Treating moderate to severe psoriasis - best use of biologics.

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Treating moderate to severe psoriasis – best use of biologics Expert Rev. Clin. Immunol. 10(2), 269–279 (2014)

Maeve Lynch*1, Brian Kirby1 and Richard B Warren2 1 Dermatology Department, St Vincent’s University Hospital, Elm Park, Dublin 4, Ireland 2 The University of Manchester, The Dermatology Centre, Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M68HD, UK *Author for correspondence: Tel.: +35 301 221 4189 Fax: +35 301 221 3717 [email protected]

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This review focuses on the efficacy, safety and best use of biologic agents in moderate-tosevere psoriasis. Recommendations from two recent guidelines are summarised. The NICE Guidelines 2012 provide recommendations on best practice for prescribing biologics. The German S3 Guidelines are based on a systematic review of published studies and report the efficacy of biologics and guidelines for treatment. Data on the safety of biologics are available for up to 5 years in psoriasis and are on the whole reassuring. Registry data is evolving and will provide data on safety to help inform long-term monitoring of patients with psoriasis on biologics agents. New anti-interleukin-17 (IL17) and anti-IL17RA biologics are in Phase 3 clinical trials and may prove to be more effective than existing biologics. KEYWORDS: biologics . efficacy . psoriasis . registries . safety

Psoriasis is a common immune-mediated skin disease affecting 1.3–2.2% of the UK population [1], with chronic plaque psoriasis being the most common (90%) form [2]. The vast majority of patients have mild psoriasis, although around 20–30% of patients have more severe involvement that warrants consideration of systemic therapy [3]. Psoriatic arthritis (PsA) is found in approximately one-third of patients with severe cutaneous disease [4]. Psoriasis has a significant impact on the quality of life with those patients with severe disease having a reduced life expectancy of approximately 4 years [5]. Cardiovascular disease accounts for the majority of this mortality. It is unclear if this reduced life expectancy is based on an excess of traditional cardiovascular risk factors present in patients with psoriasis, or if psoriasis itself, a systemic inflammatory disease is an additional independent risk factor. Patients with mild-to-moderate disease are treated traditionally with topical agents. Patients with plaque psoriasis that cannot be controlled with topical agents are often treated with phototherapy, although this has practical and long-term use limitations, which means many patients progress to traditional systemic agents (ciclosporin, methotrexate, acitretin and fumaric acid esters).

10.1586/1744666X.2014.873701

The frequency of prescribing systemic therapies for patients with severe psoriasis is suboptimal; in other words, patients who should receive systemic therapy do not receive appropriate therapy, leading to a significant unmet need [6]. Biologics have revolutionized the management of a subset of patients with more severe psoriasis since their introduction up to 10 years ago. Biologic treatments target a specific step in the pathogenesis of psoriasis and the currently used biologics can be classified into two main categories: TNF-a inhibitors and IL-12/23 inhibitors. TNF-a, IL-12 and IL-23 are cytokines that are important in both adaptive and innate immune function. Four biologics are licensed currently for use in psoriasis and PsA in Europe: etanercept, adalimumab, infliximab and ustekinumab. Two new TNF-a inhibitors, golimumab and certolizumab, are also approved for treatment of PsA. While biologics are expensive (on average £9500 per patient per year in the UK [7], and annual costs between ~US$18,000 and US$48,000 per patient in the USA [8]), they have reduced significantly indirect healthcare costs by reducing hospitalization [9,10], and improved patient outcomes [9] and patient satisfaction [11]. Multiple national and international guidelines have been published recently on psoriasis

2014 Informa UK Ltd

ISSN 1744-666X

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Lynch, Kirby & Warren

management. We present summarized recommendations from two recently published national guidelines [12,13]. The updated German S3 guidelines provide evidence-based treatment guidelines for patients with mild-to-severe psoriasis [12]. A systematic literature review of articles published up to November 2009 was included. The NICE guidelines are based on systematic reviews of the best available evidence with an emphasis on cost–effectiveness, and the recent guidelines summarize publications available up to March 2012 [13]. The Psoriasis Area and Severity Index (PASI) is an index used to define psoriasis severity. It combines the severity (erythema, induration and desquamation) and the percentage of body surface area affected, and has been widely used in clinical trials including trials involving biologic therapies. The Dermatology Life Quality Index (DLQI) is a validated quality-of-life measurement consisting of 10 simple questions with a maximum score of 30 and is used across all skin diseases. The NICE guidelines mandate that etanercept, adalimumab and ustekinumab should only be used when a patient has severe disease (defined by a PASI of 10 or more and a DLQI of more than 10) [13] in those patients who have failed to respond to traditional systemic agents, or are intolerant of, or have a contraindication to these agents [13]). A PASI of 20 or more and a DLQI of more than 18 are recommended for infliximab use. This review focuses on the practical management of biologics focusing on two recent national guidelines and the long-term safety data of biologics.

