Link to Full Paper: https://pmc.ncbi.nlm.nih.gov/articles/PMC10313987/

BACKGROUND

• ANCA-associated vasculitis (AAV) has a 93% mortality rate within two years if left untreated.
• B-lymphocytes significantly contribute to the progression of AAV. Consequently, Rituximab is effective in inducing remission in AAV patients.
• Rituximab has been shown to be superior to cyclophosphamide in treating relapsing AAV.
• Despite treatment, 50% of patients experience a relapse within 5 years of diagnosis. Patients with a previous history of relapse are especially likely to relapse again, even after achieving remission with Rituximab

• The MAINRITSAN 1 trial found that fixed-interval rituximab is superior to azathioprine for maintaining remission in newly diagnosed AAV patients after initial treatment with cyclophosphamide and glucocorticoids.
• However, rituximab carries risks, including an increased risk of infections and development of hypogammaglobulinemia (low antibody levels).
• The best strategy to maintain remission after rituximab induction, especially for preventing relapses, remains unclear.
• The RITAZAREM trial is investigating whether fixed-interval rituximab is more effective than azathioprine for maintaining remission in relapsing AAV. Also, it was hypothesised that increased doses of rituximab would reduce the risk of relapse beyond the maintenance treatment period.

METHODS

1. Study Design
   1. RITAZAREM Trial has 3 phases:
      1. Induction phase (months 0-4): Rituximab (4 doses of 375 mg/m2/week) and oral prednisone/prednisolone (1.0 mg/kg/day or 0.5 mg/kg/day, tapering to ≤10 mg/day). IV methylprednisolone (≤3000 mg) allowed 2 weeks before or 1 week after enrollment
      2. Maintenance phase (4–24 months): Patients in remission (BVAS/WG ≤1, prednisone/prednisolone ≤10 mg/day) randomized to rituximab or azathioprine.
      3. Follow-up phase: Off-treatment period from month 24 to 36-48 months post-enrollment.
2. Patients
   1. Patients were over 15 years old with GPA or MPA diagnosis (Chapel Hill Consensus Conference 2012 definitions), and positive PR3-ANCA or MPO-ANCA test. All had disease relapse (one major or three minor BVAS/WG items) after previous remission. Patients with other multisystem autoimmune diseases were excluded.
   2. Recruitment occurred from April 2013 to November 2016 across 29 centres in seven countries, with the final patient visit in November 2019.
3. Maintenance phase interventions
   1. Rituximab
      1. Intravenous rituximab 1000 mg every 4 months for five doses. Withheld if plasma IgG <3 g/L, resumed when IgG >3 g/L.
   2. Azathioprine
      1. Oral azathioprine 2 mg/kg/day for 24 months, then tapered. Alternatives: methotrexate or mycophenolate mofetil based on eGFR.
   3. Glucocorticoids
      1. Prednisone/prednisolone tapered from 10 mg/day to withdrawal at month 20. Dose increased for relapses.
   4. Other treatments
      1. Preventive medications for pneumocystis infection and osteoporosis as per local practice.
4. Assessments
   1. Regular evaluations of clinical, laboratory, and patient-reported outcomes until month 48.
5. Outcomes
   1. Primary: time to disease relapse.
   2. Secondary: remission maintenance, damage accrual, glucocorticoid exposure, quality of life, and adverse events.
6. Compliance
   1. Defined for each treatment group based on adherence to prescribed regimens.