Robert P. Baughman, M.D.; Elyse E. Lower, M.D., Ph.D.; Adam H. Kaufman, M.D.

Disclosures

Semin Respir Crit Care Med. 2010;31(4):452-462. 

In This Article

Treatment

The treatment of ocular sarcoidosis, particularly the most common manifestation uveitis, requires a stepwise approach. Figure 6 illustrates one approach to the management of uveitis in the sarcoidosis patient with the first decision the assessment of organ involvement and severity. Eye inflammation severe enough to be sight threatening warrants more aggressive treatment. For mild cases of uveitis or acute anterior uveitis, topical corticosteroids alone are usually adequate. Randomized trials comparing loteprednol etabonate 0.5% ophthalmic suspension (Lotemax, Bausch & Lomb Pharmaceuticals, Inc., Tampa, FL) with prednisolone acetate 1.0% ophthalmic suspension (Pred Forte, Allergan, Inc., Irvine, CA), confirm both drugs are effective in controlling inflammation in over 70% of cases.[54] Although loteprednol etabonate was less effective than prednisolone acetate, it was associated with a significantly lower rate of drug-induced increase in intraocular pressure.

Figure 6.

An approach to the management of uveitis in sarcoidosis patients. Patients with moderately severe disease, which is sight threatening, receive initially more aggressive therapy than those with milder forms of the disease. The four cytotoxic agents appear to be equally effective with individual choices determined based on the patient's risk factors for toxicity, treating physician preference, drug cost, and other factors.

For patients with persistent disease despite topical therapy, periocular and intravitreal administration of corticosteroids is frequently used. The intravitreal injection of steroids such as triamcinolone is associated with higher levels of intraocular pressure than the periocular administration in the sub-Tenon capsule.[55] However, both of these techniques are associated with possible increases in pressure, and patients must be monitored after injection.

Unfortunately corticosteroid injections remain effective for relatively short time periods of usually a few months. Chronic uveitis patients may require repeat injections to control inflammation. This is particularly true for patients with intermediate and posterior uveitis. Newer devices have been developed to deliver drug to the posterior eye.[56] Use of these devices has been shown to increase the time between disease flares and reduce the overall rate of uveitis recurrence compared with systemic therapy.[57] However, the delivery device has been associated with a more than 80% chance of implanted eyes requiring cataract extraction and 20% requiring surgery for increased intraocular pressure. Currently a large multicenter trial is under way to determine the overall risk and benefits of a corticosteroid implant versus immunosuppressive therapy for chronic uveitis.[58]

Immunosuppressive therapy may be considered for patients requiring one or more periocular corticosteroid injections.[59] Although systemic corticosteroids may be useful in providing rapid control of ocular inflammation, the long-term side effects, especially cataracts and glaucoma, have led to interest in use of various cytotoxic steroid-sparing drugs. Most of these drugs have been studied in nonspecific uveitis patients with only a few studies performed in sarcoidosis-associated uveitis.

Methotrexate has become a widely used steroid-sparing agent in the treatment of sarcoidosis.[60] Figure 7 summarizes six studies reporting on the efficacy of methotrexate for the treatment of sarcoidosis eye disease.[47,61–64] This summary includes one study with three patients with sarcoidosis-associated optic neuritis treated with methotrexate in which the reported response rates ranged from 63 to 100%.[65]

Figure 7.

The number of sarcoidosis patient responders and nonresponders to methotrexate for ocular disease. The first author is provided for each report.[47 61–65]

Methotrexate has been used for the treatment of many forms of chronic uveitis.[47] In a retrospective cohort study of 384 chronic uveitis patients, the immunosuppressant drug methotrexate was successful in controlling the disease in 66% and was steroid sparing in 58%.[58] Overall drug toxicity led to methotrexate discontinuation in 60 (16%) of cases. Unfortunately patients may require up to 6 months of treatment for responses to occur. This delay in onset of action with methotrexate has been noted in manifestations of sarcoidosis.[66] An interesting approach to enhance the rate and degree of response has been to give intraocular methotrexate.[67]

Azathioprine has also been widely employed in the treatment of sarcoidosis.[68,69] The drug has been reported effective in treating ocular inflammation, particularly intermediate uveitis.[70] In one retrospective series, 90% of patients with intermediate uveitis from various etiologies sustained remission within 1 year of treatment. However, ~25% of patients withdrew from treatment because of toxicity.[70] Azathioprine has been reported beneficial in some ocular sarcoidosis patients who fail to respond to methotrexate.[63]

