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In patients with retinal detachment, the major cause of recurrent redetachment is proliferative vitreoretinopathy (PVR, 5-10 %). PVR is characterized by the formation of fibrotic contractile membranes on either side of the retina, causing the retina to detach. The retinal pigment epithelium (RPE) has an important role in the homeostasis and functioning of the retina and forms the outer blood-retinal barrier by separating the retina from the blood vessels in the choroid. Coagulation proteins may come in contact with the RPE due to hemorrhage or breakdown of the blood-retinal barrier. We were the first to demonstrate that vitreous of patients with established PVR contains elevated levels of thrombin. Intravitreal thrombin (and to some extent factor Xa) can induce the release of a broad panel of cytokines, chemokines and growth factors by RPE which regulate local inflammatory and fibrotic responses, fitting PVR pathogenesis. These responses include the differentiation of monocytes into macrophages and that of RPE into myofibroblasts. Both cell types are abundantly present in fibrotic retinal membranes. The clinically available direct thrombin-inhibitor Dabigatran is able to inhibit the thrombin-induced release of cytokines, chemokines and growth factors and may thus be an interesting therapy for PVR development and other vitreoretinal disorders which are characterized by breakdown of the blood-retinal barrier. Currently, in the Rotterdam Eye Hospital, it has been found that Dabigatran reaches the eye in a potential effective concentration and a clinical trial with Dabigatran is planned with patients at risk for developing PVR.

Item does not contain fulltext, BACKGROUND: Ustekinumab is a fully human anti-p40 monoclonal antibody which neutralizes interleukin (IL)-12 and IL-23, thereby interfering with T-helper (Th)1/Th17 pathways and keratinocyte activation, and is highly effective in the treatment of psoriasis. During ustekinumab treatment, some of our patients noticed reduced koebnerization of noninvolved skin and less new plaque formation. OBJECTIVES: To determine whether ustekinumab improves psoriasis-related gene expression and tape-strip responses in noninvolved skin. METHODS: Before and 4 weeks after ustekinumab treatment, noninvolved skin was tape-stripped. After 5 h, biopsies were taken from untouched and tape-stripped skin. The mRNA expression of psoriasis-related markers such as NGF, GATA3 and IL-22RA1, and several antimicrobial peptides (AMP) was quantified. Leucocyte counts and a broad range of inflammatory serum proteins were analysed to gain insight into the systemic alterations. RESULTS: Four weeks following a single ustekinumab injection, NGF showed a significant decrease, whereas GATA3 and IL-22RA1 expression increased, indicative of reduced responsiveness to epidermal triggering. This was accompanied by an increase of the inflammation-related serum proteins GPNMB, MST1 and TRADD. The baseline and tape-strip-induced mRNA expression of the AMP human beta-defensin-2 (hBD-2), S100A7 and LL-37 remained unaltered. Clinically, after 4 weeks, eight out of 11 patients showed a 50% psoriasis area and severity index (PASI) improvement, which was accompanied by a significant reduction in serum hBD-2 levels. No changes were noted in total leucocytes, C-reactive protein and erythrocyte sedimentation rate. CONCLUSIONS: These findings indicate that ustekinumab reduces psoriasis-related gene expression in noninvolved psoriatic skin, making it more resistant to exogenous triggering, without disturbing its antimicrobial response. In parallel, ustekinumab modulates important circulating inflammation-related proteins.