat (NNT) [20]. The incremental efficacy relative to another alternative with respect to a results were extracted from pivotal clinical trials pre-determined effectiveness variable (e.g. cost of ETN versus placebo [11, 14, 17–19, 21], evi- analysis studies). In addition, costs studies eval- dence generated in Spain in a real-life clinical uating the economic impact of the optimization context [22–24] or results taken from previous of ETN doses (dose escalation, reduction or meta-analyses [25, 26] (Electronic Supplemen- spacing) or of switching to biosimilar drugs were tary Material [SEM] Table S1). grouped and analyzed separately. 482 Dermatol Ther (Heidelb) (2019) 9:479–496 Fig. 1 Flow diagram of the publication selection process based on the PRISMA criteria [10]. ETN Etanercept, HTA health technology assessment, PsA psoriatic arthritis, PSO psoriasis Partial Economic Evaluations implementation of optimization protocols Of the partial economic evaluations for moder- (n = 4) [36–39], dose spacing (n = 1) [40], opti- ate–severe PSO, four (n = 505 patients treated mization/escalation strategies (n = 1) [41], with ETN) were based on observational studies inclusion of multi-disciplinary committees in a real-life clinical context [27–30], and one (n = 1) [42] and switching to a biosimilar (n = 1) study used modeling techniques [31]. All of the [43]. The PSO studies [32, 33, 36, 37, 40, 41, 43] studies adopted the perspective of the NHS all included the pharmacological costs with a (only pharmacological costs), with the excep- time horizon of 1 year, with one exception, tion of one cost-minimization study which also namely, a solitary study that used a horizon of considered indirect costs owing to loss of pro- 4 years and failed to specify the type of cost ductivity [28]. The most commonly adminis- included in the analysis [36]. All PsA studies tered ETN regimen was 50 mg/week, followed by (n = 5) [34, 35, 38, 39, 42] used the perspective a regimen of 2 9 25 mg/week or 2 9 50 mg/week. of the NHS, with a time horizon of between We identified only one cost-analysis study 6 months and 7 years (ESM Table S3). that assessed—from the perspective of the NHS—the economic impact of ETN in patients Results of Economic Evaluations with PsA (n = 29 patients treated with ETN) over the course of 1 year [8] (ESM Table S2). Complete Economic Evaluations A PASI 75 score is considered to be a reasonably Dose Optimization satisfactory clinical outcome in the assessment The dose-optimization studies in real-life clini- of PSO. Using this criterion, our analysis of data cal contexts included in our systematic review from the original studies showed that the eco- evaluated the different types of interventions, nomic impact of ETN during the maintenance including dose reduction (n = 4) [32–35], and induction phases was €9110–9370 for those Dermatol Ther (Heidelb) (2019) 9:479–496 483 with PASI 75 response rates at 12 weeks (50 mg/ Data extracted from conference abstracts week) during the maintenance phase and provided a total annual costs for PSO of €12,797 for those with PASI 75 response rates at €15,268/patient-year (year in which the treat- 12 weeks (2 9 50 mg/week) during the induc- ment was started) [27] and the only cost anal- tion phase [11, 12], with the annual cost ysis data conducted for PsA (using the increasing to €23,034 for those with PASI 75 NHS perspective), which yielded a cost result of response rates [22]. Other results found were €8585/patient-year [8] (Table 2). €20,178/year per patient treated successfully [13]. The impact of ETN when considering a Dose Optimization PASI 90 response rate over 2 years as an out- The total annual cost of a reduced ETN regime come measure was €89,279. Analysis of the for the treatment of PSO varied from €4160 sequence of treatments of ETN with other BTs (50 mg/2 weeks) to €8320/patient-year (25 mg/ revealed an impact of €45,672–71,558 for PASI week), whereas the escalated regime increased 90 response rates after 2 years when ETN ther- the annual cost up to €23,773/patient-year [32]. apy was combined with secukinumab and Dose optimization procedures for ETN doses in adalimumab, respectively [16] (Table 1). the treatment of PSO through the implemen- A broad range of different clinical outcomes taion of optimization/escalation strategies and was also found in the selected conference protocols resulted in a saving of €859/patient- abstracts. The cost-effectiveness using PASI 75 year [37] (Table 3). as the clinical outcome over a 1-year time Conference abstracts showed savings of horizon showed an inferior cost-effectiveness €2012/patient in 2 years of ETN use to treat PSO ratio (€17,436/PASI 75 at 1 year [14]). Another by increasing the dosing interval after protocol conference abstract also provided the cost per implementation [36]. Dose spacing in all responder using this clinical outcome, although patients treated with ETN also produced savings the time horizon was not specified (€8710/re- of €15,216/year, although this strategy repre- sponder PASI 75) [17]. ETN’s NNT cost for the sented only 13% of the total saving caused by first year of treatment (2 9 50 mg/week for dose spacing in BTs (adalimumab 69%; inflix- 12 weeks followed by 50 mg/week) ranged from imab 10%, ustekinumab 8%) [40]. Further, one €29,277/NNT (PASI 75) to €226,080/NNT (PASI study found an increase in treatment cost (dif- 100), and from €23,787/NNT (PASI 75) to ference between the theoretical value and the €183,690/NNT (PASI 100) in consecutive years real value) of €4754/patient-year, owing pri- (50 mg/week) [20]. Finally, the only cost-utility marily to the increased number of patients study yielded an incremental cost-utility ratio undergoing dose escalation [41].. The only (expresses the correlation between incremental study on switching to biosimilar drugs to treat costs and QALYs) of €29,430/QALY gained (ETN PSO (reference value of 50 mg/ml ETN vs. 2 9 25 mg/week) and €52,367/QALY gained biosimilar) yielded an annual saving of 18.7% (ETN 50 mg/week) [19] (Table 1). (€6766.20 monthly saving) [43] (Table 3). For PsA, a dose regime strategy led to a total Partial Economic Evaluations saving of €81,949 over 7 years after the dose was The annual cost per patient with moder- changed from 50 to 25 mg/week [38]. When our ate–severe PSO who was treated with ETN ran- analysis was limited to results from conference ged from €4986 (maintenance phase cost in abstracts, the protocol implementation entailed patients receiving intermittent treatment) to a saving of €793–823/patient-year (€11,480/pa- €12,327/patient-year (maintenance phase cost tient-year before protocol implementation in patients receiving continuos treatment) [30]. compared to €10,657–10,687/patient-year after For patients who experienced loss of response to protocol implementation) [34, 39], Further, the ETN treatment, the annual escalation cost lengthening of the dose interval (from weekly owing to dose duplication ranged from €14,580 administration to a 10-day administration) (12-week intensification) to €18,908 (31-week produced an annual saving of €1434/patient intensification)/patient-year [31] (Table 2). [35] (Table 3). Table 1 Results in publications reporting complete evaluations on the use of etanercept to treat psoriasis in Spain 484 First author/year of publication Costs at chosen timepoint Health outcomes (time period) Cost/health outcomes [reference citation] (year of costs) (dosing regimen or biological relationship agent) Blasco/2009 [11] (2008) €2842/patient at 12 weeks (2 9 PASI 75 2 9 25 mg/week or 50 mg/week €9370/PASI 75 at 12 weeks (2 9 25 mg/week or 50 mg/week) (12 weeks): 30.33% 25 mg/week or 50 mg/week) €5683/patient at 12 weeks (2 9 PASI 75 2 9 50 mg/week (12 weeks): €12,797/PASI 75 at 12 weeks (2 9 50 mg/week) 44.41% 50 mg/week) €5683/patient at 24 weeks (2 9 PASI 75 2 9 25 mg/weeks (24 weeks): €11,213/PASI 75 at 24 weeks (2 9 25 mg/week) 50.69% 25 mg/week) Carretero/2009 [19] (ND) €2947 (2 9 25 mg/week) QALY (1 year) ETN 2 9 25 mg/week: €29,430/QALY (2 9 25 mg) 0.100 €7907/patient-year (50 mg/week) QALY (1 year) ETN 