The Role of Biologics in the Treatment of Psoriasis By Annie Dufour, BSc Phm

Transcription

1 A FREE CONTINUING EDUCATION LESSON OBJECTIVES Upon successful completion of this lesson, the pharmacist will: 1. understand the etiology and pathophysiology of psoriasis 2. understand the mechanism of action of biologic agents as well as precautions, adverse effects and risks associated with their use 3. understand the definition of moderateto-severe psoriasis and the unmet needs of this patient population in traditional treatment 4. understand the place in therapy of biologic agents in the treatment of psoriasis 5. understand the role of the pharmacist in educating patients on the treatment of psoriasis with biologic agents INSTRUCTIONS 1. After carefully reading this lesson, study each question and select the one answer you believe to be correct. Circle the appropriate letter on the attached reply card. 2. Complete the card and mail, or fax to (416) Your reply card will be marked and you will be advised of your results within six to eight weeks in a letter from Rogers Publishing. 4. To pass this lesson, a grade of 70% (14 out of 20) is required. If you pass, your CEU(s) will be recorded with the relevant provincial authority(ies). (Note: some provinces require individual pharmacists to notify them.) THIS FREE LESSON IS APPROVED FOR 2.0 CE UNITS Approved for 2.0 CE units by the Canadian Council on Continuing Education in Pharmacy. File # The Role of Biologics in the Treatment of Psoriasis By Annie Dufour, BSc Phm Annie Dufour is chief pharmacist at the Skin Care Centre Pharmacy at the Vancouver General Hospital. The centre specializes in dermatological preparations. The author, expert reviewers and Pharmacy Practice magazine have each declared that there is no real or potential conflict of interest with the sponsor of this lesson. INTRODUCTION Psoriasis is a proliferative disease of the skin and nails characterized by reddened (erythematous), sharply defined patches with distinctive silvery scales. Its course is chronic and irregular with remissions and exacerbations of unpredictable duration. This lesson will focus on plaque psoriasis or psoriasis vulgaris, which is the most common type, occurring in 80% of patients with psoriasis. The term psoriasis in the remainder of this lesson refers to plaque psoriasis. It is characterized by well-defined, flat-topped plaques with adherent silvery scale and white flakes. The plaques are reddish in colour, erythematous and typically symmetric. When deeper scales are forcibly removed, pinpoint bleeding may occur (Auspitz sign) due to increased vascularization in the plaque. The most commonly affected areas are the extensor surfaces of the body such as the elbows and knees. Other commonly affected areas include: scalp, gluteal cleft, hands, feet, trunk, fingernails, and toenails. Psoriatic arthritis is a complication of chronic plaque psoriasis that affects approximately 5-42% of patients with psoriasis. 38 INCIDENCE/EPIDEMIOLOGY Psoriasis is one of the most common dermatoses with an incidence of 1-3% of the population worldwide, with approximately one million Canadians being affected. 2 It affects both sexes equally, all races, but is primarily seen in Caucasians. It is most common at higher latitudes with colder climates, with the highest incidence occurring in Northern European and Scandinavian countries. 2 The typical age of onset of psoriasis is between 10 and 40 years, but it can start at any age and is rare in children under the age of five. Evaluation of the age of onset reveals that it occurs in two peaks: years and years. 2 There are many different types of psoriasis. A patient generally has one type of psoriasis over the course of their lifetime but it is possible to exhibit more than one type, with one type converting to another depending on the trigger. 1 PATHOGENESIS There are many factors involved in the pathogenesis of psoriasis: 3 1. Defects in the epidermal cell cycle: The epidermal cell turnover rate, SUPPORTED BY AN EDUCATIONAL GRANT FROM April 2006 The Role of Biologics in the Treatment of Psoriasis 1

2 which is the time taken for keratinocytes to migrate from the basal cell layer of the epidermis to the outer stratum corneum, is 6- to 9-fold greater than in the normal population resulting in abnormal cell maturation and keratinization, inflammation and local vascular changes with activated endothelial cells. 3,8 2. Genetic factors. 3. Exogenous triggers: Stress, streptococcal infection, cold weather, trauma to skin, certain medications (eg: lithium, β-blockers, anti-malarials, NSAIDs, ACE inhibitors, terbinafine, abrupt withdrawal of corticosteroids) 4 4. T-cell (T-lymphocyte) mediated autoimmune disorder: T-cells are mistakenly activated and migrate to the skin where they set off a chain of events that lead to rapid growth of skin cells Immunopathophysiology of plaque psoriasis Historically, the pathogenesis of psoriasis was believed to be primarily epidermal hyperproliferation, since the disease manifests as thick plaques. In the late 1970 s, when it was found that the immunosuppressants cyclosporine and methotrexate were effective in improving the symptoms of psoriasis, a positive link was established between psoriasis and the immune system. Subsequent research led to the discovery of T-lymphocytes in psoriatic tissue, which further corroborates this theory. Current belief is that psoriasis may be a primary immunological disorder leading to secondary epidermal proliferation. 8 T-lymphocytes or T-cells are white blood cells that recognize antigens, and through a series of interactions with other antigenic molecules (co-stimulatory pathway), become activated resulting in an immune response. 4 In psoriasis, the T-cells involved are mainly Type 1 helper T-cells (Th1) (CD4+) and Type 1 cytotoxic T-cells (Tc1) (CD8+). Psoriasis is therefore considered to be a T1-mediated T-cell disorder. 9 A more in-depth look at the immunopathogenesis of psoriasis will lead to a better understanding of the mechanism of action of available psoriasis treatments, particularly that of the biologic agents. 9 The psoriatic cascade FIGURE 1: Proposed immunological mechanism of psoriasis pathogenesis (adapted from 3,9) Increased rate of neutrophil migration to area increased production of arachidonic acid In lymph nodes which drain skin: Antigen-presenting cell (APC) binds antigen and presents it to naïve T-cell (T-lymphocyte)* T-lymphocyte (T-cell) recognizes antigen as foreign Ligand pairs form between APC and T-cell: T-cell becomes activated through co-stimulatory pathway (now called memory-effector T-cell) activated memory effector T-cell migrates to the epidermis activated T-cell stimulates the production of cytokines such as: tumor necrosis factor (TNF), interleukins (IL-2, IL-6, IL-8) and GRO-alpha Cytokine release results in Increased rate of keratinocyte production and maturation Recruitment of other T-cells to area * these two steps must occur for activation of T-cells to take place Increased endothelial permeability to lymphocytes Exacerbation of inflammation through positive feedback mechanism FIGURE 2: Sequence of events leading to T-cell activation and psoriasis 2 that results from the pathophysiologic process is depicted in Figure 1 and Figure 2. This pro-inflammatory cascade leads to an increase in cytokine production and in activity of cells including keratinocytes, resulting in psoriatic plaques. Cytokines are hormone-like proteins that regulate the intensity and duration of immune responses and are involved in cell-to-cell communication. In particular, TNF-α is important in the initial 2 The Role of Biologics in the Treatment of Psoriasis April 2006

