Tumor necrosis factor (TNF) inhibitors are a class of biologic agents that block the action of the inflammatory cytokine TNF. They have rapidly become a treatment option for refractory non-infectious uveitis in recent years.
The first TNF inhibitor was infliximab (1998), followed by etanercept (1998) and adalimumab (2002). These three agents are the main ones studied for ocular inflammatory diseases. Golimumab and certolizumab have not been studied for ocular inflammation.
In Japan, infliximab was approved for refractory Behçet’s disease uveitis in 2007. In 2016, adalimumab was approved for non-infectious uveitis.
In a survey of 221 specialists from the International Uveitis Society, 98.6% had experience using adalimumab as a biologic agent, and 97.7% listed adalimumab as their first-choice biologic1). Experience with infliximab was 79.6%1).
Currently, there are five TNF inhibitors on the market (infliximab, etanercept, adalimumab, golimumab, and certolizumab). However, only infliximab, adalimumab, and etanercept have been studied for ocular inflammatory diseases. In Japan, only infliximab and adalimumab have insurance coverage for ophthalmic use.
TNF inhibitors are therapeutic agents, not for a specific disease. This section describes the clinical features of uveitis that is indicated for TNF inhibitors and the evaluation indices of treatment efficacy.
The main symptoms of non-infectious uveitis for which TNF inhibitors are indicated are as follows.
The therapeutic effect of TNF inhibitors is evaluated by improvement in the following findings.
In an international survey by Branford et al. (2025), over 90% of specialists required a quiescent period of at least 3 months before cataract surgery in non-infectious uveitis 1). This is because the risk of cystoid macular edema significantly increases with inflammatory activity.
Non-infectious uveitis that is an indication for TNF inhibitors develops through autoimmune mechanisms. TNF is a central cytokine in the inflammatory cascade and is involved in ocular inflammation through the following mechanisms:
The main diseases requiring TNF inhibitors are as follows:
This section describes the tests required before and during treatment with TNF inhibitors.
Because TNF inhibitors have immunosuppressive effects, the following screening is mandatory before administration.
In an international survey, all specialists (100%) performed pre-treatment screening, with blood biochemistry tests in 98.2%, CBC in 93.7%, and QuantiFERON in 88.7% 1).
During treatment, evaluation of infectious complications and drug efficacy is essential.
| Test Item | Infliximab | Adalimumab |
|---|---|---|
| CBC and biochemistry | At each infusion | Every 6 months |
| Liver function | At each infusion | Every 6 months |
| ANA | As needed | As needed |
If other immunosuppressants are used concomitantly, more frequent monitoring every 1 to 2 months is required.
For patients with inactive uveitis, clinical evaluation and drug toxicity screening every 6 to 12 weeks are recommended1).
TNF-α plays an important role in granuloma formation that contains Mycobacterium tuberculosis. When TNF inhibitors disrupt this defense mechanism, latent tuberculosis may reactivate as active tuberculosis. Pre-treatment screening and treatment of latent tuberculosis, if necessary, are essential.
In Japan, the use of TNF inhibitors strongly recommends facility standards, ophthalmologist certification, membership in the Japanese Society of Ocular Inflammation, and completion of e-learning.
Infliximab
Indication: Refractory Behçet’s disease uveitis (covered by insurance in 2007)
Administration: 5 mg/kg intravenous infusion. Induction at weeks 0, 2, and 6, then every 8 weeks.
Characteristics: Chimeric monoclonal antibody. Binds to both free TNF-α and cell surface TNF-α.
Route: Intravenous infusion (use an in-line filter ≤1.2 μm, administer over at least 2 hours)
Adalimumab
Indication: Non-infectious uveitis (covered by insurance in 2016)
Administration: Initial 80 mg subcutaneously, then 40 mg after 1 week, followed by 40 mg every 2 weeks.
Characteristics: Fully human monoclonal antibody. Self-injection possible with a pen device.
Route: Subcutaneous injection (rotate injection sites each time)
Good indications for adalimumab are as follows:
The VISUAL I and VISUAL II trials confirmed the efficacy of adalimumab for active or inactive non-infectious intermediate, posterior, and panuveitis 1). The SYCAMORE trial demonstrated the efficacy of adalimumab in combination with methotrexate for juvenile idiopathic arthritis-associated uveitis 1).
