Sequential B Cell/T Cell Therapy to Re-induce Humoral Immune TOLErance in ACPA- Positive Rheumatoid Arthritis A Prospective, Randomized Controlled Open Label Single-centre Clinical Trial in Adult Subjects With Active ACPA-positive Rheumatoid Arthritis Failing Methotrexate

Based on fact that both a B cell-targeting therapy with Rituximab and a T cell-targeting therapy with Abatacept affect ACPA levels and can occasionally induce seroconversion and an immunological remission as well immune tolerance in ACPA-positive RA patients, we conclude that T/B cell-mediated autoimmunity can be in principle reversed in RA patients suffering from active disease. We hypothesize that we can increase the tolerance-inducing potency of Rituximab and Abatacept by combining these two approaches and delivering a sequential B cell/T cell therapy with Rituximab and Abatacept. Such a combined approach might increase the rate of seroconversions in RA patients and thus re-induce tolerance in a significant number of patients which would pave the way for a long-lasting "deep immunological" and drug-free remission.

In the proposed project, we thus plan to perform a sequential treatment with initial B cell depletion with Rituximab followed by blockade of the immunological synapse by Abatacept. Such an approach aims to deplete autoreactive B cells and plasmablasts, which constitute the major source for ACPA (3) and thus reboot part of the immune system, before blocking the immunological synapse in order to enable reconstitution of self-tolerance.

Based on their recently discovered pathogenic properties and to determine a potential immunological remission in the participating RA patients, we primarily plan to evaluate the effect of a sequential Rituximab/Abatacept treatment on changes in the levels of anti CCP2 antibodies between Baseline and Week 52 and will determine the rate of seroconversions.

Secondary, we plan to perform an additional quantitative and qualitative analysis of the ACPA response. Glycosylation of ACPA was shown to modulate their inflammatory activity and is thus considered to control the onset of arthritis in ACPA-positive individuals (9). We will therefore measure glycosylation (galactosylation, fucosylation and sialylation) of ACPA and total IgG. Moreover, we plan to determine changes in total IgG, IgA and IgM subclasses, numbers of total B cells and plasmablasts as well as of CCP2-specific B cells and plasmablasts in the peripheral blood of the participating patients. The clinical outcome will be measured at week 52 described by disease activity parameters and patient questionnaires.

The longitudinal setup of this proof of concept mode of action study is to evaluate the efficacy of a subsequent Abatacept therapy post B cell depletion in regard to ACPA seroconversion, ACPA titers and B cell phenotype changes.