50 mg/week: 0.151 €52,367/QALY (50 mg) Ferrándiz/2012 [12] (2010) €2842/patient at 12 weeks (2 9 PASI 75 2 9 25 mg/week or 50 mg/week €9110/PASI 75 at 12 weeks (2 9 25 mg/week or 50 mg/week) (12 weeks): 31.19% 25 mg/week or 50 mg/week) €5683/patient at 12 weeks (2 9 PASI 75 2 9 50 mg/week (12 weeks): €12,797/PASI 75 at 12 weeks (2 9 50 mg/week) 44.41% 50 mg/week) €5683/patient at 24 weeks (2 9 PASI 75 2 9 25 mg/weeks (24 weeks): €11,213/PASI 75 at 24 weeks (2 9 25 mg/weeks) 50.69% 25 mg/week) Galván Banquer/i 2013 [22] (ND) €12,807/patient-year (2 9 PASI 75 (1 year): 55.6% €23,034/PASI 75 at 1 year Castillo Muñoz/2013 [23] (ND) 25 mg/week) Puig/2014 [21] (2014) ND ND €8818 (€8271–9459)/PASI 50 at 12 weeks €12,735 (€11,699–13,900)/PASI 50 at 24 weeks €16,080 (€14,043–18,810)/PASI 75 at 24 weeks Dermatol Ther (Heidelb) (2019) 9:479–496 Table 1 continued First author/year of publication Costs at chosen timepoint Health outcomes (time period) Cost/health outcomes [reference citation] (year of costs) (dosing regimen or biological relationship agent) Ventayol/2014 [24] (ND) €40,160/patient persisting at N/A €40,160/patient persisting at 2 years 2 years Alfageme/2016 [18] (ND) €7026/patient at 12 weeksa PASI 75 (12 weeks): 49%b €14,337/PASI 75 at 12 weeks Puig/2016 [13] (2015) €16,286/patient-year (patient Patients treated successfully: 80.65% €20,178/patients treated treated successfully) Patients treated unsuccessfully (should be successfully at 1 year Dermatol Ther (Heidelb) (2019) 9:479–496 treated with another biological drug): 19.35% Martinez-Sesmero/2016 [14] (2016) ND ND €17,097/PASI 75 at 1 year (only pharmacological costs) €17,436/PASI 75 at 1 year (pharmacological and administrative costs) Blanch/2016 [15] (ND) €23,993/patient at 2 years NNT: €49,375/PASI 90 at 2 years (ETN ? SEC) ETN ? SEC: 1.91 (ETN ? SEC) €24,687/patient at 2 years ETN ? UST: 2.54 €70,674/PASI 90 at 2 years (ETN ? UST) (ETN ? UST) ETN ? INF: 3.19 €23,191/patient at 2 years €66,945/PASI 90 at 2 years ETN ? ADA: 3.60 (ETN ? INF) (ETN ? INF) €23,052/patient at 2 years €77,359/PASI 90 at 2 years (ETN ? ADA) (ETN ? ADA) 485 Table 1 continued 486 First author/year of publication Costs at chosen timepoint Health outcomes (time period) Cost/health outcomes [reference citation] (year of costs) (dosing regimen or biological relationship agent) Puig/2017 [16] (ND) ETN in monotherapy: NNT: ETN in monotherapy: €22,677/patient in 2 years ETN ? SEC: 1.79 €89,279/PASI 90 at 2 years Sequence of treatments: ETN ? UST: 2.20 Sequence of treatments: €22,194/patient at 2 years ETN ? INF: 3.19 €45,672/PASI 90 at 2 years (ETN ? SEC) ETN ? ADA: 3.60 (ETN ? SEC) €22,836/patient at 2 years €56,868/PASI 90 at 2 years (ETN ? UST) (ETN ? UST) €22,214/patient at 2 years €64,124/PASI 90 at 2 years (ETN ? INF) (ETN ? INF) 21,314/patient at 2 years €71,558/PASI 90 at 2 years (ETN ? ADA) (ETN ? ADA) Huete/2017 [20] (ND) First year of treatment: NNT: Cost per NNT in the first year of €12,511/patient-year PASI 75: 2.34% ETN treatment: Successive years of treatment: PASI 90: 4.59% PASI 75: €29,277/NNT €10,165/patient-year PASI 100: 18.07% PASI 90: €57,427/NNT PASI 100: €226,080/NNT Cost per NNT in subsequent years of ETN treatment PASI 75: €23,787/NNT PASI 90: €46,660/NNT PASI 100: €183,690/NNT Dermatol Ther (Heidelb) (2019) 9:479–496 Dermatol Ther (Heidelb) (2019) 9:479–496 487 ADA Adalimumab, ETN etanercept, INF infliximab, ND no data available, NNT number needed to treat, PASI 75, 90, 100 75, 90, 100% reduction in the Psoriasis DISCUSSION In our systematic review the distribution of pub- €8710 (€6,038c–15,619d)/ lications according to pathology was asymmetri- Cost/health outcomes cal, with the majority focusing on PSO (81.3% responder PASI 75 [PSO] vs. 18.8% [PsA]). Of the publications iden- Best-case scenario (upper limit of the 95% confidence interval [CI] for the incremental efficacy of the randomized controlled trial [RCT]) tified, 43.8% were complete economic evalua- relationship tions. The majority of these complete economic evaluations were models