Increase in TNF-α 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-α 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 a, 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-α production, and can be an important target for suppressive therapies

Alefacept (anti-CD2) causes a selective reduction in circulating effector memory T cells (Tem) and relative preservation of central memory T cells (Tcm) in psoriasis

<p>Abstract</p> <p>Background</p> <p>Alefacept (anti-CD2) biological therapy selectively targets effector memory T cells (Tem) in psoriasis vulgaris, a model Type 1 autoimmune disease.</p> <p>Methods</p> <p>Circulating leukocytes were phenotyped in patients receiving alefacept for moderate to severe psoriasis.</p> <p>Results</p> <p>In all patients, this treatment caused a preferential decrease in effector memory T cells (CCR7^-CD45RA^-) (mean 63% reduction) for both CD4⁺and CD8⁺Tem, while central memory T cells (Tcm) (CCR7⁺CD45RA^-) were less affected, and naïve T cells (CCR7⁺CD45RA⁺) were relatively spared. Circulating CD8⁺effector T cells and Type 1 T cells (IFN-γ-producing) were also significantly reduced.</p> <p>Conclusion</p> <p>Alefacept causes a selective reduction in circulating effector memory T cells (Tem) and relative preservation of central memory T cells (Tcm) in psoriasis.</p

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

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

Combining several ordinal . . .

... This paper proposes the use of u-statistics for scoring multivariate ordinal data and a family of simple nonparametric tests for analysis. The scoring method is demonstrated to be applicable to scoring clinical response profiles in the treatment of psoriasis and then to identifying genomic pathways that best correlate with these profiles