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J. L. Edelman, M. Castro-Paiz, Q. D. Nguyen, D. V. Do, M. R. Robinson; Kenalog-40 Induces Inflammatory Cytokines and Other Proteins in Eyes After Intravitreal Injection and In Human Macrophages: Biomarkers of Sterile Endophthalmitis. Invest. Ophthalmol. Vis. Sci. 2010;51(13):6031.
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Significant incidence of sterile endophthalmitis has been reported after intravitreal injection with Kenalog-40 triamcinolone acetonide (TA) suspension. In contrast, none was reported after 1,898 intravitreal injections in the DRCRnet DME trial (Protocol B) with a TA gel. The Kenalog component that induces sterile endophthalmitis has not been identified. To characterize immune or inflammatory involvement, biomarkers in aqueous humor (AH) from a post-Kenalog sterile endophthalmitis patient were analyzed. Kenalog-induced biomarkers were also evaluated in rat eyes and human macrophages in culture.
AH from a patient with sterile endophthalmitis 24 hrs after intravitreal Kenalog was analyzed in a Luminex-based Human MAP assay and evaluated relative to normal human plasma, serum, or aqueous humor. Rats were injected intravitreally with sterile saline or Kenalog for 24 hours, and whole eye lysates were assayed in the Rodent MAP. Human U-937 macrophages were treated with Kenalog, vehicle, or TA-saturated solution for 20 hrs; and culture supernatants were analyzed in the Human MAP. We used ANOVA and Bonferroni for statistical analysis and Ingenuity Pathway Analysis (IPA) to evaluate relationships between biomarkers.
In clinical sterile endophthalmitis AH, 21 proteins increased ≥1.5 fold; and 20 are functionally related in IPA pathways. These biomarkers include inflammatory cytokines, chemokines, growth factors, and enzymes, and the top 7 (>10 fold) are IL-6, G-CSF, IL-8, MCP-1, MPO, IL-1ra, and IL-1β. In rat eyes with intravitreal Kenalog, biomarkers of inflammation, foreign body response, and macrophage activation also increased significantly. In macrophage cell cultures, Kenalog (1 mg/ml) significantly induced hyper-secretion of 11 proteins. The top 7 (>2 fold) are G-CSF, MIP-1β, IL-1β, IL-18, MIP-1α, IL-8, and EN-RAGE. In contrast, neither TA-saturated solution nor Kenalog vehicle induced these effects.
Sterile endophthalmitis after intravitreal Kenalog is associated with elevated inflammatory biomarkers and macrophage activation. Dispersed micronized crystals of TA in the Kenalog particulate suspension - not a vehicle excipient, preservative, or other component - may induce circulating macrophages in some patients to mount an inflammatory response that presents as clinical endophthalmitis.
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