based on the results of pivotal clinical trials or prior meta-analyses, with Area and Severity Index score, respectively, PCB placebo, QALY quality-adjusted life year, SEC secukinumab, UST ustekinumab three studies using data in a real clinical context to obtain an incremental cost-effectiveness ratio [22–24]. Although the main measure of effective- ness was the PASI 75 response at 12 and 24 weeks [11, 12, 18, 21] (the end of the induction phase Health outcomes (time period) and the time of assessment of the clinical response to PSO treatment, respectively), a wide range of incremental efficacy measurements were also used (PASI 50, PASI 90, PASI 100, QALY, NNT, patients successfully treated, persisting patients) in addi- tion to various ETN administration regimens (2 9 Incremental effectiveness as this is compared with PCB, which is given an effectiveness of 0 Worst-case scenario (lower limit of the 95% CI for the incremental efficacy of the RCT) 25 mg/week, 2 9 50 mg/week, 50 mg/week)—in some studies not always specified [14–16, 24]— and time horizons (ranging from 12 weeks to ND 2 years). The NHS perspective was adopted in the majority of studies (there was only one total eco- Incremental cost as this is compared with PCB, which is given a cost of 0 nomic evaluation that included indirect costs) and (dosing regimen or biological was restricted almost exclusively to pharmaco- Costs at chosen timepoint logical costs. The cost of induction in Spain was €9110–9370 and €12,797 per PASI 75 responder at 12 weeks at 2 9 25 mg and 2 9 50 mg weekly doses, respectively [11, 12], and €11,213–16,080 per PASI 75 responder at 24 weeks [11, 12, 21] (even though the studies of Blasco et al. [11] and agent) Ferrandiz et al. [12] differ, both sets of authors ND reported practically identical results). A study by Alfageme et al. [18] yielded a cost of €14,337 per PASI 75 responder at 12 weeks (doses not detailed). Other studies reported the annual cost of [reference citation] (year of costs) First author/year of publication reaching PASI 75 or for achieving ‘‘therapeutic success’’ per patient-PASI 75 (€23,034/PASI 75 at 1 year to €20,178/patient treated successfully at 1 Rosado/2018 [17] (2017) year) [13, 22, 23], but these results were difficult to group with others due to methodological differ- Table 1 continued ences, as was the the case with results for PASI 90 patients at 2 years who also used biological drug treatment sequences [15, 16]. The only ETN cost- benefit analysis presented an incremental cost–benefit ratio for the 2 9 25 mg/week regimen d b a c 488 Dermatol Ther (Heidelb) (2019) 9:479–496 Table 2 Results of the partial economic evaluations on the use of etanercept to treat psoriasis and psoriatic arthritis in Spain First author/year of publication Direct costs Indirect Total costs [reference] (year of costs) costs Psoriasis Domı́nguez/2011 [27] (ND) Year during which ETN treatment was N/A Year during which ETN treatment was started (year 1): €15,268/patient-year started (year 1): €15,268/patient-year ETN maintenance year (year 2): ETN maintenance year (year 2): €14,420/patient-year €14,420/patient-year Ruano/2013 [28] (2012) Direct healthcare costs: €380 ± 157/ €14,844 ± 6,179/patient-year patient-year Pharmacological: €14,452 ± 5606/patient- year Consumption of healthcare resources: €251 ± 148/patient-year Direct non-healthcare costs: Transport: €173 ± 293/patient-year Puig/2014b [31] (2013) Escalation of ETN vs. ADA (every 2 weeks): N/A Escalation of ETN vs. ADA (every 2 weeks) Cost of switching to ADA: €13,602/patient- Cost of switching to ADA: €13,602/patient- year year Escalation of ETN: €14,580/patient-year Escalation of ETN: €14,580/patient-year Difference: €978/year (6.7%) Difference: €978/year (6.7%) Escalation of ETN vs. UST (every Escalation of ETN vs. UST (every 3 months) 3 months): Cost of switching to UST: €13,670/patient- Cost of switching to UST: €13,670/patient- year year Escalation of ETN: €14,580/patient-year Escalation of ETN: €14,580/patient-year Difference of €909/year (6.2%) Difference