Psoriasis
Psoriasis is a chronic, inflammatory disease which can affect the skin, tendons, ligaments, and joints (Gottlieb, 2001; Gottlieb & Bos, 2002; Lebwohl, 2003). It has a multifactorial inheritance in which several genes interact with environmental factors to produce varying degrees of severity. Prevalence rates range from 0.5% to 4.6% depending on the country and race (Lebwohl, 2003). It more commonly affects Caucasians and patients living at higher latitudes (Lebwohl, 2003). Although it is not a life-threatening condition, it can lead to significant impairment and psychological stress. Patients who are severely afflicted can have up to 100% body surface area involvement.
There are several clinical variants of psoriasis, including plaque, guttate, erythrodermic, and pustular (Lebwohl, 2003). Plaque type is the most common form, representing 80% of cases, while guttate, erythrodermic, and pustular account for 10%, 3%, and 3% of patients respectively. Cutaneous lesions usually precede joint disease in 70% of patients with psoriasis.
Psoriatic arthritis, a seronegative arthopathy, can affect upwards of 42% of patients with psoriasis (Lebwohl, 2003). Several forms exist, including polyarticular, oligoarticular, distal interphalangeal, arthritis mutilans, spondylitis, and sacroiliitis. Like rheumatoid arthritis, psoriatic arthritis can lead to joint deformities, disability, and increased mortality.Pathogenesis
While the entire pathogenesis of psoriasis remains largely unknown, recent discoveries have been made which have elucidated the pivotal role of T cells (Lebwohl, 2003). This discovery was made through the use of severe combined immunodeficiency mouse models and further supported by the dramatic response to agents such as methotrexate, cyclosporin, and denileukin diftitox, all of which modulate T-cell activity (Gottlieb, 2001). This process begins with the presence of antigens, which cause the maturation of Langerhans cells and the migration of antigen-presenting cells (APC) to the lymph node. Once in the lymph node, the APCs interact with naEFve T cells, causing T-cell activation and subsequent T-cell proliferation. Some of these proliferating T cells are memory T cells, which ultimately migrate to the inflamed target areas of the skin. When these T cells are activated, they will release type 1 cytokines (Th1), such as interferon gamma, IL-2 and IL-12, and TNF (Gottlieb, 2001; Gottlieb & Bos, 2002). These cytokines are responsible for keratinocyte proliferation and lack of maturation, and vascular changes characteristic of psoriasis.Treatment
Three broad categories of treatment options exist for psoriasis, including topical modalities, phototherapy, and systemic therapy (Lebwohl, 2003). Topical treatments are effective for patients with mild-to-moderate psoriasis, while phototherapy and systemic medications are appropriate for more severe cases. These topicals include topical steroids, tar, anthralin, vitamin D analogues, and retinoids.
Phototherapy encompasses treatment with PUVA, broadband and narrowband UVB, and the 308 nm excimer laser (Lebwohl, 2003). Prior to beginning PUVA, laboratory tests, such as antinuclear antibodies, should be performed. This is to ensure that the patient does not harbor undiagnosed collagen vascular disease/photosensitivity. Also, since psoralen, which is ingested prior to UVA exposure, is a photosensitizer and can cause heptotoxicity, liver function tests should be obtained.
In patients afflicted with severe psoriasis, systemic therapies have been effective, but some carry significant side effects (Lebwohl, 2003). Several systemic medications can be used for psoriasis, such as methotrexate, cyclosporin, retinoids, and more recently targeted immunotherapies (biologics). Patients treated with methotrexate must be monitored for bone marrow and hepatic toxicities. Retinoids can cause mucocutaneous side effects, hair loss, nail thinning, and teratogenicity. Cyclosporin use can lead to nephrotoxicity, hypertension, or development of lymphomas with prolonged use; therefore, its use is usually limited to 1 year.
