Introduction

Psoriasis is a chronic immune-mediated inflammatory skin disease [1, 2], with plaque psoriasis accounting for more than 80–90% of cases [1, 3]. Plaque psoriasis appears as well-defined, well-demarcated, erythematous plaques [1]. Psoriasis is one of the most common inflammatory diseases of the skin, with an estimated prevalence in Western countries of between 0.6% and 4.8% [4–7]. Notably, results of a recent study suggest that the incidence of the disease in adults has been steadily increasing [2].

Psoriasis is commonly categorized as mild, moderate, or severe, depending on the Psoriasis Area and Severity Index (PASI), the percentage body surface area (BSA) affected, and the Physician’s Global Assessment (PGA) [8]. There is a European consensus decision on the definition of moderate-to-severe psoriasis as BSA >10% or PASI >10 and Dermatology Life Quality Index (DLQI) >10 [9]. Epidemiological studies show that about 25% of patients have moderate-to-severe forms of the disease [10]. Moderate-to-severe psoriasis is associated with significant comorbidity [3, 11, 12] and has been shown to severely impair quality of life (QoL) of affected patients [3, 13–15]. Moreover, psoriasis is associated with high costs, including those associated with treatments. These costs have increased recently, as the treatment options for psoriasis have expanded to include biological systemic agents, most recently secukinumab [16, 17]. However, despite clear evidence of their value in the treatment of moderate-to-severe plaque psoriasis, access to these agents remains limited to centers originally involved in the Psocare network in Italy.

Objective and Methodology

The aim of this review was to present an overview of the current epidemiological data, the clinical and socioeconomic burden of moderate-to-severe psoriasis and its comorbidities, and available treatments in the context of current treatment guidelines and access to treatment. This is a narrative review and so a systematic search strategy was not performed. Ad hoc literature searches were carried out to find the most recent and relevant data and guidelines on this topic. Additional information came from a meeting of an Italian advisory board, which included a pharmacoeconomics expert, clinical dermatologists, and hospital pharmacists, convened to define the impact in terms of organization, management, and costs of secukinumab for the treatment of patients with moderate-to-severe plaque psoriasis who are eligible for systemic therapy. This article is based on previously conducted studies and does not involve any new studies of human or animal subjects performed by any of the authors.

Burden of Disease

Psoriasis is associated with a substantial burden, due to significant comorbidity, severe impact on QoL, and high costs, both direct and indirect. It is a chronic disease, for which there is no cure and hence patients need lifelong care.

Comorbidities

Patients with psoriasis are likely to suffer from comorbidities such as psoriatic arthritis (approximately 20%) [12]. Moreover, 50% of patients suffer from fingernail psoriasis and 35% from toenail involvement [18]. Psoriasis has also been shown to be associated with a number of other chronic inflammatory conditions, thought to be due to common pathogenic mechanisms. More specifically, the incidence of inflammatory bowel disease is higher in patients with psoriasis than in the general population [18–20], and there is a suggested link between multiple sclerosis and psoriasis, as psoriasis is more common in those with multiple sclerosis than in control subjects [21].

Patients with psoriasis are more likely to be overweight, have diabetes, hypertension and dyslipidemia, and often have metabolic syndrome, with an associated increase in risk of cardiovascular morbidity and mortality [3, 18, 22–27]. Additionally, patients with psoriasis are at increased risk of stroke [28] and myocardial infarction [29]. Importantly, mortality associated with myocardial infarction or stroke is 2.6-times higher in patients with early and frequent hospital admissions for psoriasis [30]. Severe psoriasis has also been shown to be associated with an increase in overall mortality risk (hazard ratio 1.5; 95% confidence interval 1.3–1.7) [31], as well as reduced life expectancy [31].

Psoriasis also has a significant psychological and emotional impact on patients and is associated with an increased incidence of mood disorders such as anxiety and depression [11, 32–34]. As many as 60% of psoriasis patients receive a diagnosis of depression [11], and psoriasis has also been found to be associated with suicidal ideation [33].

