Yosuf El-Shabrawi

Nine patients with uveitis with associated systemic disease were included (table 1). Eight of these patients had a rheumatic disease (five had a spondyloarthropathy (all were HLA-B27 positive), two had juvenile idiopathic arthritis (JIA; one Still’s disease, one antinuclear antibody (ANA) positive oligoarthritis)) and one patient had a necrotising sclero-uveitis associated with Wegener’s granulomatosis. One patient with uveitis with an associated tubulointerstitial nephritis (TINU) was also included. Disease modifying antirheumatic drug (DMARD) treatment was started at least three months before infliximab treatment. It consisted of methotrexate (MTX) in seven patients, of whom two received a combination of MTX and mycophenolate-mofetil. One patient received cyclophosphamide, and one leflunomide. Because the response was inadequate towards even combined immunosuppressant treatment (for example, MTX plus mycophenolate-mofetil) or because of the massive destructive activity of the disease (for example, necrotising sclero-uveitis) a quick acting active anti-inflammatory substance was needed. Because a quick response towards infliximab had been seen in a previous study, it was chosen again.³

Extracellular matrix‐degrading enzymes are crucial for cancer metastases. One group of enzymes that has been increasingly implicated in the breakdown of the extracellular matrix, and hence the intravasation and dissemination of tumour cells, is the family of metalloproteinases. In the recent past, increasing efforts have led to the development of more or less specific matrix metalloproteinase (MMP) inhibitors. Data concerning the molecular nature and timing of the contribution of MMPs to tumour spread is of paramount importance in clarifying which MMP is an appropriate target for more selective MMP inhibition in future tumour therapy. This study immunohistochemically characterized the expression pattern of MMP‐2, ‐3, and ‐9 in 26 uveal melanomas. Forty‐six per cent of the uveal melanomas expressed MMP‐2 and/or MMP‐9. MMP‐3 expression was seen in 17 out of 26 uveal melanomas. MMP‐9, previously shown to play an important part in tumour dissemination, was predominantly present in epithelioid melanomas (71.4%) or the epithelioid portion of mixed cell uveal melanomas (67%), whereas only one out of ten spindle cell melanomas showed MMP‐9 expression (10%). MMP‐2 and MMP‐9 expression was associated with a significantly higher incidence of metastatic disease. The survival rate of patients with MMP‐2‐positive melanomas was 31% vs. 85% for patients with MMP‐2‐negative (pp<0.04). The fact that patients suffering from TIMP‐1‐ as well as TIMP‐2‐positive uveal melanomas tended to show a better survival rate (72% vs. 45% for TIMP‐1; 88% vs. 37% for TIMP‐2) supports the view that proteolytic enzymes are of importance in tumour spread. Copyright © 2001 John Wiley & Sons, Ltd.

To determine changes in production of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) in the ciliary body, the trabecular meshwork and the retinal pigment epithelium induced by both prostaglandins and corticosteroids. Explant organ cultures were removed by a scleral incision 3 mm posterior to the limbus. Retinal pigment epithelium was grown to confluence. Organ and cell cultures were treated with latanoprost and/or dexamethasone for 72 h. The activity of MMP-2, -3 and -9 was assessed using zymography. The synthesis pattern of MMPs and TIMP-1 and -2 was identified using immunostaining. Treatment of explant organ cultures with 10 micrograms/ml of latanoprost induced a mean upregulation of MMP-2 by 36%, MMP-3 by 112% and MMP-9 by 156% as seen by zymography. Dexamethasone 500 nm reduced the amounts of secreted MMP-2 by 13%, MMP-3 by 69%. MMP-9 was not detectable in the media of corticosteroid-treated explant organ cultures. The addition of 10 micrograms/ml of latanoprost to dexamethasone-treated cultures increased MMP-2 by 14%, MMP-3 by 43% and MMP-9 by 49%. Using immunohistochemistry we found staining with antibodies against MMP-2, -3, -9 and TIMP-1 and -2 within the ciliary body, and only to a lesser degree in the trabecular meshwork. Latanoprost treatment caused an increase of 29% in MMP-2 (p < 0.0001), 98% in MMP-3 (p < 0.0001) and 108% in MMP-9 (p < 0.0001). Dexamethasone reduced the staining for MMP-2 by 32% (p < 0.0001), for MMP-3 by 33% (p < 0.0001) and for MMP-9 by 83% (p < 0.0001). Almost no change in staining for MMPs was detectable in the trabecular meshwork. Neither latanoprost treatment nor dexamethasone induced significant changes (p < 0.93) in the secretion of TIMPs. In the media of non-treated retinal pigment epithelium (RPE) cells the only MMP detected was MMP-2. RPE cells in culture did not respond to either treatment with a change in their MMP secretion. We detected a profound upregulation of both MMP-3 and MMP-9 and a mild induction of MMP-2 through latanoprost in the ciliary body, but not the trabecular meshwork or RPE cells. Corticosteroids, on the other hand, downregulated MMP expression in both tissues. This inhibiting effect of corticosteroids on MMP production was reversed by latanoprost.