adalimumab and infliximab. An annual dropout rate in the range of 15–25% was suggested based on limited long-term data [17]. By contrast, a study based on the Danish registry DERMBIO demonstrated that in anti-TNF-a-naı¨ve patients, the longest drug survival was observed for infliximab, followed by adalimumab (hazard ratio vs infliximab 3.7; 95% CI: 1.99– 6.89) and etanercept (hazard ratio vs infliximab 3.18; 95% CI: 1.72–5.86) [18]. A retrospective analysis from three Italian academic centers of 650 patients treated for at least 3 months with an anti-TNF-a agent demonstrated that global adherence to treatment after 2 years was >70% [19]. Etanercept again showed a longer survival compared with infliximab and adalimumab. Discontinuation of treatment because of primary (complete lack of failure) and secondary (loss of clinical efficacy after an initial clinical response) loss of efficacy either occurred in 5.2 and 14.5% of patients, respectively, or 4.5% because of adverse events. In a retrospective cohort of 193 patients, etanercept demonstrated drug survival rates of 77, 41 and 30% after 1, 4 and 7.5 years of treatment, respectively [20]. Inefficacy resulted in discontinuation in 34% of cases followed by adverse events (12%) [20]. The major predictors for poor drug survival include female sex [18–20], the type of TNF-a agent used [18,19], previous inefficacy with one or more anti-TNF-a agents [18] and patients who require concomitant rescue therapy with a traditional systemic agent compared with monotherapy with a biologic agent [19]. This information is important in establishing solutions to prolonging drug survival in the future and individualizing therapy for patients.

Choice of therapy

The choice of biologics is directed by the patient’s clinical condition, with the physician focusing on the patient’s likely adherence to treatment, patient co-morbidities (e.g., multiple sclerosis) and speed of onset of drug action. Other factors that influence choice of biologics include physician preference, local and national guidelines and funding agreements. The British Association of Dermatology (BAD) [14] and European treatment guidelines [15] recommend anti-TNF agents as first-line biologic therapy based on available, longer-term safety data, although both of these guidelines are 4 years old. The speed of onset of treatment may influence the choice of biologics. A systematic review analyzed the time to onset of action of the biologic and traditional systemic agents [16]. The time to onset of action was defined as the weighted mean time taken for 25% of patients treated to achieve a PASI-75 (a 75% improvement from baseline in the PASI) response. Infliximab achieved a response in the shortest time (3.5 weeks), followed by ustekinumab (high dose 4.6/low dose 5.1 weeks/not weight adapted), adalimumab (4.6 weeks) and etanercept (high dose 6.6 weeks/ low dose 9.5 weeks). The overall loss of efficacy of biologics with time is well established in the long-term management of psoriasis and is an important criterion directing choice of therapy. A review of 19 clinical trials demonstrated that 5–29% of patients discontinued treatment within the 24- to 30-week treatment period. Drug survival was highest for etanercept, followed by 270

Efficacy

Etanercept is a recombinant fusion protein consisting of the TNF receptor linked to the Fc portion of human IgG1. The efficacy of etanercept has been evaluated by the German S3 guidelines [12]. Sixteen studies that met the inclusion criteria used in the German S3 guidelines, regarding etanercept monotherapy, demonstrated that in patients treated with 2 25 mg or 1 50 mg given subcutaneously once weekly, a PASI-75 was achieved in 35–38% of patients after 12 weeks. Fifty percent of patients treated with 2 50 mg subcutaneously achieved PASI-75 after 12 weeks. The response to etanercept is maximal at 6 months after initiation of treatment. Etanercept efficacy is maintained up to 7.5 years [20]. If patients do not achieve a PASI-75 within 12 weeks of commencing treatment, or a PASI-50 and a five-point reduction in DLQI from the start of treatment, NICE recommend to discontinue etanercept [13]. Etanercept is the only biologic approved by the European Medical Agency for the treatment of juvenile psoriasis (from the age of 6 years) [21]. One Phase III study of 211 patients compared etanercept 0.8 mg/kg body weight (to a maximum of 50 mg) once weekly with placebo for 12 weeks, followed by a 24-week open-label extension period and a subsequent 12-week randomized withdrawal-retreatment period. At week 12, 57% of patients treated with etanercept achieved a PASI-75 response compared with 11% of patients who received placebo (p < 0.001). During treatment with open-label Expert Rev. Clin. Immunol. 10(2), (2014)


Treating moderate to severe psoriasis

etanercept, four serious adverse events occurred in three patients (infections in three cases), and resolved without sequelae [22]. Adalimumab is a fully human monoclonal antibody against TNF-a. Adalimumab was evaluated in seven studies by the German S3 guidelines [12]. In patients treated with adalimumab 80 mg subcutaneously, followed 1 week later by 40 mg every other week, PASI-75 is achieved in 71–80% of patients treated after 12–16 weeks. The efficacy of adalimumab has been shown to be maintained for up to 3 years [23]. Combination therapy with methotrexate may prevent the formation of drug antibodies [24]. Treatment with adalimumab should be discontinued after 16 weeks, if there has been an inadequate response (failure to achieve PASI-75 or a PASI-50 and a five-point reduction in DLQI) [13]. In patients with stable chronic plaque psoriasis, etanercept and adalimumab are recommended as first-choice biologic agents based on their favorable risk/benefit profile and ease of administration (subcutaneous injection) by the BAD guidelines [14]. Infliximab is a chimeric monoclonal antibody against TNF-a. Infliximab monotherapy was evaluated in nine studies included in the German S3 guidelines [12]. After 10 weeks of infliximab therapy (5 mg/kg of body weight), PASI-75 was achieved in 75–88% of patients [12]. The RESTORE 1 study compared infliximab with methotrexate as monotherapy in psoriasis and involved 868 patients. At week 16, PASI-75 was achieved in 78% of infliximab-treated patients compared with 42% of methotrexate-treated patients (p < 0.001). Patients who switched from methotrexate to infliximab at week 16 demonstrated at week 26 a similar response to those originally treated with infliximab [25]. RESTORE 2, an extension study of RESTORE 1, compared continuous and intermittent infliximab therapy. The study was terminated early, as discussed in detail below. No formal efficacy analyses were conducted, although 80% of patients treated continuously achieved a PASI-75 response at 52 weeks compared with 47% in the intermittently treated group [26]. The response to infliximab has been shown to be maintained in 41–75% of patients over 3 years [27]. Infliximab has demonstrated good drug survival rates, with 70% of 144 patients treated remaining on infliximab therapy after 4 years in a study involving patients in the Danish psoriasis registry DERMBIO [18]. This drug survival rate compared favorably with patients treated with adalimumab and etanercept, both of which had a drug survival rate of 40% over 4 years [18]. Combination therapy with methotrexate may help to prevent the development of neutralizing antibodies. Infliximab should be discontinued after 10 weeks, if patients have an inadequate response (failure to achieve PASI-75 or a PASI-50 and a five-point reduction in DLQI) [13]. In patients with psoriasis requiring rapid disease control, adalimumab and infliximab are recommended as first-choice biologic agents based on their speed of onset of action and good efficacy by the BAD guidelines [14]. For patients with unstable or generalized pustular psoriasis, infliximab is recommended for rapid disease control based on limited available evidence [14]. www.expert-reviews.com

