Efalizumab in the treatment of psoriasis: mode of action, clinical indications, efficacy, and safety
Introduction
Tissue-specific localization of T lymphocytes has been implicated in the pathogenesis of psoriasis and other chronic inflammatory skin disorders.1, 2, 3 Insight into molecular mechanisms of T-cell recruitment to the skin may, therefore, contribute to rational and pathogenesis-oriented approaches to treat psoriasis. Trafficking of T lymphocytes is mediated by a multitude of complex and intricate interactions of cytokines and chemokines with adhesion receptors.4
The first steps of T-cell localization to all tissues include leukocyte tethering and rolling on the endothelial lining of the vessel wall, transient adhesive interactions that are mediated primarily by selectins.5, 6 Selectins are single-chain transmembrane adhesion molecules, which are characterized by a lectinlike domain that binds to carbohydrate ligands displayed on glycoprotein scaffolds and that are up-regulated upon inflammatory stimuli.7, 8 In addition to selectin-mediated rolling, very late antigen 4 (α4β1 integrin, CD49d/CD29), a heterodimeric adhesion receptor of the integrin family that binds to the immunoglobulin-superfamily adhesion molecules vascular cell adhesion molecule 1 and mucosal addressin cell adhesion molecule 1, contributes to rolling of certain leukocyte subsets.9, 10
Stimulatory effects exerted by a growing number of chemokines and other mediators initiate the subsequent adhesive steps of cutaneous lymphocyte localization.11, 12 After transient rolling, lymphocytes become activated and firmly attach to the vessel wall through adhesion of β2-integrins, including leukocyte function-associated antigen 1 (LFA-1, CD11a/CD18, αLβ2), to immunoglobulin-superfamily members, such as intercellular adhesion molecule 1 (ICAM-1, CD54).2, 13 This mechanism appears to be of prime importance in various inflammatory skin conditions.14 In addition, β1-integrins and their ligands, such as the α4β1–vascular cell adhesion molecule 1 pair, are involved in leukocyte-endothelial cell binding.
The concept that cutaneous recruitment of T cells plays a pivotal role in psoriasis has been corroborated in several animal models.15, 16, 17, 18 Some experimental evidence in animal xenotransplantation models, however, suggests that resident T cells may be sufficient to induce psoriatic tissue alterations under certain conditions.19, 20 In human patients, the number of T cells infiltrating the skin may be correlated with disease activity of psoriasis.21 Overall, although challenging because of the sheer complexity of the process, interfering with the multistep cascade directing T cells into cutaneous compartments appears to be an attractive strategy to treat psoriasis.22
Section snippets
Mode of action of efalizumab
Efalizumab is a humanized monoclonal antibody directed against CD11a, the α-subunit of LFA-1. It leads to blockade of the interaction between LFA-1 and ICAM-1.23, 24 Given that LFA-1/ICAM-1 binding is involved in cellular interactions in several places, efalizumab presumably interferes with activation of T lymphocytes in lymph nodes, extravasation of circulating lymphocytes, T-cell reactivation by cutaneous antigen presenting cells, and interaction of activated T lymphocytes with keratinocytes.
