Adalimumab (for Uveitis Treatment)

Key points at a glance

Key points of this disease

• Adalimumab is a human monoclonal antibody that binds to TNF-α and is used worldwide as the first-line biologic for non-infectious uveitis.
• It was approved in 2016 for intermediate, posterior, and panuveitis in adults, and its indication was expanded to children in 2017.
• In an international survey, 97.7% of specialists reported adalimumab as their first-choice biologic. ¹⁾
• Tuberculosis screening (e.g., QuantiFERON) before initiation and regular systemic monitoring are mandatory. ¹⁾
• There are risks of serious infections, demyelination, and malignancy; it is contraindicated in patients with multiple sclerosis. ¹⁾
• Combination with methotrexate (84.0%) is the most common treatment strategy. ¹⁾

1. What is Adalimumab?

Adalimumab (brand name: Humira) is a recombinant human IgG1 monoclonal antibody that specifically binds to tumor necrosis factor alpha (TNF-α). It has a molecular weight of 148 kDa and consists of 1,330 amino acids.

It was first approved by the US FDA for rheumatoid arthritis in 2002. Indications later expanded to psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, plaque psoriasis, and hidradenitis suppurativa. In ophthalmology, it was approved in June 2016 for the treatment of intermediate, posterior, and panuveitis in adults. Pediatric approval followed in 2017. ²⁾

Efficacy was established in the VISUAL I trial for active non-infectious uveitis and the VISUAL II trial for inactive disease. ⁴⁾⁵⁾ For juvenile idiopathic arthritis-associated uveitis, the SYCAMORE trial demonstrated the efficacy of adalimumab plus methotrexate. ⁶⁾

An international real-world practice survey (221 specialists) showed that adalimumab was the first-choice biologic for all 11 types of non-infectious uveitis, with an overall selection rate of 97.7%. ¹⁾

Q What types of uveitis is adalimumab used for?

A

The main indications are non-infectious intermediate, posterior, and panuveitis. It is widely used for underlying diseases such as Behçet’s disease, sarcoidosis, juvenile idiopathic arthritis-associated uveitis, HLA-B27-associated uveitis, and Vogt-Koyanagi-Harada disease. It was FDA-approved in 2016 and became available in Japan the same year. ¹⁾²⁾

2. Main Symptoms and Clinical Findings

Subjective Symptoms

In non-infectious uveitis for which adalimumab is indicated, the following symptoms are observed.

• Decreased vision: Ranges from mild to severe depending on the location and extent of inflammation.
• Blurred vision: Caused by vitreous opacity or macular edema.
• Floaters: Due to vitreous opacity. Prominent in intermediate and posterior uveitis.
• Redness: Ciliary injection reflects anterior inflammation.
• Eye pain: Observed in anterior uveitis (iridocyclitis).
• Photophobia: Due to stimulation of the pupillary sphincter.

Clinical Findings

The ocular findings of the main indications for which adalimumab is used are shown below.

Behçet's Disease

Inflammation pattern: Relapsing-remitting uveitis. Panuveitis is most common.

Features: Often bilateral, accompanied by hypopyon, vitreous opacity, and retinal vasculitis. Recurrent attacks worsen visual prognosis.

Juvenile Idiopathic Arthritis-Associated Uveitis

Inflammation pattern: Chronic anterior uveitis. Often progresses asymptomatically.

Features: Bilateral, common in children. High risk of complications such as band keratopathy, posterior subcapsular cataract, and secondary glaucoma.

Sarcoidosis

Incidence: Ocular involvement occurs in 10–80% of cases, with uveitis being the most common eye symptom.

Features: Granulomatous inflammation. Presents with mutton-fat keratic precipitates, angle granulomas, and retinochoroidal granulomas.

