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ashwini ranganath, Rohit Shetty, Sharon D'Souza, Kareeshma Wadia, Debashish Das, Arkasubhra Ghosh; Matrix Metalloproteinase-9 drives disease progression of Keratoconus. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4070.
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Keratoconus is a corneal thinning disorder of unknown etiology for which no drugs or therapies are available currently. Furthermore, the exact cause of stromal thinning is not clear. Matrix metalloproteinases are upregulated during matrix remodeling and cause degradation of various types of collagen. MMP9 has been demonstrated to degrade typeI and IV collagen fibers in cancer. This activity is regulated by cytokine Interleukin 6(IL6). We therefore asked whether MMP9 is upregulation in keratoconus correlates to increasing stages of disease and depends on abnormal IL6 levels. We quantified levels of MMP9 and IL6 in tear films of keratoconus patients and correlated with severity of disease. To validate our hypothesis we investigated effect of topical CsA(cyclosporine A)treatment in keratoconus as it has been demonstrated to inhibit MMP9 and has been approved for treatment of allergic eye disease.
64 eyes with keratoconus of varying severity were included. This study and on label use od CsA to treat associated with keratoconus was approved by Narayana Nethralaya IRB. Keratoconus was graded based on topographic criteria of Keratoconus Severity Index using steep K into <48 D, 48-51 D, 51-56 D and >56D. Tear samples were collected from lower fornix with capillary tubes. Levels of MMP-9 and IL6 in each sample were measured by ELISA and were correlated with severity of keratoconus. 10 patients with progressive keratoconus were treated with topical CsA 0.05% and topography was analyzed pre and post treatment (6 months and 1 year) to evaluate stability of keratoconus.
Mean MMP9 (Normal 3.9-8.3 ng/ml) and IL6 (normal 1-4.1) respectively were 42.45 and 1.03 in <48 D group, 40.06 and 1.125 in 48-51 D group, 46.07 and 1.64 in 51-56 D group and 46.55 and 1.06 in >56 D group. Of 10 patients treated with CsA, 8 showed stabilization of keratoconus, and 6 had flattening of keratometry ranging from 0.5-1.7D, 6 months to 1 year post treatment.
Significantly higher levels of MMP9 and marginally higher levels of IL6 were detected in tear samples of keratoconus eyes, and their levels positively correlated with severity of keratoconus. Inhibiting MMP9 locally in cornea using CsA halted disease progression and even reduced the disease in few cases. This suggests MMP9 is an important factor driving keratoconus pathophysiology. Also, topical CsA may be an effective disease modifying agent in keratoconus management.
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