Immunomodulatory therapy (IMT) is a general term for steroid-sparing treatments used for non-infectious ocular inflammation that is dependent on or resistant to steroids. It encompasses a wide range of agents, from conventional immunomodulators (e.g., methotrexate, azathioprine) to biologic agents such as TNF-α inhibitors (adalimumab, infliximab).
Non-infectious uveitis is a diverse group of autoimmune and autoinflammatory diseases that can lead to blindness without appropriate treatment. It is estimated that 70% of uveitis patients experience vision loss, and about 20% meet the criteria for legal blindness within an average of 3 years1).
The Uveitis Clinical Practice Guidelines (2019) recommend methotrexate as the first-choice steroid-sparing agent for anterior uveitis persisting for 4 weeks or more and resistant to steroid eye drops3).
Infliximab was approved for refractory ocular symptoms of Behçet’s disease in 2007, and adalimumab was approved for non-infectious intermediate, posterior, and panuveitis in 20164).
QHow is immunomodulatory therapy different from steroids?
A
Steroids (glucocorticoids) have rapid effects in the acute phase, but long-term use can cause various side effects such as posterior subcapsular cataract, glaucoma, osteoporosis, diabetes, and increased susceptibility to infections. Immunomodulatory therapy is used alongside or as an alternative to steroids, aiming to “control inflammation while reducing or discontinuing steroids” (steroid sparing). Since it takes several weeks to months to take effect, it is often combined with steroids initially.
The presence or absence of long-term steroid side effects (posterior subcapsular cataract, elevated intraocular pressure, steroid-induced glaucoma) also informs the decision to initiate immunomodulatory therapy.
QAt what steroid dose should immunomodulatory therapy be considered?
A
Generally, when long-term treatment with 5–10 mg/day or more of prednisolone equivalent is required, immunomodulatory therapy as a steroid-sparing agent is indicated. In the field of uveitis, an approach of adding immunomodulatory therapy to allow steroid tapering below this threshold is widely adopted.
Diseases for Which Early Initiation of Immunomodulatory Therapy Is Recommended
Behçet’s disease: Colchicine is first-line. Systemic steroid administration is generally avoided due to the risk of triggering inflammatory attacks. For refractory cases, infliximab (Remicade 5 mg/kg every 2 months) 3).
Vogt-Koyanagi-Harada disease: Add cyclosporine (Neoral 3 mg/kg/day in two divided doses). Long-term continuation of immunomodulatory therapy determines visual prognosis.
Hepatitis B reactivation risk: Consider prophylactic antiviral therapy in HBc antibody-positive cases
In 68.8% of patients receiving immunomodulatory therapy, co-management with a rheumatologist was performed, and 93.4% involved collaboration with an internal medicine or pediatric rheumatologist1).
QWhat tests are required before starting TNF inhibitors?
A
Before starting TNF inhibitors (infliximab, adalimumab), it is mandatory to exclude tuberculosis (QuantiFERON/T-SPOT, chest X-ray) and hepatitis B virus (HBs antigen, HBc antibody, HBs antibody)4). Active infection or a history of serious infection is a contraindication. Additionally, a history of malignancy or demyelinating disease should be checked.
76.9% of specialists start with prednisolone at an initial dose of 1 mg/kg, and 93.7% begin tapering within 4 weeks1). In Behçet’s disease, systemic steroid administration carries a risk of triggering inflammatory attacks and is generally avoided.
Main side effects: Nausea, liver dysfunction, bone marrow toxicity, interstitial pneumonia3)
Prescription examples by disease (from the Uveitis Practice Guidelines):
Behçet’s disease: Colchicine 0.5–1.5 mg/day (usually 1 mg/day, off-label) orally to suppress inflammatory attacks3). If colchicine is insufficient, Neoral 5 mg/kg/day in two divided doses. For severe or refractory cases, Remicade 5 mg/kg is administered as a 1–2 hour intravenous infusion every 2 months.
Vogt-Koyanagi-Harada disease: Neoral 3 mg/kg/day in 2 divided doses (180 mg/day for 60 kg body weight). Regular trough level monitoring and monitoring for susceptibility to infections and renal/hepatic impairment are required.
Intermediate uveitis: Neoral 3–5 mg/kg/day in 2 divided doses, or MTX 2 mg every 12 hours for 3 doses (repeated once weekly).
Usage of other conventional agents (international survey)1):
Adalimumab (fully human anti-TNF-α monoclonal antibody) is adopted as the first-line biologic agent by 97.7% in international surveys1). Efficacy has been established through the VISUAL I trial (active non-infectious uveitis)5), VISUAL II trial (inactive non-infectious uveitis)7), and SYCAMORE trial (JIA-associated uveitis with MTX + adalimumab)6). It is approved by the FDA and EMA for non-infectious uveitis.
