Management of Uveitis in ANCA-Associated Vasculitis
Uveitis in ANCA-associated vasculitis should be treated as organ-threatening disease requiring immediate systemic immunosuppression with high-dose glucocorticoids (prednisolone 1 mg/kg/day, maximum 60 mg/day) combined with either cyclophosphamide or rituximab, not topical therapy alone. 1
Disease Classification and Treatment Urgency
Ocular involvement in AAV represents organ-threatening disease that places patients in the "generalized" or "severe" disease category, requiring aggressive systemic immunosuppression rather than localized treatment approaches. 2
Uveitis threatening vision is classified as a major relapse requiring intensification of immunosuppressive therapy, similar to other life- or organ-threatening manifestations like diffuse alveolar hemorrhage or rapidly progressive glomerulonephritis. 2
Do not delay treatment while awaiting additional diagnostic workup if clinical presentation is compatible with AAV and ANCA serology is positive—immediate immunosuppression is critical to prevent permanent vision loss. 2
Initial Immunosuppressive Regimen
Glucocorticoid Therapy
Initiate prednisolone 1 mg/kg/day (maximum 60 mg/day) immediately upon diagnosis of uveitis in the setting of AAV. 1
Maintain high-dose glucocorticoids for at least 1 month before initiating any taper. 1
Do not reduce below 15 mg/day during the first 3 months of treatment. 1
Taper to maintenance dose of 5-7.5 mg/day by 6 months, continuing this dose for at least 18-24 months. 1
For rapidly progressive or bilateral vision-threatening uveitis, consider IV methylprednisolone 500-1000 mg/day for 3-5 days before transitioning to oral therapy. 1
Never use alternate-day glucocorticoid regimens—this significantly increases relapse risk and is contraindicated in AAV. 1
Choice of Systemic Immunosuppressive Agent
The selection between rituximab and cyclophosphamide depends on specific patient factors:
| Clinical Scenario | Preferred Agent | Rationale |
|---|---|---|
| Relapsing disease or prior AAV flares | Rituximab 375 mg/m² IV weekly × 4 weeks | Higher remission rates (67% vs 42%) in relapsing disease; reduces major relapse rate to ~5% vs ~29% with azathioprine maintenance [1] |
| Younger patients with fertility concerns | Rituximab | Avoids cyclophosphamide-related gonadotoxicity [1] |
| Severe bilateral vision-threatening uveitis | Cyclophosphamide 2 mg/kg/day oral (max 200 mg/day) | Proven efficacy in severe organ-threatening disease [1] |
| Concomitant severe renal involvement (Cr >3.4 mg/dL) | Cyclophosphamide | Superior outcomes in severe renal disease [1] |
| Most severe presentations (bilateral panuveitis with retinal vasculitis) | Combination rituximab + cyclophosphamide | Synergistic effect for organ-saving therapy [1] |
Alternative for Non-Organ-Threatening Uveitis
Methotrexate 20-25 mg/week can be considered for isolated anterior uveitis without posterior segment involvement or vision-threatening features, but only if GFR >60 mL/min/1.73 m². 2, 1
Methotrexate is contraindicated in patients with renal impairment (GFR <60 mL/min/1.73 m²). 1
Mandatory Supportive Care
Infection Prophylaxis
Trimethoprim-sulfamethoxazole 800/160 mg on alternate days (or 400/80 mg daily) for Pneumocystis jiroveci prophylaxis in all patients receiving cyclophosphamide. 1
If sulfa-allergic, use pentamidine as alternative prophylaxis. 1
Bone Protection
- Calcium, vitamin D, and bisphosphonate therapy for all patients on glucocorticoids to prevent glucocorticoid-induced osteoporosis. 1
Cyclophosphamide-Specific Measures
Mesna (oral or IV) to bind acrolein and prevent hemorrhagic cystitis. 1
Dose adjustments for age: Reduce cyclophosphamide to 1.5 mg/kg/day if age >60 years; 1.0 mg/kg/day if age >70 years. 1
Dose adjustments for renal impairment: Reduce by 0.5 mg/kg/day (oral) or 2.5 mg/kg (IV) when GFR <30 mL/min/1.73 m². 1
Maintenance Therapy After Remission
- After achieving remission (typically 3-6 months), transition to maintenance therapy with low-dose glucocorticoids plus one of the following agents. 1
First-Line Maintenance Options
Rituximab 500 mg IV every 6 months (MAINRITSAN protocol) or 1000 mg IV every 4 months (RITAZAREM protocol)—preferred for patients with relapsing disease or those initially treated with rituximab. 1
Azathioprine 1.5-2 mg/kg/day for 18-24 months, then taper to 1 mg/kg/day until 4 years after diagnosis—first-line choice with strongest evidence for patients initially treated with cyclophosphamide. 1
Alternative Maintenance Agents
Mycophenolate mofetil 2000 mg/day (divided doses) if azathioprine intolerant. 1
Methotrexate 20-25 mg/week only if GFR >60 mL/min/1.73 m². 1
Duration of Maintenance
Minimum 18-24 months of maintenance therapy; extending to 4 years further reduces relapse risk. 1
Factors favoring extended therapy include: PR3-ANCA positivity, prior relapses, persistent or rising ANCA titers, and posterior segment involvement. 1
Monitoring Requirements
During Induction Phase
CBC weekly for the first month on cyclophosphamide, then every 2 weeks; adjust or discontinue if leukopenia develops. 1
Structured ophthalmologic examination at every visit to assess disease activity, including visual acuity, intraocular pressure, slit-lamp examination, and dilated fundoscopy. 2
Urinalysis and basic laboratory tests (comprehensive metabolic panel, ESR, CRP) at every clinical visit to monitor for systemic disease activity. 1
Long-Term Surveillance
Investigate any persistent unexplained hematuria in patients previously exposed to cyclophosphamide due to bladder cancer risk—this risk is higher in tobacco smokers who develop bladder cancer at lower cumulative doses. 1
ANCA titers: Persistence, increase, or change from negative to positive may predict future relapse and should inform treatment decisions. 2
Critical Pitfalls to Avoid
Never rely on topical therapy alone for uveitis in AAV—this represents systemic vasculitis requiring systemic immunosuppression. 3
Never use methotrexate when GFR <60 mL/min/1.73 m²—this significantly increases toxicity risk. 1
Never omit Pneumocystis prophylaxis in patients receiving cyclophosphamide—this is a potentially fatal complication. 1
Never use alternate-day glucocorticoid regimens—this increases relapse risk. 1
Do not mistake atypical P-ANCA positivity for typical ANCA-associated vasculitis—atypical P-ANCA in isolated ocular inflammation without systemic features typically has a favorable prognosis with topical/local therapy and does not require aggressive systemic immunosuppression. 4
Maintain high vigilance for opportunistic infections in immunosuppressed patients presenting with new ocular symptoms—disseminated nocardiosis can mimic vasculitis exacerbation and requires antimicrobial rather than increased immunosuppression. 5
Multidisciplinary Management
Patients with AAV should be treated at centers with experience in AAV management, equipped with adequate facilities for rapid diagnosis, access to rituximab and plasma exchange, and intensive care/dialysis capabilities. 2
Coordinate care with ophthalmology for ongoing assessment of ocular disease activity and complications. 2
Holistic approach: Assess for permanent damage to other organs (kidneys, lungs, nervous system) and provide necessary therapies or support, as AAV is a systemic disease with potential for multiorgan involvement. 2