Quality of Life

Studies have shown that the impairment of health-related QoL (HRQoL) in patients with psoriasis is comparable with that due to hypertension, diabetes, cancer, depression, and heart disease [3, 13, 15, 35]. The negative impact of psoriasis on patient QoL can be attributed to the fact that it interferes with many day-to-day activities, activities related to work/school and leisure time, and impacts interpersonal and social relations [14]. Disease symptoms such as itching and pain can interfere with ordinary day-to-day activities such as washing, dressing, and sleeping, and psoriasis on the hands and feet can hinder many activities of daily living [36].

A study performed in Italy in 11 centers of the Psocare program showed that at least 50% of the assessed patients reported a minimum 20% decrease in their QoL related to their health state [15]. Factors associated with these decreases in QoL include frequent medical appointments, hospitalization, missing work, and reduced productivity [37]. The most important determinants of the impact of psoriasis on HRQoL are the sites affected and patients’ attitude to their condition [13]. QoL reduction is greater if visible areas, the soles of the feet, and nails are involved [38–41]. Unfortunately, stigmatization is frequently experienced by patients with psoriasis, with associated reductions in QoL [42, 43].

Cost Burden

Psoriasis has high direct, indirect, and intangible costs—the more severe the disease the higher the costs [44]. Direct costs of psoriasis include those related to prescription drugs, hospital admissions, medical examinations, phototherapy, laboratory tests, and the costs of the over-the-counter products [45]. The indirect costs associated with psoriasis include those related to reduced work productivity, due to days of work missed because of the disease, and the time required for medical examinations and non-pharmacological treatments, such as phototherapy and prescribed diagnostic procedures [45]. Key cost drivers in psoriasis include costs due to hospitalization, pharmaceutical products, and physician visits. Patients with the most severe psoriasis account for a disproportionate amount of total psoriasis costs [46]. Additionally, psoriasis has been shown to have a significant impact on productivity and income [47, 48], and more than half of all patients with psoriasis report missing an average of 26 days of work per year [47].

Costs associated with psoriasis are high worldwide, indicating a continued need for treatments that offer good value for money. In 2004, the annual total cost (direct and indirect) of psoriasis in the US alone was approximately US$1.40 billion [49]. Among European countries, recent studies reported annual total costs per patient of €11,928 in Sweden [50], €8372 in Italy [45], and €2866–6707 in Germany [51]; this cost was estimated to be CDN$7999 in Canada [52].

Treatment

The therapeutic approach to psoriasis depends on disease severity. The treatments available include topical drugs, phototherapy, systemic drugs such as methotrexate and, more recently, biological drugs. Treatment of psoriasis on limited areas of skin is initiated with topical therapies or a combination of potent topical steroids and calcipotriene (a form of vitamin D) [53]. Topical therapies for mild psoriasis include coal tar, anthralin, vitamin D analogues, retinoids, and calcineurin inhibitors (tacrolimus and pimecrolimus) [53]. Patients who do not respond to topical therapy, or who have lesions covering >10% of their BSA, are candidates for light therapy, conventional systemic therapy, or biologicals [54, 55]. Conventional systemic treatments include methotrexate, cyclosporine A, acitretin, and fumaric acid esters, which are associated with a number of side effects and organ-specific toxicity [3, 18].

Biological Agents

There are now several biological agents available for the treatment of patients with moderate-to-severe psoriasis (Table 1). Etanercept, infliximab, adalimumab, and ustekinumab have all been shown to be effective, easing symptoms and improving QoL [56]. Secukinumab has recently been added to the list of approved biologicals for the treatment of plaque psoriasis [16, 17]. Compared with conventional systemic treatments, biologic drugs have reduced toxicity, lack of drug interactions, and fewer contraindications [56, 57].

