Rituximab Treated Non Responder Rheumatoid Arthritis Patients are Generating a New Autoantibody Repertoire
Zoltan Konthur1, Melvin Wiemkes2, Thomas Häupl2, Gerd R. Burmester2, Karl Skriner 2,*
1Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, 2Department of Rheumatology and Clinical Immunology, Humboldt University and Free University, Berlin, Germany
Background: Rituximab (RTX) has shown clinical efficacy in cancer and autoimmune diseases but up to 40 % of RTX treated rheumatoid arthritis (RA) patients are poor responders (ref:1) and the commonly used RA biomarkers (RF/ACPA) are poor predictors for therapy response.
Objectives: Analysis of the autoantibody repertoire from RA patients under RTX treatment on human genome protein macroarrays (engine-gmbh) and it´s correlation to clinical DAS28 response.
Methods: Screening of RA sera was conducted on 37.830 unique human expression clones with sera taken before and 24 weeks after treatment. The autoantibody response of different immunoglobulin classes IgD, IgA, and IgG was recorded and bioinformatically evaluated. Response was determined according to DAS28 criteria
Results: In the cohort of 26 patients 1292 different autoantigens (IgD,IgA,IgG) were detected. Using protein array we investigated clusters of autoantigen responses that disappeared or developed during RTX treatment of RA patients. Post treatment developing responses against new autoantigens can be correlated to mRNA tissue expression data.. RA autoantigenic patterns before and 6 month after RTX treatment were patient-specific and no relevant autoantigenic cluster was found that was shared between patients or associated with response. However, RTX reduced the repertoire of autoantibodies after 24 weeks of treatment in the tested RA patient cohort on average by 60%. RA patients which do not respond are generating on average 63% new autoantibodies. In good responders to RTX only 5,5% (+/-3%) new autoantibodies can be detected. The IgA and IgG autoantibody repertoire in the serum after 24 weeks of RTX treatment is reduced (IgA: 41%, IgG :31%) in good responders whereas it is increased (IgA: 1,3%, IgG: 24%) in non responders to RTX.
Conclusions:,Non responders to RTX change their autoantibody repertoire directed against new but patient specific antigens. The fast rebuilding of antibody producing functional B cells is a mechanistic difference between responders and non-responders to rituximab.