¹Charité Universitätsmedizin Berlin, Medizinische Klinik mit Schwerpunkt Rheumatologie und Klinische Immunologie, Berlin
²Deutsches Rheuma-Forschungszentrum, Berlin
³Uniklinikum Erlangen, Erlangen
⁴Deutsches Zentrum für Immuntherapie (DZI), Erlangen

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Introduction: Rheumatoid arthritis (RA) treatment concepts focus primarily on suppressing inflammatory processes, but fail to achieve a reset of autoimmunity and a stable state of drug-free remission. We hypothesize that the synergistic effect of abatacept [ABC] and daratumumab [DARA] may eliminate autoreactive antibody-producing cells while simultaneously disrupting the immunological synapse between autoreactive T cells and repopulating autoreactive B cells [1], [2], [3].

Methods: We designed the CURACTA trial, a two-stage, interventional, prospective, multicentre, randomized, controlled, open-label, parallel-group Phase I/II trial. A total of 23 patients with active RA (DAS28-ESR > 3.2), anti-cyclic citrullinated peptide (CCP2) positivity, and inadequate response to DMARDs will be enrolled. In phase I the safety of the combination therapy (ABC s.c. weekly + methotrexate [MTX] + DARA s.c. (week 4, 5, 6, 7) will be assessed in three subjects. In Phase II, 20 patients will be randomized 1:1 into the combination therapy and a control arm (ABC + MTX).

The primary endpoint across both phases is safety, while in Phase II, the co-primary endpoint is the percentage of patients achieving anti-CCP2 antibody seroconversion at week 24. In addition, serological (e.g. glycosylation profiles of total IgG and CCP2 antibodies) and clinical endpoints will be evaluated.

The trial is funded by the Deutsche Gesellschaft für Rheumatologie und Klinische Immunologie (Forschungsinitiative 2025), emphasizing its importance in rheumatology and clinical immunology.

Results: The study protocol of the CURACTA trial received full approval from the respective ethics committees and the Paul-Ehrlich Institute, ensuring regulatory compliance. Preparation for the Phase I/II trial was successfully completed, and the study has been initiated. Initial screening visits were conducted, and Phase I recruitment has been concluded with n=3 patients. The first baseline visit and initial dosing have occurred. Once all safety data have been collected and assessed in a DSMB, Phase II can be initiated.

Conclusion: We designed and successfully initiated a phase I/II trial to test the safety and effectiveness on seroconversion of ABC/DARA combination therapy in active RA. Phase I recruitment has been completed and recruitment for Phase II is now planned. Supported by key funding, this trial represents a significant step toward innovative therapies in rheumatology.

Literatur

[1] Scarsi M, Paolini L, Ricotta D, Pedrini A, Piantoni S, Caimi L, Tincani A, Airò P. Abatacept reduces levels of switched memory B cells, autoantibodies, and immunoglobulins in patients with rheumatoid arthritis. J Rheumatol. 2014 Apr;41(4):666-72. DOI: 10.3899/jrheum.130905
[2] Cambridge G, Leandro MJ, Edwards JC, Ehrenstein MR, Salden M, Bodman-Smith M, Webster AD. Serologic changes following B lymphocyte depletion therapy for rheumatoid arthritis. Arthritis Rheum. 2003 Aug;48(8):2146-54. DOI: 10.1002/art.11181
[3] Yalcin Mutlu M, Wacker J, Tascilar K, Taubmann J, Manger B, Krönke G, Schett G, Simon D. Effective and safe treatment of anti-CD38 therapy in systemic lupus erythematosus-associated refractory cerebral vasculitis induces immune tolerance. Rheumatology (Oxford). 2023 Feb 1;62(2):e21-e23. DOI: 10.1093/rheumatology/keac393