3 FIGURE 3: Treatment algorithm for psoriasis 7,39,40 STEP 1 Mild to moderate psoriasis STEP 2 Moderate to severe psoriasis Note: Supplementary therapies such as moisturizers, keratolytics and judicious sun exposure (climatotherapy) can be used at any stage of psoriasis treatment. Topical corticosteroids*: Medium to high potency Intralesional corticosteroids: for notably localized fixed plaques STEP 3 Moderate to severe psoriasis (10-20% of body surface area) not sufficiently controlled by Steps 1 & 2 cytokine cascade and in keratinocyte activation. 17 For this reason, it plays a central role in the mechanism of action of some biologic agents. In a normal immune response, this process would result in the elimination of the antigen followed by termination of the immune response. However in psoriatic patients, this T-cell reaction to an antigen persists. PROGNOSIS AND DEFINITION OF PSORIASIS SEVERITY Psoriasis is a lifelong chronic disease characterized by recurrent exacerbations and remissions that are generally more emotionally than physically disabling. Mortality from psoriasis is very rare and is usually secondary to adverse effects Use emollients; avoid triggers such as trauma Combine other topicals: 1st line: coal tar, calcipotriol 2nd line: anthralin, tazarotene Clear Control No improvement Control Clear Clear Control Control Tar + UVB or narrow band UVB No improvement PUVA bath (step 1 agent can be added) No improvement Systemic treatment: Systemic PUVA, acitretin, cyclosporine, methotrexate Biologics if appropriate Continue Clear Stop Rotational: months of cyclosporine, MTX, acitretin *corticosteroids should be tapered upon discontinuation; they can be restarted as needed for flare-ups rotate use of each agent for every months as efficacy agents can decrease over time from systemic treatments. However, morbidity is significant due to the effects of psoriasis on patients quality of life. Clinical depression and suicidal ideation are frequent comorbid illnesses in psoriatic patients. The expression the heartbreak of psoriasis describes the feelings often encountered by patients suffering from the disease. 1 Approximately one-third of patients with psoriasis have a moderate-to-severe form of the disease. 12 The severity of psoriasis is generally defined according to the percentage of body surface area (BSA) affected, with severe psoriasis being classified as 10-20% BSA. In a recent publication, the Canadian Psoriasis Expert Panel suggests that this definition of severity should be reserved for defining study populations and should not be the sole criterion on which severity of psoriasis is clinically assessed. They recommend defining moderate-tosevere psoriasis as having any one the following criteria: 12 10% or more body surface area (BSA) affected less than 10% BSA affected with very thick, red and/or scaly plaques psoriasis causing a significant impact on quality of life, regardless of BSA involved (eg., functional impairment involving hands or feet, marked pruritus or discomfort, psoriasis in certain locations significantly impacting quality of life and self-esteem) less than 10% BSA affected and resistant to therapy The PASI score is a commonly used measurement tool that qualifies the severity of psoriasis based on the size, redness, thickness and scaliness of lesions. A 75% reduction in the Psoriasis Area and Severity Index (PASI) score (PASI 75) is the current benchmark of primary endpoints for most clinical trials of psoriasis. A less stringent endpoint that is commonly used and considered to represent a meaningful change in a patient s quality of life is PASI 50 (50% reduction in PASI score). 13,16 TREATMENT OF PSORIASIS There are many treatment options available to reduce the extent and severity of the disease and improve patients quality of life. They include topical therapies, phototherapy, systemic therapy and the newer biologic therapies. The choice of treatment depends on many factors such as severity of disease, convenience, patient compliance, and financial/geographical accessibility to treatment. 5 In order to minimize adverse effects and toxicities from more aggressive therapies, current treatment recommendations suggest a stepwise approach, starting with topical agents, followed by phototherapy, then systemic agents for severe forms of psoriasis that are resistant to topical treatment and phototherapy (see Figure 3). 12 In clinical practice, treatment is generally customized to each patient based on concomitant diseases, adverse effects and quality of life issues. It is common to April 2006 The Role of Biologics in the Treatment of Psoriasis 3

4 use combinations of treatments or a rotating therapeutic approach in order to prevent adverse events such as tachyphylaxis from overuse of topical corticosteroids, toxicities from systemic agents and skin cancer/damage from phototherapy. 12 Traditional therapy for psoriasis 1. Topical agents 1 Topical agents are the most commonly prescribed psoriasis treatment, with 87% of patients receiving them. Adequate hydration of the skin with effective emollients is key in the treatment of all stages of psoriasis and helps to improve the absorption of other topical agents. The topical agents available for the treatment of psoriasis are: Topical corticosteroids (most commonly used topical agents) Calcipotriol Coal tar products Anthralin Keratolytics (eg: salicylic acid) Tazarotene Topical tacrolimus 2. Phototherapy 1 Phototherapy is one of the oldest and most reliable tools in the treatment of moderate to severe or extensive plaque psoriasis. It is usually combined with other treatment modalities for increased efficacy in clearing psoriasis. It requires a certain level of commitment and motivation from the patient as it can be timeconsuming. The types of phototherapy used are: Broadband UVB phototherapy PUVA photochemotherapy (psoralen and UVA) Narrow band UVB phototherapy (UV Wavelength 311 nm) 3. Traditional systemic therapy 1 Due to the potential for serious adverse effects and end-organ toxicities, systemic therapy with the following traditionally used agents is usually reserved for moderate to severe psoriasis resistant to adequate trials of topical treatments. The most commonly used are methotrexate, cyclosporine and acitretin. 12 Methotrexate (MTX): Methotrexate was the first systemic treatment approved for the treatment of psoriasis. It is still considered to be one of the most effective treatments for psoriasis and psoriatic arthritis. Cumulative doses should not exceed 1.5 g unless a liver biopsy is performed to assess hepatotoxicity. 