# Immunomodulatory Therapy for Uveitis

## Introduction

Immunomodulatory therapy (IMT) is the cornerstone of management for chronic, recurrent, or sight-threatening non-infectious uveitis. The goal is to achieve durable disease quiescence while minimizing corticosteroid-related adverse effects. Selection of the appropriate agent requires an understanding of mechanism of action, efficacy data, monitoring requirements, and patient-specific factors.

## Indications for Immunomodulatory Therapy

**Steroid dependence**: inability to taper below a prednisone equivalent of 7.5 mg/day within 3 months. **Steroid intolerance**: unacceptable side effects (glucose intolerance, osteoporosis, weight gain, psychosis) **Sight-threatening disease**: Behcet disease, VKH, sympathetic ophthalmia, severe intermediate or posterior uveitis. **Bilateral chronic uveitis** with risk of cumulative steroid toxicity. Recurrent disease requiring repeated corticosteroid rescue.

## General Principles

**Bridge with corticosteroids** while waiting for IMT to take effect (onset typically 4-12 weeks) Monotherapy is preferred; combination therapy is reserved for refractory cases. Regular laboratory monitoring (CBC, hepatic function, renal function) is mandatory. Pregnancy considerations: methotrexate and mycophenolate are **teratogenic**; coordinate with the patient's obstetrician. Treat-to-target: aim for complete quiescence (no cells, no macular edema) on no or minimal corticosteroids.

## Antimetabolites

### Methotrexate (MTX)

**Mechanism**: dihydrofolate reductase inhibitor; inhibits purine and pyrimidine synthesis. Dose: 15-25 mg weekly (oral or subcutaneous); supplement with folic acid 1 mg daily. Onset: 4-8 weeks. Efficacy: effective for anterior, intermediate, and posterior uveitis; scleritis. Monitoring: CBC and LFTs every 4-8 weeks; chest X-ray at baseline. Side effects: hepatotoxicity, cytopenias, mucositis, pneumonitis.

**Contraindication**: pregnancy (Category X), significant liver disease, immunodeficiency.

### Mycophenolate Mofetil (MMF)

**Mechanism**: inosine monophosphate dehydrogenase inhibitor; selectively targets lymphocyte proliferation. Dose: 1-1.5 g twice daily. Onset: 6-12 weeks. Well tolerated; main side effects are GI disturbance and cytopenias. Preferred in patients who cannot tolerate methotrexate.

### Azathioprine

**Mechanism**: purine analogue; inhibits DNA synthesis in rapidly dividing cells. Dose: 1-3 mg/kg/day. Check **thiopurine methyltransferase (TPMT)** activity before starting; deficiency increases risk of severe myelosuppression. Generally considered less effective than MTX or MMF; used when others are contraindicated.

![Stepladder approach to immunomodulatory therapy in uveitis](images/imt-stepladder-approach.jpg)

## Immunomodulatory Agents Summary

| Agent | Class | Mechanism | Dose | Onset | Key Monitoring | Key Side Effects | Pregnancy |
|-------|-------|-----------|------|-------|----------------|------------------|-----------|
| Methotrexate | Antimetabolite | DHFR inhibitor | 15-25 mg/wk | 4-8 wk | CBC, LFTs q4-8wk | Hepatotoxicity, cytopenias, pneumonitis | Category X |
| Mycophenolate | Antimetabolite | IMPDH inhibitor | 1-1.5 g BID | 6-12 wk | CBC, LFTs | GI disturbance, cytopenias | Category X |
| Azathioprine | Antimetabolite | Purine analogue | 1-3 mg/kg/day | 6-12 wk | TPMT level, CBC, LFTs | Myelosuppression, pancreatitis | Safer (Category D) |
| Cyclosporine | Calcineurin inhibitor | Blocks IL-2/T-cells | 2-5 mg/kg/day | 4-6 wk | BP, creatinine, drug level | Nephrotoxicity, HTN | Category C |
| Adalimumab | Biologic (anti-TNF) | TNF-alpha inhibitor | 40 mg q2wk SC | 4-8 wk | TB screen, hepatitis panel | Infection, demyelination, lymphoma | Category B |
| Infliximab | Biologic (anti-TNF) | TNF-alpha inhibitor | 5 mg/kg IV q4-8wk | 2-4 wk | TB screen, hepatitis panel | Infusion reactions, infection | Category B |
| Rituximab | Biologic (anti-CD20) | B-cell depletion | 1g IV x2 | 4-8 wk | Immunoglobulins, B-cell count | Infusion reaction, PML (rare) | Category C |
| Tocilizumab | Biologic (anti-IL-6) | IL-6R antagonist | 4-8 mg/kg IV or SC | 4-8 wk | CBC, LFTs, lipids | Infection, neutropenia, GI perforation | Category C |

## Calcineurin Inhibitors

### Cyclosporine A

**Mechanism**: inhibits calcineurin, blocking IL-2 transcription and T-cell activation. Dose: 2-5 mg/kg/day in divided doses. Effective for Behcet disease, VKH, birdshot chorioretinopathy. Monitoring: blood pressure, renal function (creatinine), trough drug levels. Side effects: nephrotoxicity, hypertension, hirsutism, gingival hyperplasia.