Table 1 Summary of biologic agents approved in Europe for use in moderate-to-severe psoriasis [84]
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The licensed indication for etanercept, infliximab, adalimumab, and ustekinumab is ‘treatment of patients with moderate to severe chronic plaque psoriasis who have failed to respond to, or who have a contraindication to, or are intolerant to other systemic therapies including cyclosporine, methotrexate, and psoralen with ultraviolet-A light (PUVA)’ [56, 58]. However, as ustekinumab was introduced later than the tumor necrosis factor antagonists, and due to the limited experience with this agent relative to other biologicals, it has been recommended as second-line biologic therapy for psoriasis by the British Association of Dermatologists [58]. There have been three cases of confirmed progressive multifocal leukoencephalopathy with efalizumab, with consequent withdrawal of the European marketing authorization for this agent by the European Medicines Agency (EMA) [58].

New Therapeutic Approaches

Until recently, biological drugs were indicated in moderate-to-severe psoriasis where there was no response to, and/or the presence of intolerance or contraindications to, traditional systemic therapies. However, this has now changed with the EMA and US Food and Drug Administration (FDA) approval in January 2015 for secukinumab as first-line systemic treatment of moderate-to-severe plaque psoriasis patients [16, 17].

Secukinumab is a first-in-class fully human anti-interleukin (IL)-17 monoclonal antibody [59–61]. Secukinumab targets the IL-17A ligand and acts by inhibiting the interaction of the IL-17A ligand with its receptor, which is expressed on various cell types [60]. This inhibits release of pro-inflammatory cytokines, chemokines, and mediators of tissue damage, reducing IL-17A-mediated processes involved in autoimmune and inflammatory diseases such as psoriasis. Secukinumab is the first biological drug approved for the first-line treatment of patients eligible for systemic therapy; all other available biological agents for psoriasis are approved as second-line systemic therapy.

The efficacy of secukinumab for moderate to severe plaque psoriasis is supported by the findings of the ERASURE (n = 738) and FIXTURE (n = 1306) trials (ClinicalTrials.gov identifiers: NCT01365455 and NCT01358578, respectively), both of which were 52-week phase III trials, the first one placebo-controlled and the second one with an active comparator (etanercept) [62]. In these trials, secukinumab was given as a 300-mg or 150-mg dose once weekly for 5 weeks, then once every 4 weeks. Secukinumab was superior to placebo for the co-primary endpoints of ≥75% reduction in PASI (PASI 75) and a score of 0 or 1 on a 5-point modified investigator global assessment scale (Table 2). Two additional placebo-controlled randomized trials, JUNCTURE (n = 182) [63] and FEATURE (n = 177; ClinicalTrials.gov identifiers: NCT01636687 and NCT01555125, respectively) [64], evaluated the efficacy of secukinumab 300 mg or 150 mg administered with an autoinjector or prefilled syringe on moderate to severe psoriasis. In these trials, secukinumab was given once weekly up to week 4, then every 4 weeks, with findings again supporting the efficacy of secukinumab (Table 2).

Table 2 Summary of key phase III clinical trial data for secukinumab
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Importantly, in the FIXTURE trial the efficacy of secukinumab was compared with etanercept, and it was found that secukinumab was significantly more effective than subcutaneous etanercept 50 mg administered twice weekly with respect to the co-primary efficacy end points of PASI 75 and a response of 0 or 1 on the modified investigator’s global assessment at week 12 [62]. Furthermore, the CLEAR trial (n = 676; ClinicalTrials.gov identifier: NCT02074982), a 52-week, multicenter, randomized, double-blind study, compared secukinumab 300 mg, administered weekly for up to 4 weeks then every 4 weeks until week 48, with ustekinumab, with results revealing secukinumab to be significantly superior [65]. Overall, the safety profile of secukinumab has been shown to be comparable with those of etanercept and ustekinumab. In the FIXTURE study, the number of adverse events per 100 patient-years was similar in patients receiving secukinumab 300 mg, secukinumab 150 mg, or etanercept (252.0, 236.4, and 243.4 cases per 100 patient-years, respectively), as was the number of serious adverse events (6.8, 6.0 and 7.0 cases per 100 patient-years) and the number of patients who discontinued due to adverse events (n = 14, 10, and 12) [62]. In the CLEAR study, 64.2% and 58.3% of patients receiving secukinumab or ustekinumab experienced at least one adverse event, and 3% of each treatment group experienced a serious adverse event [65]. A significantly higher proportion of the secukinumab group versus the ustekinumab group in the CLEAR study self-reported no impairment of HRQoL scores due to skin impairment at week 16 (71.9% vs. 57.4%; P < 0.0001) [65].

