What alternative drug can be used instead of rituximab for peripheral ulcerative keratitis in a PR3‑ANCA‑positive patient?

Alternative Drug to Rituximab for PUK in PR3-ANCA Positive Patients

Cyclophosphamide combined with glucocorticoids is the primary alternative to rituximab for peripheral ulcerative keratitis in PR3-ANCA positive patients, particularly when rituximab is unavailable or contraindicated.

Primary Alternative: Cyclophosphamide

The most robust alternative is cyclophosphamide in combination with high-dose glucocorticoids 1, 2, 1. Current KDIGO 2024 guidelines explicitly recommend that glucocorticoids combined with either rituximab OR cyclophosphamide be used as initial treatment for ANCA-associated vasculitis (AAV), which encompasses the systemic disease causing PUK 2.

Cyclophosphamide Dosing Options:

• Oral: 2 mg/kg/day for 3 months (maximum 6 months if ongoing activity)

  • Reduce to 1.5 mg/kg/day if age >60 years
  • Reduce to 1.0 mg/kg/day if age >70 years
  • Reduce by 0.5 mg/kg/day if GFR <30 ml/min/1.73 m² 2

• Intravenous: 15 mg/kg at weeks 0,2,4,7,10,13 (with additional doses at weeks 16,19,21,24 if required)

  • Reduce to 12.5 mg/kg if age >60 years
  • Reduce to 10 mg/kg if age >70 years
  • Reduce by 2.5 mg/kg if GFR <30 ml/min/1.73 m² 2

Important Considerations for Cyclophosphamide:

While rituximab is preferred for PR3-ANCA positive patients (particularly those with relapsing disease), cyclophosphamide remains highly effective 1. The RAVE trial demonstrated rituximab superiority specifically in PR3-ANCA positive patients with relapsing disease, but cyclophosphamide achieved equivalent remission rates in newly diagnosed cases 1.

Critical caveat: Cyclophosphamide is actually preferred over rituximab in patients presenting with severe kidney failure (serum creatinine >4.0 mg/dL), as the RAVE trial excluded such patients 1. For PUK with severe systemic involvement, cyclophosphamide may be the better choice.

Secondary Alternatives for Less Severe Disease

Mycophenolate Mofetil (MMF)

MMF at 2000 mg/day (divided doses) can be considered for mild to moderate disease 2, 1. However, this comes with a significant warning: MMF resulted in higher relapse rates in PR3-ANCA patients compared to cyclophosphamide in the MYCYC trial 1. MMF is more appropriate for MPO-ANCA patients with non-severe disease where avoidance of both cyclophosphamide and rituximab is necessary 1.

For PR3-ANCA positive PUK, MMF should be considered a last-resort option only.

Methotrexate

Methotrexate (20-25 mg/week, oral or parenteral) is an option for non-organ threatening, non-life threatening disease 3. Start at 15 mg/week and escalate to 20-25 mg/week over 1-2 months 3.

Critical limitation: Methotrexate should NOT be used if GFR <60 ml/min/1.73 m² 2. Additionally, methotrexate was noninferior to cyclophosphamide for remission induction of nonsevere extrarenal disease but resulted in higher relapse rates 1.

Glucocorticoid Regimen (Essential with All Alternatives)

Regardless of which alternative you choose, high-dose glucocorticoids are mandatory 3, 2:

• Initial: Oral prednisolone/prednisone 50-75 mg/day (depending on body weight) OR 1 mg/kg/day (max 80 mg/day) 2, 4
• For rapid effect: Add intravenous methylprednisolone 1-3 g/day for 1-3 days 2, 5
• Tapering: Maintain high dose for 1 month, do not reduce below 15 mg/day for first 3 months, then taper to 5-7.5 mg/day by 4-5 months 3, 2, 4

Adjunctive Therapy: Avacopan

Avacopan (30 mg twice daily) is a newer option that can be used as an alternative to glucocorticoids in combination with rituximab or cyclophosphamide 2, 1. This C5a receptor inhibitor allows substantial reduction in glucocorticoid exposure, which may be particularly valuable given the toxicity concerns with long-term steroid use.

Clinical Decision Algorithm

For PR3-ANCA positive PUK:

1. First choice: Rituximab + glucocorticoids
2. If rituximab unavailable/contraindicated:
   • Severe disease or kidney involvement (Cr >4.0): Cyclophosphamide + glucocorticoids
   • Non-severe disease: Cyclophosphamide + glucocorticoids (still preferred over other alternatives)
3. If cyclophosphamide contraindicated (fertility concerns, prior cumulative dose >36g, patient refusal):
   • Consider avacopan + glucocorticoids if available
   • Methotrexate + glucocorticoids (only if GFR >60 and non-severe disease)
4. Avoid MMF in PR3-ANCA positive patients unless all other options exhausted

Essential Supportive Measures

With cyclophosphamide or any intensive immunosuppression 3, 4:

• Pneumocystis jirovecii prophylaxis: Trimethoprim-sulfamethoxazole 800/160 mg alternate days or 400/80 mg daily
• Mesna: With pulse cyclophosphamide to reduce bladder toxicity
• Osteoporosis prophylaxis: Per local guidelines for all patients on glucocorticoids
• Monitor: Complete blood count, liver function, urinalysis regularly

Case Report Evidence

Real-world evidence supports cyclophosphamide as effective for PUK in PR3-ANCA positive GPA patients 6. One case report documented successful treatment with cyclophosphamide followed by rituximab maintenance 6. Another case showed cyclophosphamide failure requiring switch to rituximab 7, reinforcing that rituximab remains the preferred agent when available, but cyclophosphamide is a legitimate first-line alternative.