Recently targeted immunotherapies have become popular alternatives for patients with severe psoriasis. These treatments target specific cells, cytokines, or interactions to achieve remission (Lebwohl, 2003). Not only are these alternatives effective, but they have a more favorable side effect profile than the traditional systemic agents. Alefacept (Amevive®) and denileukin diftitox (Ontak®) are fusion proteins which eliminate activated T cells by targeting the interaction between LFA3 on APC and CD2 on T cells, and by binding to IL2 receptor (CD25) to release diphtheria toxin, respectively. Inhibition of T-cell activation/proliferation has been achieved with several therapies, including a monoclonal antibody to anti-CD4, anti-CD80, anti-CD25 (daclizumab), anti-CD11a (efalizumab), and anti-CD2 (siplizumab). Also, CTLA4Ig is a fusion protein which binds to CD80 and CD86 on APCs to inhibit T-cell activation. Immune deviation has been achieved through the use of IL4 and 10, which are type 2 cytokines (Th2) that counteract the Th1 predominance found in psoriasis. Finally, inhibition of cytokines is accomplished with infliximab (Remi cade®), a chimeric mouse-human monoclonal antibody which inhibits TNFα (see Figures 1 & 2); etanercept (Enbrel®), a fusion protein which inhibits TNFα (see Figures 3-6); adalimumab (Humira®), a fully humanized monoclonal antibody to TNFα; and anti-IL8.
Figure 1. (click image to zoom)
Severe psoriatic involvement of most of the trunk, prior to the start of infliximab therapy.
Figure 2. (click image to zoom)
Resolution of psoriasis, after completion of infliximab therapy.
Figure 3. (click image to zoom)
Significant psoriatic involvement of the hands, prior to the use of etanercept.
Figure 4. (click image to zoom)
Resolution of psoriasis, after 16 weeks of etanercept therapy.
Figure 5. (click image to zoom)
Large psoriatic plaques on the breast, prior to starting etanercept.
Figure 6. (click image to zoom)
Complete resolution of psoriatic plaques, after 16 weeks of etanercept.
Infliximab (Remicade®)
Infliximab is a chimeric monoclonal IgG antibody which inhibits TNFα activity and triggers complement mediated lysis of TNFα expressing cells in vitro (Gottlieb, 2001; Gottlieb & Bos, 2002; LaDuca & Gaspari, 2001; Lebwohl, 2003; Victor & Gottlieb, 2002; Williams & Griffiths, 2002). It is made from human constant and mouse variable regions of IgG. It neutralizes soluble and blocks membrane-bound TNFα. It is FDA approved for the treatment of Crohn's disease and rheumatoid arthritis (RA) at intravenous doses of 5 mg/kd and 3 mg/kg respectively. The infusion is given over at least 2 hours and has a half life of 8 to 10 days (Williams & Griffiths, 2002). Crohn's disease without fistulas is treated with one dose of infliximab at 5 mg/kg, while the presence of fistulas requires three doses of 5 mg/kg at weeks 0, 2, and 6. RA is treated with 3 mg/kg at weeks 0, 2, 8, and every 8 weeks thereafter.
It was discovered that infliximab was effective in treating psoriasis after a patient with recalcitrant Crohn's and psoriasis was treated with infliximab for her Crohn's (LaDuca & Gaspari, 2001; Victor & Gottlieb, 2002). After the infusion, not only did her Crohn's improve, but also her psoriasis. In a randomized double blind placebo controlled trial, 33 patients were randomized to a placebo arm, a 5 mg/kg arm, or a 10 mg/kg arm and treated on weeks 0, 2, 6 (Chaudhari et al., 2001). Eighty-two percent of patients in the 5 mg/kg arm, 91% of patients in the 10 mg/kg arm, and 18% of patients in the placebo arm achieved a greater than 75% improvement on Psoriasis Index and Severity Score (PASI) after 10 weeks. Treatment began working within 2 weeks and sustained this improvement for more than 6 months. Immunohistochemical staining showed decreased epidermal inflammation and normalization of keratinocyte differentiation. No serious adverse effects were noted.
