Corticosteroids have a broad mechanism of action. They inhibit phospholipase A2, an enzyme that converts membrane phospholipids to arachidonic acid. Thus, the inhibition of the cyclooxygenase and lipoxygenase pathways dramatically reduces the formation of all eicosanoids, which are the active mediators of inflammation. Corticosteroids effectively suppress both the early (capillary dilation, increased vascular permeability, recruitment of leukocytes) and late (deposition of fibrin, proliferation of inflammatory cells and chemokines) phases of inflammation.

Local corticosteroids may be used either topically (for anterior uveitis) or as periocular and intravitreal injections, or as implant devices (for inflammation of posterior segment) and remain the drugs of choice in management of ocular inflammation. Systemic corticosteroids are reserved for chronic uveitis involving the posterior segment, invariably affecting both eyes. However, chronic use of corticosteroid therapies is known to cause glaucoma, cataract, impaired glucose tolerance, hypertension, fluid retention, osteoporosis, mental disturbance, impaired wound healing, gastrointestinal bleeding and perforation, thromboembolic disorders, and weight gain. Of these, increased IOP is of most importance as it is understood to be due to structural and biochemical changes in the trabecular meshwork leading to rise in the resistance to aqueous humor outflow. The incidence of steroid-induced IOP elevation is quite high in as many as 18–36 % of users. Older corticosteroids, such as prednisolone and dexamethasone, are associated with a greater impact on IOP compared to newer corticosteroids. The limitations of chronic use of steroids, vis-a-vis lack of efficacy and need for reinjections, have led to the development of novel sustained-release intravitreal steroid delivery methods. These formulations have lower dose of corticosteroids and, therefore, less secondary side effects.

Multiple formulations like oral prednisone, intravenous methylprednisolone sodium succinate, topical prednisolone acetate or difluprednate, and intravitreal triamcinolone are preferentially used as they offer the benefit of avoiding systemic complications (Geltzer et al. 2013).

Recently, fluocinolone acetonide implant (Retisert) has been developed to deliver corticosteroid for up to 30 months for chronic noninfectious posterior uveitis. Dexamethasone implant for intravitreal use (Ozurdex) has also been approved by the FDA for the treatment of noninfectious posterior uveitis. It is available as 0.7 mg biodegradable implant that delivers extended release of dexamethasone through solid polymer delivery system. Although dexamethasone and prednisolone acetate offer good anti-inflammatory efficacy, their use suffers from clinically significant increase in IOP (up to 10 mmHg). In contrast, corticosteroids such as loteprednol etabonate, a novel C-20 ester-based derivative of prednisolone, offer potent anti-inflammatory efficacy, with limited adverse impact on IOP. Loteprednol etabonate (0.5 %) has been established as effective treatment of postoperative inflammation and resolving anterior chamber cells and flare (Amon and Busin 2012).

Another prednisolone derivative, difluprednate with structural modifications that include the addition of fluorine atoms at C-6 and C-9 positions, a butyrate ester at the C-17 position, and acetate ester at the C-21 and C-20 ketone moiety, is significantly effective in controlling secondary events of ocular inflammation like photophobia, chemosis, and corneal edema. The incidence of clinically significant increase in IOP is low.

The efficacy of loteprednol etabonate, rimexolone, and difluprednate in resolving ocular inflammation is similar. The difference lies in the degree of side effect like corticosteroid-induced ocular hypertension and is often the determining factor in clinical use.

Antimetabolites refer to a class or drugs which inhibit nucleic acid synthesis to inhibit cell proliferation. Drugs belong to this class include methotrexate, azathioprine, and mycophenolate mofetil.

Methotrexate was first introduced in 1948 as an antineoplastic agent. It is a folate analogue that acts by inhibiting dihydrofolate reductase. It interferes with the synthesis of thymidylate and purine nucleotide, to inhibit the growth of rapidly dividing cells. The most serious side effects of methotrexate include hepatotoxicity, cytopenias, and interstitial pneumonitis. Monitoring of liver function tests is required during treatment. It is teratogenic and thus contraindicated in pregnancy.

Azathioprine is widely used in organ transplantation, inflammatory bowel disease, systemic lupus erythematosus, and other autoimmune conditions. It is a prodrug of 6-mercaptopurine, a purine nucleoside analogue that interferes with DNA replication and RNA transcription. It also inhibits actively dividing immune cells to restrain inflammatory process.

Mycophenolate mofetil (MMF) is commonly used in management of organ transplant rejection and other autoimmune conditions. Its mechanism of action is selective inhibition of inosine-5-monophosphate dehydrogenase in the de novo purine synthesis pathway. As B and T lymphocytes depend on the de novo pathway for proliferation, its selective inhibition effectively curtails inflammatory state. MMF has been shown to be effective in combination with steroids or another immunomodulatory treatment as well as monotherapy.