3. Causes and Risk Factors

Non-infectious uveitis, which adalimumab treats, results from immune diseases with excessive TNF-α production. The main underlying diseases are as follows:

• Behçet’s disease: Relapsing-remitting panuveitis. Damage to the optic nerve and retina tends to be severe.
• Juvenile idiopathic arthritis: Complicated by chronic anterior uveitis, which often progresses asymptomatically.
• Sarcoidosis: A systemic granulomatous disease with a high frequency of ocular involvement.
• HLA-B27-associated diseases: Acute anterior uveitis associated with ankylosing spondylitis, reactive arthritis, etc.
• Vogt-Koyanagi-Harada disease: Bilateral granulomatous uveitis.
• Birdshot chorioretinopathy: Posterior uveitis common in HLA-A29-positive individuals.

In an international survey, the main indications for starting systemic immunomodulatory therapy were poor control with prednisolone (94.1%), specific diagnosis (89.1%), and prednisolone intolerance (84.2%). ¹⁾

TNF-α inhibition is known to be associated with demyelination, and adalimumab is contraindicated in patients with multiple sclerosis. ¹⁾

Prevention and Daily Care

During adalimumab treatment, immune function is reduced, so it is especially important to watch for infections. Please keep the following points in mind:

• Make sure to have regular ophthalmology and internal medicine checkups.
• If symptoms of infection such as fever, cough, or malaise appear, consult your doctor promptly.
• Live vaccines (measles, rubella, varicella, BCG, etc.) are generally contraindicated. Check the vaccination schedule with your doctor in advance.
• If you have a history of or contact with tuberculosis, be sure to inform your doctor.

Q When are systemic immunomodulators initiated?

A

The main indications for initiation are when uveitis is poorly controlled with prednisolone (94.1%), when there is a specific diagnosis (such as Behçet’s disease or juvenile idiopathic arthritis-related uveitis) (89.1%), and when prednisolone is intolerant (84.2%). ¹⁾ For details, see the section on “Standard Treatment.”

4. Diagnosis and Examination Methods

This section explains the screening tests required before initiating adalimumab and the monitoring system during administration.

Pre-initiation Screening

In an international survey, all 221 patients underwent some form of screening. The following tests are frequently performed. ¹⁾

The implementation rates of pre-treatment screening are shown below.

Test Item	Implementation Rate
Blood Chemistry Screen	98.2%
Complete blood count	93.7%
QuantiFERON	88.7%

Tuberculosis screening (QuantiFERON test or tuberculin skin test) is particularly important. If latent tuberculosis infection is confirmed, treatment should be initiated after prophylactic chemotherapy. Hepatitis B virus testing is also mandatory.

Monitoring after treatment initiation

• Frequency of evaluation in stable patients: every 6–12 weeks (72.9%)¹⁾
• Toxicity monitoring: blood biochemistry (96.4%) and complete blood count (88.2%) checked every 12 weeks (52.5%)¹⁾
• Concomitant steroids during induction: 97.7% used oral prednisolone until drug efficacy was achieved¹⁾

Due to the risk of serious infections, systemic monitoring based on the guidelines of the Japanese Society of Ocular Inflammation is essential.

5. Standard treatment

Administration method and dosage

Standard dosages for adults and children are shown below.

Adults

Standard administration: 40 mg subcutaneously every other week

Dosing interval: Although some reports describe once-weekly administration, the standard is every other week.

Children (juvenile idiopathic arthritis-related)

10 kg to less than 15 kg: 10 mg every other week

15 kg to less than 30 kg: 20 mg every other week

30 kg or more: 40 mg every other week

In pediatric uveitis, administration of 24 mg/m² every 2 weeks up to a maximum of 40 mg has been reported.

Treatment strategies (international real-world clinical patterns)

• First-line conventional drug: Methotrexate (57.0%)¹⁾
• First-line biologic: Adalimumab (97.7%)¹⁾
• Most common combination regimen: Methotrexate + adalimumab (84.0%)¹⁾
• Criteria for inefficacy: Switch to an alternative drug after a 3- to 6-month trial period if no effect (81.9%)¹⁾
• Prior use of biologics: 60.2% of specialists have used adalimumab before conventional drugs. Reasons: specific uveitis diagnosis (91.0%), contraindications to conventional drugs (71.4%)¹⁾

Treatment generally needs to be continued for at least 2 years, with the goal of maintaining inflammation control.¹⁾

Treatment selection by disease

The first-line adalimumab selection rates by disease are shown below.¹⁾

Type of uveitis	Usage rate
Juvenile idiopathic arthritis-associated	97.3%
HLA-B27-associated	96.4%
Sarcoidosis	92.8%
Behçet’s disease	72.4%

In juvenile idiopathic arthritis-associated uveitis, combination therapy with adalimumab is an important option for cases with residual activity despite methotrexate. The SYCAMORE trial established the efficacy of adalimumab plus methotrexate ⁶⁾.