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Ustekinumab is a fully human monoclonal antibody that binds to the p40 subunit of IL-12 and IL-23. Ustekinumab has been evaluated in three studies included in the German S3 guidelines [12]. After treatment with ustekinumab 45 mg subcutaneously in weeks 0 and 4, PASI-75 was achieved in 67% of patients treated after 12 weeks [12]. A favorable treatment response with ustekinumab has been shown to be maintained for up to 5 years [28]. Although the manufacturers recommend an ustekinumab dose of 45 mg for patients weighing £100 kg and 90 mg for patients weighing >100 kg [29], the threshold may be set too high, as one multicenter case cohort study of 129 patients demonstrated that patients weighing 90–100 kg achieved PASI-75 significantly less (29.4%) than the whole group (PASI-75 achieved in 63%) (p = 0.024) [30]. The authors recommend that patients weighing 90–100 kg who fail to respond to ustekinumab 45 mg should be considered for the higher dose regimen. Ustekinumab should be discontinued after 16 weeks if there has been an inadequate response [13]; continuous therapy is recommended if it is tolerated. There are few comparator studies of biologic agents. The majority of the studies compared biologics with placebo. The CHAMPION trial demonstrated that after 16 weeks, 79.6% of patients achieved PASI-75 with adalimumab, compared with 35.5% for methotrexate and 18.9% for placebo [31]. The ACCEPT study compared etanercept and ustekinumab. In the group of patients treated with ustekinumab, PASI-75 was achieved in 67.5% who received 45 mg and 73.8% who received 90 mg at week 12 [32]. In comparison with ustekinumab, PASI-75 was achieved by 56.8% of patients treated with etanercept 50 mg twice weekly [32]. Switching therapy

There are no randomized controlled trials evaluating sequential drug therapy. Patients may be switched to an alternative biologic agent because of lack of response (either primary or secondary), the development of an alternative disease which contradicts further therapy for example, solid organ cancer or an adverse effect. Sequential anti-TNF therapy may be beneficial in patients who have failed a first anti-TNF agent [33,34] and is recommended by the BAD guidelines [14]. A poor response may be due to individual drug structure, metabolism or pharmacokinetics as opposed to a class effect of anti-TNF agents. The development of antibodies to biologic agents may also explain different patient responses to several anti-TNF agents. Infliximab has the highest rate of antibody formation occurring in 28% of treated psoriasis patients [35], 8% of treated patients with adalimumab [36] and 5% with ustekinumab [29] treatment. The Summary of Product Characteristics states that antibodies develop in 7% of patients treated with etanercept [21], although two recent studies did not establish anti-drug antibodies in patients treated with etanercept [37,38]. These studies on the detection of antibodies to biologics were done using ELISA, which may underestimate the detection of anti-drug antibodies. Radioactive immunoassay may be a more sensitive assay for detecting anti-drug antibodies [39]. Primary 271

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failure with an anti-TNF agent may be a result of a class effect and switching to an alternative class such as anti-IL-12/-23 therapy may be beneficial [40]. Secondary failure may be due to the development of drug antibodies, and switching to an alternative anti-TNF agent in this situation may be useful. Registry data in the future should provide evidence on best practice in relation to switching biologics. Safety

