Relationship Between T LYmphocytes Depletion and Clinical Response to RITUXimab in Rheumatoid Arthritis (LYRITUX)
- Registration Number
- NCT02304354
- Lead Sponsor
- University Hospital, Tours
- Brief Summary
Rituximab, an anti CD-20 monoclonal antibody targeting B lymphocytes is prescribed in rheumatoid arthritis (RA) patients refractory to TNF alpha antagonists. According to previous studies, 25 to 50% of patients have an insufficient or absence of response to rituximab at week 24.
In a recent retrospective study, a CD4+ T-lymphocytes depletion was observed after a first course of rituximab in RA patients. The absolute CD4+ number at week 12 was 37% (±33) of the baseline value, leading to \< 200 cells/µL in 5% of patients. Interestingly the absence of CD4+ T-lymphocytes depletion was observed in clinical non-responders, suggesting the involvement of T-lymphocytes in the mechanism of action of rituximab. So far no prospective study have supported the usefulness of lymphocyte phenotyping, in particular T-lymphocytes, to monitor rituximab-treated RA patients.
- Detailed Description
Rituximab, an anti CD-20 monoclonal antibody targeting B lymphocytes is prescribed in rheumatoid arthritis (RA) patients refractory to TNF alpha antagonists. According to previous studies, (Edwards, Szczepanski et al. 2004; Cohen, Emery et al. 2006; Emery, Fleischmann et al. 2006) 25 to 50% of patients have an insufficient or absence of response to rituximab at week 24. In the pathogenesis of RA, B and T lymphocytes are tightly linked through the APC fonction and cytokines production of B lymphocytes. At present, a white blood cells count is recommended in routine every 3 months in patients receiving rituximab, since cases of neutropenia have been observed in approximately 8% of patients with lymphoma after treatment. In RA patients, B lymphocytes count before each rituximab course should be done to prevent opportunistic infections (Pham, Fautrel et al. 2008).
In a recent retrospective study, a CD4+ T-lymphocytes depletion was observed after a first course of rituximab in RA patients. The absolute CD4+ number at week 12 was 37% (±33) of the baseline value, leading to \< 200 cells/µL in 5% of patients. Interestingly the absence of CD4+ T-lymphocytes depletion was observed in clinical non-responders, suggesting the involvement of T-lymphocytes in the mechanism of action of rituximab (Mélet, Mulleman et al. 2013). Moreover, few case reports of RA patients developing opportunist infections in conjunction with CD4+ T-lymphocyte depletion have been published (Teichmann, Woenckhaus et al. 2008; Clifford, Ances et al. 2011). So far no prospective study have supported the usefulness of lymphocyte phenotyping, in particular T-lymphocytes, to monitor rituximab-treated RA patients.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 70
- RA according to the American College of Rheumatology (ACR) criteria
- Treatment with adalimumab in accordance to the SPC
- Disease modifying anti rheumatic drugs (DMARDs) stable 4 weeks before enrollment and during 16 weeks.
- Signed consent
- No anti TNF-alpha failure or contraindication
- Previous adalimumab treatment
- Contraindication to adalimumab, methylprednisolone or methotrexate (when used in combination with adalimumab)
- methotrexate-naive patient
- Any hematologic disease affecting the lymphocytes (in particular lymphomas)
- Any osteo-articular disease which could interfere with the interpretation of the influence of the rituximab on RA
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Rituximab Rituximab two intravenous infusions of 1000 mg with a two-week interval between them
- Primary Outcome Measures
Name Time Method T-lymphocyte count up to week 48 T-lymphocyte count will be measured at baseline, week 2, week 4, week 16 and at the end of the study (i.e. between week 24 and week 48).
DAS28 up week 48 Disease Activity Score on 28 joints (DAS28) is a composite score that comprise tender joints count, swollen joints count, patient's disease activity on visual analog scale and erythrocyte sedimentation rate. DAS28 will be measured at baseline, week 2, week 4, week 16 and at the end of the study (i.e. between week 24 and week 48).
- Secondary Outcome Measures
Name Time Method FCGR3A 156 F/V gene polymorphism Baseline FCGR3A 156 F/V gene genotyping. Measurements will be carried out at baseline.
Immunoglobulines G Baseline up to 48 weeks Immunoglobuline G concentrations will be measured at baseline, week 16 and at the end of the study (i.e. between week 24 and week 48).
Pharmacokinetics (Systemic Clearance and central volume of distribution) Baseline up to 48 weeks Rituximab concentrations will be measured at baseline, will be measured at baseline, week 2, week 4, week 16 and at the end of the study (i.e. between week 24 and week 48). Pharmacokinetics will be described using a two-compartment model.
Metabolomic profil Baseline up to 16 weeks Urines will be analysed at baseline, week 4 and week 16
C reactive Protein (CRP) Baseline up to 48 weeks CRP will be measured at baseline, week 2, week 4, week 16 and at the end of the study (i.e. between week 24 and week 48).
Cytokine profile Baseline up to 48 weeks the following cytokines (APRIL, BAFF, TNF, IL-1 alpha, IL-17 and IL-6) will be measured at baseline, week 2, week 4, week 16 and at the end of the study (i.e. between week 24 and week 48).
Occurrence of infections Baseline up to 48 weeks Number of participants with infectious adverse events
RNA Baseline Gene expression will be analysed at baseline.
Trial Locations
- Locations (8)
Rhumatologie, CHRU de BREST
🇫🇷Brest, France
Rhumatologie / IPROS, CHR d'ORLEANS
🇫🇷Orleans, France
Rhumatologie, CHR du MANS
🇫🇷Le Mans, France
Rhumatologie, CHD LA ROCHE SUR YON
🇫🇷La Roche Sur Yon, France
Rhumatologie, CHRU de NANTES
🇫🇷Nantes, France
Rhumatologie, CHRU de ROUEN
🇫🇷Rouen, France
Rhumatologie, CHRU de POITIERS
🇫🇷Poitiers, France
Rhumatologie, CHRU de TOURS
🇫🇷Tours, France