• Uveitis

    The TNF inhibitors are drugs that have revolutionized the treatment of autoimmune diseases such as rheumatoid arthritis and Crohn’s disease. TNF, a cytokine, is produced by activated white cells, vascular endothelium, fibroblasts, and many other cells, and it mediates many pro-inflammatory processes. Although not approved by the U.S. Food and Drug Administration (FDA) for the treatment of uveitis, the TNF inhibitors are more and more often taking a therapeutic place in our armamentarium for treating severe cases of uveitis. It is the purpose of this article to describe the known efficacy of these drugs and their potential use and harm should standard treatment options fail.

    Infliximab (Remicade)

    Infliximab is a chimeric IgG monoclonal antibody composed of human constant and murine (mouse) variable regions. The antibody binds to TNF and lyses TNF-producing cells. The drug is given intravenously at a dose of 3 mg/kg at weeks 0, 2, and 6. If the patient is stable, the regimen is then reduced to every 8 weeks. If the patient does not respond, however, the dose can be increased up to 10mg/kg and the interval increased to every 4 weeks (Nash et al, 2005:205-208). In cases of rheumatoid arthritis, infliximab is licensed to be used in combination with low-dose methotrexate. Investigators have found that antichimeric antibody formation can occur and result in infusion reactions and a reduction in efficacy of this drug.

    Infliximab has been the most used TNF inhibitor for recalcitrant uveitis and appears to be a truly beneficial drug for the treatment of severe uveitis. Given that systemic corticosteroids at a dose over 7.5–10 mg/day should be used for no longer than 3 months, and that steroid-sparing agents such as methotrexate, azathioprine, mycophenolate mofetil, and cyclosporine can be used as second-line drugs, infliximab should be reserved as a second- or third-line systemic agent. For consideration only when the aforementioned medications fail, infliximab may help avoid the use of very powerful and potentially dangerous alkylating agents.3-7

    A prospective non-randomized study of refractory uveitis in 23 patients using infliximab found a 78% improvement rate. Improvement was measured as a composite of visual acuity, inflammation levels, tapering of other medications, and a reduction of cystoid macular edema (CME). At 10 weeks of therapy, 18 of 23 patients showed marked improvement; 14 patients completed 1 year of therapy. Patients ended their therapy for several and varied reasons such as lupus-like reactions, congestive heart failure, participation in other patient studies, noncompliance, a drop in efficacy of treatment, endometrial cancer, and positive drug tests.

    Adalimumab (Humira)

    Adalimumab is a fully human monoclonal IgG antibody to TNF. This drug is injected subcutaneously every other week with a 40-mg preloaded syringe, but the dose can be increased to weekly injections as necessary. Adalimumab is licensed to be used with or without methotrexate.

    Adalimumab has little or no published data describing its efficacy in the treatment of uveitis. On the basis of its mode of action, adilumumab may be similar to infliximab and more useful than etanercept, and initial clinical impressions include at least 2 patients who have benefited from this particular drug. One patient with multifocal choroiditis secondary to sarcoidosis became allergic to infliximab and responded well to a change to adalimubab. Another patient, who suffered from juvenile idiopathic arthritis and recalcitrant uveitis, failed therapy with etanercept and responded positively to adalimubab.

    Etanercept (Enbrel)

    Etanercept is a fully human protein that contains soluble TNF receptor; it is not an antibody. It binds soluble TNF and thus competes with cellular TNF receptors. Etanercept is given subcutaneously twice a week. It must be refrigerated and reconstituted as a 25-mg injection.

    Etanercept has not been shown to be useful for the treatment of uveitis, and specialists are not using or recommending etanercept for such an application.8,9 Nonetheless, there is a single report suggesting the drug has potential for preventive therapy. This study on the use of TNF agents for ankylosing spondylitis analyzed data from 4 placebo-controlled studies and 3 open-label studies. The TNF inhibitors were not examined for their treatment of uveitis. The study showed that both etanercept and infliximab reduced the incidence of anterior uveitis in patients with ankylosing spondylitis and that infliximab appears to be more effective than etanercept in the prevention of uveitis (Braun et al, 2005:2447-2451). But even for those few patients with frequent and recurrent uveitis associated with ankylosing spondylitis, the use of TNF inhibitors is probably excessive; most of these patients can be safely treated with oral nonsteroidal anti-inflammatory drugs (NSAIDs), methotrexate, or mesalamine (Asacol).

