Tumor Necrosis Factor Inhibitors
The best-studied inhibitors of TNF-α for uveitis are adalimumab and infliximab; their emergence over the last decade has changed the management of some types of uveitis. There is expert consensus that the TNF inhibitors should be considered first-line for Behçet disease. Other TNF inhibitors include certolizumab and golimumab, which have far fewer uveitis data, and etanercept, which is not effective for ocular inflammatory diseases. TNF-α is believed to play a major role in the pathogenesis of JIA, ankylosing spondylitis, and other spondyloarthropathies. These drugs are generally prescribed and administered by uveitis specialists and rheumatologists experienced with their use, adverse effects, and toxicities. TNF inhibitors have been associated with central nervous system demyelination (promoting or unmasking multiple sclerosis), increased risk of malignancy (such as lymphoma), hepatitis B reactivation, and deep fungal and other serious atypical infections. Their use may be contraindicated in congestive heart failure, and latent tuberculosis must be ruled out or completely treated with oversight of a specialist in infectious diseases prior to use. Live vaccines should not be administered to a patient taking TNF inhibitors. Although individual case reports have been made for intravitreal TNF inhibitors, their intravitreal use is untested, potentially retinotoxic, and should not be used without further study.
Adalimumab, a fully human monoclonal immunoglobulin G1 (IgG1) antibody directed against TNF-α is the first US FDA–approved systemic medication for noninfectious uveitis. Self-administered via subcutaneous injection, the initial dosage is 80 mg, followed by a maintenance dose of 40 mg/0.8 mL every other week starting 1 week after the initial dosage. Because it is a fully human antibody, risk of antidrug–antibody formation is lower than in infliximab, a mouse/human chimeric antibody. Injection site reactions may occur and are usually mild. An industry-sponsored, randomized, double-masked controlled trial in adults with noninfectious uveitis (VISUAL I/II), with an open label extension arm (VISUAL III) demonstrated that adalimumab was associated with significant reductions in treatment failure compared to placebo for both active and controlled uveitis. Also, significantly higher rates of quiescence and steroid-free quiescence were achieved and maintained through 52 weeks compared to placebo, regardless of disease status at entry. Adverse events and serious adverse events were reported more frequently among patients who received adalimumab compared to placebo.
Adalimumab has been shown to be as effective as infliximab in controlling inflammation, with success rates of up to 88% without relapse in pediatric patients with uveitis and 100% in adult patients with Behçet uveitis, posterior uveitis, and panuveitis. However, uveitis relapses requiring local corticosteroid injections may occur.
Adalimumab has been shown to reduce the rate of anterior uveitis flares and recurrences in HLA-B27–associated uveitis. Another randomized, placebo-controlled trial—involving patients with JIA-associated uveitis (SYCAMORE) comparing methotrexate alone to methotrexate plus adalimumab—demonstrated that the addition of adalimumab reduced time to treatment failure and increased likelihood of reducing topical steroid usage. Adverse events in this pediatric study were seen in 5% of the adalimumab group, 22% of which were considered serious adverse events. (See also Table 6-1.)
Infliximab is a mouse/human-chimeric, immunoglobulin G1 kappa (IgG1κ) monoclonal antibody directed against TNF-α. It is administered through infusions at weeks 0, 2, and 4 and every 4–8 weeks thereafter for maintenance. It is effective in controlling current inflammation and decreasing the likelihood of future attacks in Behçet uveitis, undifferentiated uveitis, sarcoidosis, VKH syndrome, and many other entities in more than 75% of patients. Similar favorable effects have been reported in patients with HLA-B27–associated anterior uveitis treated with infliximab. However, one study showed that despite treatment success, nearly one-half of patients could not complete the 50 weeks of therapy because of adverse events, including drug-induced lupus, systemic vascular thrombosis, congestive heart failure, new malignancy, demyelinating disease, and vitreous hemorrhage. As many as 75% of patients receiving more than 3 infusions developed antinuclear antibodies; greater likelihood of antibody formation may occur with higher doses and more frequent infusions. Increasing the dose and frequency may benefit the most severe ocular inflammatory diseases, however. Low-dose methotrexate (5–7.5 mg/week) may be administered concomitantly to reduce the risk of drug-induced lupus syndrome and the formation of human antichimeric antibodies, which can lead to reduced efficacy of infliximab.
Biester S, Deuter C, Michels H, et al. Adalimumab in the therapy of uveitis in childhood. Br J Ophthalmol. 2007;91(3):319–324.
Giganti M, Beer PM, Lemanski N, et al. Adverse events after intravitreal infliximab (Remicade). Retina. 2010;30(1):71–80.
Ramanan AV, Dick AD, Jones AP, et al; SYCAMORE study group. Adalimumab plus methotrexate for uveitis in juvenile idiopathic arthritis. N Engl J Med. 2017;376(17):1637–1646.
Sfikakis PP, Markomichelakis N, Alpsoy E, et al. Anti-TNF therapy in the management of Behçet’s disease—review and basis for recommendations. Rheumatology (Oxford). 2007;46(5):736–741.
Suhler EB, Adán A, Brézin AP, et al. Safety and efficacy of adalimumab in patients with noninfectious uveitis in an ongoing open-label study: VISUAL III. Ophthalmology. 2018;125(7):1075–1087.
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 Behçet’s disease: an open-label trial. Arthritis Rheum. 2005;52(8):2478–2484.
Excerpted from BCSC 2020-2021 series: Section 9 - Uveitis and Ocular Inflammation. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.