P. J. Mease, MD
Seattle Rheumatology Associates, Swedish Hospital Medical Center, Division of Clinical Research, and Department of Medicine, University of Washington, Seattle, Washington, USA
Etanercept (Enbrel®, Amgen and Wyeth), a tumor necrosis factor (TNF) antagonist, was approved in January 2002, for the treatment of psoriatic arthritis (PsA). The anti-inflammatory effects of etanercept are due to its ability to bind to the pro-inflammatory cytokine TNF, preventing it from interacting with cell-surface receptors and rendering it biologically inactive. Etanercept was evaluated for the treatment of PsA and psoriasis in a preliminary study of 60 patients and in a confirmatory phase III study of 205 patients. In both studies, etanercept was shown to be significantly superior to placebo for the treatment of PsA, evaluated by Psoriatic Arthritis Response Criteria (PsARC) and American College of Rheumatology (ACR) criteria. It also was superior to placebo in improving psoriatic skin lesions, evaluated by the Psoriasis Area and Severity Index (PASI) and target lesion scores. Side-effects were minimal; mild injection site reactions, which resolved during continued therapy, were experienced by approximately onequarter of the patients. Overall, etanercept is highly effective and well tolerated by patients with PsA, with a safety profile similar to that seen in rheumatoid arthritis.
Key Words: psoriatic arthritis, etanercept, tumor necrosis factor
Psoriatic arthritis (PsA), an inflammatory arthropathy, affects 7% to 31% of patients with psoriasis.1,2 This broad range of potential prevalence varies based on the method of case finding and whether the study is population-based or arises from a referral center. PsA is characterized by flares and remissions, but the number of affected joints and the severity of joint damage tend to increase over time. Although oligoarticular presentation is often seen initially, over time up to 61% of PsA patients develop polyarticular disease, and deforming, erosive joint changes have been reported in 40% of patients.3 Nonsteroidal anti-inflammatory drugs and physical therapy may be useful for mild symptoms, but corticosteroids or disease-modifying antirheumatic drugs (DMARDs) are usually required for more severe disease.
Tumor necrosis factor (TNF) is a naturally occurring cytokine that is involved in normal immune responses and inflammatory conditions. Elevated levels of TNF are found in the synovium and psoriatic plaques of patients with PsA.4 TNF mediates a number of biologic processes that can result in joint damage. These include stimulation of bone resorption, inhibition of bone formation, inhibition of proteoglycan synthesis, and induction of collagen- and cartilage-degrading metalloproteinases and prostaglandin E2, as well as further production of TNF and other pro-inflammatory cytokines such as IL-1.5-8
Two TNF antagonists, etanercept (Enbrel®) and infliximab (Remicade®, Centocor), have shown considerable efficacy in the treatment of rheumatoid arthritis and have been approved by the US FDA for this indication. Etanercept has also been approved for the treatment of juvenilerheumatoid arthritis and, in January 2002, for the treatment of PsA. Infliximab has additionally been approved for the treatment of Crohn’s disease. The following is a brief review of phase II and III placebocontrolled trials of etanercept in PsA. The value of anti-TNF therapy is further underlined by preliminary results from a phase II placebo-controlled evaluation of infliximab in PsA.9 In this trial of 102 patients, infliximab was significantly more effective than placebo in improving both joint symptoms and skin lesions.
Mechanism Of Action/Pharmacology
Two distinct TNF receptors, a 55-kilodalton and a 75-kilodalton protein, exist naturally as monomeric molecules on cell surfaces. The biological activity of TNF is dependent on binding to either cell-surface receptor. Etanercept is a dimeric, soluble form of the 75-kilodalton TNF receptor. The anti-inflammatory effects of etanercept are due to its ability to bind to TNF, preventing it from interacting with cell-surface receptors and rendering it biologically inactive. Etanercept can also modulate biological responses that are induced or regulated by TNF, including both expression of adhesion molecules responsible for leukocyte migration and serum levels of cytokines and matrix metalloproteinase-3. Etanercept is self-administered at a dose of 25mg subcutaneously twice weekly. Etanercept may be given as monotherapy or in combination with other DMARDs.
