R. Bissonnette MD, FRCPC
Innovaderm Research, Montreal, Quebec, Canada
Etanercept has recently been approved for the treatment of moderate-to-severe plaque psoriasis at a dose of 50mg twice per week for 12 weeks followed by a maintenance dose of 50mg once weekly thereafter. Clinical studies have shown excellent efficacy and a good safety profile in patients with psoriasis. Extensive information on etanercept safety is available as this biological agent has been used for many years for other indications such as rheumatoid arthritis, and psoriatic arthritis.
etanercept, plaque psoriasis, Enbrel®, psoriatic arthritis
Etanercept (Enbrel®, Amgen/Wyeth Pharmaceuticals) is a fusion protein with affinity for soluble tumor necrosis factor alpha (TNF-a) and has been US FDA approved for the treatment of rheumatoid arthritis (RA) since 1998. This biologic treatment is currently approved in several countries, including recent approval in Canada, for the treatment of moderate-to-severe plaque psoriasis. The approved dosage for treatment of psoriasis is 50mg subcutaneous (SC) twice per week for 3 months followed by 50mg once per week thereafter. This dosage regimen is different from the dose commonly used to treat RA, which is 25mg SC twice weekly.
Current Therapies for Psoriasis
Current treatment options for mild psoriasis include topical treatments such as calcipotriol, corticosteroids, and tar. For patients with more severe or extensive disease, phototherapy, including narrow band UVB and PUVA, has been shown to be very effective. Patients with severe and/or extensive disease, disease unresponsive to topical treatment and phototherapy, or disease that has a severe impact on quality of life, such as hand or foot involvement, are usually candidates for systemic therapy.
The three most frequently used oral medications for psoriasis in North America are methotrexate, acitretin, and cyclosporine. Biologics are a new therapeutics class for the treatment of psoriasis, and three agents are currently approved in the US and Canada for the treatment of psoriasis: alefacept (Amevive®, Biogen Idec), efalizumab (Raptiva®, Serono and Genentech/Xoma), and etanercept (Enbrel®, Amgen/Wyeth Pharaceuticals). This article will review safety and efficacy of etanercept in the treatment of moderate-to-severe plaque psoriasis.
Efficacy of Etanercept in the Treatment of Psoriasis
PASI (Psoriasis area severity index) is the primary endpoint used in studies assessing the efficacy of biologics for the treatment of psoriasis. PASI takes into account the extent of the disease, as well as the severity of erythema, scaling, and thickness in different body areas affected by psoriasis. Clinical improvement in biologics trials for psoriasis is usually reported as PASI-50 or PASI-75. A PASI-75 represents an improvement in the PASI score of at least 75% as compared with baseline (i.e., before the biologic was administered). Etanercept at a dose of 50mg SC twice per week has been shown to induce a PASI-75 response in 49% of patients after 12 weeks.1,2 Papp, et al. reduced the dose to 25mg twice per week for an additional 12 weeks and found that the percentage of patients exhibiting a PASI-75 response increased to 54%.2 In this study, 23% of patients lost their PASI-75 response when the etanercept dose was lowered to 25mg twice weekly; however, only 3% of these patients lost their PASI-50 response.2 Despite lowering the dose after 12 weeks, 32% of patients who did not reached PASI-75 at week 12 reached PASI-75 at week 24.2 Studies conducted with 25mg of etanercept twice weekly for 6 months (the last 3 months being open-label) demonstrated that 42%-44% of patients reached PASI-75 at week 24.1,2
Studies were also conducted where etanercept was stopped after 3 months of continuous treatment to determine if this would lead to a rebound phenomenon, as this can be seen with other systemic agents used to treat psoriasis. Rebound was defined as an increase in PASI of at least 25% compared with baseline, or an erythrodermic, pustular, or severe inflammatory flare within 12 weeks of treatment cessation. Of the 409 patients studied, only one etanercept treated patient presented with an increase of PASI of more than 25% above baseline.3 This patient received a lower starting dose of etanercept (i.e., 25 mg weekly.) No cases or erythrodermic or pustular psoriasis were reported, suggesting that etanercept can be safely stopped.
In the same study etanercept was reintroduced when the disease relapsed, and the PASI-75 response was assessed following retreatment. The percentage of patients achieving a PASI-75 response was the same after retreatment as that seen in patients who received etanercept for the first time.3 These studies suggest that etanercept can be stopped and reinitiated without the induction of rebound or loss of clinical response.