Other new therapeutic approaches for the treatment of moderate-to-severe plaque psoriasis include apremilast, a phosphodiesterase-4 inhibitor, approved by the US FDA in September 2014 for use in patients who are candidates for systemic therapy [66], with European approval in January 2015 for the treatment of moderate-to-severe chronic plaque psoriasis in adult patients who failed to respond to or who have a contraindication to or are intolerant to other systemic therapy including cyclosporine, methotrexate, or PUVA [67]. Apremilast has not yet been addressed in published guidelines. Other agents in development for the treatment of moderate-to-severe plaque psoriasis include brodalumab (monoclonal antibody against IL-17 receptor A), ixekizumab (a humanized anti-IL-17A antibody) [60], guselkumab and tildrakizumab (antagonists of the p19 subunit of IL-23) [68], and tofacitinib (a Janus kinase inhibitor) [69]. In the AMAGINE phase III clinical trials of brodalumab (AMAGINE-I, -II, and -III, ClinicalTrials.gov identifiers: NCT01708590, NCT01708603, and NCT01708629, respectively), there was some suggestion of an increase in suicide/suicide ideation [70, 71]; on May 22, 2015, Amgen announced that it would terminate its participation in the development of brodalumab because of these events [72], and the AMAGINE clinical trials have been terminated.

Cost Effectiveness of the Biological Agents

Biologicals are an important option in moderate-to-severe plaque psoriasis, but are associated with significant costs and are a considerable strain for the national health systems (NHSs) of various countries. For this reason, many countries have strict criteria for refunding the cost of biologicals. In Italy the expenditure for biologicals used in psoriasis, rheumatic diseases, and oncology represents 13.7% of the drug expenditure for the NHS [37].

Various estimates of annual costs of these therapies have been found to range between US$13,000 and US$30,000 in one study [73], with a more recent study providing estimates of annual treatment costs with biological agents ranging from US$6800 for low-dose alefacept (no longer marketed) to US$56,000 for high-dose ustekinumab [74]. Another study estimated the cost of 1 year of induction and maintenance treatment to be as follows: ustekinumab US$53,909; etanercept US$46,395; and adalimumab US$39,041 [75]. In a recent review of data from high-quality randomized trials (n = 27), cost-effectiveness ratios (determined over a 12-week period) were calculated as cost per patient achieving a PASI 75 response and the cost per patient achieving the minimal important difference in the DLQI score [74]. In this study, intravenous infliximab 3 mg/kg was the most cost-effective biologic agent (Table 3). Although costs of biologics are higher, adherence rates are better and patients require fewer hospitalizations with biologic therapy versus non-biologics; a longitudinal cohort study of 186 patients with psoriasis in the US showed that adherence rates were 0.66 with biologics versus 0.35 with other psoriasis medications (P < 0.001), and the mean number of hospitalizations was reduced from 0.9 in the 6 months before starting biologics to 0.4 in the 6 months after patients started therapy with biologics (P < 0.001) [76]. Italian-based studies have shown that hospitalization costs constitute a significant proportion of total costs; in one study, hospitalization costs were >80% of total costs, and more than 90% of the cost of physician visits, day hospital stays, and hospitalizations were incurred by the 20% of patients who were hospitalized [77]. In another study of Italian patients with moderate-to-severe psoriasis, hospitalization cost was the most significant direct cost associated with treatment, accounting for 30% of total costs [45]. A cost-utility analysis of psoriasis treatment in Italy has shown that etanercept treatment is a cost-effective therapy from the health service perspective and that the cost-effectiveness of etanercept increases with disease severity (incremental cost-effectiveness ratios for moderate-to-severe and severe psoriasis: €33,216 and €25,486 per QoL year, respectively) [78]. A study of adherence to therapy with infliximab, adalimumab, or etanercept in Italian patients with psoriasis, rheumatoid arthritis or Crohn’s disease showed that non-pharmacological costs were reduced in patients who were adherent to therapy versus those who were not (€988 vs. €1255). Taken together, these data suggest that the use of biological therapies to treat psoriasis in Italy reduces healthcare costs.

