Cellcept

Abstract

Background: Although major advances in the understanding of its pathogenesis have been achieved, psoriasis remains an incurable disease. In April 2004, etanercept, an antagonist of TNF-[alpha], was approved by the Food and Drug Administration for the treatment of chronic, moderate to severe plaque psoriasis in adults. In this study we intend to document the efficacy and further establish the safety profile of etanercept for the treatment of moderate to severe psoriasis in our population and compare our data to the Leonardi et al study published in 2003. (2)

Methods: A total of 26 patients were followed for a period of 24 weeks. Subjects were administered 25 mg of etanercept subcutaneously twice weekly for 24 weeks. Patients were seen every 4 weeks to measure clinical improvement by means of the psoriasis area and severity index (PASI) scores. Development of side effects was also assessed.

Results: Ninety-two percent of the patients had an improvement of greater than 50% in their PASI score, with 79% of these patients with a PASI improvement of 75% or greater. Adverse events were uncommon and none required the permanent discontinuation of treatment.

Conclusion: Treatment with etanercept was well-tolerated and resulted in significant sustained improvement of psoriasis throughout a period of 24 weeks. Our data strongly correlates with the findings reported by Leonardi et al in 2003. (2)

Introduction

Psoriasis is a chronic, autoimmune disease that has a world prevalence of about 2%. (1) It affects people of both sexes equally and may appear at any age. (1,2) In the past decade, the immunopathogenesis of psoriasis has been linked to a T-cell dysfunction in the Th1 profile. Cytokines such as TNF-[alpha] and interferon gamma are responsible for the skin proliferation which characterizes the psoriatic lesions. Psoriasis is usually a life long disease that has a deep impact on patients' quality of life, affecting their social interactions and ability to work. (3,4) Rapp et al (5) demonstrated that psoriasis causes as much physical and mental disability as other major diseases. (5)

Although major advances in the understanding of its pathogenesis have been achieved, psoriasis remains an incurable disease. (6) Nevertheless various treatments are available to induce remission. Topical therapies consisting mainly of corticosteroids have been the most common approach to treat localized lesions. Other treatments consisting of phototherapy with UVB (both broad and narrow band), photochemotherapy with PUVA, and systemic medications (methotrexate, retinoids, and cyclosporine) have been employed for more extensive involvement of the disease. Most of these treatments have been of limited use since they are marginally effective in providing long-term remissions and/or have many unwanted side effects.

The pathophysiology of psoriasis is a complex one and involves both a polygenic predisposition and an antigen induced derangement of T-cell mediated immunity. Psoriatic skin has an increased concentration of Th1 derived cytokines such as TNF-[alpha], IL2, and interferon gamma as a result of infiltration of activated T-cells. (6)

Immunohistochemical investigations have detected elevated TNF-[alpha] in involved skin from psoriasis patients when compared to normal volunteers. (6-9) TNF-[alpha] is considered the major cytokine responsible for the epidermal proliferation that is the hallmark of the disease. Clinical improvement of skin lesions correlates with decreased levels of serum and lesional TNF-[alpha]. (6) This evidence led to various clinical trials where biological drugs that antagonize TNF-[alpha] and alter macrophage along with T-cell interaction and proliferation were investigated for their effectiveness and safety in the treatment of psoriasis.

Etanercept was approved in 1998 for the treatment of rheumatoid arthritis. In 2003, a new indication for psoriatic arthritis was added. Two clinical studies were undertaken to investigate the effectiveness and safety in patients with moderate to severe plaque psoriasis. About 1,400 patients were assessed between both studies with favorable results. In April 2004, etanercept was finally approved by the Food and Drug Administration (FDA) for the treatment of chronic, moderate to severe plaque psoriasis in adults.

Etanercept is one of the new emerging biological agents that interrupt the immunologic cascade leading to the hyperproliferative state in psoriasis. Etanercept is a fusion protein which binds soluble TNF-[alpha], thus antagonizing this cytokine's action. Two other immunomodulators have been approved by the FDA for the treatment of moderate to severe chronic plaque psoriasis: alefacept and efalizumab. These agents exert their anti-inflammatory action by directly inhibiting T-cells. The former blocks the leukocyte function antigen-3 (LFA-3)/CD2 interaction while the latter targets the CD11a component of LFA-1. (10) There is another antagonist of TNF-[alpha], infliximab, which is approved for psoriatic arthritis, but not yet for psoriasis.

