Biological Agents

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Biological agents (see Chapters 38 and 52) are highly specialized systemic therapies that target specific mediators of the immunologic/inflammatory reactions that are, at least in part, responsible for the clinical manifestations of a disease. The rapidly advancing knowledge of cutaneous immunology has brought with it equally impressive innovations in the therapy of malignant disorders such as cutaneous T-cell lymphoma and of immunologic diseases such as psoriasis and psoriatic arthritis. Investigational studies are evaluating a variety of biological agents for the treatment of malignancy and autoimmune diseases. This section will focus on agents that have been well studied or applied widely to the treatment of dermatological disease.

Once thought to be primarily a disorder of keratinocyte hyperproliferation, psoriasis now is known to be an autoimmune process mediated by T lymphocytes that can react with epidermal keratinocytes (Figure 62-2). The mechanism of biological therapies in psoriasis can be illustrated

Lesional psoriatic skin

Lesional psoriatic skin

Non-lesional skin

Epidermis

FIGURE 62-2 Immunopathogenesis of psoriasis. Psoriasis is a prototypical inflammatory skin disorder in which specific T-cell populations are stimulated by as yet undefined antigen(s) presented by antigen-presenting cells. The T cells release proinflammatory cytokines such as TNF-a and IFN-y that induce keratinocyte and endothelial cell proliferation.

Non-lesional skin

Epidermis

FIGURE 62-2 Immunopathogenesis of psoriasis. Psoriasis is a prototypical inflammatory skin disorder in which specific T-cell populations are stimulated by as yet undefined antigen(s) presented by antigen-presenting cells. The T cells release proinflammatory cytokines such as TNF-a and IFN-y that induce keratinocyte and endothelial cell proliferation.

by a conceptual model that outlines four strategies in the treatment of psoriasis: (1) reduction of pathogenic T cells; (2) inhibition of T-cell activation; (3) immune deviation (from a TH1 to a TH2 immune response); and (4) blockade of the activity of inflammatory cytokines.

Although there are limited long-term data regarding the efficacy and safety of biological agents solely for the treatment of psoriasis, similar, if not identical, therapies have been used extensively in the treatment of rheumatoid arthritis and Crohn's disease. The major advantage of biological agents in the treatment of psoriasis appears to be that they specifically target the activity of T lymphocytes and cytokines that mediate inflammation with fewer side effects than traditional systemic immunosuppressive/cytotoxic agents.

Alefacept (amevive) was the first immunobiological agent approved for the treatment of moderate-to-severe psoriasis in patients who are candidates for systemic therapy. Alefacept consists of a recombinant fully human fusion protein composed of the binding site of the leukocyte function-associated antigen 3 (LFA-3) protein and a human IgG1 Fc domain. The LFA-3 portion of the alefacept molecule binds to CD2 on the surface of T cells, thus blocking a necessary cos-timulation step in T-cell activation (Figure 62-3). Importantly, since CD2 is expressed preferentially on memory-effector T cells, naive T cells largely are unaffected by alefacept. A second important action of alefacept is its ability to induce apoptosis of memory-effector T cells through simultaneous binding of its IgG1 portion to immunoglobulin receptors on cytotoxic cells and its LFA-3 portion to CD2 on T cells, thus inducing granzyme-mediated apoptosis of memory-effector T cells.

Alefacept is administered by intramuscular injection at a dose of 15 mg/week for 12 weeks. An additional 12-week course can be initiated if required, and a continuous 24-week regimen is under investigation. Significant reductions in psoriatic lesions have been shown for significant numbers of patients. Alefacept may induce longer remissions than do other biological agents. Adverse effects include a reduction in CD4+ lymphocyte counts, requiring a baseline T-lymphocyte count before initiating alefacept and weekly monitoring of T cells during therapy.

Efalizumab (rapttva) is a humanized monoclonal antibody against the CD11a molecule of LFA-1. By binding to CD11a on T cells, efalizumab prevents binding of LFA-1 to intercellular adhesion molecule 1 (ICAM-1) on the surface of antigen-presenting cells, vascular endothelial cells, and cells in the dermis and epidermis (see Figure 62-3), thereby interfering with T-cell activation and migration and cytotoxic T-cell function. Efalizumab is FDA-approved for the treatment of moderate-severe psoriasis in patients who are candidates for systemic therapy.

