HISTORY OF UVEITIS TREATMENT

Therapy for intraocular inflammation during the mid-18th century included dilation of the pupil with tincture of belladonna, as well as the use of fever therapy of cold water bath and ice, which persisted into the early 1950s. During these nearly 100 years, most cases of uveitis were thought to be attributable to infectious diseases such as syphilis and tuberculosis. The importance of autoimmune uveitis became apparent after antibiotic therapy became widespread so that immune causes were no longer generally culpable.

A major advance in the care of patients with systemic and ocular inflammatory diseases was made during the 1950s when corticosteroid therapy was introduced. Corticosteroid was discovered by E.C. Kendall in 1935 and introduced for ophthalmic clinical use by DM Gordon and JM McLean in 1950. Today, corticosteroids in various forms are the most widely used anti-inflammatory and immunosuppressive drugs in ophthalmology and are the primary therapy for patients with noninfectious uveitis.

In 1963, antimetabolite methotrexate (MTX) was discovered, and its initial use was for the treatment of cancer. The utility of MTX for treating systemic autoimmune diseases was recognized shortly thereafter, eventually including its efficacy in autoimmune eye diseases. This drug is commonly utilized for juvenile idiopathic arthritis associated uveitis.

Two decades after corticosteroids were introduced clinically, J.F. Borel discovered the fungal metabolite cyclosporine. This agent was initially developed for the management of solid organ transplantation. Its immune suppressive properties made it a likely candidate for treating autoimmune diseases, and cyclosporine was first successfully employed against autoimmune uveitis by RB Nussenblatt and colleagues in the 1980s. It is commonly used to treat a wide variety of ocular immune-mediated disorders.

The alkylating agents like cyclophosphamide and chlorambucil are also used for the treatment of autoimmune inflammatory disease. These agents are derivatives of nitrogen mustard, which itself was a chemical weapon used in the First World War. Cyclophosphamide was first used to treat uveitis in the 1950s, and today, it plays a major role in the management of several systemic vasculitides with ocular involvement, such as Wegener granulomatosis and polyarteritis nodosa. Chlorambucil was first synthesized in the early 1950s and used for the treatment of malignant lymphoma. In 1970, J.G. Mamo reported the use of chlorambucil in the treatment of Adamantiades-Behçet disease, and it continues to be used for this purpose, as well as for severe recalcitrant ocular inflammatory diseases.

Mycophenolate mofetil was approved by the FDA in 1995 for the treatment of solid organ transplant rejection. Its safety, efficacy, and tolerability make it an increasingly common off-label therapy for chronic noninfectious autoimmune inflammatory eye diseases.

Drugs that target specific inflammatory mediators may potentially provide a safer alternative to therapies which suppress immune function globally. A number of such drugs, termed “biologic” immunomodulators, or simply “biologics,” have emerged since the year 2000. Typically, these agents are molecules that neutralize cytokines or cell surface receptors that are involved in the inflammatory cascade. The rationale for their use is their often dramatic efficacy with much smaller side effect profiles compared with more traditional immunosuppressive agents. The main disadvantage of most biologic agents is their cost.

FUTURE OF UVEITIS TREATMENT

In the near future, one may anticipate marked expansion in the use of biologic immunomodulatory agents, with increasing specificity of various therapies to the point where it is tempting to speculate that drugs will be selected based on genetic and biologic markers particular to each patient’s disease. In addition, sustained-release technologies are being developed which may enable the more widespread application of site-directed uveitis therapy, using drug-impregnated implants placed inside or around the eye for local effect with minimal systemic exposure.