Data regarding safety of long-term treatment with etanercept for psoriasis is not yet available, but evidence from clinical trials involving rheumatoid arthritis patients shows that this biological modulator was well-tolerated for up to 5 years. (11) Injection site reactions and upper respiratory tract infections have been the most common adverse effects reported to this date. (13) Although no serious adverse events have been documented, concern still exists about lymphoproliferative diseases, autoimmune diseases, and demyelinating conditions. (1) A randomized trial by Mease (7) consisting of 60 patients treated over a 12-week period was able to demonstrate the efficacy of the medication, but it could not clearly predict its safety. In this study we intend to document the efficacy and further establish the safety profile of etanercept for the treatment of moderate to severe psoriasis in our population and compare our data to the Leonardi study. (2)

Methods

This prospective study was conducted in a private dermatologic practice at the Medical Sciences Campus of Puerto Rico. A total of 26 patients were selected for the study, and all were evaluated by one author. Prior to the beginning of the study each patient signed an informed consent form.

Eligible patients were within the ages of 16 and 66, most with severe recalcitrant plaque-type psoriasis, most of them having PASI scores of 10 or greater. No other skin conditions were present. All patients had been unresponsive to topical or systemic treatments such as corticosteroids, retinoids, phototherapy, tars, or methotrexate, among others. They had been off treatment for at least 4 weeks prior to the beginning of the study and no concomitant treatments were used.

Before starting etanercept therapy, each patient was ordered a baseline tuberculin test and baseline blood tests: basic metabolic panel and complete blood count. All results were within the normal range for age and sex.

Subjects were administered 25 mg of etanercept subcutaneously twice weekly. Monthly follow-up was done to evaluate improvement of PASI scores and to assess the development of side effects. The study was conducted for 24 weeks.

Results

The study included 26 Puerto Rican patients, most of them with severe, recalcitrant psoriasis of the plaque type with PASI scores more than 10 at the start of treatment with a mean score of 29 (Table 1). Fifty-four percent of the sample consisted of male subjects. Age ranged from 16 to 66 years with a mean age of 47; distribution is depicted on Table 1. Psoriatic arthropathy was present in 31% of the patients.

All subjects had been previously managed with numerous treatments, including topical corticosteroids, phototherapy, and/or some form of systemic treatment without improvement. As shown in Table 2, 17 patients had used Soriatane, 16 had used methotrexate, 12 used PUVA, and 12 had tried topical corticosteroids. Neoral and narrow band UVB had been used by 7 patients each before the study. Four patients had previous treatment with Amevive, 2 with PUVA bath and 2 with UVB. Hydrea, Tazorac, Cellcept, 6-thioguanine, PUVA + UVB and PUVA + methotrexate had been used by one patient each. All treatments were suspended for 1 month prior to starting the etanercept injections and no other therapy was used concurrently with etanercept for the duration of the study.

As shown in Figure 1, the majority of patients had significant sustained improvement throughout the duration of treatment. Ninety-two percent of the patients had an improvement in their PASI score of over 50%, with 79% of these patients with a PASI improvement of 75% or greater. The mean PASI score after treatment was 6. Only 2 patients failed to respond to treatment and remained with an unchanged PASI score as shown in Table 1. Most of the patients who responded did so within the first 12 weeks of study. No flares were reported during the duration of treatment.

Adverse events were uncommon; upper respiratory tract infections being the most common side effect, which was observed in 2 patients. Edema, dry cough, and weight loss were observed in 1 patient each. Twenty-one patients did not report any side effects. No side effects resulted in patient hospitalization and no subject required the permanent discontinuation of treatment. Contrary to other reports, cutaneous reactions at injection site were not reported in our sample.

Our data strongly correlates with the findings reported by Leonardi et al (2) in 2003 (Figure 2). In both studies there was significant improvement from baseline since the first month of therapy. Our sample achieved superior improvement, which can be explained by their significantly increased initial PASI score. This variation will be discussed below.

[FIGURE 2 OMITTED]

Discussion

Psoriasis is a cutaneous disease that continues to evade more effective and safer treatment options for the patients. The National Psoriasis Foundation conducted a survey of more than 17,000 patients which revealed that 78% of them were frustrated with their treatment and 50% were unsatisfied. (4) Thanks to the knowledge acquired about the T-cell dysfunction, which triggers the psoriatic lesions, immunomodulatory agents that interfere with this cascade of immune events have been on the rise. Currently, three biologic immunomodulator drugs are already approved by the FDA for psoriasis and several others are on stage 3 of clinical investigation. TNF is a natural occurring cytokine that is involved in normal inflammatory and immune responses and plays an important role in the inflammatory process in psoriasis.