Long-term toxicity is a potential risk with all biologic therapies. Patients treated with biologic agents should be enrolled in registries to capture long-term safety data. One registry used to monitor long-term safety is PSONET, which is a network of 10 psoriasis registries [41]. Pooling data from different registries increases the power of the data and analyses information from a more diverse population than individual registries alone. The long-term safety (defined by the author as ‡12 months) of biologics was analyzed in a recent review of randomized controlled trials and extension studies in which patients had received a biologic for ‡1 year [42]. Etanercept was evaluated in two Phase III randomized controlled trials and open-label extension studies. One hundred and eight patients completed 48 weeks of treatment. The incidence of adverse events and serious adverse events, specifically infections, malignancies and cardiovascular events, did not increase over time. Nasopharyngitis (26.1/100 patient-years) and upper respiratory tract infections (14.9/100 patient-years) were most commonly reported. Tuberculosis or opportunistic infections were not reported in association with etanercept. The exposureadjusted event rate for malignancies (1.5/100 patient-years) was similar to the general population. Twelve non-melanoma skin cancers (NMSC) and 7 non-skin malignancies were reported, but these did not increase in frequency over time. The exposureadjusted event rates for all reported cardiovascular and serious cardiovascular events were 2.8 and 1.7 events per 100 patientyears, respectively and remained consistent over time. These data demonstrate that etanercept has a good safety profile in psoriasis over 4 years of treatment [42]. Infliximab was evaluated in two Phase III randomized controlled trials for 12 months or longer and was generally well tolerated up to 78 weeks. One trial evaluated 835 patients over 12 months. Two cases of tuberculosis were reported. Hepatotoxicity associated with elevated transaminases occurred in 3–5% of patients. Lupus-like syndrome occurred in two patients. Malignancies were reported in 12 patients in one trial including 10 skin carcinomas, 1 breast carcinoma and a salpingeal adenocarcinoma. Serious infusion reactions were reported in five patients [42]. A trial of 54 patients with psoriasis and PsA evaluated the safety of infliximab over 78 weeks. Adverse events occurred in 100% of patients and serious adverse events occurred in 12%. The incidence of infections was 86%. One case of herpes zoster was reported and was defined as a serious infection. Hepatotoxicity associated with elevated transaminases occurred in 10% of the population. A malignant tumor was reported in one patient 272

who had a history of benign pleomorphic adenoma of the submandibular gland. Infusion reactions occurred in 14% of patients treated and required discontinuation of therapy in 6%. The long-term data over 78 weeks demonstrate that hepatotoxicity and non-serious infections are common adverse events [42]. In the RESTORE 1 trial, the incidence of serious adverse events was slightly greater in the infliximab group compared with the methotrexate group [25]. In the RESTORE 2 trial, patients were re-randomised to receive either continuous (5 mg/kg 8 weekly) or intermittent (no infliximab treatment until >50% loss of PASI improvement) infliximab. The study was terminated early, after a mean duration of infliximab exposure of 40 weeks, due to the high rate of serious infliximab infusion reactions (8 of 219 patients) occurring in the intermittently treated group compared with those treated with continuous infliximab (1 of 222 patients) [26]. Adalimumab safety data have been reported long-term from two randomized controlled trials. In a Phase II trial of 147 patients, adalimumab was compared with placebo for 12 weeks and then followed by an open-label extension trial. Common adverse events included nasopharyngitis (13% patients) and upper respiratory tract infections (11% patients). Serious adverse events occurred in 22% of patients receiving 40 mg weekly of adalimumab (including migraine, bronchitis, osteoarthritis, kidney stones, palpitations, coronary artery disease, malignant melanoma, breast carcinoma, cerebrovascular accident and gastric adenocarcinoma) and 3% of patients (including accidental fall, malignant melanoma and squamous cell carcinoma) receiving fortnightly adalimumab. In the REVEAL trial of 1212 patients, there were 33 serious adverse events including 12 serious infections (frequently cellulitis or abscess). Adverse events included seven NMSC, two other malignancies, one case each of tuberculosis, congestive heart failure and opportunistic infection. The open-label follow-up extension study to REVEAL followed patients over 3 years of treatment. Rates of infection and malignancy were similar between the REVEAL and extension studies [42]. A comprehensive analysis of patients treated with adalimumab in 13 clinical trials and open-label extension studies demonstrated that up to 5 years on treatment, there was no evidence of cumulative toxicity. Adverse event rates remained stable or decreased with increased mean per-patient exposure. There was no difference in the incidence of adverse events in patients treated with adalimumab every other week compared with patients treated with weekly adalimumab. There was a small but significant increase in the risk of NMSC (significantly increased risk: 1.51 [1.04, 2.11], 95% CI) compared with the National Cancer Institute Survey [43]. An analysis of adalimumab across many different indications (rheumatoid arthritis [RA], juvenile idiopathic arthritis, ankylosing spondylitis, psoriasis, PsA, Crohn’s disease [CD]) in 23,458 patients treated for up to 12 years in 71 clinical trials demonstrated that infections were the most common adverse event and were more commonly found in RA and CD. Malignancy rates were similar to the general population (National Expert Rev. Clin. Immunol. 10(2), (2014)