For Behçet’s disease ocular involvement, the American Academy of Ophthalmology strongly recommends infliximab or adalimumab as first- or second-line steroid-sparing agents. In Behçet’s disease, azathioprine is chosen as the first-line conventional drug in 52.0% of cases. ¹⁾

For birdshot chorioretinopathy, mycophenolate is chosen as the first-line conventional drug in 39.8% of cases. ¹⁾

Treatment guidelines in Japan

Adalimumab is used for non-infectious uveitis refractory to existing treatments (steroids and conventional immunomodulatory drugs), and its efficacy including steroid-sparing effect has been reported. Guidelines from the Japanese Society of Ocular Inflammation require pre-treatment screening and monitoring during administration considering the risk of serious infections.

Association with Cataract Surgery

Over 90% of specialists require at least 3 months of inflammation control before cataract surgery in uveitis patients. ¹⁾ In Behçet’s disease, a symptom-free period of 6 months or longer is particularly desirable.

Precautions and Side Effects in Treatment

Adalimumab administration carries the following serious side effect risks:

• Serious infections: Tuberculosis (including reactivation), bacterial sepsis, invasive fungal infections, opportunistic infections
• Reactivation of hepatitis B: Screening must be performed before initiation
• Malignancy risk: Reports of lymphoma, leukemia, and hepatosplenic T-cell lymphoma
• Severe allergic reactions: Anaphylaxis, angioneurotic edema
• Other side effects: Headache, hyperglycemia, nausea, dizziness, psoriasis, cardiotoxicity, hepatotoxicity ³⁾
• Demyelination risk: Contraindicated in patients with multiple sclerosis ¹⁾

Q How are adalimumab and methotrexate used differently?

A

Methotrexate is the first-choice conventional immunosuppressant (57.0%), and adalimumab is the first-choice biologic (97.7%). Combination therapy (84.0%) is the most common treatment strategy. ¹⁾ Depending on the type and severity of the disease, adalimumab may be used first.

Q What laboratory monitoring is needed during adalimumab treatment?

A

It is standard to check blood biochemistry (96.4%) and complete blood count (88.2%) every 12 weeks. In stable patients, ophthalmologic evaluation is performed every 6 to 12 weeks. Tuberculosis screening (QuantiFERON 88.7%) and hepatitis B testing are mandatory before starting treatment. ¹⁾

6. Pathophysiology and Detailed Mechanism of Onset

Role of TNF-α

TNF-α (tumor necrosis factor alpha) is a multifunctional inflammatory cytokine. It is produced by macrophages, T cells, mast cells, granulocytes, NK cells, and others.

Its main functions are as follows:

• Promotion of NF-κB production: Activates nuclear transcription factors and induces expression of inflammatory genes.
• Cell activation: Promotes activation, migration, and tissue infiltration of immune cells.
• Induction of apoptosis: Involved in the elimination of infected cells.
• Induction of downstream cytokines: Amplifies production of inflammatory cytokines such as IL-1, IFN-γ, and IL-2.

The physiological role of TNF-α is dose-dependent. At low doses, it enhances immune responses against infection; at high doses, it causes excessive inflammation and organ damage. Massive rapid release can lead to septic shock.

Mechanism of Action of Adalimumab

Adalimumab inhibits TNF-α through the following two mechanisms:

1. Blockade of receptor signaling: Specifically binds to both soluble and membrane-bound TNF-α, inhibiting interaction with p55/p75 TNF receptors.
2. Lysis of TNF-expressing cells: Induces lysis of cells expressing membrane-bound TNF-α in the presence of complement.