of €909/year (6.2%) Escalation of ETN vs. UST (every 12 weeks): Escalation of ETN vs. UST (every 12 weeks) Cost of switching to UST: €14,681/patient- Cost of switching to UST: €14,681/patient- year year Escalation of ETN: €15,719/patient-year Escalation of ETN: €15,719/patient-year Difference: €1037/year (6.6%) Difference: €1037/year (6.6%) Escalation of ETN vs. INF (every 2 months): Escalation of ETN vs. INF (every 2 months) Cost of switching to INF: €16,763/patient- Cost of switching to INF: €16,763/patient- year year Escalation of ETN: €17,769/patient-year Escalation of ETN: €17,769/patient-year Difference: €1005/year (5.7%) Difference: €1005/year (5.7%) Escalation of ETN vs. INF (every 8 weeks): Escalation of ETN vs. INF (every 8 weeks) Cost of switching to INF: €17,911/patient- Cost of switching to INF: €17,911/patient- year year Escalation of ETN: €18,908/patient-year Escalation of ETN: €18,908/patient-year Difference: €997/year (5.3%) Difference: €997/year (5.3%) Dermatol Ther (Heidelb) (2019) 9:479–496 489 Table 2 continued First author/year of publication Direct costs Indirect Total costs [reference] (year of costs) costs Fernández-Torres/2015 [29] (ND) €244.60 ± 45.20/PASI 75 in 1 week N/A €244.60 ± 45.20/patient-week Ruiz-Villaverde/2016 [30] (ND) 11,299 (95% CI €10,551–12,046)/patient- N/A 11,299 (95% CI €10,551–12,046)/patient- year year Continuous treatment: Continuous treatment: Cost of the induction phase (year 1): Cost of the induction phase (year 1): €12,294/patient-year €12,294/patient-year Cost of the maintenance phase (year 2): Cost of the maintenance phase (year 2): €12,327/patient-year €12,327/patient-year Intermittent treatment: Intermittent treatment: Cost of the induction phase (year 1): Cost of the induction phase (year 1): €10,302/patient-year €10,302/patient-year Cost of the maintenance phase (year 2): Cost of the maintenance phase (year 2): €4986/patient-year €4986/patient-year Psoriatic arthritis Acosta/2012 [8] (ND) €8585/patient-year N/A €8585/patient-year that was higher than those reported in Germany the annual cost per patient reported by the only (€18,154/QALY) [44] and Italy (€25,840/QALY) publication on the use of ETN in the treatment [45], although this could be considered to be an of PsA in Spain is significantly lower than the efficient alternative conditioned to the cost-ef- referenced study (€8,585/patient-year vs. fectiveness thresholds routinely considered in €10,924–17,050 USD-PPP/patient-year) [4]. Spain (€25,000–30,000/QALY) [46, 47]. A third analysis category, namely study type, Similar to the complete economic evalua- includes publications on dose optimization tions, the partial economic evaluations primar- (37.5%), observational and cross-sectional ily focused on treatment of PSO, with only one studies with types of procedures (dose escala- evaluation (cost analysis) presenting economic tion, spacing and optimization protocols, impact data on treatment of PsA. The majority switching to biosimilars) and highly heteroge- of these were observational studies with a time neous cost measures (cost before and after pro- horizon of between 1 and 2 years and restricted tocol implementation, percentage of saving, to evaluations of the costs of ETN treatment. actual or theoretical annual cost) that hinder The perspective in all studies but one was that the standardization of the results, although of the NHS [28], which contrasts with the per- they do highlight the importance of these types spective used in another review on the overall of procedures for health professionals. impact of these pathologies in Europe [4] in There are various limitations to our sytem- which the social perspective was primarily used. atic review which need to be taken into account The annual cost per PSO patient receiving ETN when interpreting the results. First, given the treatment varied widely (€4,986–€15,268/pa- exhaustiveness of the search strategy, a high tient-year) [27, 30], resulting in an annual cost proportion of communications to national and of €18,908/patient if