Cancer Institute Database). Lymphoma occurred more commonly in RA patients than the general population, but was as expected for patients with RA who had not been treated with anti-TNF agents. The incidence rates for NMSC were higher in patients with psoriasis and RA and CD. Overall mortality was equivalent or less than the general population (WHO) [44]. While there were disease-specific variations in adverse event rates on adalimumab, it is reassuring that mortality is not increased and no new safety signals were demonstrated. The long-term safety of ustekinumab was evaluated in two randomized controlled trials and a combined follow-up safety study. The PHOENIX 1 study involving 766 patients demonstrated that patients on maintenance ustekinumab did not have a higher rate of adverse events than those who received interrupted therapy. The most common adverse events were upper respiratory tract infections (13.7% of patients), nasopharyngitis (9.9% of patients), headaches (3.7% of patients) and arthralgia (1.9% of patients). The most common serious adverse events in 749 patients receiving ustekinumab between weeks 12 and 76 were infections (4 cases), malignancies (3 cases) and cardiovascular events (3 cases). In the PHOENIX 2 study, patients were treated with 45 or 90 mg of ustekinumab until 28 weeks and compared with patients treated with placebo. After 28 weeks, partial responders were randomized to receive ustekinumab 12 weekly or 8 weekly. In this study, adverse events were more frequent in patients receiving ustekinumab every 8 weeks (72.7%) rather than every 12 weeks (63%) during the dose intensification stage, but serious adverse events were more common in the patients receiving ustekinumab every 12 weeks. There was no dose–response relationship in the rate of adverse events, serious adverse events or events leading to discontinuation of treatment. The most common serious adverse events in patients treated with ustekinumab were infections (0.7% of patients) and cardiac disorders (0.7% of patients) [42]. The cumulative long-term safety of ustekinumab was reported from a Phase II study, PHOENIX 1, PHOENIX 2 and ACCEPT. During the placebo-controlled periods of a Phase II study, PHOENIX 1 and PHOENIX 2 adverse event rates did not differ between ustekinumab-treated groups (ustekinumab 45 mg: 57.6%; ustekinumab 90 mg: 51.6%) and placebo (50.4%). In the ACCEPT trial similarly, adverse event rates were similar across all groups (etanercept: 70.0%, ustekinumab 45 mg: 66.0% and ustekinumab 90 mg: 69.2%). Serious adverse event rates during the controlled periods of the trials were low across all groups (1.2–1.9%). Over 3 years of follow-up, rates of adverse events and serious adverse events were similar across ustekinumab doses. Another study analyzed 3117 patients who received at least one dose of ustekinumab in the Phase II, PHOENIX 1, PHOENIX 2 or ACCEPT trials and demonstrated safety for up to 5 years on treatment. Rates of adverse events and infections decreased yearly. The rates of mortality and malignancies other than NMSC were similar to that of the general US population [42]. Long-term safety data from PHOENIX 1 have been reported recently over a period of follow-up of 5 years [22]. Over 3104 patient-years of followwww.expert-reviews.com

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up, there was no increased risk of toxicity over time and rates of adverse events, serious adverse events, serious infections, malignancies and major adverse cardiovascular events (MACE) were stable and did not differ between doses [28]. A meta-analysis of randomized controlled studies demonstrated no significant difference in the rate of major MACE with anti-IL-12/-23 agents or anti-TNF agents (adalimumab, etanercept and infliximab) versus placebo throughout the study periods, although the study may have been underpowered to detect a significant difference [45]. Special considerations Combination treatment

There is no approved indication for combining a biologic agent with a traditional systemic agent, although combining methotrexate with a biologic agent is frequently used in clinical practice. Methotrexate may be a recommended comedication with anti-TNF agents in certain circumstances for example, the presence of PsA, to improve efficacy or to prevent the development of neutralizing antibodies [12,14]. The combination of methotrexate (5–15 mg/week) with infliximab and etanercept has been demonstrated as safe and effective [46]. In addition, a retrospective case note review of ustekinumab therapy from 10 centers, which includes information on combining therapy with methotrexate, has been published [30]. A case series of combining methotrexate and adalimumab therapy in psoriasis has been published recently [46]. According to a recent European Consensus Group, combining ciclosporin with biologics should be done with caution due to a lack of efficacy evidence and the potential risk of increased toxicity [46]. Etanercept 25 mg/week combined with retinoid therapy has demonstrated a similar efficacy and safety profile to etanercept 25 mg twice weekly [46], and limited evidence is available on the combination of adalimumab [47] and ustekinumab [48] with acitretin. The European Consensus Group recommend adding a traditional systemic agent to a biologic at the lowest dose (e.g., methotrexate 5–10 mg/week) [46]. There is evidence to support the useful combination of phototherapy with etanercept and less experience but favorable results reported with the combination of phototherapy and adalimumab and ustekinumab, respectively [49]. Pregnancy & lactation

There is no consensus regarding the use of biologics during pregnancy, although the BAD and European S3 guidelines recommend discontinuing biologics prior to conception [14,15]. The manufacturer guidelines advise discontinuing treatment 3 weeks, 5 months, 6 months and 15 weeks before conception for etanercept [21], adalimumab [36], infliximab [35] and ustekinumab [29], respectively. Anti-TNF agents approved for use in psoriasis contain an IgG Fc portion and can cross the placenta in the second and third trimesters potentially affecting the fetus. The half-life of immunoglobulins is up to several months in children increasing the potential risk of infections, and may require delaying scheduled live-attenuated vaccinations [50]. One expert recommends discontinuing therapy before 30 weeks 273


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gestation [51]. The use of infliximab and adalimumab during pregnancy has not demonstrated an increased risk of congenital malformations based on studies from 2010 to 2012 [52]. One review of the US FDA database from 1999 to 2005 reported adverse events in patients treated with anti-TNF agents [53]. There were >120,000 adverse events and 61 congenital anomalies reported in 41 children born to mothers taking etanercept or infliximab, and no reported adverse events in mothers taking adalimumab. These anomalies could be classified into 34 different types and 19 of these were associated with VACTERL (vertebral, anal atresia, cardiac abnormalities, tracheoesophageal fistula, esophageal atresia, renal abnormalities and limb abnormalities) syndrome. One patient was diagnosed with VACTERL syndrome. The authors’ conclusions were challenged because the events in the database were based on voluntary reporting with no known denominator for exposed and nonmalformed live births, therefore, a report of increased risk could not be substantiated [54]. The BAD guidelines advise that breastfeeding should be avoided in patients receiving biologics, although limited evidence suggests that infliximab is not excreted in breast milk [14]. Biologics are class B, and may be used in pregnancy, at the discretion of the obstetrician. Alternative treatment options to biologics during pregnancy are narrowband UVB phototherapy and ciclosporin. Perioperative use of biologics