Table 3 Summary of cost-effectiveness analyses of biological agents for psoriasis based on US pricing [75]
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National Institute for Health and Clinical Excellence (NICE) Guidelines on Biological for Psoriasis

The guidance documents produced by the UK National Institute for Health and Clinical Excellence (NICE) provide evidence-based recommendations regarding clinically effective and cost-effective treatments and interventions to improve outcomes for local populations.

At the time of writing, technology appraisal guidance documents were available for adalimumab, etanercept, efalizumab, infliximab, ustekinumab, and secukinumab in the treatment of adults with psoriasis. Regarding etanercept, the NICE guidance recommends etanercept for moderate-to-severe psoriasis not responding to, intolerant to or with contraindications to, standard systemic therapy [79]; efalizumab is no longer included in the NICE guidelines due to its withdrawal from market by the EMA [79]. Evaluation of infliximab found that infliximab was only considered cost effective in the subgroup of patients with very severe disease [80]. Adalimumab is only recommended for people with severe plaque psoriasis when standard systemic therapies have failed [81]; limitations of the clinical effectiveness data and uncertainty around cost-effectiveness results mean that adalimumab cannot be recommended in preference to etanercept, with clinicians needing to exercise clinical judgment in choosing the appropriate therapy.

Ustekinumab is recommended for patients with severe plaque psoriasis not responding to, intolerant of, or with contraindications to standard systemic therapies, although it is noted that no robust differences in cost effectiveness between adalimumab and ustekinumab have been shown [82]. Notably, if etanercept is given continuously, rather than intermittently, ustekinumab is, in comparison, less costly and more effective.

Secukinumab is only recommended by NICE for patients with severe plaque psoriasis when the disease has failed to respond to standard systemic therapies, or the standard systemic therapies are contraindicated or the patient is unable to tolerate them and if the company provides secukinumab with the discount agreed in the patient access scheme [83].

The Italian Situation

Access to Biologicals for Psoriasis in Italy

There is a substantial body of evidence demonstrating the value of using effective therapies for psoriasis. Biologicals have changed psoriasis treatment standards, not only effectiveness, but in allowing the management of patients in an out-patient setting. However, the biological therapies are expensive. In the Italian NHS, biological drugs amount to €30.1 per capita (13.7% of the Italian NHS pharmaceutical expenditure), with biological agents for psoriasis representing 28.9% of the expenditure for biologic drugs [37].

Psocare

In 2005, AIFA, the Italian Medical Agency, formalized the Psocare project and defined the operating methods for prescribing biological drugs in Italy. The Psocare project launched as part of a program promoted by AIFA, based on the philosophy that psoriasis treatment strategies have resulted in the consolidation of habits or behavior amongst doctors rather than in clear outcomes in terms of efficacy [37]. The aim of the project was to evaluate the long-term efficacy and safety of the treatments available, based on comparisons between different care strategies, to obtain realistic estimates of benefits and risks [37]. The Italian Regions identified reference centers for psoriasis, restricting the prescription of biological drugs to Psocare centers. The Psocare project ended in 2009, but despite evidence proving that biologicals are safer and better tolerated than conventional treatments for psoriasis, in Italy, these agents continue to mostly only be prescribed by Psocare centers.

Biological drugs could be managed by territorial specialists who work in collaboration with general practitioners (GPs). A collaboration network between Psocare centers and specialized territorial healthcare units may help achieve Psocare center quality standards in other units. Biologicals could be used in an outpatient setting, while still requiring that the patient be assessed by a dermatologist experienced in internal medicine aspects. Psocare centers could continue with a role in coordinating research activities, in addition to having an organizational, educational, and monitoring role.

Impact of Secukinumab Entry on the Market

The entry of secukinumab among first-line therapy options for psoriasis treatment places the new drug outside currently established treatment paradigms and opens the door for new scenarios. Secukinumab is a potential competitor of cyclosporine and all conventional first-line therapies, with approximately 30–40,000 patients in Italy expected to be eligible for treatment with this agent. The impact and sustainability of secukinumab in the psoriasis treatment market in Italy will largely depend on its position in the cost pyramid, which has methotrexate and cyclosporine at the base, and biotechnological drugs at the top.