12 Cyclosporine Acitretin Mycophenolate Hydroxyurea 6-thioguanine Biologic response modifiers Whereas most traditional medications are comprised of combinations of chemicals, biologic response modifiers, or biologics are derived from living materials such as human, animal, plant and microorganism materials. They are a new class of drugs that target the immunological causes of psoriasis through the following mechanisms: 15 Decrease in the number of activated T-cells Inhibition of cell-to-cell interactions that cause activation and migration Immune deviation: induction of changes in cytokine balance Binding and inactivation of postsecretory cytokines involved in keratinocyte activation and up-regulation of the inflammatory process There are currently three biologic agents that have been approved by Health Canada for use in moderate to severe psoriasis in adults who are candidates for phototherapy or systemic therapy: Etanercept (Embrel ) Alefacept (Amevive ) Efaluzimab (Raptiva ) Infliximab is currently under review by Health Canada for this indication. A number of other biologics are currently being investigated for the treatment of psoriasis: siplizumab, HuMax- CD4, daclizumab, and denilukin difitox. 16,17 The nomenclature of biologics is an indicator of their origin and mechanism of action. Drugs that end in mab are monoclonal antibodies. The suffix ximab is for chimeric monoclonal antibodies that are composed of parts of animal and human origin and are known to form neutralizing antibodies. Drugs ending with zumab are humanized monoclonal antibodies and have less or no animal sequences, which makes them less likely to form neutralizing antibodies. Drugs ending in cept involve the fusion of a receptor to the Fc portion of the human immunoglobulin G1 (IgG1). 18 BIOLOGIC AGENTS: DESCRIPTION, ADVERSE EFFECTS AND SAFETY Alefacept, efalizumab and etanercept have all been approved by Health Canada for the treatment of moderate to severe chronic plaque psoriasis in adults who are candidates for phototherapy or systemic therapy. Etanercept also has indications for moderate to severe rheumatoid arthritis in adults, juvenile rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis in adults. Infliximab is under review by Health Canada for the treatment of psoriasis and currently has indications for the treatment of rheumatoid arthritis (RA) and Crohn s disease in adults Due to their recent introduction into the treatment of psoriasis, the long-term safety of biologics in this patient population has yet to be elucidated. 2 Based on the available information, there are important precautions and contraindications for health-care providers to consider when choosing an appropriate agent for their patient. They are presented in Table 3. Special populations: Since none of the biologic agents have been evaluated in pregnant and breastfeeding women, they should not be used in these patient populations. Contraception is recommended for women in childbearing years, and in the case of infliximab for at least 6 months after the last treatment There is no safety data in children under 18 years of age for the treatment of psoriasis. Limited post-marketing surveillance data for the use of etanercept in children 4 years of age with juvenile rheumatoid arthritis (JRA) reports serious infections in 3% of patients and sepsis in 0.8%. During clinical trials, no differences in effectiveness or in incidence of infections or malignancy were observed between elderly patients and younger patients. However, caution should be exercised in this patient population as the elderly are predisposed to 4 The Role of Biologics in the Treatment of Psoriasis April 2006

5 TABLE 1: Summary of efficacy and safety data from major randomized, double-blind, placebo-controlled trials of available biologics Biologic Study design Number of Dose/ length of treatment Time of % of patients reaching agent patients evaluation PASI 75 Alefacept Ortonne et al. 12, mg IM once weekly for 12 weeks 14 weeks 21% vs. 5% placebo Length of 33% vs 13% placebo entire study including 12- week followup period Krueger GG et al. 12, mg IV once weekly x2 12-week After one 12-28% vs 8% placebo courses (12 weeks follow-up between week course courses) After two 12 week courses 40% Efalizumab Gordon K. et al. 33 1,651 1 mg/kg/wk SC for 12 weeks 12 weeks 27% vs 4% placebo Pooled results from 3 trials mg/kg/wk SC for an extension of weeks 44% weeks Leonardi et al. 20 2,700 1 mg/kg/wk SC for 12 weeks 12 weeks n/a Summary of safety data from all clinical trials Gottlieb AB et al mg/kg/wk SC 12 weeks 41% Open-label trial 15 months 50% Etanercept Leonardi CL et al mg twice weekly 12 weeks 49% vs 4% placebo 24 weeks 59% Papp et al weeks 49% vs 3% placebo 24 weeks 50 mg: 54% vs 3% placebo Infliximab Chaudhari U et al Patients assigned to 5 mg/kg or 10 weeks 5 mg/kg: 82% 10 mg/kg IV once weekly or placebo 10 mg/kg: 73% placebo: 18% Gottlieb AB et al Patients assigned to 3 mg/kg, 5 mg/kg 10 weeks 3 mg/kg: 72% or placebo IV at weeks 0, 2 and 6 5 mg/kg: 88% placebo: 6% infections and may be more susceptible to the increased risk of infections with biologics Immunizations: The safety and efficacy of administering vaccines in patients taking immunomodulating agents is unknown. Manufacturers of currently used biologics recommend not giving live vaccines or live-attenuated vaccines to patients receiving a biologic agent. The manufacturers of efaluzimab further recommend withholding the drug for 8 weeks before and 2 weeks after vaccination Hepatotoxicity/nephrotoxicity: There are no reports of end-organ toxicities with alefacept, efalizumab and etanercept. However, there have been rare reports of severe hepatic reactions in patients taking infliximab All agents are contraindicated in patients with known hypersensitivity to the drug or any of the components of its formulation. Clinical data on efficacy and effect on quality-of-life measurements There are currently no direct comparative studies of the biologic agents available in Canada for the treatment of psoriasis. The efficacy data from all major psoriasis clinical trials involving alefacept, efalizumab, etanercept and infliximab have been summarized in Table 1, with PASI 75 as a primary outcome measure. 12 Based on the efficacy data from major clinical trials presented in Table 1, biologic agents are considered to be highly effective in the treatment of moderateto-severe psoriasis. For comparison to traditional systemic treatment, in a small comparative trial in which patients received either methotrexate or cyclosporine for 16 weeks, the percentage of patients reaching PASI 75 was 60% and 72% respectively. 41 In clinical trials, at week of treatment, alefacept has the lowest number of patients reaching PASI 75, at 21%, efaluzimab had 27%, etanercept 49%, and infliximab 88%. The proportion of patients reaching PASI 75 increased at later evaluation times or with subsequent courses of treatment (see Table 1). In the absence of direct comparative studies, some experts have made some observations on the efficacy data of individual agents in order to make a proper therapeutic choice for their patients (see Table 1). 19 Alefacept has a slow onset of action and does not appear to be efficacious in April 2006 The Role of Biologics in the Treatment of Psoriasis 5

