Management

Systemic corticosteroids are the mainstay of treatment of posterior uveitis in sarcoid patients. They inhibit the inflammatory process by suppressing the arachidonic acid metabolism and activation of complement.

Depending on the severity of the disease, oral prednisone is started at an initial dose of 1 mg/kg/ day for 8–12 weeks, followed by a slow taper over few months to establish the minimal effective dose. In some cases, intravenous high-dose methylprednisolone therapy may be necessary.

A meta-analysis of randomized, controlled clinical trials of systemic steroid therapy in pulmonary sarcoidosis failed to show alteration on long-term disease progression, but there was radiologic improvement following 6–24 months of treatment and a small improvement in vital capacity and diffusing capacity [63]. It is unclear if the absence of long-term disease modification also applies to ophthalmic involvement, due to the lack of adequate studies. Moreover, in cases of chronic disease, prolonged corticosteroid therapy is often poorly tolerated, necessitating other steroid-sparing medications. Alternative therapies have therefore been sought [64].

Methotrexate is the most common immunosuppressive agent used. It was introduced in 1958 for the treatment of leukemia and acts as an inhibitor of dihydrofolate reductase, the enzyme responsible for the conversion of dihydrofolate to tetrahydrofolate. This process inhibits the production of thymidylate, which is essential for DNA synthesis and cell division. The exact mechanism of methotrexate in ocular inflammatory diseases is not currently completely understood. It has the added benefit of potentially helping to control other systemic manifestations of sarcoidosis. In 1999, Dev et al. reported the successful use of low-dose methotrexate in 11 patients with chronic sarcoid panuveitis. All patients showed response to the medication (defined as an improvement in visual acuity or a decrease in inflammation), although some required incrementally increased dosages before a response was achieved. The side-effect profile was fairly mild and included

mainly gastrointestinal symptoms [65]. Other series have also shown a high response rate with methotrexate in the management of ocular sarcoidosis [35, 66].

Whether methotrexate provides a better visual prognosis than that obtained with corticosteroids in patients with sarcoid-associated posterior uveitis is currently unknown, and randomized clinical trials are necessary to assess and compare the outcomes.

Methotrexate has also been combined with azathioprine. The purpose of combination therapy is to minimize the toxicity while increasing the immunosuppression by multiple mechanisms of action [5].

Leflunomide, an immunomodulatory drug that inhibits dihydroorotate dehydrogenase, with antiinflammatory effects, has been shown in small series to have similar efficacy to methotrexate in ocular sarcoidosis and may be better tolerated in some patients [67].

Mycophenolate mofetil, an immunosuppressant which acts as a reversible inhibitor of inosine monophosphate dehydrogenase in purine biosynthesis, has also been used in sarcoid patients. In a recent retrospective study by Bhat et al., it was shown to be effective in controlling sarcoidosisrelated ocular inflammation with a manageable side-effect profile. The best corrected visual acuity improved in all 14 eyes studied [68].

Since tumor necrosis factor-alpha (TNF-a) plays an important role in granuloma formation, agents that inhibit TNF-a(alpha) could potentially be useful in treating sarcoidosis. However, etanercept, a biologic tumor necrosis factor antagonist, demonstrated disappointing results in chronic ocular sarcoidosis in a series by Baughman et al. It appeared not to be steroid sparing, and despite being well tolerated, it was not associated with a significant improvement of chronic sarcoid uveitis [69].

Cases of refractory ocular sarcoidosis responsive to infliximab, a monoclonal antibody to TNF-a(alpha), have been reported including resolution of retinal vasculitis and optic neuropathy [70, 71]. Another study by Baughman et al. enrolled seven patients with ocular sarcoidosis and persistent inflammation despite systemic

immunosuppressive therapy. All patients demonstrated significant improvement in ocular inflammation with infliximab [72]. The molecular structure of infliximab allows it to initiate the classical complement pathway and cause cell lysis, which does not occur with etanercept. Moreover, infliximab may also lead to apoptosis of TNFexpressing T cells and macrophages [73].

In selected uveitic patients, bevacizumab may be an option for managing neovascularization. Among varied factors involved in sarcoidosis, vascular endothelial growth factor (VEGF) has been reported to be associated with prognosis in systemic disease. This knowledge was the basis of Kurup et al. in attempting anti-VEGF therapy in a sarcoid patient with prominent peripapillary neovascularization. The patient demonstrated dramatic resolution in the subretinal fluid and decrease in the intraretinal hemorrhage associated with the neovascularization over a period of a week [74].

Photocoagulation has also been used in the treatment of neovascularization secondary to sarcoidosis. Spalton et al. have emphasized that ocular inflammation should be well controlled before laser therapy is attempted [48].

It has been suggested that intravitreal triamcinolone injections may be effective in controlling cystoid macular edema in patients with posterior uveitis. It has the advantages of achieving a high therapeutic drug level for maximal local antiinflammatory effects. Larsson et al. reported the clinical course of two patients with sarcoid uveitis and refractory macular edema, who improved only when intravitreal injections of triamcinolone were given. It was possible to discontinue systemic treatment in both patients [75].

Chan et al. reported a case of a 29-year-old man with retinal periphlebitis and retinal granulomas that responded well to oral corticosteroids. The patient also had a choroidal granuloma, which grew slowly in size and threatened the fovea, despite systemic steroids. Intravitreal triamcinolone acetonide (4 mg) was injected three times at 2-month intervals. The choroidal mass began to shrink after the second injection and became a scar, with no angiographic leakage. The patient’s visual acuity improved and remained

stable during a 6-month follow-up period. Further studies are necessary to evaluate the long-term efficacy of intravitreal triamcinolone in cases refractory to systemic therapy [76].

Surgical interventions, such as vitrectomy for vitreous opacities, have been reported as beneficial in restoring vision, stabilizing vitreous inflammation, and reducing systemic corticosteroid requirements, in a small number of patients with refractory ocular disease [77].

Controversies and Perspectives

The cause of sarcoidosis remains obscure, despite much research in the last few years. Several new agents with immunosuppressive properties have shown efficacy and an acceptable side-effect profile. However, the long-term impact of the new drugs in altering the course of sarcoidosis, particularly in ocular disease, remains unknown. Developing randomized, controlled trials to test and compare new therapies is paramount.

Future studies will help clarify and provide a better understanding of the genetics of sarcoidosis and allow for the development of new diagnostic, prognostic, and therapeutic modalities that may decrease systemic and ocular morbidity further.

Focal Points

•Sarcoidosis is a multiorgan systemic disease capable of producing a wide variety of ocular manifestations, being one of the greatest mimickers in ophthalmology.

•A combination of signs of intraocular inflammation and systemic studies can be used for the clinical diagnosis of ocular sarcoidosis.

•Posterior segment manifestations of the disease are numerous and may include vitritis, vasculitis, chorioretinitis, retinal neovascularization, and the presence of granulomas in the retina, choroid, or optic nerve.

•All sarcoidosis patients need comprehensive and periodic eye examinations, as untreated ocular disease may lead to poor visual prognosis.

•Corticosteroids are the mainstay of treatment of sarcoidosis. Alternative immunomodulatory therapies have been developed, but their impact on long-term disease progression remains unclear.

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