### Tacrolimus

10-100 times more potent than cyclosporine at equivalent doses. Similar mechanism but different binding protein (FKBP-12 vs. cyclophilin) Lower incidence of cosmetic side effects; nephrotoxicity remains a concern.

## Biologic Agents

### Adalimumab (Humira)

**Anti-TNF-alpha monoclonal antibody**; FDA-approved for non-infectious intermediate, posterior, and panuveitis. Dose: 40 mg subcutaneously every 2 weeks (80 mg loading dose) VISUAL I and VISUAL II trials demonstrated significant reduction in uveitis flare risk. Screen for **latent tuberculosis** and hepatitis B before initiation. Side effects: injection site reactions, increased infection risk, rare demyelination, lupus-like syndrome.

### Infliximab

Chimeric anti-TNF-alpha monoclonal antibody; intravenous infusion. Dose: 5-10 mg/kg at weeks 0, 2, 6, then every 4-8 weeks. Particularly effective for **Behcet disease** with ocular involvement. Risk of infusion reactions; anti-drug antibody formation (consider concomitant MTX)

### Other Biologics

**Tocilizumab** (anti-IL-6): emerging evidence for refractory macular edema in uveitis. **Rituximab** (anti-CD20): used in refractory scleritis and orbital inflammation. **Secukinumab** (anti-IL-17): studied in uveitis but showed mixed results. **Abatacept** (CTLA-4-Ig): case series in JIA-associated uveitis.

![Mechanism of action of biologic agents targeting TNF-alpha, IL-6, and B-cells](images/biologic-moa-uveitis.jpg)

## Alkylating Agents

### Cyclophosphamide

Reserved for severe, refractory, or life-threatening disease (e.g., necrotizing scleritis with systemic vasculitis) Dose: oral 1-2 mg/kg/day or IV pulse 750-1000 mg/m2 monthly. Serious side effects: hemorrhagic cystitis, bone marrow suppression, infertility, secondary malignancy. Limit cumulative dose; transition to a safer agent once remission is achieved.

### Chlorambucil

Rarely used today due to high toxicity profile. Historical use in Behcet disease before biologic era.

## Local Corticosteroid-Sparing Options

### Intravitreal Dexamethasone Implant (Ozurdex)

Biodegradable implant releasing dexamethasone over 4-6 months. Useful adjunct for unilateral disease or as a bridge to systemic IMT. Risk of cataract and IOP elevation.

### Fluocinolone Acetonide Implant (Retisert / Yutiq)

Long-acting intravitreal implant (Retisert: 30 months; Yutiq: 36 months) High rates of cataract surgery and glaucoma intervention with Retisert. Yutiq has a lower steroid burden and reduced (but still present) IOP risk.

![Intravitreal sustained-release corticosteroid implant positioning](images/intravitreal-implant-uveitis.jpg)

## Monitoring and Follow-Up

Baseline labs before starting any IMT: CBC, CMP, hepatitis B/C serologies, TB screening, chest X-ray. Ongoing monitoring schedule varies by agent (see individual drug sections) Ophthalmic follow-up every 4-8 weeks during active treatment; assess for inflammation, macular edema, IOP. Attempt slow corticosteroid taper once IMT reaches therapeutic effect. Duration of therapy: minimum 2 years of quiescence before considering taper of IMT.

## Key Clinical Pearls

The goal of IMT is complete inflammatory quiescence on prednisone less than or equal to 7.5 mg/day (or off steroids entirely). Adalimumab is the only FDA-approved biologic for non-infectious uveitis and should be considered early in the treatment algorithm for sight-threatening disease. Always screen for latent tuberculosis and hepatitis B before starting anti-TNF therapy. Coordination with a rheumatologist or internist experienced in IMT enhances patient safety and compliance.

## References

1. Jabs DA, Rosenbaum JT, Foster CS, et al. Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders. *Am J Ophthalmol*. 2000;130(4):492-513.
2. Jaffe GJ, Dick AD, Brezin AP, et al. Adalimumab in patients with active noninfectious uveitis. *N Engl J Med*. 2016;375(10):932-943.
3. Nguyen QD, Merrill PT, Jaffe GJ, et al. Adalimumab for prevention of uveitic flare (VISUAL II). *Lancet*. 2016;388(10050):1183-1192.
4. Dick AD, Rosenbaum JT, Al-Dhibi HA, et al. Guidance on noncorticosteroid systemic immunomodulatory therapy in noninfectious uveitis. *Ophthalmology*. 2018;125(5):757-773.