6 TABLE 2: Advantages and disadvantages of biologic agents used to treat moderate-to-severe psoriasis Drug Advantages Disadvantages Cost of treatment 12-week course Cost per year 28 Alefacept increased specificity towards memory- not effective in all patients: PASI 75 at 14 $18,000 $18,000 effector T-cells rather than naïve T-cells: weeks: 21% 31 (cost increases could imply less susceptibility to disease response is slow; peak response occurs after with multiple although that is inconclusive at this time 10,37 12 weeks courses) antibody formation not clinically weekly for IM injections in physician's office 19 significant 10,21 bi-weekly monitoring of CD4+ lymphocyte induces long remissions of a median of counts required 10 7 months in clinical trials 10 Efalizumab onset of action as early as 4 weeks 10 potential exacerbation upon discontinuation $5,400 $23,500 PASI 75 at 24 weeks: 44% (0.7%): long-term therapy may be needed 21 (12 injections) antibody formation not clinically clinically significant thrombocytopenia significant 21 reported: platelets must be monitored can be administered subcutaneously by antibody formation does not affect efficacy patient at home once weekly 21 or safety 21 sustained efficacy with no increase in adverse events for up to 15 months 34 Infliximab high efficacy rate: up to 88% of patients administered by I.V. infusion over a period of $12, 500 $27, 000 reached PASI 75 at 10 weeks 21,37 at least 2 hours (12 vials for a rapid onset of action (median to response: neutralizing auto-antibodies decrease efficacy 68 kg patient) 4 weeks) 37 and rarely cause lupus-like syndrome 21 may result in long-lasting remissions tuberculosis testing: possible reactivation of (in trials median of 7 months duration) latent TB 10 well-tolerated in most patients association of TNF-α antagonists with 984,000 patient-years exposure as of 2003 granulomatous infections 21 possible exacerbation of demyenlinating diseases with TNF-α antagonists (eg: multiple sclerosis) increased risk of lymphoma (rare) Etanercept effective for plaque psoriasis and psoriatic injection-site reactions, headache $8,500 $22, 000 arthritis 20 possible reactivation of latent TB 10 (24 vials) in year one, PASI 75 at 24 weeks: 59% possible exacerbation of demyelinating not weight based $18,000 after rapid improvement as early as 2 weeks in diseases with TNF-α antagonists (eg: multiple (maintenance some patients 10 sclerosis) dose usually can be administered subcutaneously by increased risk of infection (particularly required) patients at home in pre-filled syringes 21,24 tuberculosis) 24 antibody formation does not affect lupus erythematosis (rare) efficacy or safety 10 increased risk of lymphoma (rare) over 450,000 cumulative patient-years intended for long-term therapy with 50 mg exposure in controlled clinical trials and once-weekly maintenance dose post-marketing surveillance 21 all patients. 31 It is not considered to be as effective as cyclosporine or methotrexate. 41 However, in clinical trials it was shown to induce remissions of a median of 7 months after treatment in some patients. Efalizumab shows a faster initial clearance than alefacept, but does not induce long remissions at the end of treatment. 19 The results of etanercept for the treatment of psoriasis are considered to be similar to those of efalizumab, but etanercept is effective in treating psoriatic arthritis. 19 Trials of efalixumab for the treatment of psoriatic arthritis were halted due to lack of efficacy. 46 In clinical trials of infliximab, which is not yet approved for the treatment of psoriasis in Canada, more than 80% of patients achieved PASI 75 after about 2 months of treatment. 19 How to choose The choice of biologic agent not only depends on its efficacy rate, but also side effects, contraindications, and convenience of use, cost, and on the patient s individual needs. 19 Factors such as route of administration, laboratory monitoring and frequency of injection are factors that come into play when choosing a biologic agent. Table 2 summarizes the advantages and disadvantages of each agent that would influence a clinician s or a patient s choice. Impact of biologic agents on quality-oflife measurements in psoriasis patients The impact of biologic agents on quality-of-life measurements is well evaluated in most clinical trials. Patients treated with biologic agents have shown significant improvements in various measures of quality-of-life, which appear to be related to the dose and efficacy of the drug. 12,14,20 Patients taking etanercept report improvements in quality-of-life measurements starting as early as 2 weeks after the initiation of treatment. 6 The Role of Biologics in the Treatment of Psoriasis April 2006

7 Furthermore, the results of a recent double-blind randomized trial with etanercept shows not only an improvement of the skin and joint manifestations of psoriasis, but also the accompanying symptoms of depression and fatigue. 20,43 PLACE IN THERAPY OF BIOLOGIC AGENTS 12 According to a recent consensus of the Canadian Psoriasis Expert Panel, the current recommendations for the management of moderate-to-severe psoriasis result in inadequate treatment in those patients and in many unmet needs. In their consensus, the Panel identified the following shortcomings with currently approved therapies and step-wise approach in treating moderate-to-severe psoriasis. Topical therapies patients are generally dissatisfied with their efficacy not practical and time-consuming to apply to extensive psoriasis severe disease may require higher potency or large amounts leading to safety considerations due to systemic absorption and to tachyphylaxis in the case of topical corticosteroids they are effective for treating existing lesions but are not preventative Phototherapy use of maintenance phototherapy (8 or fewer session per month) is controversial due to potential risks of malignant skin cancer adjunctive therapy is usually required to improve efficacy and reduce longterm UV exposure cumulative high doses of PUVA have been associated with squamous cell carcinoma inconvenience of frequent treatments, and travel distance for patients not living near a treatment centre may lead to poor compliance Systemic agents methotrexate: serious side effects such as bone marrow toxicity, hepatic fibrosis and cirrhosis limit its use cyclosporine: dose-dependant renal impairment and hypertension limit its use; prolonged use for over one year is not recommended acitretin: response rates perceived to be lower than other systemic agents; hepatotoxicity and teratogenicity limit its use; alcohol consumption can lead to formation of etretinate thus to prolonged retention Furthermore, the Canadian Psoriasis Expert Panel identified unmet needs of patients with moderate-to-severe psoriasis that might be addressed through a treatment paradigm other than the traditionally used step-wise approach. 