The efficacy of etanercept in rheumatoid arthritis10 raised the possibility that this agent might also be efficacious in patients with PsA, thus leading to an initial placebo-controlled, randomized clinical study in which 60 patients with PsA received either etanercept (25mg subcutaneously, twice weekly) or placebo.11
Patients previously achieving partial benefit from methotrexate were allowed to continue its use. This subgroup of 47% of patients was evenly randomized to placebo or etanercept. Background use of nonsteroidal anti-inflammatory drugs or prednisone ≤10mg/day was allowed. All other DMARDs and topical medicines for psoriasis were discontinued.
The primary arthritis efficacy response measure was the Psoriatic Arthritis Response Criteria (PsARC). Four clinical improvement criteria make up this scale: an improvement of at least 1 unit (0-5 Likert scale) on the physician global assessment, an improvement of at least 1 unit (0-5 Likert scale) on the patient global assessment, and at least 30% improvement in tender and swollen joint counts. To achieve a clinical response, the patient had to improve in two of the four PsARC criteria, one of which was required to be tender- or swollen-joint score, and none of the four scores could worsen. At 12 weeks, 87% of etanercept-treated patients were responders by PsARC criteria compared with 23% of placebo-treated patients (p<0.0001). The effect was rapid. By 4 weeks, 77% of patients receiving etanercept qualified as responders. Also evaluated were the percentages of patients who met the American College of Rheumatology (ACR) criteria for 20% (ACR20), 50% (ACR50), and 70% (ACR70) improvement in rheumatoid arthritis. At 12 weeks, an ACR20 response was achieved by 73% of the etanercept group vs. 13% of the placebo group (p<0.0001); an ACR50 response by 50% vs. 3% (p=0.0001), respectively; and an ACR70 response by 13% vs. 0% (p>0.05), respectively.
Of the 60 patients with active PsA, 38 (19 etanercept, 19 placebo) had ≥3% body surface area involved with psoriasis, the minimum requirement for the evaluation of skin response. Evaluating dermatologists used the Psoriasis Area and Severity Index (PASI) and target lesion score to evaluate skin lesions. The PASI is a composite measure based on scale, erythema, and induration that is weighted by severity and body surface area. The target lesion is a prospectively identified psoriatic lesion assessed for plaque elevation, scale, erythema, and induration. At 12 weeks, the median improvement in PASI score in etanercept-treated patients was 46% compared with 9% for the placebo group (p=0.0032). Twenty-six percent of the etanercept group achieved at least a 75% improvement in PASI score. A median 50% improvement in target lesion score was observed for the etanercept group.
Patients who completed this trial (n=58) were given etanercept during a 6-month, open-label extension.12,13 The patients originally assigned to placebo had prompt and dramatic PsARC responses. The median improvement in PASI score in patients receiving etanercept during the blinded phase of the study improved from 46% at 12 weeks to 62% at 9 months. Patients who had originally received placebo during the double-blind phase and then were switched to etanercept also achieved a 62% median improvement in PASI score during the 6 months of etanercept treatment. Twenty-five percent of patients previously taking methotrexate and 44% of those previously taking low-dose prednisone were able to discontinue those drugs.
A Phase III clinical trial of etanercept in patients with PsA confirmed and extended these observations.14 In this double-blind, placebo-controlled study, 205 patients with PsA and psoriasis were randomized to receive 25mg etanercept (n=101) or placebo (n=104) twice weekly for 24 weeks. An ACR20 response at 12 weeks, the primary endpoint of the study, was achieved by 59% of the etanercept group and 15% of the placebo group (p<0.001). By PsARC criteria, 72% of the etanercept group achieved a clinical response at 12 weeks vs. 31% of the placebo group (p<0.001).
