Rituximab (Non-infectious Uveitis)

Key Points at a Glance

Key Points of This Disease

• Rituximab is a human-mouse chimeric monoclonal antibody that targets CD20-positive B cells.
• In the treatment of non-infectious uveitis, it is the third most frequently used biologic agent after adalimumab and infliximab.¹⁾
• In an international survey, 139 out of 221 uveitis specialists (62.9%) had experience using rituximab. ¹⁾
• It is rarely chosen as a first-line biologic (0.9%) and is usually positioned as second- or third-line therapy for cases refractory to adalimumab. ¹⁾
• In gene therapy-associated uveitis (GTAU), it is also attracting attention as a candidate for B-cell depletion therapy aimed at suppressing humoral immune responses. ²⁾
• The emergence of anti-drug antibodies may reduce efficacy, and concomitant use of methotrexate or mycophenolate mofetil is expected to mitigate this. ²⁾

1. What is rituximab?

Rituximab is a human-mouse chimeric monoclonal antibody that binds to the CD20 surface antigen on CD20-positive B cells and depletes B cells via antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). It was originally developed as a treatment for B-cell non-Hodgkin lymphoma and rheumatoid arthritis.

In the field of non-infectious uveitis, it is used for refractory cases that are resistant to standard immunosuppressive therapy or TNF-α inhibitors. In a survey by the International Ocular Inflammation Society (IOIS) of 221 specialists from 53 countries, rituximab ranked third in frequency of use among 14 biologics ¹⁾. Following adalimumab (98.6%) and infliximab (79.6%), 62.9% of specialists had clinical experience with it ¹⁾.

However, only 0.9% of specialists use rituximab as a first-line biologic, which is low compared to adalimumab (97.7%) and infliximab (1.4%) ¹⁾. It is usually positioned as second- or third-line therapy when other biologics are ineffective.

Q In what situations is rituximab used?

A

It is used for refractory non-infectious uveitis when TNF-α inhibitors such as adalimumab are ineffective or contraindicated. It is rarely chosen as a first-line biologic (0.9%) and is positioned as later-line therapy ¹⁾.

2. Main symptoms and clinical findings

Subjective symptoms

In non-infectious uveitis that is the target of rituximab treatment, the following symptoms are the main complaints.

• Decreased vision: Symptoms associated with macular edema or vitreous opacity.
• Floaters: Due to inflammatory cells in the vitreous.
• Eye pain and redness: Seen in anterior uveitis.
• Photophobia: Associated with inflammation of the anterior segment.

Clinical Findings

Clinical findings relevant to the indication for rituximab vary depending on the underlying disease. Non-infectious uveitis includes various autoimmune and autoinflammatory diseases.

• Anterior chamber inflammation: Hypopyon or keratic precipitates.
• Vitreous opacities: Prominent in intermediate and posterior uveitis.
• Macular edema: A major complication affecting visual prognosis.
• Choroidal neovascularization: A complication of posterior uveitis.
• Glaucoma and hypotony: Sequelae of chronic inflammation.

Approximately 70% of patients with non-infectious uveitis develop visual impairment, and about 20% progress to legal blindness within an average of 3 years ¹⁾.

3. Causes and Risk Factors

Non-infectious uveitis treated with rituximab is due to autoimmune or autoinflammatory mechanisms. The main factors indicating the initiation of systemic immunomodulatory therapy are as follows ¹⁾.

• Uncontrolled with prednisolone: 94.1% of specialists considered it an indication.
• Specific uveitis diagnosis: 89.1% considered it an indication.
• Prednisolone intolerance: 84.2% considered it an indication.

Prevention and Daily Care

• During immunosuppressive therapy, you are more susceptible to infections. Please practice hand hygiene and wear a mask.
• During rituximab treatment, regular blood tests and infection screening are necessary. Follow your doctor’s instructions.
• If you experience symptoms such as fever, fatigue, or persistent cough, contact your doctor immediately.