Mycophenolate has also been reported effective in the management of chronic uveitis. In one retrospective study of 35 patients, control of uveitis was achieved in 86% of cases,[71] and less than 5% of patients discontinued drug due to toxicity. For sarcoidosis, only one small series of seven patients reported the drug beneficial in controlling chronic uveitis.[72]

Leflunomide is also an effective treatment for ophthalmic sarcoidosis. In a retrospective study of leflunomide therapy for chronic sarcoidosis, 28 patients displayed ocular disease. Fifteen of these patients experienced complete responses, eight patients reported partial improvement, and only two patients discontinued treatment because of toxicity.[73]

Table 6 summarizes the findings of a single-institution study of 321 patients with nonspecific ocular inflammation treated with three antimetabolite agents: methotrexate, azathioprine, and mycophenolate.[59] Approximately 30% of the 257 evaluable patients had systemic diseases, including sarcoidosis. All forms of ocular disease were treated, and two thirds of the patients had uveitis. Mycophenolate was associated with a more rapid rate of response than methotrexate. Although the time to response was similar to mycophenolate, patients treated with azathioprine encountered more toxicity. Patients with either scleritis and/or pan- or posterior uveitis experienced a significantly higher rate of response to mycophenolate compared with either azathioprine or methotrexate. This was a retrospective study over a 22-year period. During the time of the study, one would presume the investigators became more comfortable with dosage and administration. This may partly explain some of the perceived benefits of mycophenolate, a relatively new drug compared with azathioprine and methotrexate. Despite this limitation, this study demonstrates that the clinician has several options when choosing a cytotoxic agent for treatment of chronic ocular disease. The study did not consider the considerable difference in cost for mycophenolate versus methotrexate or azathioprine. This difference in cost may lessen over the next few years as a generic version of mycophenolate becomes available.

Combination immunosuppressive therapy has been discussed as a treatment approach for ocular sarcoidosis with the most common combinations including methotrexate plus azathioprine[63] and methotrexate plus leflunomide.[73]Table 6 indicates that other investigators have used combination therapy for ocular inflammation in a clinically significant percentage of cases.[59] These combinations have provided safe and effective alternative treatments for some patients.

Anti-TNF biologic therapies may be helpful for those patients experiencing persistent disease or an intolerance to cytotoxic immunosuppressive therapy. Etanercept, a soluble TNF receptor antagonist that blocks TNF activity by competitively binding TNF, has been reported in a small series beneficial in treating chronic uveitis.[74] However, it was not better than placebo in double-blind, randomized trials of etanercept for chronic uveitis.[75,76] In addition etanercept was found no better than placebo in treating chronic ocular sarcoidosis patients with persistent disease after at least 6 months of methotrexate therapy.[30] Brief reports, including one case of sarcoidosis-associated uveitis, suggest that uveitis can develop during etanercept therapy.[77,78]

Infliximab, a chimeric monoclonal antibody that binds TNF, was reported efficacious in 13 of 14 patients with chronic ocular inflammation, including three patients who had previously failed etanercept.[35] In a retrospective study, 22 patients treated with either etanercept or infliximab were analyzed. Patients treated with infliximab experienced significant reduction in uveitis and topical corticosteroid dosages.[79] In an additional study of juvenile rheumatoid arthritis patients with uveitis, eye disease was better controlled in the 21 patients receiving infliximab compared with the 24 patients treated with etanercept.[80]

Adalimumab, a humanized monoclonal antibody directed against TNF, has also been reported effective in treating chronic uveitis,[81] including in patients who have failed other anti-TNF therapies.[82] In other disease states, adalimumab has been shown as a safe alternative for patients intolerant to infliximab. In our own experience adalimumab is effective in treating sarcoid uveitis, and it can be used as an alternative to infliximab, especially in patients who develop significant allergic reactions to infliximab.[83]

Several groups noted the development of uveitis in patients receiving anti-TNF therapy.[77,80] Although this is more frequently reported with etanercept, it has also been noted with infliximab.[80] To determine whether anti-TNF therapy could be a causative agent for uveitis, Lim et al examined several registries that track ocular events including uveitis. Although they identified cases of uveitis associated with all three anti-TNF agents, the rate of uveitis was significantly higher for etanercept than for the other two agents.[84]

Several reports of anti-TNF therapy leading to a sarcoidosis-like reaction have been reported with all three agents.[85] However, the prevalence rate appears highest with etanercept. This granulomatous reaction is only one of several inflammatory diseases associated with anti-TNF therapy.[86] Although the mechanism of granulomatous development during anti-TNF therapy remains unclear, it must be remembered that the intense inflammatory reaction of sarcoidosis is probably not limited to a single cytokine pathway.[87]

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