12 Among the unmet needs identified: long-term sustainable relief (most patients do not experience prolonged remission without maintenance therapy) safe and convenient control without treatment-limiting toxicities treatment individualized to patients needs: some patients need systemic therapy from the outset patient satisfaction with current therapy: surveys suggest patient dissatisfaction with treatment in moderate-tosevere psoriasis 12 increased recognition of quality-of-life issues in treatment improved education on impact of psoriasis for patients and physicians While acknowledging the need for further assessment of the long-term safety of biologics, based on the currently available efficacy and safety data on monotherapy with these agents, the Panel further suggests a new treatment algorithm that places all categories of therapy for moderate-to-severe plaque psoriasis in parallel rather than in a stepwise progression. 12 COST OF BIOLOGIC AGENTS Although biologics can significantly improve symptoms of psoriasis as well as quality of life, they cost significantly more than traditional therapies. An approximation of the cost of each agent for a 12-week course and for one year in a typical patient is shown in Table 2. For the treatment of moderate-to-severe psoriasis for 1 year, the cost of cyclosporine and methotrexate are approximately $7,100 and $560 respectively. 28,29 Treatment with biologic agents can be cost-prohibitive for many patients, particularly if they do not have thirdparty coverage, only partial coverage, or if their plan imposes a lifetime limit on costs. Cost is an important factor to consider in the decision to initiate treatment with a biologic agent. The needs and circumstances of each individual patient play an important role in this decision. Some manufacturers of biologics provide financial assistance to qualifying patients who cannot pay for any outstanding costs not covered by third-party plans. These patient-assistance programs also provide services to help patients with insurance reimbursements, self-injection training by qualified nurses, and education about the product. 12,29 ROLE OF THE PHARMACIST Although new biologic agents and current research offer great hope in the management of psoriasis, it is a chronic disease that is unfortunately not yet curable. Pharmacists can play an important supportive role in the treatment of psoriasis due to their accessibility to patients and their knowledge of pharmacological and non-pharmacological agents for its treatment. The chronic and frustrating nature of psoriasis requires encouragement and positive reinforcement with regard to its sometimes unpleasant and messy treatment options. It is important for patients to be well informed about the proper use of agents such as topical corticosteroids in order to prevent tachyphylaxis and rebound flares of psoriasis. Pharmacists can also guide patients in the proper use of the many over-the-counter preparations available for the treatment of psoriasis such as emollients, tar preparations, anthralin preparations and keratolytics. Some additional sources of support and information for patients include National Psoriasis Foundation s website ( and the Psoriasis Society of Canada ( ). Finally pharmacists have an important role to play in educating patients on biologic agents, particularly on issues regarding their safety and adverse effect monitoring. There is an important role to play in helping patients set realistic expectations regarding the onset of action of biologics that can take a few weeks to months in some cases. Pharmacists can further assist patients April 2006 The Role of Biologics in the Treatment of Psoriasis 7

8 TABLE 3: Profiles of biologic agents used in the treatment of psoriasis Alefacept Efalizumab Etanercept Infliximab Description Dimeric fusion protein Humanized monoclonal Dimeric fusion protein Chimeric monoclonal (human-hamster) 10,22 antibody to CD11a 23 consisting of a TNF-α receptor antibody (humanfused to the Fc portion of mouse) 25 human IgG 24 Mechanism of action Dual mechanism: Inhibits cell-to-cell interactions Binds specifically to soluble Binds with high affinity binds receptors on T-cells that cause T-cell activation and and cell surface tumour to TNF-α and inhibits preventing activation migration 23 necrosis factor (TNF) and binding to its binds receptors on cytotoxic blocks its interaction with cell receptors 25 cells leading to cell death 10,22 surface TNF receptors 24,43 Warnings and Precautions Cardiovascular Congestive heart failure: Congestive heart failure: associated with worsening associated with CHF 24 worsening of CHF 25 Immune system/ Potential to reactivate latent, Potential to reactivate latent, reactivation of latent, chronic reactivation of latent, Infections chronic infections 22 chronic infections 23 infections including hepatitis B chronic infections Induces dose-dependant and TB 24,27 including hepatitis B reductions in circulating CD4+ granulomatous infections and TB 25,27 and CD8+ T-cell counts 22 sepsis (rare reports) 24 Neurologic events associated with CNS associated with CNS - demyelinating disorders disorders: demyelinating (eg. MS, optic neuritis) 24 disorders 25 Malignancies Immunomodulating agent: may Immunomodulating agent: Lymphoma: higher incidence in Lymphoma: higher inciincrease risk of malignancies 22 may increase risk of patients treated with TNF-α dence in patients treated malignancies 23 antagonists (definitive with TNF-α antagonists correlation not established) 24,43 (definitive correlation not established) 25 Hemalotogic events thrombocytopenia neutropenia, leukopenia, hemolytic anemia: severe thrombocytopenia, anemia, cases reported 4 to 6 months pancytopenia (rare) 24 after treatment 23 Skin worsening and/or change in psoriasis during therapy rebound upon abrupt discontinuation 23 Monitoring/ CD4+ T-cell count: monitor Platelets must be monitored None recommended by Tuberculosis testing 10,25 lab tests every 2 weeks 22 before and during therapy 23 manufacturer but some hepatitis B screening Discontinue if T-cell count monitor platelets and TB prior to treatment 16 below normal (250 cells/µl) 22 hepatitis B screening prior to treatment 16 Immunogenicity Antibodies to alefacept Antibodies to efaluzimab Antibodies to etanercept Antibodies to infliximab: detected do not decrease detected (do not decrease detected: can cause a lupus- can decrease efficacy efficacy) 10,22,43 efficacy 23 like syndrome (rare) 24 and rarely cause a lupus-like syndrome 25 Continued on opposite page with the third-party reimbursement process should patients choose not to partake in the manufacturer-sponsored patient assistance programs. CONCLUSION Biologic agents are an important addition to systemic psoriasis therapies for patients with moderate-to-severe psoriasis. They help to address the needs of these patients for more aggressive therapy that addresses the underlying cause of the disease, without evidence of endorgan toxicities. Although their safety and efficacy is supported by a number of randomized placebo-controlled clinical trials, there is a need to further investigate their long-term safety and efficacy, as well as their comparative efficacy as a class and to other treatments in head-tohead trials. Owing to their unique mechanisms of action, it is has been postulated that biologic agents may have an additive therapeutic effect when combined with other agents, which is currently under investigation. 12 REFERENCES 1. Koda MA, Y.L. Applied Therapeutics: The Clinical Use of Drugs Sixth Ed. 7th ed. 2003, Vancouver, WA: Applied Therapeutics Inc. 2. Lui H, Langley R, Poulin Y, Aditya GK, Carey W, Guenther L, Searles G, Toole J, Lynde C, Gulliver W, 8 The Role of Biologics in the Treatment of Psoriasis April 2006