Through these mechanisms, TNF-α is inhibited, and the inflammatory cytokine cascade is suppressed. ³⁾

Significance in Non-Infectious Uveitis

Most cases of non-infectious uveitis involve T cell-mediated autoimmune mechanisms, with TNF-α playing a central role in amplifying inflammation. For cases inadequately controlled by conventional immunosuppressive drugs, the efficacy of TNF-α inhibition was established in the VISUAL I/II trials⁴⁾⁵⁾.

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7. Latest Research and Future Perspectives (Investigational Reports)

For Patients: Please Read Carefully

The following content is currently under investigation or in clinical trials and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

Advances in Pediatric Treatment for Juvenile Idiopathic Arthritis-Associated Uveitis

Methotrexate has traditionally been used as a standard conventional drug for pediatric juvenile idiopathic arthritis-associated uveitis. However, 27–48% of children have poor inflammation control, and 20% experience side effects. ²⁾

The SYCAMORE trial (2017, published in NEJM) compared adalimumab plus methotrexate versus placebo plus methotrexate in children with juvenile idiopathic arthritis-associated uveitis. The adalimumab combination group showed significant superiority over the placebo group in time to treatment failure, establishing the efficacy of adalimumab for juvenile idiopathic arthritis-associated uveitis. ⁶⁾

Long-Term Safety Data

The VISUAL III trial (long-term open-label extension study) has accumulated long-term safety and efficacy data. ⁷⁾ Long-term safety evaluation including real-world data remains an ongoing challenge.

Research on Biosimilar Products

Studies have shown that biosimilars of adalimumab (follow-on biologics) have equivalent safety and efficacy to the originator product. Further evidence accumulation is ongoing.

Exploration of Intravitreal Administration

To avoid systemic administration, a small-scale report exists on intravitreal injection of adalimumab (1.5 mg, initial, after 2 weeks, then every 4 weeks for a total of 26 weeks). ⁸⁾ However, it is currently at the research stage.

Q Are biosimilar products as effective as the original?

A

Studies have shown that biosimilars are equivalent to the original product in safety and efficacy. However, further evidence accumulation is ongoing, and it is important to discuss switching with your doctor thoroughly.

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8. References

1. Branford JA, et al. Practice patterns of systemic immunomodulatory drug treatment of non-infectious uveitis: an international study. Br J Ophthalmol. 2025;109:482-489.
2. Cann M, et al. Childhood uveitis in a tertiary centre: outcomes in the era of biologic treatment. Pediatric Rheumatology. 2018;16:51.
3. Purdy R, et al. Immunosuppression for retinal gene therapy. Prog Retin Eye Res. 2025;106:101354.
4. Jaffe GJ, Dick AD, Brezin AP, Nguyen QD, Thorne JE, Kestelyn P, et al. Adalimumab in patients with active noninfectious uveitis. N Engl J Med. 2016;375(10):932-943. doi:10.1056/NEJMoa1509852.
5. Nguyen QD, Merrill PT, Jaffe GJ, Dick AD, Kurup SK, Sheppard J, et al. Adalimumab for prevention of uveitic flare in patients with inactive non-infectious uveitis controlled by corticosteroids (VISUAL II): a multicentre, double-masked, randomised, placebo-controlled phase 3 trial. Lancet. 2016;388(10050):1183-1192. doi:10.1016/S0140-6736(16)31339-3.
6. Ramanan AV, Dick AD, Jones AP, McKay A, Williamson PR, Compeyrot-Lacassagne S, et al. Adalimumab plus methotrexate for uveitis in juvenile idiopathic arthritis. N Engl J Med. 2017;376(17):1637-1646. doi:10.1056/NEJMoa1614160.
7. Suhler EB, Adan A, Brezin AP, Fortin E, Goto H, Jaffe GJ, 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. doi:10.1016/j.ophtha.2017.12.039.
8. Hamam RN, Barikian AW, Antonios RS, Abdulaal MR, Alameddine RM, El Mollayess G, et al. Intravitreal adalimumab in active noninfectious uveitis: a pilot study. Ocul Immunol Inflamm. 2016;24(3):319-326. doi:10.3109/09273948.2014.990041.