This class of agents includes cyclosporine, tacrolimus, and sirolimus.

Cyclosporine is an 11 amino acid peptide derived from fungus. Cyclosporine acts by forming a complex with cyclophilin which binds calcineurin that then inhibits the cytosolic translocation of nuclear factors. Consequently, there is preferential inhibition of antigen-triggered signal transduction of T lymphocytes. It is available in two formulations, as oil-based gelatin capsules (Sandimmune, Novartis Pharmaceuticals) and a microemulsion (Neoral, Novartis Pharmaceuticals). Cyclosporine has been used safely in children with severe, sight-threatening uveitis. The adverse effects of cyclosporine therapy include gastrointestinal upset, metabolic abnormalities, paresthesias, tremor, gingival hyperplasia, and hirsutism.

Voclosporin is a calcineurin inhibitor that has been developed for the treatment of uveitis. It has been shown to be more potent and less toxic than cyclosporine. In extensive placebo-controlled clinical studies, voclosporin has been reported to improve vitreous haze that is part of active posterior disease. It significantly reduced eye inflammation but failed to meet the primary endpoint of all-cause therapeutic failure. In the condition of anterior inflammation, voclosporin failed to establish itself from placebo.

Sirolimus (Rapamune) is another immunosuppressive drug. Its binds to FK-binding protein-12 (FKBP-12) to form a complex that binds to and inhibits the activation of the mammalian target of sirolimus (mTOR) to suppress cytokine-driven T-cell proliferation.

Cyclophosphamide and chlorambucil belong to the class of drugs called alkylating agents as they act by alkylating DNA leading to DNA cross-linking and inhibition of DNA synthesis. Although they were originally developed for the treatment of cancers, they are now widely being used for management of rheumatologic conditions. Owing to their serious, life-threatening side effects, their use is limited to severe, sight-threatening uveitis.

Cyclophosphamide, a mustard gas derivative, alkylates the purines of DNA and RNA resulting in cross-linking and impaired cell division. Thus, the number of inflammatory cells like T and B lymphocytes is reduced.

Conventional therapy with corticosteroids and immunosuppressive agents may not be sufficient to control ocular inflammation or prevent non-ophthalmic complications in refractory patients. Off-label use of biologic response modifiers has been studied as primary and secondary line of therapy and reported to be very useful in such conditions. Strategies for biologics employ formulating new drugs that target specific receptors, cytokines, or signaling pathways (Pasadhika and Rosenbaum 2014).

Vascular endothelial growth factor (VEGF) is a potent vasoactive cytokine that is involved in the breakdown of blood-retinal barrier and angiogenesis in the ischemic retina. The VEGF levels are significantly elevated in patients with DME and its intravitreal concentration increases with the progression of DR. Antiangiogenic therapy acts to reduce vascular permeability, reduce the breakdown of the blood-retinal barrier, inhibit leukocyte adhesion to vascular walls, and inhibit VEGF gene transcription and translation and therefore finds use in ocular inflammatory conditions (Geltzer et al. 2013).

Bevacizumab (Avastin) and ranibizumab (Lucentis) are also monoclonal antibodies to vascular endothelial growth factor (VEGF). Ranibizumab was designed specifically for ocular use and received FDA approval for the treatment of choroidal neovascularization in age-related macular degeneration. Bevacizumab is increasingly finding off-label use for ocular diseases.

Ranibizumab (Lucentis), a recombinant humanized antibody fragment, is active against all isoforms of VEGF-A and approved for the treatment of exudative AMD and DME.

As a key mediator in inflammation, oxidative stress serves as an important target for anti-inflammatory therapy. The etiology of ocular inflammation involves free radical-mediated oxidative damage, hypoxia, decreased blood supply to ocular tissues, angiogenesis, increased vascular permeability, and leakage of vascular contents.

Flavonoids have been attributed with multi-thronged action including antioxidant, antiangiogenic, reducing fluid retention, and strengthening capillary walls that together contribute to anti-inflammatory activities. Bioflavonoids have been found effective in the prevention and treatment of diabetic retinopathy, macular degeneration, and cataract (Majumdar and Srirangam 2010). Some of the common bioflavanoids that have been documented for their anti-inflammatory action are quercetin, apigenin, hesperidin, hesperetin, luteolin, epigallocatechin gallate, epicatechin gallate, rutin, cyanidin, naringenin, myricetin, chrysin, eriodictyol, and kaempferol.