Clinical trial NCT02304354: Relationship Between T LYmphocytes Depletion and Clinical Response to RITUXimab in Rheumatoid Arthritis (LYRITUX)
Official title: Relationship Between T LYmphocytes Depletion and Clinical Response to RITUXimab in Rheumatoid Arthritis (LYRITUX)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Rheumatoid Arthritis
Keywords: rheumatoid arthritis
T lymphocytes
rituximab
Lead sponsor: University Hospital, Tours
Sponsor class: OTHER
First posted: 2014-12-01
Enrollment: 70
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: DAS28
timeFrame: up week 48
measure: T-lymphocyte count
timeFrame: up to week 48
Secondary outcomes:
measure: C reactive Protein (CRP)
timeFrame: Baseline up to 48 weeks
measure: Immunoglobulines G
timeFrame: Baseline up to 48 weeks
measure: Cytokine profile
timeFrame: Baseline up to 48 weeks
measure: Occurrence of infections
timeFrame: Baseline up to 48 weeks
measure: Pharmacokinetics (Systemic Clearance and central volume of distribution)
timeFrame: Baseline up to 48 weeks
measure: FCGR3A 156 F/V gene polymorphism
timeFrame: Baseline
measure: RNA
timeFrame: Baseline
measure: Metabolomic profil
timeFrame: Baseline up to 16 weeks
Other outcomes:
Locations:
city: Brest
country: France
facility: Rhumatologie, CHRU de BREST
city: La Roche Sur Yon
country: France
facility: Rhumatologie, CHD LA ROCHE SUR YON
city: Le Mans
country: France
facility: Rhumatologie, CHR du MANS
city: Nantes
country: France
facility: Rhumatologie, CHRU de NANTES
city: Orleans
country: France
facility: Rhumatologie / IPROS, CHR d'ORLEANS
city: Poitiers
country: France
facility: Rhumatologie, CHRU de POITIERS
city: Rouen
country: France
facility: Rhumatologie, CHRU de ROUEN
city: Tours
country: France
facility: Rhumatologie, CHRU de TOURS
Study officials:
affiliation: CHRU de TOURS
name: Denis MULLEMAN, MD-PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.