Evaluation of 200 mg of Rituximab Every 6 Months as Maintenance Treatment of Rituximab-treated Patients With Rheumatoid Arthritis

Rheumatoid arthritis (RA) is the most prevalent chronic inflammatory rheumatic disease in Europe, affecting 0.3%-0.5% of the population. Treatment follows a Treat-to-Target (T2T) approach, where patients are initially managed with conventional synthetic DMARDs (csDMARDs), such as methotrexate, and if necessary, escalated to biologic DMARDs (bDMARDs) like Rituximab, a monoclonal antibody that depletes CD20-positive B cells.

The current standard maintenance therapy for RA patients receiving Rituximab consists of 1g infusions every six months. However, concerns about long-term safety, immune suppression, and cost have led researchers to explore lower doses. Studies suggest that 200 mg of Rituximab may be sufficient to maintain disease control while potentially reducing the risks associated with B-cell depletion, such as hypogammaglobulinemia and serious infections.

Study Rationale and Objectives The RADAR trial aims to provide definitive evidence on the feasibility of reducing Rituximab doses without compromising efficacy. A previous randomized trial indicated that a 500 mg dose was non-inferior to 1g, but the 200 mg arm lacked sufficient statistical power. Subsequent long-term follow-up data suggest that 200 mg may also be effective, warranting further investigation.

The primary objective of this study is to demonstrate that the 200 mg Rituximab maintenance dose is non-inferior to 1g in terms of disease activity, measured by DAS28-CRP at 12 months.

Secondary objectives include:

* Comparing disease activity at 6 and 12 months * Evaluating treatment failure rates (need for additional Rituximab doses, switching to other bDMARDs, corticosteroid use) * Assessing flare occurrence and patient-reported outcomes (quality of life, disability index) * Investigating B and T lymphocyte subpopulations and immunoglobulin levels (IgG, IgA, IgM) * Analyzing vaccine responses and Human Anti-Chimeric Antibody (HACA) levels * Monitoring immunosuppression markers, such as Torque Teno Virus (TTV) viral load * Documenting adverse and serious adverse events Study Design

This is a multicenter, double-blinded, non-inferiority, randomized controlled trial (RCT). Patients will be randomized 1:1 to receive either:

1. 200 mg of Rituximab (experimental group) 2. 1g of Rituximab (control group) Participants will receive two infusions: one at baseline (Month 0) and one at 6 months, with follow-up visits at 4, 6, 10, and 12 months. The primary endpoint is the mean reduction in DAS28-CRP between baseline and 12 months.

Blinding Procedure:

* Infusions will be prepared in the central pharmacy to ensure identical appearance in both groups. * Neither patients nor clinicians will know the assigned dosage.

Inclusion criteria:

* Adults (≥18 years) with RA (EULAR/ACR 2010 criteria) * Low disease activity (DAS28-CRP \<3.2) on Rituximab * Prior treatment with Rituximab (at least one infusion in the past year) * Stable on csDMARDs (if applicable) * Corticosteroid dose ≤10 mg/day

Non-inclusion criteria:

* Autoimmune diseases other than RA * Severe infections, immunodeficiency, or uncontrolled disease * Active or untreated tuberculosis, hepatitis B/C * Pregnancy, breastfeeding, or planned pregnancy * Drug/alcohol addiction * Patients unable to give informed consent Study Assessments and Data Collection

The study will include clinical, biological, and immunological assessments:

* DAS28-CRP scores at baseline, 6, and 12 months * Immunological assays (B/T cell phenotyping, immunoglobulin levels, HACA) * Vaccine serologies (Diphtheria, Pneumococcus, Tetanus, Haemophilus, SARS-CoV-2) * Quality-of-life surveys (EQ-5D-5L, SF-36, RAPID-3) * Adverse event monitoring

Sample Size Calculation:

The trial requires 260 patients to achieve 92% power to detect non-inferiority, using a linear mixed model with a non-inferiority margin of -0.3 on DAS28-CRP.

Expected Impact

If 200 mg of Rituximab proves non-inferior to 1g, this study could redefine maintenance therapy guidelines, reducing:

* Drug exposure and immune suppression risks * Serious infections and adverse events * Healthcare costs, improving access in resource-limited settings By providing definitive clinical and immunological data, the RADAR trial has the potential to influence global RA management and enhance long-term treatment safety.

• Compare the disease activity measured by DAS28-CRP between the two arms [Time frame: at inclusion, 6 and 12 months]
• DAS28 categories [Time frame: at inclusion, 6 months and 12 months]
• Number of Rituximab infusions [Time frame: 12 Months]
• Number of patients switching or initiating a cDMARD or switching from Rituximab to another bDMARD [Time frame: 12 Months]
• Number of patients using oral corticosteroids at a dose greater than 10 mg/day [Time frame: 12 Months]
• Number of flares throughout study period [Time frame: 12 Months]
• FLARE questionnaire (FLARE ASSESSMENT IN RHEUMATOID ARTHRITIS) [Time frame: at 6 and 12 months]
• RAPID-3 score (ROUTINE ASSESSMENT OF PATIENT INDEX DATA 3) [Time frame: at inclusion, 6 and 12 months]
• RAID score (RHEUMATOID ARTHRITIS IMPACT OF DISEASE) [Time frame: at inclusion, 6 and 12 months]
• EQ5D-5L (EUROQOL GROUP) [Time frame: at inclusion, 6 and 12 months]
• SF-36 to compare the patient quality of life [Time frame: at inclusion, 6 and 12 months]
• B, T and NK cell phenotyping to compare cell subpopulations [Time frame: at inclusion, 6 and 12 months]