The evidence to date on the effects of the perioperative use of biologic agents is largely based on small retrospective studies in inflammatory bowel disease and RA patients. Wound dehiscence and wound infection has not been found to be increased on treatment, although these studies are underpowered to detect a difference [55]. The BAD guidelines recommend discontinuing anti-TNF agents at specific times pre-operatively based on four-times of their half-lives and to recommence treatment provided that wound healing is satisfactory, and there is no evidence of infection [14]. Vaccinations

Live vaccines should be avoided in patients on biologic therapy. Patients should not receive live or live-attenuated vaccines less than 2 weeks before treatment, during or for 6 months after discontinuation of treatment with a biologic agent [14]. Inactivated vaccines are safe to administer to patients on biologic treatment, although reduced antibody responses to influenza vaccine may occur on biologic monotherapy [14]. In addition, reduced responses to pneumococcal vaccine may occur in patients treated with a combination of biologics and methotrexate [14]. Patients should be advised to receive the influenza and pneumococcal vaccines while on biologic therapy. New agents

Multiple novel psoriasis agents are under investigation including anti-IL-17 agents, anti-IL-22 agents, IL-20 as a potential therapeutic target, janus kinase and phosphodiesterase 4 inhibitors and A3 adenosine receptor agonists. 274

Anti-IL-17 agents

Three new biologic agents that target IL-17 have undergone Phase II clinical trials and are undergoing currently or have completed Phase III clinical trials. Ixekizumab is a humanized IgG4-type anti-IL-17 monoclonal antibody. It was evaluated in a study of 142 patients who were divided into five groups: four groups were randomized to one of four different doses of ixekizumab and the 5th group was randomized to placebo [56]. PASI-75 was achieved in 82.1, 82.8, 76.7, 29 and 7.7% of patients treated with 150, 75, 25 and 10 mg ixekizumab or placebo, respectively [56]. Adverse events were mild and included upper respiratory tract infection, headache and injection site reaction [56]. The frequency of adverse events was similar across all study groups [56]. There were no serious adverse events during the 12-week study [56]. There are several Phase III studies underway including a head-to-head trial with etanercept, and a head-to-head trial with adalimumab in PsA. Brodalumab is a human monoclonal antibody that targets IL-17RA. Brodalumab was evaluated in a study of 198 patients who were also divided into 5 groups and treated with one of four doses of brodalumab or placebo [57]. PASI-75 was achieved in 45, 85.9, 86.3, 76 and 16% of patients randomized to treatment with 280, 210, 140 and 70 mg brodalumab or placebo, respectively [57]. Common adverse effects were more frequent in the group treated with high-dose brodalumab [57]. Two cases of neutropenia occurred [57]. Brodalumab is undergoing Phase III clinical trials in psoriasis and Phase II and Phase III clinical trials in PsA. One study compares brodalumab with ustekinumab and placebo. Secukinumab, another anti-IL-17 agent is in Phase III of development. It is a fully human monoclonal antibody of the IgG1 kappa isotype. Two Phase II clinical trials have been completed [58,59]. In one dose-ranging study, 125 patients were treated for 12 weeks with a single dose of secukinumb 25 mg or monthly secukinumab 25, 75 or 150 mg or placebo and followed-up for a further 24 weeks. PASI-75 was achieved by 81.5, 57.1 and 9.1% of patients treated with 150 and 75 mg secukinumab or placebo, respectively [58]. Common adverse events were worsening of psoriasis, upper respiratory tract infection and nasopharyngitis [58]. Two patients in secukinumab study groups experienced serious adverse events and two patients discontinued secukinumab due to adverse events [58]. A second regimen-finding Phase II clinical trial evaluated secukinumab 150 mg in 404 patients with psoriasis [59]. Patients were randomly assigned to three different induction regimens (duration weeks 0–12) and two different maintenance regimens (weeks 12–36) [59]. The induction period of early (weeks 0, 1, 2, 4) and monthly (weeks 0, 4, 8) dosing versus placebo demonstrated a better PASI-75 response achieved in 54 and 42% versus 1.5% of patients, respectively [59]. The maintenance regimen of fixed-interval administration versus on-demand administration achieved better PASI-75 responses with 84.6% of patients versus 67.2% achieving PASI-75 at least once from weeks 20 to 28 [59]. The most common adverse effects included worsening of psoriasis, nasopharyngitis and headache [59]. Expert Rev. Clin. Immunol. 10(2), (2014)