9 TABLE 3: Profiles of biologic agents used in the treatment of psoriasis Alefacept Efalizumab Etanercept Infliximab Allergic reactions Urticaria and angioedema Reported in <2% of patients reported 22 during trials latex (needle cover) 24 Miscellaneous Arthritis has been reported: Wegener's granulomatosis 24 discontinue if this occurs 23 Adverse reactions Clinical trials: Clinical trials: Clinical trials: Clinical trials: (not previously chills: only adverse reaction Most common: Rates similar to placebo Most common: mentioned in seen in 5% of patients over moderate dose-related acute Most common: infusion reactions: Precautions) placebo flu-like symptoms (headache, injection-site reactions hypotension, flushing, flu-like symptoms, headache fever, chills, nausea, myalgia) during first 3 months (14%), tachycardia, myalgias, injection site reactions tend to occur with first headaches (6-18%) rash, headache, GI upset, (16% vs 8% placebo) and second dose 23 upper respiratory tract fatigue 25,43 infections occurring in over no increase of adverse infections (5-11%) 5% or patients: pharyngitis, reactions with prolonged use 23 unspecified infections flu syndrome, common cold, Post-marketing surveillance: (29-30%) 24 viral infection aseptic meningitis (rare) multiple courses: incidence similar to single course 22 serious infections: necrotizing fasciitis and turbeculous pneumonia 23 Dosage and 15 mg once weekly as an initial subcutaneous single starting dose: 50 mg twice 3 mg/kg - 5 mg/kg IV administration intramuscular injection 22 dose of 0.7 mg/kg body weekly subcutanesouly (3 to 4 over 120 minutes on can be self-administered by weight followed by weekly days apart) for 3 months days 0,2,6 then every patient at home if deemed injections of 1 mg/kg. maintenance dose: 50 mg 8 weeks 12 appropriate and with proper maximum single dose: weekly 24 training mg 23 can be self-administered by can be self-administered by patient at home if deemed patient at home if deemed appropriate and with proper appropriate and with proper training 24 training 23 Barber K. Incorporating Biologics into the Treatment of Psoriasis. J Cutan Med Surg 2004; Aug;8 Suppl: Guenther LC, O.J. Pathophysiology of Psoriasis: Science Behind Therapy. J Cutan Med Surg 2002;6 (Suppl 2): Miller P, B.P. Taking the "heartbreak" out of psoriasis. UBC Continuing Pharmacy Education University of British Columbia. 5. Lui, H.M., FRCPC, Plaque Psoriasis. Accessed Jan NJ, L. Practical Psoriasis Therapy. 1986, Year Book Medical Publishers Inc: Chicago. p DesGroseilliers, JP. Psoriasis. In: Gray, J, editor. Therapeutic Choices. 4th ed. Ottawa: Canadian Pharmacists Association p Federman DG, F.C., Krisner RS. Topical Psoriasis Therapy. American Family Physician 1999; Feb 15: Gupta AK, Langley R, Poulin Y, Lui H, Searles G, Carey W, Toole J, Inniss K. Pathogenesis of psoriasis and current challenges. J Cutan Med Surg 2004; Aug;8 Suppl: Sauder DN, Mamelak AJ. Understanding the new clinical landscape for psoriasis: a comparative review of biologics. J Cutan Med Surg 2004;Jul- Aug;8(4): Dirckx JH ed. Stedman s Concise Medical Dictionary for the Health Professions. 4th Ed. Lippincott Williams & Wilkins. 12. Guenther L, Langley RG, Shear NH, Bissonnette R, Ho V, Lynde C, Murray E, Papp K, Poulin Y, Zip C. Integrating biologic agents into management of moderate-to-severe psoriasis: a consensus of the Canadian psoriasis expert panel. J Cutan Med Surg 2004;Sep-Oct;8(5): Carlin CS, Feldman SR, Krueger JG, Menter A, Krueger GG. A 50% reduction in the Psoriasis Area and Severity Index (PASI 50) is a clinically significant endpoint in the assessment of psoriasis. J Am Acad Dermatol 2004;Jun;50(6): Lebwohl M, A.S., Treatment of psoriasis. Part 2. Systemic therapies. J Am Acad Dermatol 2001;45(5): MA Menter, G.K., SR Feldman, GD Weinstein. Psoriasis treatment 2003 at the new millenium: Position paper on behalf of the authors. J Am Acad Dermatol 2003;49:s Law Rm, Gulliver WP. Psoriasis: The harried school teacher. Section 14: Dermatologic Disorders, No In: Schwinghammer TL, ed. Pharmacotherapy casebook: A patient-focused approcach, 6th edition, Gottlieb A. Immunobiologic agents for the treatment of psoriasis. Arch Dermatol 2003;139: Lebwohl, M., Targeting Psoriasis with New Treatments, Accessed Jan Schleyer V, Landthaler M, Szeimies RM. Novel pharmacological approaches in the treatment of psoriasis. J Eur Acad Dermatol Venereol 2005;Jan;19(1): Leonardi CL, P.J., Matheson RT, Goffe BS, Zitnik R, Wang A, Gottlieb AB, Etanercept Psoriasis Study Group, Etanercept as monotherapy in patients with psoriasis. N Engl J Med 2003;Nov 20;349(21): Kipnis CD, Myers WA, Opeola M, Gottlieb AB. Biologic Treatments for Psoriasis. J Am Acad Dermatol 2005;Apr;52(4): Alefacept Product Monograph. October Manufactured by Biogen Idec Canada Inc. 23. Efalizumab Product Monograph. October Manufactured by Serono Canada Inc. 24. Etanercept Product Monograph. December 20th, Manufactured by Amgen Canada Inc. 25. Remicade Product Monograph. In: Repchinsky C, Acharya S, Hill L, Levesque J, Marcotte S, editors. Compendium of pharmaceuticals and specialties.ottawa: Canadian Pharmacists Association, p Ortonne JP, Khemis A, Koo JY, Choi J. An openlabel study of alefacept plus ultraviolet B light as combination therapy for chronic plaque psoriasis. J Eur Acad Dermatol Venereol 2005;Sep;19(5): April 2006 The Role of Biologics in the Treatment of Psoriasis 9

