Vera M. R. Heydendael

Cyclosporin trough levels: is monitoring necessary during short‐term treatment in psoriasis? A systematic review and clinical data on trough levels

Summary Background Cyclosporin is an effective treatment for severe plaque psoriasis. Unfortunately, its use may be limited by time‐ and dose‐related nephrotoxicity. Serum trough levels may be useful for monitoring the risk of nephrotoxicity.

Systemic Treatment with Either Cyclosporin A or Methotrexate Does Not Influence the T Helper 1/T Helper 2 Balance in Psoriatic Patients

Cyclosporin A and methotrexate are highly effective drugs in the treatment of psoriasis. It was hypothesized that these therapies might modulate T helper cell cytokine secretion patterns or T cell migration patterns. Flow cytometric determination of interferon-gamma (IFNγ) and interleukin 4 (IL4) producing T helper cell frequencies, as well as of cutaneous lymphocyte associated antigen (CLA) expressing T cell frequencies was performed in patients suffering from severe psoriasis, before, during, and after a scheduled immunosuppressive regimen with either cyclosporin A or methotrexate. Both cyclosporin A and methotrexate treatment reduced the psoriasis area severity index score after 12 weeks of treatment. Cyclosporin A treatment reduced the frequencies of IL4-producing CD4pos T cells, without significantly affecting the T helper 1 to T helper 2 (Th1/Th2) balance but in conjunction with the decreasing number of peripheral blood eosinophil counts. In methotrexate-treated patients, the Th1/Th2 balance was unaffected. Cessation of both therapies resulted in increased numbers of IFNγ- as well as IL4-producing CD4pos T cells as compared to before initiation of oral therapy. Methotrexate, but not cyclosporin A, treatment reduced the frequencies of circulating skin-homing CLApos T cells. This effect was reversed by 4 weeks after withdrawal of methotrexate therapy. We conclude that (1) neither cyclosporin A nor methotrexate affects the balance between Th1 and Th2 cells; (2) exaggerated cytokine production by T helper cells after cessation of oral cyclosporin A or methotrexate drug treatment may contribute to the reappearance of psoriatic skin lesions; and (3) decrease of circulating skin-homing T cells may be responsible for part of the therapeutic effect of methotrexate in severe psoriasis.

In situ demonstration of CD40- and CD154-positive cells in psoriatic lesions and keratinocyte production of chemokines by CD40 ligation in vitro

In psoriatic lesions, T cells and keratinocytes are in an activated state. Ligation of CD40 expressed on activated keratinocytes with CD154 expressed on activated T cells is thought to be involved in the pathogenesis of psoriasis. However, the presence of CD40+ and CD154+ cells in psoriatic skin has not been thoroughly studied. The present study has therefore examined their presence by immunohistochemistry in the lesional and non‐lesional skin of ten patients. The influence of CD154–CD40 ligation on the release of chemokines (IL‐8, RANTES, and MCP‐1) and complement components (C3 and factor B) from keratinocytes was also investigated in vitro. Studies using single and double staining showed that clusters of CD40+ keratinocytes were present in both lesional and non‐lesional skin; CD40+CD1a+ Langerhans cells in lesional, non‐lesional, and normal skin; and numerous CD40+CD83+ cells in lesional skin. CD1a+ and CD83+ cells always expressed CD40 strongly. Numerous T cells were seen in lesional skin. A small number of T cells expressed CD154. CD154+ T cells were seen in the lesional epidermis of seven of ten patients—in six, in juxtaposition to CD40+ cells including keratinocytes. In non‐lesional epidermis, CD154+ T cells were seen in two patients—in one, in juxtaposition to CD40+ keratinocytes. In vitro studies showed that IFN‐γ‐treated keratinocytes released small amounts of IL‐8, RANTES, and MCP‐1; ligation of these cells with CD154‐transfected J558 cells or soluble CD154 greatly enhanced the release. This ligation did not enhance the release of C3 and factor B. These results warrant further studies on the role of CD40 ligation in the pathogenesis of psoriasis. Copyright