Corticosteroids: Targeting Multiple Cytokines and Chemokines
Drugs that inhibit vascular endothelial growth factor (VEGF) are effective for center-involving diabetic macular edema (DME) since most eyes respond well to regimens that include repeated intravitreal injections. A significant minority of patients (approx
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Corticosteroids: Targeting Multiple Cytokines and Chemokines
5.1 Introduction Drugs that inhibit vascular endothelial growth factor (VEGF) are effective for center-involving diabetic macular edema (DME) since most eyes respond well to regimens that include repeated intravitreal injections. A significant minority of patients (approximately 40%), however, exhibit an inadequate response and require additional or alternate therapy. In the phase III anti-VEGF registration trials, laser photocoagulation served as secondary therapy for patients with inadequate responses after 3–6 months of monthly anti-VEGF injections [52, 66]. Supplemental laser usually resolves persistent edema slowly, but it has not been shown to incrementally improve VA in most cases [26, 62]. Glucocorticoids were the first drug class shown to improve DME in randomized clinical trials [34–36]. Triamcinolone acetonide, the first drug to be tested (Kenalog®; Bristol-Myers Squibb, New York, NY), was not originally formulated for intraocular use, and it was associated with a high risk of cataract and elevated intraocular pressure. Topical and periocular corticosteroids [24] do not significantly improve DME because they do not penetrate the sclera sufficiently to produce therapeutic concentrations within the retina. Intravitreally injected corticosteroids resolve macular edema and improve visual acuity in both treatment-naïve eyes and those previously treated with laser and/or anti-VEGF therapy. As a result, significant interest in treating DME with intravitreal corticosteroids has developed, and this chapter reviews the current state-of-the art corticosteroid use in the management of patients with DME.
5.2 Characteristics of Corticosteroids The primary structure of VEGF – a long amino acid sequence – prevents it from crossing the cell membrane’s lipid bilayer, whereas the lipophilic ring structures of corticosteroids enable them to pass easily. Corticosteroids bind to heat shock © Mayo Foundation for Medical Education and Research 2017 M.W. Stewart, Diabetic Retinopathy, DOI 10.1007/978-981-10-3509-8_5
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5 Corticosteroids: Targeting Multiple Cytokines and Chemokines
proteins and several soluble steroid receptors within the cytoplasm [20] and the resultant complex migrates to the cell nucleus (Fig. 5.1). The heat shock protein dissociates, leaving the corticosteroid-receptor complex to bind to the promoter or repressor regions of several genes [11, 29]. The corticosteroid-receptor complex can
Fig. 5.1 This drawing shows the mechanisms through which corticosteroids exert their effects. Corticosteroids dissociate from serum transport proteins, enter target cells by crossing cell membranes, and bind to cytoplasmic receptors that include heat shock proteins (hsp90). The corticosteroid-receptor complexes enter cell nuclei, interact with DNA receptor sites, and suppress nuclear factor (NF)-κB. This increases the expression of many species of mRNA and suppresses others; both mechanisms affect the synthesis of thousands of proteins. Corticos
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