Relationship Between T LYmphocytes Depletion and Clinical Response to RITUXimab in Rheumatoid Arthritis (LYRITUX) (LYRITUX)

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.

Study Overview

• Status: Completed
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Drug: Rituximab

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.

• Study Type: Interventional
• Enrollment (Actual): 70
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Brest, France, 29609
    • Rhumatologie, CHRU de BREST
  • La Roche Sur Yon, France, 85925
    • Rhumatologie, CHD LA ROCHE SUR YON
  • Le Mans, France, 72037
    • Rhumatologie, CHR du MANS
  • Nantes, France, 44093
    • Rhumatologie, CHRU de NANTES
  • Orleans, France, 45000
    • Rhumatologie / IPROS, CHR d'ORLEANS
  • Poitiers, France, 86021
    • Rhumatologie, CHRU de POITIERS
  • Rouen, France, 76031
    • Rhumatologie, CHRU de ROUEN
  • Tours, France, 37044
    • Rhumatologie, CHRU de TOURS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Rituximab; two intravenous infusions of 1000 mg with a two-week interval between them	Drug: Rituximab; For rheumatoid arthritis, MabThera is given as two intravenous infusions of 1000 mg with a two-week interval between them. Patients usually respond to treatment within 16 to 24 weeks of initial treatment. After 24 weeks, treatment can be repeated depending on the patient's response.; Other Names: MabThera

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
DAS28	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).	up week 48
T-lymphocyte count	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).	up to week 48

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
C reactive Protein (CRP)	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).	Baseline up to 48 weeks
Immunoglobulines G	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).	Baseline up to 48 weeks
Cytokine profile	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).	Baseline up to 48 weeks
Occurrence of infections	Number of participants with infectious adverse events	Baseline up to 48 weeks
Pharmacokinetics (Systemic Clearance and central volume of distribution)	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.	Baseline up to 48 weeks
FCGR3A 156 F/V gene polymorphism	FCGR3A 156 F/V gene genotyping. Measurements will be carried out at baseline.	Baseline
RNA	Gene expression will be analysed at baseline.	Baseline
Metabolomic profil	Urines will be analysed at baseline, week 4 and week 16	Baseline up to 16 weeks

Collaborators and Investigators

• Sponsor: University Hospital, Tours
• Investigators: Principal Investigator: Denis MULLEMAN, MD-PhD, CHRU de Tours

Publications and helpful links

General Publications

• Melet J, Mulleman D, Goupille P, Ribourtout B, Watier H, Thibault G. Rituximab-induced T cell depletion in patients with rheumatoid arthritis: association with clinical response. Arthritis Rheum. 2013 Nov;65(11):2783-90. doi: 10.1002/art.38107.

Study record dates

Study Major Dates

• Study Start (Actual): March 9, 2015
• Primary Completion (Actual): April 9, 2019
• Study Completion (Actual): December 18, 2019

Study Registration Dates

• First Submitted: November 4, 2014
• First Submitted That Met QC Criteria: November 25, 2014
• First Posted (Estimate): December 1, 2014

Study Record Updates

• Last Update Posted (Actual): May 6, 2021
• Last Update Submitted That Met QC Criteria: May 4, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: rheumatoid arthritis; rituximab; T lymphocytes
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Rituximab
• Other Study ID Numbers: PHRI13-JM/LYRITUX; 2014-000859-91 (EudraCT Number); 2014-R24 (Other Identifier: CPP); 140896A-32 (Other Identifier: ANSM)