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      Eruptive papules during efalizumab (anti-CD11a) therapy of psoriasis vulgaris: a case series

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          Abstract

          Background

          Newer biological therapies for moderate-to-severe psoriasis are being used more frequently, but unexpected effects may occur.

          Case presentations

          We present a group of 15 patients who developed inflammatory papules while on efalizumab therapy (Raptiva, Genentech Inc, anti-CD11a). Immunohistochemistry showed that there were increased CD11b +, CD11c + and iNOS + cells (myeloid leukocytes) in the papules, with relatively few CD3 + T cells. While efalizumab caused a decreased expression of CD11a on T cells, other circulating leukocytes from patients receiving this therapy often showed increased CD11b and CD11c. In the setting of an additional stimulus such as skin trauma, this may predispose to increased trafficking into the skin using these alternative β2 integrins. In addition, there may be impaired immune synapse formation, limiting the development of these lesions to small papules. There is little evidence for these papular lesions being "allergic" in nature as there are few eosinophils on biopsy, and they respond to minimal or no therapy even if efalizumab is continued.

          Conclusion

          We hypothesize that these papules may represent a unique type of "mechanistic" inflammatory reaction, seen only in the context of drug-induced CD11a blockade, and not during the natural disease process.

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          Most cited references18

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          Characterization of human blood dendritic cell subsets.

          Dendritic cells (DCs) are key antigen-presenting cells for stimulating immune responses and they are now being investigated in clinical settings. Although defined as lineage-negative (Lin(-)) HLA-DR(+) cells, significant heterogeneity in these preparations is apparent, particularly in regard to the inclusion or exclusion of CD14(+), CD16(+), and CD2(+) cells. This study used flow cytometry and a panel of monoclonal antibodies (mAbs), including reagents from the 7th Leukocyte Differentiation Antigen Workshop, to define the cellular composition of 2 standardized peripheral blood mononuclear cell (PBMCs)-derived Lin(-) HLA-DR(+) preparations. Lin(-) cells were prepared from PBMCs by depletion with CD3, CD14, CD19, CD11b, and either CD16 or CD56 mAbs. Analysis of the CD16-replete preparations divided the Lin(-) HLA-DR(+) population into 5 nonoverlapping subsets (mean +/- 1 SD): CD123 (mean = 18.3% +/- 9.7%), CD1b/c (18.6% +/- 7.6%), CD16 (49.6% +/- 8.5%), BDCA-3 (2.7% +/- 1.4%), and CD34 (5.0% +/- 2.4%). The 5 subsets had distinct phenotypes when compared with each other, monocytes, and monocyte-derived DCs (MoDCs). The CD85 family, C-type lectins, costimulatory molecules, and differentiation/activation molecules were also expressed differentially on the 5 Lin(-) HLA-DR(+) subsets, monocytes, and MoDCs. The poor viability of CD123(+) DCs in vitro was confirmed, but the CD16(+) CD11c(+) DC subset also survived poorly. Finally, the individual subsets used as stimulators in allogeneic mixed leukocyte reactions were ranked by their allostimulatory capacity as CD1b/c > CD16 > BDCA-3 > CD123 > CD34. These data provide an opportunity to standardize the DC populations used for future molecular, functional and possibly even therapeutic studies.
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            Dendritic cell subsets and lineages, and their functions in innate and adaptive immunity.

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              Increase in TNF-alpha and inducible nitric oxide synthase-expressing dendritic cells in psoriasis and reduction with efalizumab (anti-CD11a).

              We find that CD11c(+) cells with many markers of dendritic cells (DCs) are a major cell type in the skin lesions of psoriasis. These CD11c(+) cells, which are evident in both epidermis and dermis, are the sites for the expression of two mediators of inflammation, inducible nitric oxide synthase (iNOS) and TNF-alpha in diseased skin. These cells express HLA-DR, CD40, and CD86, lack the Langerin and CD14 markers of Langerhans cells and monocytes, respectively, and to a significant extent express the DC maturation markers DC-LAMP and CD83. Treatment of psoriasis with efalizumab (anti-CD11a, Raptiva) strongly reduces infiltration by these DCs in patients responding to this agent. Disease activity after therapy was more related to DC infiltrates and iNOS mRNA levels than T cell infiltrates, and CD11c(+) cells responded more quickly to therapy than epidermal keratinocytes. Our results suggest that a type of DC, which resembles murine "Tip-DCs" that can accumulate during infection, has proinflammatory effects in psoriasis through nitric oxide and TNF-alpha production, and can be an important target for suppressive therapies.
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                Author and article information

                Journal
                BMC Dermatol
                BMC Dermatology
                BioMed Central (London )
                1471-5945
                2007
                26 February 2007
                : 7
                : 2
                Affiliations
                [1 ]Laboratory for Investigative Dermatology, The Rockefeller University, New York, New York, USA
                [2 ]Central Dermatology, St Louis, Missouri, USA
                [3 ]Genentech Inc., San Francisco, California, USA
                [4 ]Probity Medical Research, Waterloo, Canada
                Article
                1471-5945-7-2
                10.1186/1471-5945-7-2
                1817648
                17324275
                b06ba0f8-0612-4e22-be31-b59a1ce70363
                Copyright © 2007 Lowes et al; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 7 November 2006
                : 26 February 2007
                Categories
                Case Report

                Dermatology
                Dermatology

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