10 27. Health Canada Health Products and Food Branch. Health Canada Endorsed Important Safety Information On anti-tnf Therapy: ENBREL (etanercept), HUMIRA (adalimumab), and REMICADE (infliximab). January 13th, The Patented Medicines Prices Review Board. Report on New Patented Drugs - Amevive. October 12, &mp=117&pf=1. Accessed January 22nd, Stein KR, Pearce DJ, Feldman SR. The impact of biologics on the quality or life of psoriasis patients and the economics of psoriasis care. Semin Cutan Med Surg 2005;Mar;24(1): Health Canada Health Products and Food Branch. Health Canada Endorsed Important Safety Information on Remicade: Updated Safety Information addressing the risk of malignancies associated with REMICADE (infliximab). November 29th, Ortonne JP. Clinical response to alefacept: Results of a phase 3 study of intramuscular administration of alefacept in patients with chronic plaque psoriasis. J Eur Acad Dermatol Venereol 2003;Jul;17 Suppl 2: Krueger GG, Papp KA, Stough DB, Loven KH, Gulliver WP, Ellis CN; Alefacept Clinical Study Group. A randomized, double-blind, placebo-controlled phase III study evaluating efficacy and tolerability of 2 courses of alefacept in patients with chronic plaque psoriasis. J Am Acad Dermatol 2002;Dec;47(6): Gordon K. Efalizumab for patients with moderate to severe plaque psoriasis: A randomized controlled trial. JAMA 2003; Dec 17;290(23): Gottlieb AB, Gordon KB, Lebwohl MG, Caro I, Walicke PA, Li N, Leonardi CL; EFALIZUMAB STUDY GROUP.Extended efalizumab therapy sustains efficacy without increasing toxicity in patients with moderate to severe chronic plaque psoriasis. J Drugs Dermatol 2004;Nov-Dec;3(6): Papp KA, Tyring S, Lahfa M, et al. A global phase III randomized controlled trial of etanercept in psoriasis: Safety, efficacy and effect of dose reduction. Br J Derm 2005;152: Gottlieb AB, Evans R, Li S, Dooley LT, Guzzo CA, Baker D, Bala M, Marano CW, Menter A. Infliximab induction therapy for patients with severe plaque-type psoriasis: A randomized, double-blind, placebo-controlled trial. J Am Acad Dermatol 2004; Oct;51(4): Chaudhari U, R.P., Mulcahy LD, Dooley LT, Baker DG, Gottlieb AB. Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: A randomised trial.the Lancet 2001;357(9271). 38. Goldsmith DR, Wagstaff AJ.Etanercept: A review of its use in the management of plaque psoriasis and psoriatic arthritis. Am J Clin Dermatol 2005;6(2): Pardasani AG, F.S., Clark AR. Treatment of Psoriasis: An Algorithm-Based Approach for Primary Care Physicians. American Family Physician 2000; Feb 1. Accessed online Feb 5, 2006: org/afp/ /725.html 40. Peters BP, Weissman FG, Gill MA. Pathophysiology and treatment of psoriasis. Am J Health Syst Pharm 2000;Apr 1;57(7): Heydendael VM, S.P., Opmeer BC, de Borgie CA, Reitsma JB, Goldschmidt WF, Bossuyt PM, Bos JD, de Rie MA. Methotrexate versus cyclosporine in moderate-to-severe chronic plaque psoriasis. N Engl J Med 2003; Aug 14;349(7): Krueger GG, C.K. Development and use of alefacept to treat psoriasis. J Am Acad Dermatol 2003;49: Bos JD, de Korte J. Effects of etanercept on quality of life, fatigue, and depression in psoriasis. Lancet 2006;Jan 7;367(9504): Gupta S, Tripathi CD. Current status of TNF blocking therapy in heart failure. Indian J Med Sci 2005;59: Accessed online Feb 12, 2006: = ;year=2005;volume=59;issue=8; spage=363;epage=366;aulast=gupta. 45. Callen JP, Krueger GG, Lebwohl M, McBurney EI, Mease P, Menter A, Paller AS, Pariser DM, Weinblatt M, Zimmerman G; AAD. AAD consensus statement on psoriasis therapies. J Am Acad Dermatol 2003;Nov; 49(5): Mease PJ. Psoriatic Arthritis Therapy Advances. Curr Opin Rheumatol 2005;Jul 17(4): The Role of Biologics in the Treatment of Psoriasis April 2006

11 QUESTIONS 1. What is implicated in the pathogenesis of psoriasis? a) Defects in the epidermal cell cycle b) T-cell mediated auto-immunity c) Genetic factors d)all of the above 2. Which statement about psoriasis is FALSE? a) It affects 1 million Canadians. b)it is a proliferative disease of the skin and nails. c) It is most common in southern latitudes and warmer climates. d)it is chronic and irregular with remissions and exacerbations. 3. All of the following are exogenous triggers of psoriasis EXCEPT a) climate: cold weather b. close contact with psoriatic patients c. stress d. trauma to the tissue 4. Plaque psoriasis is characterized by the all of the following EXCEPT a) it is the least common type of psoriasis b) well-defined, flat-topped plaques with adherent silvery scale and white flakes c) the most commonly affected areas are extensor surfaces like elbows and knees d) it affects both sexes equally 5. Current belief about the pathogenesis of psoriasis is that a) since cyclosporine is effective in its treatment, it is primarily a B-lymphocyte-mediated immune disorder b) the finding of B-lymphocytes in psoriatic tissue corroborates statement a. c) current belief is that psoriasis is primarily an immunological disorder with secondary epidermal proliferation d)all of the above 6. Which statement about the immunopathophysiology of psoriasis is FALSE? a) The pathophysiology of psoriasis is associated with T-lymphocytes, or T- cells that become activated once they recognize antigens. b) The T-cell-dependant inflammatory process which occurs in psoriasis can be broken down into 3 steps: initial activation of naïve T-cells, conversion of naïve T-cells to memory-effector T- cells, and response of activated T- cells in reaction to an antigen. c) In psoriasis, the activation process of T-cells results in the elimination of the antigen followed by termination of the immune response. d) T-cells involved in psoriasis are mainly Type 1 helper T-cells (Th1)(CD4+) and Type 1 cytotoxic T-cells (Tc1) (CD8+). 7. Which statement about T-cell activation in the pathogenesis of psoriasis is TRUE? a) Initial activation of naïve T-cells requires ONLY the binding of an antigen to an antigen presenting cell (APC) to occur. b) Initial activation of naïve T-cells requires ONLY that ligands be formed between surface proteins on T-cells and APCs to occur. c) Cytokines are hormone-like proteins secreted by many cells such as inactivated T-cells. d) Tumour necrosis factor-α (TNF-α) is a pro-inflammatory cytokine that is of particular importance in the initial cytokine cascade leading to keratinocyte activation. 8. The nomenclature of biologics is an indicator of their origin and mechanism of action. Which statement is FALSE? a) Drugs with names ending with the letters mab are monoclonal antibodies. b)drugs that ending with ximab are less likely to form neutralizing antibodies. c) Drugs ending with the letters zumab are humanized with intermittent animal sequences or fully humanized and are less likely to form neutralizing antibodies. d)drugs with names ending in cept involve the fusion of a receptor to the Fc portion of the human immunoglobulin G1 (IgG1). 9. Which statement on the prognosis of psoriasis is FALSE? a) Severity of psoriasis cannot be defined solely by its effect on quality of life and self-esteem. b) Psoriasis is a lifelong chronic disease characterized by recurrent exacerbations and remissions which are generally more emotionally than physically disabling. c) Approximately one-third of patients with psoriasis have a moderate-tosevere form of the disease. d) The effect of psoriasis on quality-oflife is a criterion considered in determining the severity of psoriasis. 10. Which criteria is NOT one suggested by the Canadian Psoriasis Expert Panel as defining moderate-to-severe psoriasis? a) less than 10% BSA affected with very thick, red and/or scaly plaques b)at least 10% BSA must be affected for psoriasis to be considered moderate-to-severe c) causing a significant impact on quality of life, regardless of BSA involved d)less than 10% BSA affected and resistant to therapy 11. Which statement about the Psoriasis Area and Severity Index (PASI) score is TRUE? a) The PASI score is commonly used by health-care providers to assess the severity of psoriasis. b)pasi 75 is defined as a 75% reduction in the PASI score and is the primary endpoint for most clinical trials. c) Some researchers and health-care providers consider this endpoint to be too stringent or difficult to attain and use PASI 50 as a primary outcome measure. d)all of the above. 12. Which statement about current treatment strategies for psoriasis is FALSE? a) Current treatment recommendations suggest a step-wise approach, starting with topical agents, followed by phototherapy, then systemic agents for severe forms of psoriasis which are resistant to topical treatment and phototherapy. b) Available treatment options help to reduce the extent of severity of psoriasis and improve quality of life. April 2006 The Role of Biologics in the Treatment of Psoriasis 11