an extension of 31 weeks international congresses were included—a for- of escalated treatment is considered [31], sug- mat which, given its limited extension, rou- gesting that it may be higher than the overall tinely includes little information on cost of the pathology reported in Europe methodological aspects. This approach led us to (13,132 USD-PPP) [4]. In contrast to the above, not evaluate the quality of the publications 490 Dermatol Ther (Heidelb) (2019) 9:479–496 Table 3 Results of the studies on modification of the dosing regimen used to treat psoriasis and psoriatic arthritis in Spain First author/year of Effectiveness results Cost results publication [reference] (year of costs) Psoriasis Fernández-Espı́nola/ Variation of average treatment rest Estimated potential saving due to increasing the 2013/ [36] (ND) time after protocol vs. before dosing interval (more rest) after protocol protocol: 8.5 weeks implementation over 2 years: €2012/patient in Before protocol 2 years Baseline PASI: NR Time until reaching PASI 75: NR Time until disease remission: 22.5 weeks (SD 8.8) Number of restarts per patient: 1.8 (SD 0.6) After protocol Baseline PASI: 23.2 (SD 10.1) Time until reaching PASI 75: 30.4 weeks Time until disease remission: 31 weeks (SD 15 weeks) Number of restarts per patient: 2.6 (0.7) Baniandres/2015 [32] Average dose reduction/patient-year: Saving of ETN (%): 13.8 (total expenditure: (2014) 13.8% €246,046) Patient with standard regimen: 54% Average actual cost for ETN, taking into account all Dose reduction of standard regimen modifications (standard, reduction and escalation): (2 9 25 mg/week) to: €10,252/patient-year 25 mg/week: 4.2% Actual annual cost of the standard ETN regimen: €11,886/patient-year 25 mg/10 days: 8.3% Actual annual cost of the reduced ETN regimen: 50 mg/10 days: 20.8% 25 mg/week: €8320/patient-year 50 mg/2 weeks: 8.3% 25 mg/10 days: €5943/patient-year Dose escalation to 100 mg/week over a period of longer than 12 weeks: 50 mg/10 days: €5943/patient-year 4.2% 50 mg/2 weeks: €4160/patient-year Actual annual cost of escalated ETN regimen: €23,773/patient-year Dermatol Ther (Heidelb) (2019) 9:479–496 491 Table 3 continued First author/year of Effectiveness results Cost results publication [reference] (year of costs) Romero-Jiménez/2015 Dose spacing in patients receiving Annual saving after protocol implementation with [40] (ND) ETN treatment: 37.5% ETN: €15,216/year Doses used vs. doses on the ETN SPC: 92.8% Rı́os-Sanchez/2015 [33] % patients with PASI 75: 90% Actual cost: €10,389/patient-year (ND) Estimated theoretical cost (theoretical prescribed doses): €11,576/patient-year Estimated actual cost (actual prescribed doses): €9445/patient-year Romero-Jiménez/2016 % patients with dose reduction Pre-protocol period [37] (2014) (increased administration interval): Actual cost of the pre-protocol period/patient-year 37.5% (95% CI) €11,661 (€9702–13,620)/patient-year Pre-protocol period Saving corresponding to the pre-protocol period % patients who reached PASI 75: (actual dose vs. standard dose) (95% CI) €225 (€- 60% 1734–2184) patient-yeara % standard dose used (95% CI) 98.1 Post-protocol period (79.8–116.4) Actual cost of the post-protocol period (95% CI) Post-protocol period €11,028 (€8951.60–13,104.40)/patient-year % patients who reached PASI 75: Saving corresponding to the post-protocol period 63% (actual dose vs standard dose) (95% CI) €859 (€- % standard dose used (95% CI) 92.8 1217–2935.40)/patient-year (77.1–108.6) Corregidor/2016 [41] % patients receiving standard regimen Difference between the actual overall cost and the (ND) of ETN (50 mg/week): 51.1% theoretical overall cost: €99,832/year (representing % patients receiving optimized an increase of €4754/patient-year for ETN) regimen: 6.2% % patients receiving the escalated regimen (100 mg/week): 42.7% Rosado/2017/) [43] Same PASI level as before switching Monthly saving of €6766.20 (percentage saving: (ND) to biosimilar 18.7%) No adverse effect was recorded during the process 492 Dermatol Ther (Heidelb) (2019) 