    Cost

    The TNF inhibitors are relatively expensive, their annual costs ranging from about $12,000 to $14,000. The comparative annual cost of methotrexate is $400 to $900 (Gonzalez, 2002:34-47). Because none of these drugs has been approved by the FDA for the treatment of uveitis, it is often difficult for patients to get insurance coverage for these medications.

    Adverse Effects

      dot Reactivation of latent tuberculosis. All patients should have a screening chest x-ray and a purified protein derivative (PPD) skin test. Prophylactic isoniazid (INH) is recommended if either indicator is positive.
      dot Reactivation of demyelinating diseases such as multiple sclerosis. In patients with intermediate uveitis and who are at risk for multiple sclerosis, MRI studies of the brain should be performed to rule out plaques or signs of demyelinating disease.
      dot Lupus-like syndromes. Antinuclear antibodies are frequent.
      dot An increased incidence of malignancy. No good data show that these drugs may increase the incidence of malignancy, though much controversy surrounds the subject.
      dot Congestive heart failure may worsen.
      dot Decreased ability to fight off infections and an increased risk of infection. These drug therapies may need to be stopped when there is bacterial, viral, or fungal disease in any part of the body. Histoplamosis may become life threatening. One report, however, found infliximab to be safe in the presence of hepatitis C.

    Summary

    The TNF inhibitors are proving to be an increasingly important part of our armamentarium in the treatment of uveitis, and at present, infliximab appears to be the drug of choice. Although prospective randomized studies have not yet been reported, ophthalmologists must be aware of these drugs—and their associated costs and potential adverse reactions—when considering treatment options for severe uveitis. Be advised that most ophthalmologists will need support from a rheumatologist or internist in the administration of these agents.

    References

    1. Nash PT, Florin TH. Tumor Necrosis factor inhibitors. Med J Aust. 2005;183:205-208.
    2. Gonzalez EB. Management of Rheumatoid arthritis in the elderly. Clin Geriatrics. 2002;10:34-47.
    3. Richards JC, Tay-Kearney ML, Murray K, Manners P. Infliximab for juvenile idiopathic arthritis-associated uveitis. Clin Experiment Ophthalmol. 2005;33:461-468.
    4. Tugal-Tutkun I, Mudun A, Urgancioglu M, et al. Efficacy of infliximab in the treatment of uveitis that is resistant to treatment with the combination of azathioprine, cyclosporine, and corticosteroids in Behcet’s disease: an open-label trial. Arthritis Rheum. 2005;52:2478-2484.
    5. 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.
    6. Lindstedt EW, Baarsma GS, Kuijpers RW, van Hagen PM. Anti-TNF-alpha therapy for sight threatening uveitis. Br J Ophthalmol. 2005;89:533-536.
    7. Benitez-del-Castillo JM, Martinez-de-la-Casa JM, Pato-Cour E, et al. Long-term treatment of refractory posterior uveitis with anti-TNFalpha (infliximab). Eye. 2005;19:841-845.
    8. Foster CS, Tufail F, Waheed NK, et al. Efficacy of etanercept in preventing relapse of uveitis controlled by methotrexate. Arch Ophthalmol. 2003;121:437-440.
    9. Smith JA, Thompson DJ, Whitcup SM, et al. A randomized, placebo-controlled, double-masked clinical trial of etanercept for the treatment of uveitis associated with juvenile idiopathic arthritis. Arthritis Rheum. 2005;53:18-23.
    10. Braun J, Baraliakos X, Listing J, Sieper J. Decreased incidence of anterior uveitis in patients with ankylosing spondylitis treated with the anti-tumor necrosis factor agents infliximab and etanercept. Arthritis Rheum. 2005;52:2447-2451.

    Author Disclosure

    The author states that he has no significant financial relationship with the manufacturer or provider of any product or service discussed in this article or with the manufacturer or provider of any competing product or service.