Immune agents target inflammation

October 1, 2009

Corticosteroids remain the primary treatment for inflammatory diseases that involve the eye and orbit. However, side effects and treatment failures have provided the impetus for the use of safer and more specific immunosuppressive agents. The selection of a specific agent will depend on multiple factors. The next step in the use and development of alternative immune agents will likely involve both the identification of inflammatory conditions that are most responsive to a particular agent and identifying patient-specific factors that might predict a response to that agent.

Key Points

The majority of the ophthalmic literature about immunosuppressive agents pertains to inflammation of the uvea. In immunologic diseases followed by the neuro-ophthalmologist, inflammation also may occur in other locations, including the brain parenchyma, cranial nerves, nerve-muscle synapse, orbital tissue, and vessels supplying the globe.

• Tumor necrosis factor-alpha (TNF-α), a cytokine released by leukocytes and other cell types, is a key component of the inflammatory response. Infliximab, the TNF-α blocker most studied, is a chimeric (mouse-human) monoclonal antibody that acts by binding to free and membrane-bound TNF-α and by inciting complement-mediated destruction of cells that express TNF-α. Use of TNF-α blockers in ophthalmology has been limited to small case series including patients with giant cell arteritis (GCA), sarcoidosis, idiopathic orbital inflammation, and Vogt-Koyanagi-Harada syndrome (VKH).

• Cyclophosphamide is a nitrogen mustard derivative alkylating agent that is metabolized to compounds that covalently bind to purines in DNA and RNA, inhibiting production of both T and B cells. Cyclophosphamide has been used successfully in patients with idiopathic orbital inflammation refractory to corticosteroids and radiation, with remission extending 3 years after treatment.

• Methotrexate is a potent inhibitor of dihydrofolate reductase, an enzyme necessary for the conversion of folate to tetrahydrofolate, limiting the production of thymidylate, an enzyme essential for DNA synthesis. Methotrexate has been shown to be beneficial in neurosarcoidosis and sarcoid-associated uveitis and optic neuropathy. Methotrexate has been studied as a potential corticosteroid-sparing medication in GCA.

• Azathioprine is a purine nucleoside analog that interferes with purine synthesis, decreasing both B and T cell production. It has been used in patients with myasthenia gravis, GCA, and orbitopathy due to Wegener granulomatosis.

• Cyclosporine is an oil-soluble fungal metabolite affecting T lymphocytes. Multiple case reports have suggested it is beneficial in VKH.

The selection of a specific agent will depend on multiple factors including the presumed mechanism of inflammation, co-morbid medical conditions, side effect profile of the immune agent, cost of therapy, and anticipated duration of use of therapy.

The next step in the use and development of alternative immune agents likely will involve both the identification of inflammatory conditions that are most responsive to a particular agent and identifying patient-specific factors (perhaps enhanced by genetic studies) that might predict a response to that agent.

Rod Foroozan, MD, is an assistant professor at Baylor College of Medicine, Houston. He has no financial disclosures related to the subject matter.

Andrew G. Lee, MD, editor of The Neuro-Connection, reviewed this column. He is professor and chairman, Department of Ophthalmology, The Methodist Hospital, Houston.

References

1. Cantini F, Niccoli L, Salvarani C, Padula A, Olivieri I. Treatment of longstanding active giant cell arteritis with infliximab: report of four cases. Arthritis Rheum. 2001;44:2933–2935.

2. Jabs DA, Rosenbaum JT, Foster CS, et al. Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel. Am J Ophthalmol. 2000;130:492–513.

3. Maini R, St Clair EW, Breedveld F, et al. Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet. 1999;354:1932–1939.

4. Suhler EB, Smith JR, Wertheim MS, et al. A prospective trial of infliximab therapy for refractory uveitis: preliminary safety and efficacy outcomes. Arch Ophthalmol. 2005;123:903–912.