Clinical improvement was maintained through 24 weeks of etanercept treatment, demonstrated by an ACR20 response of 50% and a PsARC response of 70%, compared with 13% and 24%, respectively, for placebo (p<0.001 for each evaluation).
Improvement in psoriasis was also observed. Of the 205 patients in this study, 66 in the etanercept group and 62 in the placebo group met the criteria for evaluation by the PASI. At 24 weeks, the etanercept group showed a median PASI improvement of 47% and a median target lesion improvement of 33% compared with no improvement in the placebo group for either evaluation (p<0.001).
TNF antagonists, including etanercept, affect host defenses and have been rarely associated with development of new infections and exacerbation of existing infections. The only reaction that occurs with any frequency is injection site reaction, occurring in less than one-third of patients. This is usually mild, well tolerated, and resolves within a few weeks to months after initiation of drug without need to interrupt therapy. Overall, the safety profile of etanercept in PsA is similar to that in rheumatoid arthritis.
During the initial 12-week, placebo-controlled trial in PsA,11 etanercept was well tolerated. No serious adverse events were reported in the 30 patients receiving etanercept, and no patients developed infections that required hospitalization or intravenous antibiotics. Injection site reactions occurred in 20% of the etanercept patients. Of note, no patient developed Koebner phenomenon at the sites of injection. During the 6-month open-label extension of this initial trial,12,13 etanercept continued to be well tolerated. Etanercept was also generally safe and well tolerated during the phase III study in PsA.14 During the course of the trial, eight adverse events that were considered serious were reported for four placebo-treated patients (one each with angina, gastroenteritis, and gastritis, and the fourth patient with atrial fibrillation, gastrointestinal bleed, congestive heart failure, bowel perforation, and intraperitoneal hemorrhage). In the etanercept group, four serious adverse events were reported for four patients (one each with transient symptoms consistent with demyelinating disease, chest pain, syncope, and renal calculus).
|DMARD||Regimen/Control||n||Statistically Significant Results|
|Methotrexate15||Pulse 7.5-15mg once weekly vs. placebo||37||Small improvement in physician assessment of disease activity and skin involvement|
|Gold16||50mg IM once weekly vs. auranofin 3mg b.i.d. vs. placebo||82||Improvement in joint pain and erythrocyte sedimentation rate at 23 and 24 weeks with IM gold (no significant changes with oral gold)|
|Sulfasalazine17||2gm per day vs. placebo||30||Improvement in arthritis at 1 and 6 months; no effect on psoriasis|
|Sulfasalazine18||2gm per day vs. placebo||221||Slightly better overall response in arthritis|
|Infliximab9||5mg/kg IV at 0, 2, 6, and 14 weeks vs. placebo||102||Significant improvement in arthritis and psoriasis at 16 weeks|
|Etanercept11||25mg SC twice weekly vs. placebo||60||Significant improvement in arthritis and psoriasis at 4, 8, and 12 weeks|
|Etanercept14||25mg SC twice weekly vs. placebo||205||Significant improvement in arthritis and psoriasis through 24 weeks|
Table 1: Controlled, Double-Blind Studies of DMARDs in Psoriatic Arthritis
PsA is an inflammatory arthropathy that commonly affects patients with psoriasis, with a significant and often severe impact on their health and well-being. Levels of the pro-inflammatory cytokine TNF are elevated in the synovium and psoriatic plaques of patients with PsA. The anti-inflammatory effects of etanercept arise from its ability to bind to TNF and block its interaction with cell-surface receptors. Etanercept has been shown to be effective and generally well tolerated in the treatment of PsA. Based on the results of two randomized, placebo-controlled studies, etanercept is the first biologic to be approved for the treatment of PsA. With respect to psoriasis, preliminary data suggest that both etanercept19 and infliximab20 have promise in treating plaque-type psoriasis in patients without PsA. Given the favorable clinical results achieved with etanercept, it is likely that other targeted biologics currently in development will also prove to be useful in PsA and psoriasis. The availability of targeted therapies will increase the opportunity for more effective management of these difficult diseases.