Phase II open label data showed that 55% of patients with psoriasis treated with infliximab retained a 50% or greater reduction in the original PASI scores after 26 weeks, with no further infusions (Gottlieb, Chaudhari, Mulcahy, Dooley, & Baker, 2003).
Infliximab was also successful in the treatment of pustular psoriasis, a severe, debilitating, and recalcitrant variant of psoriasis. Elewski (2002) treated two patients with infliximab 5mg/kg on weeks 0, 2, and 6. The patients tolerated the infusion well without any side effects. Clearance began within the first few days after the first infusion with continued improvement until complete clearance. This complete clearance was maintained for 10 weeks after the last infusion. Newland, Weinstein, and Kerdel (2002) reported one case of pustular psoriasis treated successfully with one infusion of infliximab 5 mg/kg. Complete resolution of the pustules occurred by day 4. The infusion was well tolerated without any side effects.
In a 6-month trial, 12 patients with recalcitrant psoriatic arthritis were treated with infliximab 5 mg/kg on weeks 0, 2, 6, 14, 22 along with their previous treatments of steroids and methotrexate (Provenzano, Termini, Le Moli, & Rinaldi, 2003). No infusion reactions were noted. Two patients were withdrawn from the study, one for angina pectoris and one for pulmonary malignancy, which were not considered a result of the infliximab infusions. Significant improvement was noted in all patients.
An open label pilot study was conducted with 21 patients with recalcitrant spondyloarthropathy, 9 of which had psoriatic arthritis (Van Den Bosch et al., 2000). They were treated with infliximab 5 mg/kg at weeks 0, 2, 6, along with methotrexate. Rapid and significant improvement was noted in all patients without any significant side effects. PASI scores showed significant improvement at day 14 compared to baseline, and this improvement was sustained at day 84. Global and peripheral assessment of psoriatic arthritis showed significant improvement in all areas at day 14 compared to baseline, and this significant improvement was maintained at day 84.
Drawbacks are few and include headache, diarrhea, rash, pharyngitis, rhinitis, cough, upper respiratory infection, and urinary tract infection (LaDuca & Gaspari, 2001; Lebwohl, 2003; Mease, 2002; Provenzano et al., 2003; Van Den Bosch et al., 2000; Williams & Griffiths, 2002). Rare instances of more severe side effects have occurred, such as reactivation of pulmonary tuberculosis, aseptic meningitis, sepsis, and development of anti-dsDNA and systemic lupus. Keane et al. (2001) reported 70 cases of TB developing after the use of infliximab, 40 of which had extrapulmonary disease. The incidence of TB with infliximab is much higher than with etanercept. This reactivation of TB has been attributed to immune system disruption, manifested as the failure of granulomas to compartmentalize the bacilli, and inhibition of macrophage apoptosis after the use of infliximab. Patients are required by the Food and Drug Administration to have a negative purified protein derivative (PPD) test and negative chest radiograph prior to starting infliximab therapy. There is also concern of long-term development of antibodies to the drug. In patients with Crohn's treated with repeated infusions of infliximab, 13% developed antibodies against the medication (Tan, Gordon, Lebwohl, George, & Lebwohl, 2001). The presence of these antibodies has lead to the loss of clinical efficacy, the development of infusion reactions, chest pain, bronchospasm, and anaphylactic shock. The rate of antibody formation is inversely related to dose and decreases with the addition of low-dose methotrexate (Lebwohl, 2003). How this will translate in patients with psoriasis remains to be seen. Infusion reactions, such as anaphylaxis and bronchospasm, can occur rarely, and can be treated by slowing the infusion rate and pretreating with antihistamines or steroids. Relative contraindications to the use of infliximab include congestive heart failure, demyelinating disorders, lupus, lymphoma/malignancy, antibody formation to infliximab, hypersensitivity to murine products, and sepsis. Infliximab is a pregnancy class B drug.Etanercept (Enbrel®)
Etanercept is a recombinant human TNFα receptor fusion protein, which consists of the extracellular domains of two TNFα receptor p75 receptors and the constant (Fc) region of IgG1, which inhibits soluble TNFα. In contrast to infliximab, etanercept binds to and inhibits only soluble TNFα (Gottlieb, 2001; Gottlieb & Bos, 2002; LaDuca & Gaspari, 2001; Lebwohl, 2003; Victor & Gottlieb, 2003; Williams & Griffiths, 2002). It is FDA approved for the treatment of adult rheumatoid (RA) and psoriatic arthritis (PA) at doses of 25 mg twice a week administered subcutaneously.