Etanercept has also been shown to reduce the signs and symptoms of psoriatic arthritis and has been approved in the US since June 2002 and in Canada since Jan 2004 for this indication.4 Etanercept should be considered as a treatment option in patients with both plaque psoriasis and active psoriatic arthritis.
Mechanism of Action
Etanercept binds soluble TNF-a, thus preventing its interaction with TNF-a cell surface receptors. This inhibits the effects of TNF-a in the skin, such as the release of proinflammatory cytokines by keratinocytes and lymphocytes, as well as the increase in expression of adhesion molecules on endothelial cells. This mechanism seems to differ from some of the other TNF-a antagonists that have an affinity for soluble as well as membrane bound TNF therefore enabling cell lysis following interaction with TNF-a.5,6
The current information on etanercept safety comes from clinical studies conducted in patients with various diseases such as psoriasis, psoriatic arthritis, RA, ankylosing spondylitis, and juvenile arthritis as well as from post-marketing experience. To date it is estimated that more than 337,000 patients worldwide, including over 74,000 patients with psoriasis, have received etanercept. Clinical studies are ideal to study the incidence and severity of frequent side-effects but are usually not powerful enough to assess less frequent adverse events. For example, clinical studies conducted with etanercept have given precise information on injection site reactions but cannot adequately assess the incidence of less frequent events such as serious infections.
The most commonly reported adverse event is injection site reactions, which occurred in 14%-20% of patients in psoriasis studies.1 These are characterized by erythema and edema at injection sites and are usually mild.
Serious infections, sometimes resulting in death, have been reported in patients treated with all anti-TNFa agents including etanercept. In patients with psoriasis who participated in placebo-controlled studies, the number of serious infections per patient per year was similar in patients treated with placebo and patients treated with etanercept.1,2 In an ongoing long-term, open-label study of patients treated with etanercept for RA, there was no increase in serious infections.7 There were 1272 patients with either early RA or long-standing RA enrolled in this trial, with some having received continuous etanercept for more than 8 years. The rate of serious infections did not increase over time, and there was no significant difference between what had been observed in the etanercept group vs. the placebo-treated patients, as well as cohorts of patients with RA. The exact role of etanercept in these serious infections is currently unknown.
Cases of demyelinating disorders have been reported in patients treated with anti-TNFa, including etanercept. A study conducted in the past with another anti-TNFa agent (lenercept), used to treat patients with multiple sclerosis, was stopped because of worsening of the disease under study.8 Cases of new onset multiple sclerosis, exacerbation of established multiple sclerosis, as well as optic neuritis and myelitis have been reported in patients treated with anti-TNFa agents, including etanercept.9 Some of these cases were reversible upon cessation of etanercept whereas others were not. In an ongoing long-term, open-label study in patients with RA, two cases of MS were reported.7 The causality of etanercept in these events as well as the exact risk of demyelinating disease with etanercept is unknown.
Patients with active tuberculosis should not be initiated on anti-TNFa agents. Cases of reactivation of latent TB have been reported with anti-TNFa agents, including etanercept, infliximab and adalimumab.10 Most cases were reported from patients treated with anti-TNFa antibodies as opposed to the etanercept fusion protein. The current US and Canadian monographs do not require TB screening before initiating etanercept,9,11 but many physicians currently prefer to perform a purified protein derivative of Mycobacterium tuberculosis (PPD) skin test and/or a chest X-ray. This should at least be considered for patients at higher risk of TB including patients coming from countries where TB is more frequent.