The drug is administered by subcutaneous injection once a week at a dose of 1 mg/kg, usually for 12 or 24 weeks. Significant reductions in psoriatic lesions have been shown for significant numbers of patients. After discontinuation of therapy, patients may experience rebound of disease. It is recommended that periodic evaluation of platelet levels be performed during therapy. Side effects

figure 62-3 Mechanisms of action of selected biological agents in psoriasis. Newer biological agents can interfere with one or more steps in the pathogenesis of psoriasis, resulting in clinical improvement. See text for details.

T cell figure 62-3 Mechanisms of action of selected biological agents in psoriasis. Newer biological agents can interfere with one or more steps in the pathogenesis of psoriasis, resulting in clinical improvement. See text for details.

generally are mild, and there is no evidence to date of increased risk of malignancy, infection, or end-organ toxicity.

Etanercept (enbrel) is FDA-approved for the treatment of psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, and ankylosing spondylitis. Etanercept is a soluble, recombinant, fully human TNF receptor fusion protein consisting of two molecules of the ligand-binding portion of the TNF receptor fused to the Fc portion of IgG1. As a dimeric molecule, it can bind two molecules of TNF-a. Etanercept binds soluble and membrane-bound TNF-a, thereby inhibiting the action of TNF-a.

Etanercept is administered by subcutaneous injection at doses of either 25 or 50 mg twice a week. As with alefacept and efalizumab, significant reductions in psoriatic lesions have been shown for significant numbers of patients. Except for injection-site reactions, the drug is well tolerated. Monthly complete blood counts with a differential should be monitored for the first 3 months of treatment. Potential side effects include aplastic anemia, increased risk of infection, and exacerbation of congestive heart failure and demyelinating disorders. The risk of malignancy is unknown but may be increased with the use of etanercept.

Infliximab (remicade) is a mouse-human chimeric monoclonal antibody that binds to soluble and membrane-bound TNF-a and inhibits binding with its receptors. Infliximab is a complement-fixing antibody that induces complement-dependent and cell-mediated lysis when bound to cell-surface-bound TNF-a. It also induces proinflammatory cytokines, such as IL-1 and IL-6, and enhances leukocyte migration. Infliximab is FDA-approved for the treatment of Crohn's disease and rheumatoid arthritis, but it is also in phase 3 trials for the treatment of psoriasis.

Infliximab is administered by intravenous infusion over 2 hours at doses of 3 or 5 mg/kg, usually at weeks 0, 2, and 6. As with the other biological agents discussed above, significant reductions in psoriatic lesions have been shown for significant numbers of patients. Complications of therapy include infusion reactions, reactivation of latent tuberculosis infection, exacerbation of congestive heart failure, and multiple sclerosis—like syndromes. Purified protein derivative (PPD) testing is required before initiating therapy. Neutralizing antibodies to infliximab may develop, and concomitant administration of methotrexate or glucocorticoids may suppress antibody formation.

Denileukin diftitox or DAB389-IL-2, (ontak) is a fusion protein composed of diphtheria toxin fragments A and B and the receptor-binding portion of IL-2. DAB389-IL-2 is indicated for advanced cutaneous T-cell lymphoma in patients with >20% of T cells expressing the surface marker CD25. The IL-2 portion of the fusion protein binds the CD25 marker on the T cell and promotes destruction of the T cell by the cytocidal action of diphtheria toxin.

When 9 or 18 mg/kg/day of DAB3sg-IL-2 is given as an intravenous infusion for 5 consecutive days every 3 weeks for up to 6 months, the overall response rate was 36% with 18 mg/kg/day and 23% with 9 mg/kg/day. Adverse effects included pain, fevers, chills, nausea, vomiting, and diarrhea. Immediate hypersensitivity manifested by hypotension, back pain, dyspnea, and chest pain occurred in 60% of patients within 24 hours of drug administration; other serious side effects are edema, hypoalbuminemia, and/or hypotension, occurring in 20-30% of patients, and elevated blood levels of hepatic transaminases.

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