Japan was the first country to approve infliximab for refractory uveitis in Behçet’s disease, and many findings have been reported. It not only suppresses inflammatory attacks but also improves quality of life and alleviates extraocular symptoms of Behçet’s disease.
Infliximab is introduced in cases where existing treatments do not sufficiently suppress inflammatory attacks, or when fundus findings with severe visual impairment occur early in the disease.
Expert recommendations for the use of TNF inhibitors in ocular inflammatory diseases are as follows.
The combination of methotrexate and adalimumab is most commonly used 1). In an international survey, 84.0% of patients on combination therapy chose this regimen 1). The benefits of combination therapy are as follows.
Etanercept is a decoy-type fusion protein of the TNF receptor. It binds to soluble TNF but not to cell surface TNF. Due to this pharmacological difference, its efficacy for ocular inflammatory diseases is lower than that of monoclonal antibody preparations.
Etanercept does not reduce the risk of developing uveitis; rather, reports indicate a higher incidence of uveitis compared to other TNF inhibitors (infliximab, adalimumab) 3)4). This paradoxical reaction is thought to be due to cytokine imbalance and secondary effects on the blood-retinal barrier 4).
No direct comparative trials have been conducted. Infliximab requires hospital visits for intravenous infusion but has a long track record for Behçet’s disease. Adalimumab can be self-injected, offering convenience, and has broad insurance coverage for non-infectious uveitis. The choice depends on the disease type, patient situation, and physician judgment.
TNF-α is a cytokine involved in acute inflammation and is strongly associated with uveitis activity. The TNF family includes TNF-α (formerly TNF) and plays an important role in immune responses through the following mechanisms.
Monoclonal antibodies
Infliximab: A chimeric (human-mouse) anti-TNF-α monoclonal antibody. Binds to both free TNF-α and cell surface TNF-α.
Adalimumab: A fully human anti-TNF-α monoclonal antibody. Binds to TNF-α with high affinity, similar to infliximab.
Fusion proteins
Etanercept: A decoy fusion protein of TNF receptor P75. Captures free TNF but cannot bind to cell surface TNF.
Lymphotoxin A binding: Etanercept also binds to lymphotoxin A (formerly TNF-β). Monoclonal antibodies bind specifically to TNF-α only.
The most important factor for etanercept’s inferiority to monoclonal antibodies in ocular inflammation is its inability to bind to cell surface TNF. Additionally, it has been suggested that etanercept may paradoxically induce uveitis by disrupting cytokine balance and interfering with normal immune responses4).
When anti-idiotype antibodies against infliximab are produced, efficacy decreases over time. Concomitant use of methotrexate or mycophenolate mofetil may reduce or delay this antibody production5). In patients who cannot tolerate combination therapy, increasing the dose of infliximab may be considered.
Etanercept has been reported to have a higher risk of developing uveitis compared to other TNF inhibitors4). Recent evidence suggests that although etanercept is less effective in preventing ocular disease, it is unlikely to be a direct causative factor. Monoclonal antibody agents (infliximab or adalimumab) are recommended for ocular inflammatory diseases.
The traditional step-ladder approach involved starting with conventional immunosuppressive drugs, but in recent years, clinical practice has increasingly adopted upfront use of biologics.
An international survey found that 60.2% of specialists had experience using biologics before conventional drugs, and 91.0% of those decisions were based on a specific diagnosis of uveitis 1).
Weekly dosing is being investigated for cases with insufficient response to standard every-other-week dosing. In a retrospective case series of 25 patients with ocular inflammatory disease, weekly dosing achieved treatment success in 56% (14/25) at 6 months and 54% (13/24) at 12 months.
The use of biologics in juvenile idiopathic arthritis-associated uveitis is increasing.
Cann et al. (2018) reported that in 2007, anti-TNF agents were used in 11% of juvenile idiopathic arthritis-associated uveitis cases, but over the past decade, biologics have become more widely adopted 2). In pediatric uveitis, 27–48% have poor inflammation control, and adverse events occur in 20% 2).
Combination therapy with adalimumab and methotrexate has been reported to reduce the risk of developing uveitis in patients with juvenile idiopathic arthritis to a hazard ratio of 0.09 3).