Many specialists (81.9%) try a drug for 3–6 months before deeming it ineffective and switching to the next drug1). The FOCUS guidance also recommends early initiation of IMT for corticosteroid-dependent non-infectious uveitis10).
85.1% of specialists combine multiple immunomodulatory drugs, with the most common combination being methotrexate + adalimumab (84.0%)1).
QWhich biologics are covered by insurance in Japan?
A
The main biologics with insurance coverage for uveitis in Japan are as follows 4):
Infliximab (Remicade): Approved in 2007, indicated for refractory Behçet’s ocular symptoms.
Adalimumab: Approved in 2016, indicated for non-infectious intermediate, posterior, and panuveitis.
Tocilizumab and etanercept: Have insurance coverage for JIA-associated uveitis.
All have specific indications, so please consult your doctor.
Methotrexate inhibits dihydrofolate reductase, interfering with the synthesis of purine nucleotides and thymidylate, thereby suppressing DNA replication, repair, and cell proliferation. At low doses, its anti-inflammatory effects are primarily mediated through the release of extracellular adenosine, which suppresses T-cell activation and cytokine production.
Cyclosporine (Neoral) inhibits calcineurin, suppressing IL-2 production and activation in T cells. Nephrotoxicity and hypertension are the main side effects.
TNF-α (tumor necrosis factor alpha) is a central cytokine in intraocular inflammation, contributing to the recruitment and activation of inflammatory cells and increased vascular permeability. Adalimumab (fully human) and infliximab (chimeric) bind to TNF-α and inhibit its binding to receptors. Infliximab is more likely to generate anti-drug antibodies than adalimumab, with a relatively higher risk of reduced efficacy due to neutralizing antibodies.
Mechanism of action of anti-IL-6 receptor antibody (tocilizumab)
By blocking the IL-6 receptor and suppressing IL-6 signal transduction, it improves intraocular inflammation and macular edema. Its efficacy in refractory uveitic macular edema has been reported 9).
7. Latest Research and Future Perspectives (Investigational Reports)
The survey of 221 specialists from 53 countries published by Branford et al. (2025) is the first to capture international real-world patterns of immunomodulatory therapy for non-infectious uveitis1). This study is expected to provide practical information as a future clinical guide for ophthalmologists.
Anti-drug antibody monitoring and drug trough level measurement (therapeutic drug monitoring, TDM) are theoretically attractive personalized strategies, but currently clinical trials have not shown that therapeutic drug monitoring improves clinical outcomes, and its routine use in daily clinical practice is not supported.
Application of immunomodulatory therapy for uveitis after gene therapy
In immune-related uveitis that develops after ophthalmic gene therapy (using adeno-associated virus vectors), methotrexate has been reported to reduce the frequency and severity of recurrence of chronic uveitis that is difficult to control with steroids alone 2).
Branford JA, et al. IOIS report on systemic immunomodulatory drug treatment of non-infectious uveitis. Br J Ophthalmol. 2025;109(4):482–489.
Purdy R, John M, Bray A, et al. Gene Therapy-Associated Uveitis (GTAU): Understanding and mitigating the adverse immune response in retinal gene therapy. Prog Retin Eye Res. 2025;106:101354. doi:10.1016/j.preteyeres.2025.101354.
Jaffe GJ, Dick AD, Brézin AP, et al. Adalimumab in patients with active noninfectious uveitis (VISUAL I). N Engl J Med. 2016;375(10):932-943.
Ramanan AV, Dick AD, Jones AP, et al. Adalimumab plus methotrexate for uveitis in juvenile idiopathic arthritis (SYCAMORE). N Engl J Med. 2017;376(17):1637-1646.
Nguyen QD, Merrill PT, Jaffe GJ, et al. Adalimumab for prevention of uveitic flare in patients with inactive non-infectious uveitis controlled by corticosteroids (VISUAL II). Lancet. 2016;388(10050):1183-1192.
Kempen JH, Daniel E, Dunn JP, et al. Overall and cancer related mortality among patients with ocular inflammation treated with immunosuppressive drugs (SITE). BMJ. 2009;339:b2480.
Mesquida M, Molins B, Llorenç V, et al. Long-term effects of tocilizumab therapy for refractory uveitis-related macular edema. Ophthalmology. 2014;121(12):2380-2386.
Dick AD, Rosenbaum JT, Al-Dhibi HA, et al. Guidance on Non-Corticosteroid Systemic Immunomodulatory Therapy in Noninfectious Uveitis (FOCUS). Ophthalmology. 2018;125(5):757-773.
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