12 QUESTIONS continued c) The goal of current therapy is to ultimately cure psoriasis. d) In clinical practice, treatment is generally customized to each patient based on concomitant diseases, adverse effects and quality-of-life issues. 13. New biologic therapies are useful in the treatment of psoriasis because a) they change the cytokine profile in a process called immune deviation. b) they increase the number of T-cells. c) they increase cell-to-cell interactions and cause activation and migration. d) they bind and activate post-secondary cytokines that affect keratinocytes. 14. Which statement about biologic agents is FALSE? a) They are a new class of drugs derived from living materials such as human, animal, plant and microorganism materials. b) There are currently 4 biologic agents approved by Health Canada for the treatment of moderate-to-severe psoriasis: infliximab, etanercept, alefacept, efalizumab. c) They have shown significant impact on quality-of-life measures in clinical trials. d) There are currently no direct comparative clinical studies between biologic agents and other treatment modalities, or between the different biologic agents. Case Study: Mr. BD is a 56-year-old air traffic controller with severe chronic plaque psoriasis and psoriatic arthritis. He struggles with frequent exacerbations of his psoriasis, which does not respond adequately to topical treatment or ultraviolet therapy. His dermatologist has recently prescribed methotrexate 7.5 mg every 12 hours for 3 doses per week for 6 weeks. His last blood test showed a modest increase in liver enzymes and Mr. BD is concerned about the effects of methotrexate on his liver. The methotrexate has been effective at controlling the symptoms of both his psoriasis and arthritis and he is discouraged that his physician may discontinue the drug. His dermatologist is considering prescribing a biologic agent as a substitute for methotrexate. Mr. BD comes to the pharmacy asking questions about biologic agents and their safety. He is also concerned that his drug plan will not pay for these medications as he has heard that they are very expensive. 15. What information can you give Mr. BD? a) In light of his occupation, discuss the link between stress and psoriasis with Mr. BD so that he may better understand the importance of stress management. b) Discuss the effects of methotrexate on the liver and the potential need for a liver biopsy if his cumulative dose reaches 1.5 g. c) Inform Mr. BD about the advantages and disadvantages different biologic agents available and help him find out if his third-party insurer would pay for any of them. d. All of the above. 16. Which statement about the potential choices of biologics for Mr. BD is TRUE? a) Efaluzimab can lead to long remissions of up to a median 7 months. b)alefacept usually has a fast onset of action which can occur as early as 4 weeks after initiating treatment. c) Etanercept has shown efficacy in treating both psoriasis and psoriatic arthritis. d) Infliximab can be conveniently injected subcutaneously at home with proper training. 17. Which statement is FALSE about necessary monitoring if Mr. BD is prescribed a biologic agent? a) If the physician prescribes alefacept, the patient s CD4+ counts will need to be monitored bi-weekly. b) If the physician prescribes infliximab, he will need to perform regular TB tests. c) If etanercept is prescribed, CD4+ counts will need to be monitored regularly. d) If efalizumab is prescribed, platelet counts will need to be monitored before and during treatment. 18. Which statement is FALSE regarding the mechanism of action of the biologic agents available for the treatment of moderate-to-severe psoriasis? a) Efalizumab inhibits cell-to-cell interactions that cause T-cell activation and migration. b) Alefacept binds receptors on memoryeffector T-cells preventing their effects, and also binds receptors on cytotoxic cells leading to cell death. c) Alefacept is a TNF-α antagonist. d) Etanercept and infliximab are TNF-α antagonists which are effective against TNF-α, a cytokine which plays a central role in the pathogenesis of psoriasis. 19. The following are shortcomings of traditionally-used treatments for moderate-to-severe psoriasis which were identified by the Canadian Psoriasis Expert Panel EXCEPT a) topical therapies are generally inconvenient and time-consuming to apply in patients with extensive psoriasis b) risk of squamous cell carcinoma with PUVA, inconvenience and lack of accessibility of treatment and the need to use adjunctive therapy are disadvantages of phototherapy c) risk of hepatotoxicity with cyclosporine and renal toxicity with methotrexate with prolonged use d) acitretin poses risks of hepatotoxictity and teratogenicity; it is converted to etretinate with alcohol consumption leading to prolonged retention 20. Which statement is FALSE regarding the safety of the biologic agents available for the treatment of moderate-to-severe psoriasis? a) TNF-α antagonists such as etanercept and infliximab have been associated with reactivation of latent tuberculosis and hepatitis B. b) A common adverse reaction of infliximab is infusion-related reactions such as hypotension, flushing and tachycardia. c) There have been reports of lymphomas associated with efalizumab but a definitive correlation between the two has not been established. d) Clinically significant thrombocytopenia, which is associated with bruising and bleeding, has been reported with efalizumab, and platelet counts should be monitored regularly. 12 The Role of Biologics in the Treatment of Psoriasis April 2006

13 TO ANSWER THIS CE LESSON ONLINE If currently logged into our ONLINE CE PROGRAM, please return to the "Lessons Available Online" Page and click on "Link to questions" for this CE Lesson. If not logged in but already registered to our ONLINE CE PROGRAM, please click here: If you have not registered for our ONLINE CE PROGRAM and wish to answer online, please click here: If you have any questions. Please contact: Pharmacy Practice, Pharmacy Post, Novopharm CE Compliance Centre, More CCCEP-approved CE s, or Tech Talk (English and French CE's) Mayra Ramos Fax: (416) or Quebec Pharmacie and L'actualite Pharmaceutique Stephane Paradis Fax: (514)