Pharmacokinetics and pharmacodynamics of efalizumab
Seventy patients who have moderate-to-severe plaque psoriasis received weekly subcutaneous injections of either 1 mg/kg (n = 33) or 2 mg/kg (n = 37) efalizumab for 12 weeks in an open, multicenter, phase 1 study.26 Peak plasma concentrations were reached after 2 to 3 days. When 1.0 mg/kg per week of efalizumab was administered, the average estimated bioavailability was about 50%, and steady-state serum concentrations of efalizumab were reached after 4 weekly doses of 1 mg/kg (mean plasma
Biotransformation of efalizumab
After either binding to CD11a on the cell surface or direct endocytosis, efalizumab is internalized and degraded intracellularly, apparently independent of cytochrome P450 enzymes, and the resulting small peptides are eliminated by glomerular filtration.29 The compound is cleared by dose-dependent nonlinear saturable elimination, whereby the nonlinearity can be explained by the saturable binding to CD11a. As a consequence, clearance of efalizumab was more rapid at lower doses, suggesting a
Tissue alterations induced by efalizumab
After subcutaneous administration of efalizumab, a significant thinning of the epidermis and restoration of normal skin was observed after 28 days of treatment. In addition, a marked reduction of keratin 16, corresponding to decreased disease activity, was noted within psoriatic plaques. Intercellular adhesion molecule 1 expression on keratinocytes also was reduced, suggesting amelioration of cytokine-driven inflammation. These epidermal changes were accompanied by diminution of cutaneous T
Other preclinical studies
In vitro, efalizumab bound to human and chimpanzee leukocytes blocked lymphocyte binding to ICAM-1 on keratinocytes and inhibited T-cell proliferation. This was paralleled by down-regulation of LFA-1 expression on murine and chimpanzee lymphocytes in vivo.34 When antimouse CD11a antibodies were administered at doses as high as 30 times the equivalent recommended for clinical use (ie, 1 mg/kg), no adverse effects were observed on reproductive parameters. As expected, the antibody was secreted in
Clinical efficacy of efalizumab
Efalizumab was approved by the Food and Drug Administration in the United States in 2003 for continuous treatment of adult patients with moderate-to-severe plaque psoriasis who are eligible for systemic therapy. The European Medicines Agency approved the drug in 2004 for adult patients with moderate-to-severe chronic plaque psoriasis who have failed to respond to, or have contraindications to, or are intolerant to other systemic therapies including cyclosporin, methothrexate, and psoralen–UV-A
Health-related quality of life
Psoriasis may cause significant psychosocial distress and disability. Its impact on the patient's perceived quality of life equals or even exceeds that of other major illnesses.45 On the basis of Dermatology Life Quality Index, PSA, and an itch scale in 1242 patients, patients receiving efalizumab reported an at least 2-fold greater improvement in all parameters assessed as compared to placebo-treated patients after 12 weeks.46 In addition, when patients randomized to placebo treatment during
Safety and tolerability
Mild-to-moderate flulike symptoms represent the most frequent adverse reactions during efalizumab treatment. The incidence of such symptoms after the first injection was 27.4% in the group receiving efalizumab as compared with 21.2% in the placebo-treated group. The frequency of such symptoms decreased markedly when the treatment was continued for 3 or more injections (3.7% in the efalizumab group versus 3.9% in the placebo group).37
Exacerbation of psoriasis including erythrodermic, guttate, or
Practical considerations
Although efalizumab is usually safe and well tolerated, some practical issues need to be mentioned.35, 54 Transient localized papular eruptions may occur within 4 to 8 weeks after start of therapy. Discontinuation of efalizumab is usually not required in those cases; continued treatment with efalizumab, if necessary in combination with a topical corticosteroid, will suffice in most cases.25, 37 Efalizumab should be discontinued in patients showing generalized inflammatory exacerbations (an
Acknowledgment
This work was supported by a Rudolf Virchow Award and a research grant from the Deutsche Forschungsgemeinschaft to MPS. I thank Dr K Schmitt-Rau (Munich, Germany) for providing important background information.
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2016, HomeopathyCitation Excerpt :This phenomenon continues to be described also with other classes of immunomodulatory drugs (fingolimod, for example) employed in the treatment of MS.73–80 In view of efalizumab be a human monoclonal antibody with structure and action similar to natalizumab, it also presents similar explanation for the rebound effect: after a primary reduction in T cell activation by the direct action of the drug, occurs a secondary reactivation of T lymphocytes in lymphnodes, increasing the circulating lymphocytes and exacerbating the trafficking and recruitment of T cells to the dermis and epidermis, which promote hyperproliferation and abnormal differentiation of keratinocyte (rebound psoriasis).81 Analogously, the occurrence of cases of ‘PML’ with efalizumab29,30 can be explained by the IRIS-PML, in which “the rebound restoration of immune and inflammatory response is overwhelming with potentially fatal results”, as we described with natalizumab.17,82
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