9:479–496 Table 3 continued First author/year of Effectiveness results Cost results publication [reference] (year of costs) Psoriatic arthritis Borras-Blasco/2014 [36] Average time receiving treatment Total saving made by switching ETN 50 mg/week to (2012) with ETN 25 mg/week: 0.9 ± 0.2 ETN 25 mg/week (7 years): €81,949 in 7 years. DAS 28/BASDAI Baseline (ETN 50 mg/week): 2.4 ± 1.2 Start of regimen 25 mg/week: 1.7 ± 0.4 Regimen 25 mg/week C 6 months: 2.1 ± 0.4 Borras-Blasco/2014a [34] NR Cost corresponding to the pre-protocol period: (ND) €11,480/patient-year Borras-Blasco/2014b [39] Cost corresponding to the post-protocol period: (ND) €10,687/patient-year (€10,657/patient-year for Borrás-Blasco et al. [36]) Rentero/2016 [42] (ND) NR Intervention period: €883.82 per patient in 6 months Pre-intervention period: €824.74 per patient in 6 months Prada-Ojeda/016 [35] NR Saving entailed by switching from the standard (ND) regimen procedure to: 25 mg/week regimen: €3937.96/year 25 mg/10 days regimen: €2503.80/year BASDAI Bath Ankylosing Spondylitis Disease Activity Index, DAS Disease activity Score, N/A not applicable, NR not reported, SD standard deviation, NHS Spanish National Health Service, SPC summary of product characteristics a Statistically significant differences between the pre-protocol period and the post-protocol period (p \ 0.05) selected through a valid tool, such as the Con- different ETN treatment regimens have been solidated Health Economic Evaluation Report- reviewed, as well as the different outcome ing Standards (CHEERS) [48]. Second, the cost measurements, in an attempt to succinctly col- outcomes obtained were not updated to 2019 lect all available information. values (€, 2019), thus hindering comparability with other results. However, given the diversity of the incremental efficacy variables and the CONCLUSION time horizons used (patient-year, patient/PASI 75 at 12 weeks, QALY) in the selected studies, it To conclude, the economic evaluations con- is difficult to unify the results. Third, the ducted in Spain on the use of ETN to treat PSO heterogeneity of this review is assumed, given and PsA should be framed within the context of that two pathologies (PSO and PsA) and the high heterogeneity, mainly due to substantial Dermatol Ther (Heidelb) (2019) 9:479–496 493 differences in the design of the studies per- Data Availability. All data generated or formed to date (e.g. different dosing regimens, analyzed during this study are included in this different efficacy measurements, different time published article/as supplementary information horizons, etc.), yielding a wide range of costs files. and leading to a lack of consistent evidence. Open Access. This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International ACKNOWLEDGEMENTS License (http://creativecommons.org/licenses/ by-nc/4.0/), which permits any non- Funding. Pfizer S.L.U. has unconditionally commercial use, distribution, and reproduction financed the execution of this project and the in any medium, provided you give appropriate journal’s article processing charges. All authors credit to the original author(s) and the source, had full access to the articles reviewed in this provide a link to the Creative Commons license, manuscript and take complete responsibility for and indicate if changes were made. the integrity and accuracy of this manuscript. Authorship. All named authors meet the International Committee of Medical Journal REFERENCES Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of 1. World Health Organization. Global report on Pso- riasis. Ginebra: World Health Organization; 2016. the work as a whole, and have given their http://apps.who.int/iris/bitstream/10665/204417/ approval for this version to be published. 1/9789241565189_eng.pdf. Accessed 27 Oct 2017. Authorship Contributions. All authors have 2. Ferrándiz C, Carrascosa JM, Toro M. Prevalencia de had access to the data and have contributed to la Psoriasis en España en la era de los biológicos. 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