The approval of secukinumab as a first-line treatment in moderate-to-severe psoriasis can be seen as the first step in breaking down the fixed therapy pyramid that currently defines the sequence of therapies for psoriasis. The introduction of secukinumab in this position begins to outline a new way of choosing among treatments, according to factors such as effectiveness, tolerability, comorbidity, etc., rather than simply following a set pathway from one treatment to the next. In order to allow for such choice, the well-established ‘silo-type’ patterns of funding and budgets need to be broken down, but in doing so, there is likely to be conflict between the existing therapy pyramid and the traditional economic pyramid in which the cheaper drug is preferred.

It is important to consider the particular strengths of secukinumab, including the excellent results compared with placebo, the good safety profile, and the demonstrated superiority to both etanercept and ustekinumab. Moreover, an important opportunity arising with the change in psoriasis management that may potentially occur with the entry into the market of secukinumab as first-line systemic therapy is that for increased education on, and increased awareness of, psoriasis as a currently under-diagnosed and under-treated pathology. This could be achieved by collaboration between scientific societies and patient associations. This is of particular importance given the current lack of interest from decision-makers and the public regarding the impact of psoriasis on patient QoL. Moreover, the excellent results seen for secukinumab using the reduction of PASI of at least 90% (PASI 90) as an efficacy measure may lead to this becoming the new standard of effectiveness for agents useful for the treatment of psoriasis, although many physicians at present are happy with achievement of PASI 75.

However, there are a number of potential hurdles for secukinumab to overcome in Italy so that it reaches its full potential in the treatment of moderate-to-severe psoriasis. An important potential weakness of secukinumab in terms of access to the drug is the possibility that it could be subject to prescribing restrictions. In Italy, sofosbuvir, used in the treatment of chronic hepatitis C, is subject to monitoring, and prescriptions, including renewals, are restricted to hospitals or specialized physicians. Similarly, denosumab, used in the prevention of osteoporosis-induced bone fractures, is subject to restrictions imposed by AIFA and is only allowed to be used by specialized physicians; this situation is in contrast to that in Germany where denosumab is available from GPs as an alternative to bisphosphonates.

It is likely that prescription of secukinumab will be limited to specialized physicians in Italy, although it is possible that permission to prescribe the drug may be extended to accredited public or private non-Psocare health centers. However, it is unlikely that GPs will be authorized to prescribe the agent. Nevertheless, even in the presence of such restrictions, the access to secukinumab should be guaranteed to all patients that are candidates, while balancing the need to maintain sustainability of the treatment and the safety for patients. While the population of patients in Italy who will be able to access secukinumab is likely to be restricted initially, it is possible that the eligible population will gradually increase as more data on the agent becomes available, with associated changes in the prescribing model. Furthermore, it is expected that distribution channels would change over time to include an increased number of hospitals as well as territorial outpatient services. There are already tools available from the AIFA that could be used to monitor and control health costs, while guaranteeing access and sustainability at the same time; these tools could be used with secukinumab to ensure that it is used appropriately.

Factors which may influence the positioning of secukinumab in the Italian marketplace include the fact that refundability may be limited only to Psocare centers, that clinicians have to choose among several drugs in the same budget and that there have been budget cuts in Italian regulatory framework File F, which already has too many drugs and not enough room for dermatology.

Conclusions

Moderate-to-severe psoriasis is associated with significant comorbidity and has a substantial impact on patient QoL. The introduction of the biological agents for the treatment of moderate-to-severe psoriasis has vastly improved available treatment options for patients, with the addition of secukinumab as a first-line systemic therapy further broadening options. However, the biological agents are costly and pose a significant burden on NHSs. In Italy, the introduction of secukinumab as a first-line therapy should influence a reconsideration of the way dermatological care for psoriasis is organized, moving to a larger involvement of specialists under the coordination of Psocare centers.