Several Phase III clinical trials with secukinumab are in progress including a trial of withdrawal-and-retreatment with secukinumab, a trial evaluating patients with moderate-to-severe palmoplantar psoriasis and a trial involving PsA patients. The FIXTURE study, a Phase III trial, recruited 1306 patients and compared two doses of secukinumab (300 and 150 mg) with etanercept (50 mg) and placebo over 52 weeks [60]. Secukinumab demonstrated superior efficacy to etanercept and placebo with 54% of patients achieving a PASI-90 response within 12 weeks on secukinumab 300 mg compared with 21% of patients on etanercept therapy [60]. The peak response was seen at week 16 with 86.7% of patients in the secukinumab 300 mg group achieving a PASI-75, and 72.4% of patients in this group achieving a PASI-90 [61]. The incidence of adverse events was similar between both arms of secukinumab and comparable with patients treated with etanercept [61]. The most common adverse event was nasopharyngitis, which occurred in approximately a third of patients across all four study arms [61]. The serious infection rate was 1–1.2% in all study arms [61]. There were no signals of an increase of malignancies or MACE in the actively treated groups [61]. Candidal infections occurred in 4.7% of patients on secukinumab 300 mg, 2.3% of patients on secukinumab 150 mg and 1.2% of the etanercept group [61]. The SCULPTURE study, another Phase III study of 966 patients, demonstrated that patients who achieved a PASI-75 response at week 12 were more likely to maintain this response when treated with secukinumab at fixed monthly intervals rather than when recommenced on treatment at the time of relapse [62]. At week 52, 78.2% of patients randomized to secukinumab 300 mg on a oncemonthly fixed schedule maintained a PASI-75 response which was a statistically significant outcome, compared with 67.7% in the secukinumab 300 mg as-needed treatment group, 62.1% in the secukinumab 150 mg once-monthly treatment group and 52% in the secukinumab 150 mg as-needed treatment group [62]. The week 52 PASI-90 rate was 59.7% in patients treated with secukinumab 300 mg once-monthly [62]. Anti-drug antibodies on intermittent treatment was not a concern, as antibodies arose in only three patients on fixed monthly secukinumab treatment and two patients in the asneeded treatment groups and had no effect on clinical response or safety [62]. IL-17 activates the innate immune system driving the immune response against extracellular bacterial (Klebsiella pneumoniae, Streptococcus pneumoniae), parasitic (Toxoplasma gondii) and fungal (Candida albicans) infections [63]. IL-17 and IL-17RA inhibitors may predispose patients to these infections. Patients with chronic mucocutaneous candidiasis tend to have genetic defects in the IL-17-IL-17RA pathway [64]. IL-22 is a proinflammatory cytokine produced by both Th17 and Th22 cells. IL-22 is produced by T cells in psoriasis plaques [65]. If IL-22 is overexpressed in transgenic mice psoriasis lesions develop [66]. Fezakinumab is a humanized monoclonal IgGy antibody to IL-22, which is undergoing clinical trials. www.expert-reviews.com

Review

Non-biologics agents in clinical trials Janus kinase inhibitors

Tofacitinib is a Janus kinase inhibitor that inhibits isoforms 1 and 3 of the JAK kinase. Inhibition of JAK1 and 3 inhibits specific cytokine (including IL-2, -4, -7, -9, -15 and -21) signaling and modulates multiple aspects of the immune response [67]. In addition, inhibition of JAK1 attenuates signaling by proinflammatory cytokines such as IL-6 and IFN-g [67]. Tofacitinib has completed Phase III clinical trials in psoriasis. A Phase IIb trial of oral tofacitinib demonstrated that after 12 weeks of treatment, PASI-75 was achieved by 25% (2 mg twice daily [b.i.d.]; p < 0.001), 40.8% (5 mg b.i.d.; p < 0.0001) and 66.7% (15 mg b.i.d.; p < 0.0001) compared with placebo (2%) [67]. Dose-dependent increases in serum high-density lipoprotein, low-density lipoprotein, total cholesterol from baseline and decreases in neutrophils and hemoglobin occurred [67]. Two tofacitinib 2% ointments were evaluated and each compared with a vehicle in a Phase IIa trial [68]. Tofacitinib ointment 1 resulted in a significantly reduced Target Plaque Severity Score (least squares mean: -54%) versus vehicle 1 (least squares mean: -41.5%) after 4 weeks of treatment, but this improvement was not shown for ointment 2 versus vehicle 2. Changes in neutrophil counts and lipids have been noted with topical tofacitinib. Larger studies are required to evaluate topical tofacitinib in psoriasis. Apremilast is an oral phosphodiesterase 4 inhibitor that increases cyclic adenosine monophosphate levels and ultimately reduces TNF production [69]. The advent of an oral and potentially less costly systemic agent for psoriasis is desirable given the cost involved in the production of biologic injectable agents. Four Phase II trials have been published to date evaluating apremilast in psoriasis and PsA, and Phase III trials are ongoing. The two largest trials demonstrated good short-term efficacy, with 24.4% (20 mg b.i.d.) [70] and 41% (30 mg b.i.d.) [71] of patients treated achieving PASI-75 responses, and apremilast treatment was well tolerated. Phase III trials may establish the best dose to achieve therapeutic effect balanced with the risk of potential adverse events. Expert commentary

Biologics were introduced up to 10 years ago for the treatment of psoriasis. Over the last 5 years, important evidence on longterm safety associated with biologics has been demonstrated through open-label extension studies [42]. Real-life data are being captured by registries and will prove beneficial in the near future [41,72]. While long-term safety data on these relatively novel agents continue to emerge, we have been reassured that mortality is not increased after 5 years on treatment [42–45]. The loss of efficacy with biologics after several years continues to be a problem with numerous potential mechanisms, including immunogenicity [17–20,40]. The association of psoriasis with co-morbidities including cardiovascular disease raises awareness that we should not only be caring for patients’ skin, but every 275


Review


consultation with a psoriasis patient is an opportunity for the primary prevention of cardiometabolic disease. The development of various novel topical, oral and injectable agents under ongoing investigation is exciting [56–59,60,63,67–71]. There is also the potential for stratification of treatments as new molecular technologies combined with more effective bioinformatics allow us to harness data captured from both patients’ skin and blood at early stages of treatment, in order to understand possible signatures of response. Psoriasis is the current frontrunner of the inflammatory skin conditions, where the biologics era has led to a greater profile of the condition and as such further funding for research has followed. This has ultimately improved knowledge of the condition and factors which influence shortand long-term treatment response. Five-year view