It was noted that in the treatment of patients with PA, their psoriasis improved as well (Davison, Bunker, & Basarab, 2002; Galadari, Fuchs, & Lebwohl, 2003; Iyer, Yamauchi, & Lowe, 2002; Kurschat et al., 2001). Mease et al. (2002a) enrolled 60 recalcitrant psoriatic arthritis patients in a double-blind placebo-controlled study comparing subcutaneous injections of etanercept 25 mg twice a week to placebo. Patients continued on metho trexate. After 12 weeks, 87% of etanercept-treated patients versus 23% of placebo-treated patients responded significantly based on the Psoriatic Arthritis Response Criteria (PsRC). Using the American College of Rheumatology criteria (ACR20), statistically significant improvement was noted in 73% of the etanercept-treated patients and 13% of the placebo-treated patients at 12 weeks. Also, 26% of the etanercept-treated patients had a 75% improvement in PASI scores, while none of the placebo patients improved. Only 20 of the patients reported side effects, namely injection site reactions, but no significant side effects were noted. After 4 months of followup, five patients had no joint pain and 55 had only mild symptoms. In the phase III trial of etanercept for PA, there was a median improvement in PASI in 33% in the etanercept group and none in the placebo groups (Mease et al., 2000a).
In a subsequent 12-week double-blind placebo-controlled study of etanercept for psoriasis, 70% of patients given etanercept had improvement in their PASI scores (Gottleib, Matheson, Lowe, & Zitnik, 2002). Fifty-six percent of patients treated with etanercept and 5% of placebo-treated patients had a 75% reduction in PASI scores at 24 weeks.
The most common side effect was injection site reactions (Gottleib et al., 2002; Mease et al., 2000a; Mease, Goffe, & Betz, 2000b). Other uncommon side effects were upper-respiratory infections, headache, rhinitis, abdominal pain, vomiting, pharyngitis, nausea, gastrointestinal infection, and rash. Antibody formation is less likely to occur in etanercept-treated patients compared to infliximab (Lebwohl, 2003). Thirteen cases of TB reactivation have been reported (Goffe & Cather, 2003; Keane et al., 2001). Unlike infliximab, etanercept-associated TB occurs sporadically and later in the course of treatment. Even though the FDA does not require a negative chest radiograph and PPD, both should be performed. More serious reactions have occurred, including demyelinating disorders, aplastic anemia, allergic reactions, and development of positive ANA, anti-dsDNA, and drug-induced systemic lupus. No malignancies have been discovered during the FDA trials; however, Smith and Skelton (2001) reported seven cases of squamous cell carcinoma occurring in patients with RA treated with etanercept (Smith & Skelton, 2001). It has been found in long-term RA studies using etanercept that the incidence of malignancy was not increased over age-matched controls (Goffe & Cather, 2003). Relative contraindications to use of etanercept include sepsis, malignancy, congestive heart failure, and demyelinating diseases. It is a pregnancy class B drug. Printer- Friendly Email This
Dermatol Nurs. 2005;17(2):97-108. ©2005 Jannetti Publications, Inc.
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