Etanercept is a TNF-[alpha] receptor protein, consisting of 2 extra-cellular ligand-binding domains of the human p-75 TNF-[alpha] receptor fused to the Fc portion of human IgG1. (3,4,11,12) The drug acts by binding soluble TNF-[alpha], thus preventing it to activate its cellular-bound receptor. Consequently, there is a reduction of the inflammatory and proliferative response. Since etanercept is 100% human, it does not elicit a neutralizing antibody response. This is in contrast with the other TNF-[alpha] antagonist infliximab, which is a murine-human monoclonal antibody. In one study, antibodies against infliximab were detected in 61% of patients. (14)

Etanercept has been approved for the treatment of rheumatoid arthritis since 1998. Over this period of time, more than 500,000 patients have been prescribed this medication, which, by itself, speaks highly of its safety profile over the long term. Efficacy and safety in patients with psoriasis have been evaluated by 2 large cohort studies, the global and US studies with approximately 600 hundred patients each prior to its final approval for psoriasis in April of 2004. Both studies have confirmed a high efficacy and safety profile so far for this disease as well.

Our patients' PASI scores were significantly higher compared to other studies. This may be attributable to various reasons. First, our sample is small. Second, the study was carried out at a supra-tertiary medical center where patients from all over the island are referred when their illnesses are refractive to conventional treatment. All of our patients were referred to our clinic due to their failure to respond to other treatment options. We thus cannot conclude that our sample is representative of the entire population of Puerto Rican psoriasis patients. Further investigation is still needed for appropriate long-term maintenance protocols, combined treatment modalities, and post-marketing long-term side effects.

We are on the verge of unlocking the genetic and immunological derangements that characterize psoriasis. As we approach this end, new drugs that target the immunological pathways involved in this disease are bringing new hope to these patients.

References

1. Lebwohl M. Psoriasis. Lancet. 2003;361:1197-204.

2. Leonardi CL, Powers JL, Matheson RT, Goffe BS, et al. Etanercept as monotherapy in patients with psoriasis. N Engl J Med. 2003;349(21):2014-22.

3. Mease P. TNF alpha therapy in psoriatic arthritis and psoriasis. Ann Rheum Dis. 2004;63(7):755-8.

4. Bohjanen KA, Prawer SE. New biologic therapies for psoriatic disease. Minn Med. 2004;87(3):34-6.

5. Rapp SR, et al. The promise and challenge of new biological treatments for psoriasis: How do they impact quality of life? Dermatol Ther. 2004;17(5):376-82.

6. Krueger G, Callis K. Potential of tumor necrosis factor inhibitors in psoriasis and psoriatic arthritis. Arch Dermatol. 2004;140(2):218-25.

7. Mease PJ, Goffe BS, Metz J, VanderStoep A, et al. Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomised trial. Lancet. 2000;356(9227):385-90.

8. Gottlieb AB, Matheson RT, Lowe N, Krueger GG, et al. A Randomized trial of etanercept as monotherapy for psoriasis. Arch Dermatol. 2003;139(12):1627-32; discussion 1632.

9. Iyer S, Yamauchi P, Lowe NJ. Etanercept for severe psoriasis and psoriatic arthritis: observations on combination therapy. Br J Dermatol. 2002;146(1):118-21.

10. Kipnis C, et al. Biologic treatments for psoriasis. J Am Acad Dermatol. 2005;52 (4):671-82.

11. Weinberg JM, Saini R. Biologic therapy for psoriasis: the tumor necrosis factor inhibitors infliximab and etanercept. Cutis. 2003;71(1):25-9.

12. Galadari H, Fuchs B, Lebwohl M. Newly available treatments for psoriatic arthritis and their impact on skin psoriasis. Int J Dermatol. 2003;42(3):231-7.

13. Zeltser R, Valle L, Tanck C, Holyst MM, et al. Clinical, histological, and immunophenotypic characteristics of injection site reactions associated with etanercept: a recombinant tumor necrosis factor alpha receptor: Fc fusion protein. Arch Dermatol. 2001;137(7):893-9.

14. Baert F, Noman M, Vermeire S, Van Assche G, D'Haens G, Carbonez A, et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease. N Engl J Med. 2003;348:601-8.

Address for Correspondence

Dr. Gonzalez-Chavez

Universidad de Puerto Rico

RCM-Escuela de Medicina

Departamento de Dermatologia

GPO BOX 365067

San Juan, PR 00936-5067

Jose R. Gonzalez-Chavez MD, Alma C. Berlingeri-Ramos MD, Mary Ann Sanchez Casiano MD

Department of Dermatology, School of Medicine, University of Puerto Rico, San Juan, Puerto Rico

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