Severe psoriasis is a chronic, disfiguring and frequently a liferuining disease, with a reduced life expectancy of approximately 4 years [5]. Psoriasis has had its therapeutic armamentarium transformed through the development of biologic agents. Other agents such as small molecule inhibitors are currently in development. The study of the pathogenesis of psoriasis has evolved to allow the development of agents with targeted mechanisms of action. The ideal therapeutic goal is to develop a treatment paradigm individualized to each patient. The information required to achieve this goal will depend on the collection of clinical, genomic [73] and metabolomic data in longitudinal studies. Biologic registries will provide a robust clinical platform for the generation of such data with aligned bioresources. The advent of various novel agents (being trialed in psoriasis before other diseases) with great therapeutic promise could mean that the approach to treatment could change, with a new direction for treatment goals in psoriasis evolving in the future. Head-to-head comparator trials between new (IL-17) and established biologic agents, including ustekinumab, are in Phase III trials. It remains to be seen if the newer therapies prove to be more efficacious, perhaps most likely at the PASI-90 response. Oral agents that are safe and have less expensive production costs are welcome developments [69]. The US patent for etanercept expired in October 2012 and the other biologic patents will expire over the next 10 years.

Biosimilars will be introduced with less expensive manufacturing costs, which could improve patient access to treatment. Biosimilars will be inherently different to current biologics due to variations in molecular structure, and regulatory authorities have approved scientific guidelines for quality assessment, nonclinical and clinical standards. Data on biosimilars should be comprehensive to support their clinical adoption and use [74]. A novel potential therapeutic target under investigation is IL-20 which is upregulated in psoriasis. Keratinocytes express IL-20R1 and IL-20R2. In a human skin xenograft transplantation model blocking IL-20 with IL-20 antibodies, resolution of psoriasis and inhibition of psoriasis induction occurred. This evidence promotes IL-20 as a potential target in psoriasis treatment [75]. A further target in psoriasis treatment is IL-22, which is a proinflammatory cytokine found in high levels in blood and skin specimens of patients with psoriasis [65]. Transgenic overexpression of IL-22 in mice leads to psoriasis-like skin changes [66]. Fezakinumab is a humanized monoclonal IgGy antibody to IL-22, which is undergoing clinical trials in psoriasis and rheumatoid arthritis. Novel options for topical therapy are much needed and perhaps highlight the greatest unmet need for psoriasis, as many patients have limited body surface area involvement that would be best managed with topical therapy. Financial & competing interests disclosure

M Lynch is in receipt of an unrestricted research grant from Merck-SharpDohme. In the last 3 years, B Kirby is in receipt of unrestricted research grants from Pfizer, Abbvie, Janssen Cilag. B Kirby is a principal investigator for clinical trials for Abbvie, Janssen Cilag, Novartis and MerckSharp-Dohme. B Kirby has acted as a consultant/advisory board member for Pfizer, Abbvie, Janssen Cilag, Novartis and Roche. RB Warren has acted as a consultant and/or speaker for Abbott (now Abbvie), Janssen Cilag, Leo Pharma, Pfizer, Novartis and Schering-Plough (now MSD), all of whom manufacture therapies used in the treatment of psoriasis. He has received unrestricted grant support from Abbvie, Leo and Pfizer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Key issues .

There is an unmet need among patients with severe psoriasis for systemic and biologic therapies.

.

The use of comprehensive and updated guidelines by physicians, based on the highest quality of evidence available, such as the recent NICE 2012 or the German S3 guidelines, is essential for safe and effective prescribing.

.

Long-term data from open-label extension studies demonstrate the safety of biologics up to 5 years, but real-life data from registries will give a true reflection of the efficacy and safety of biologics in their main target population.

.

Newer biologic agents are in Phase III clinical trials including anti-IL-17 and anti-IL-17RA agents with a narrower spectrum of action than anti-TNF agents and promising efficacy.

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Papers of special note have been highlighted as: . of interest .. of considerable interest


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Biologics in nail psoriasis.

Biological therapies in moderate and severe psoriasis: perspectives and certainties.

A Review of Biologic Therapies Targeting IL-23 and IL-17 for Use in Moderate-to-Severe Plaque Psoriasis.

Spotlight on ixekizumab for the treatment of moderate-to-severe plaque psoriasis: design, development, and use in therapy.

Phototherapy, psoriasis, and the age of biologics.

Use of cefoxitin sodium in moderate to severe surgical infections.

Distribution pattern of psoriasis, anxiety and depression as possible causes of sexual dysfunction in patients with moderate to severe psoriasis.

Treatment challenges in the management of moderate-to-severe plaque psoriasis - role of secukinumab.

Brodalumab: an evidence-based review of its potential in the treatment of moderate-to-severe psoriasis.

Management of moderate to severe psoriasis in patients with metabolic comorbidities.

Population Pharmacokinetic Modeling of Secukinumab in Patients With Moderate to Severe Psoriasis.

Apremilast for the Treatment of Moderate to Severe Plaque Psoriasis: A Critique of the Evidence.

Apremilast in the therapy of moderate-to-severe chronic plaque psoriasis.

Burden of Moderate-to-Severe Plaque Psoriasis and New Therapeutic Approaches (Secukinumab): An Italian Perspective.

Systematic review and meta-analysis of ustekinumab for moderate to severe psoriasis: comment.

Long-term Management of Moderate to Severe Plaque Psoriasis Patients With Etanercept: A Case Series.

Patient reported health outcomes and non-adherence in psoriasis patients receiving adalimumab or ustekinumab for moderate to severe plaque psoriasis.

Association between moderate to severe psoriasis and periodontitis in a Scandinavian population.