4. Diagnosis and Testing Methods

Pre-treatment Screening

Before starting systemic immunomodulatory therapy, comprehensive testing is necessary. According to the IOIS survey, all specialists (221, 100%) performed pre-treatment testing ¹⁾.

The main pre-treatment test items and their implementation rates are shown below ¹⁾.

Test Item	Implementation Rate
Blood biochemistry tests	98.2%
Complete blood count	93.7%
QuantiFERON test	88.7%

In addition, chest X-ray (83.3%), hepatitis B and C virus serological tests (72.4%), and HIV serological tests (57.5%) are also performed ¹⁾.

Monitoring

Patients under treatment are usually evaluated every 6 to 12 weeks. For inactive uveitis, 72.9% of specialists evaluate every 6 to 12 weeks, and 74.7% screen for drug toxicity at the same interval ¹⁾.

5. Standard Treatment

Role of Treatment in Non-Infectious Uveitis

Treatment for non-infectious uveitis is carried out in a stepwise manner. According to the IOIS survey, the typical treatment steps are as follows ¹⁾.

Step 1

Oral prednisolone: The most common initial dose is 1 mg/kg/day (76.9%). The maximum dose is usually used for 4 weeks or less. 97.7% of specialists use it in combination with immunomodulatory drugs at the start.

Step 2

Conventional immunomodulatory drugs: Methotrexate is the first choice (57.0%), followed by mycophenolate mofetil (19.9%) and azathioprine (14.9%).

Step 3

Biologic agents: Adalimumab is the first choice (97.7%). In non-responders, switching to infliximab or rituximab is considered.

Rituximab is positioned later in the step-ladder approach that includes conventional drugs and biologics. However, 60.2% of specialists have used biologics before conventional drugs due to specific uveitis diagnoses (91.0%) or contraindications to conventional drugs (71.4%) ¹⁾.

Usage by Disease Type

The use of rituximab varies depending on the type of disease ¹⁾.

• Behçet’s disease uveitis: Most reports of rituximab use (1.8%).
• Vogt-Koyanagi-Harada disease: Used by 1.8% of specialists.
• Pars planitis: Used by 0.9% of specialists.
• Sarcoidosis uveitis: Used by 0.9% of specialists.
• Sympathetic ophthalmia: Used by 1.4% of specialists.

It takes 3 to 6 months to assess drug efficacy, and 81.9% of specialists switch to another drug after a 3- to 6-month trial period if ineffective¹⁾.

Combination Therapy

Combination of systemic immunomodulatory drugs was used by 85.1% of specialists¹⁾. The most common combination is methotrexate plus adalimumab (84.0%), but rituximab is also used in combination with methotrexate or mycophenolate mofetil. Combining these immunosuppressants may suppress the appearance of anti-drug antibodies and help maintain treatment efficacy²⁾.

Criteria for Drug Discontinuation

The required inactive period before drug discontinuation is 2 years for 64.3% of specialists¹⁾.

Precautions and Side Effects in Treatment

• Rituximab depletes B cells and may cause long-term humoral immunodeficiency.
• Hepatitis B screening before administration is mandatory. There is a risk of hepatitis B reactivation.
• Efficacy may decrease due to the appearance of anti-drug antibodies²⁾. Combination with methotrexate or mycophenolate mofetil is considered as a mitigation strategy²⁾.
• Since the mechanism of action differs from TNF-α inhibitors, the risk of demyelinating disease complications differs from adalimumab.

Q Can rituximab be used when adalimumab is ineffective?

A

It is used as a subsequent treatment for refractory cases where TNF-α inhibitors such as adalimumab or infliximab are ineffective. An international survey found that 62.9% of specialists have experience using it ¹⁾. However, it is not a first-line treatment, so consultation with a specialist is essential.

6. Pathophysiology and Detailed Mechanisms

Mechanism of Action of B-cell Depletion

Rituximab binds to the CD20 antigen. CD20 is expressed on pre-B cells and mature B cells but not on stem cells or plasma cells. After binding, it eliminates B cells through the following mechanisms:

• Antibody-dependent cellular cytotoxicity (ADCC): Natural killer cells recognize the Fc portion of rituximab and damage target B cells.
• Complement-dependent cytotoxicity (CDC): Activation of the complement cascade leads to formation of the membrane attack complex, causing B cell lysis.
• Direct induction of apoptosis: Intracellular signaling via CD20 cross-linking induces programmed cell death.