Clinical trials with etanercept, including a long-term, open-label RA trial, have not shown that patients are at higher risk of solid tumors.7 Cases of lymphoma were reported in patients treated with etanercept.7 In a long-term, open-label RA study, four cases of lymphoma were reported in patients with early RA and 7 cases in patients with long-standing RA when the expected number, based on the SEER database, were 0.8 and 1.1, respectively.7 These data should be interpreted with caution as patients with RA are at higher risk of developing lymphoma, and the risk increases with severity of the disease.12,13 It is currently unknown if the lymphoma cases seen in etanercept treated patients represent the fact that severe patients with RA are more at risk of lymphoma than the general population, or if etanercept has a role in the genesis of lymphomas. Interestingly patients with psoriasis (not treated with biologics) have also been reported to have an increased risk of lymphoma.14
Cases of an increase in pre-existing as well as new onset congestive heart failure (CHF) have been reported.9 The role of etanercept in these cases is unknown. Two clinical trials that were designed to assess the safety and efficacy of etanercept in the treatment of CHF were stopped because of lack of efficacy.9
|Injection site reactions1|
|Solid tumors/ lymphomas7,9-11|
|Congestive heart failure (CHF)|
|Hepatitis B Virus (HBV) relapse16|
|Table 1: Reported adverse events for anti-TNFá agents|
Cases of an increase in liver enzymes, as well as cases of liver failure, have been reported in post-marketing experience in patients taking etanercept.15 It is difficult to assess the relationship of these adverse events to etanercept, as many of these cases occurred in patients taking concomitant hepatotoxic medications or in patients who were previously exposed to hepatotoxic drugs like methotrexate. Health Canada recently sent out a Dear Healthcare Professional letter reporting very rare cases of hepatitis B virus (HBV) in patients receiving biologic agents, including etanercept.16 Other side-effects reported with etanercept include an increase in antinuclear antibody (ANA) and anti-dsDNA (double-stranded) antibody sometimes associated with lupus-like symptoms, as well as rare cases of neutropenia, leucopenia, thrombopenia, anemia, or pancytopenia.9
Etanercept is a biological agent that has shown excellent efficacy for the treatment of psoriasis. As opposed to other biologics previously approved for psoriasis, etanercept has been extensively used in rheumatology both in adults and in children.
The current information on safety is based on more than 337,000 patients treated with the product and includes a long-term, open-label study in patients with rheumatoid arthritis where patients have been on continuous therapy for as long as 8 years.
- Leonardi CL, Powers JL, Matheson RT, et al. Etanercept as monotherapy in patients with psoriasis. N Engl J Med 349(21):2014-22 (2003).
- 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 Dermatol 152(6):1304-12 (2005).
- Gottlieb AB, Gordon KB, Wang AT, Jahreis A. Etanercept can safely be withdrawn from patients with psoriasis and re-establishes disease control on retreatment. Poster presented at the American Academy of Dermatology Meeting (2005).
- Mease PJ, Kivitz AJ, Burch FX, et al. Etanercept treatment of psoriatic arthritis: safety, efficacy, and effect on disease progression. Arthritis Rheum 50(7):2264-72 (2004).
- Van den Brande JM, Braat H, van den Brink GR, et al. Infliximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn’s disease. Gastroenterology 124(7):1774-85 (2003).
- Shen C, Maerten P, Geboes K, Van Assche G, Rutgeerts P, Ceuppens JL. Infliximab induces apoptosis of monocytes and T lymphocytes in a human-mouse chimeric model. Clin Immunol 115(3):250-9 (2005).
- Weinblatt ME, Genovese MC, Moreland LW, et al. Efficacy and safety of over 8 years of etanercept (Enbrel) therapy in North American patients with early and long-standing rheumatoid arthritis. Arthritis & Rheumatism 52(9 (Supplement)):S541 (2005).
- TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. The Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. Neurology 53(3):457-65 (1999).
- Enbrel® Canadian product monograph. Amgen/Wyeth Pharmaceuticals.
- Rychly DJ, DiPiro JT. Infections associated with tumor necrosis factor-alpha antagonists. Pharmacotherapy 25(9):1181-92 (2005 Sep).
- Enbrel® US Product Monograph. Amgen/Wyeth Pharmaceuticals.
- Thomas E, Brewster DH, Black RJ,Macfarlane GJ. Risk of malignancy among patients with rheumatic conditions. Int J Cancer 88(3):497-502 (2000).
- Baecklund E, Ekbom A, Sparen P, Feltelius N, Klareskog L. Disease activity and risk of lymphoma in patients with rheumatoid arthritis: nested case-control study. BMJ 317(7152):180-1 (1998).
- Hannuksela-Svahn A, Pukkala E, Laara E, Poikolainen K,Karvonen J. Psoriasis, its treatment, and cancer in a cohort of Finnish patients. J Invest Dermatol 114(3):587-90 (2000).
- Cannon GW, Strand V, Scarazzini L, Holden WL. Comparison of adverse event reporting rates for etancercept, infliximab, leflunomide and methotrexate between September 1998 and June 2003. Arthristis Rheum 50(Suppl 9):S56. Abstract 1469 (2004).
- Dear Healthcare Professional Letter from HPB Canada (2006 Jan 18).