B cells are precursors for antibody production and also participate in antigen presentation and cytokine production. In non-infectious uveitis, there are cases where B cells contribute to the maintenance of inflammation, and in such cases, B-cell depletion with rituximab can be effective.

Role in Gene Therapy-Associated Uveitis

In recent years, rituximab has gained attention for preventing gene therapy-associated uveitis that occurs after intravitreal injection of AAV (adeno-associated virus) vectors used in gene therapy ²⁾.

Intravitreal AAV vector administration induces the production of neutralizing antibodies (NAbs), making re-administration to the same eye or administration to the contralateral eye difficult. It has been suggested that concomitant use of rituximab at the time of initial administration, temporarily depleting the B cell population, may suppress the rise in NAbs ²⁾. However, in experimental models, anti-drug antibodies (ADAs) appeared after B cell recovery and limited the expression of the therapeutic transgene ²⁾.

Strategies combining corticosteroids or other immunomodulatory drugs with rituximab to reduce ADAs and improve NAb suppression are being investigated ²⁾.

Q Is rituximab also related to gene therapy?

A

In retinal gene therapy using AAV vectors, neutralizing antibodies are produced after administration, posing a barrier to treatment of the contralateral eye. B-cell depletion with rituximab is being studied as a means to suppress this humoral immune response ²⁾. However, it is not yet an established treatment.

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7. Latest Research and Future Prospects (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. This is reference information for professionals regarding future medical developments.

Immunomodulatory Strategies in Gene Therapy

Retinal gene therapy using AAV vectors is rapidly advancing, but immune reactions after intravitreal injection remain a major challenge. Immunomodulatory strategies including rituximab are being explored as follows²⁾.

• Pre-treatment B-cell depletion: Systemic administration of rituximab at the time of the first intravitreal injection to prevent the production of neutralizing antibodies (NAbs).
• Combination with corticosteroids: Since rituximab alone can lead to the emergence of anti-drug antibodies, combination with immunomodulatory drugs is important.
• Treatment of gene therapy-associated uveitis with methotrexate: In three cases of chronic uveitis following AAV gene therapy for X-linked retinoschisis, methotrexate reduced the frequency and severity of attacks²⁾.

Comparison with Anti-TNF-α Therapy

Anti-TNF-α therapy is already established as a standard second-line treatment for severe refractory uveitis, but it shares the common challenge of anti-drug antibodies limiting efficacy, similar to rituximab²⁾. Concomitant use of mycophenolate mofetil or methotrexate may reduce anti-drug antibodies for both biologics²⁾.

Biologics in Pediatric Non-Infectious Uveitis

Treatment outcomes for pediatric non-infectious uveitis have improved with the introduction of biologics³⁾.

Cann et al. (2018) analyzed 166 children with non-infectious uveitis, reporting that 72.9% received methotrexate, and 58 of them progressed to biologics³⁾. The incidence of visual loss (>0.3 LogMAR) was 0.05 per eye-year, and severe visual loss (≥1.0 LogMAR) was 0.01 per eye-year, showing improvement compared to previous reports.

In children, the incidence of cataract was highest (0.05 per eye-year), with glaucoma more common in juvenile idiopathic arthritis-associated uveitis and macular edema more common in idiopathic uveitis³⁾. Further investigation is needed regarding the role of rituximab in pediatric uveitis.

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8. References

1. Branford JA, Bodaghi B, Ferreira LB, et al. Use of immunomodulatory treatment for non-infectious uveitis: an International Ocular Inflammation Society report of real-world practice. Br J Ophthalmol. 2025;109:482-489.
2. 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.
3. Cann M, Ramanan AV, Crawford A, et al. Outcomes of non-infectious paediatric uveitis in the era of biologic therapy. Pediatr Rheumatol Online J. 2018;16:51.