Background: Double anti-CCP (anti-cyclic citrullinated peptides antibodies (Ab))/anti-CarP (anti-carbamylated protein Ab) positivity appears to be associated with a poorer prognosis in rheumatoid arthritis (RA). As the in situ antigenic targets of anti-CarP are still unknown, carbamylated fetal calf serum (FCS) has so far been used as a target for ELISA assays. In our previous work, we showed that the presence of IgG anti-carbamylated fibrinogen Ab (ACa-Fib) appeared to be associated with systemic inflammation at baseline, while the poor structural prognosis remained associated with ACPA in patients from the regional VeRA cohort [1]. Truchetet et al. showed more severe radiological damage in anti-CCP+/anti-CarP+(FCS) RA patients in the ESPOIR national cohort at a given time [2].

Objectives: Our aim was to confirm our results in the ESPOIR cohort and to determine the clinical significance of IgG and IgA ACa-Fib at different time points, compared with anti-CCP.

Methods: We developed ELISA assays for the detection of IgG and IgA ACa-Fib in patient sera from the ESPOIR cohort [3], and thus assessed their prognostic values at baseline, 6 months and 24 months. Prognosis was defined by persistent disease activity at 2 years, degree of structural damage at 2 years (Total Sharp score), rapid radiological progression (delta-total sharp score > 5 over the first 1-year follow up period).

Results: We show that 28% of RA patients in the ESPOIR cohort (n=575) are positive for IgG ACa-Fib and 8% for IgA ACa-Fib. The prevalence of IgG ACa-Fib positivity decreased after 2 years (11%) like rheumatoid factors but remained stable for IgA ACa-Fib (6%) as observed with anti-CCP. Among ACPA- patients, 17% are ACa-Fib+ for IgG and 6% for IgA, demonstrating that carbamylated fibrinogen (Ca-Fib) could be a major antigen of anti-carbamylated FCS response of IgG isotype whereas Ca-Fib probably belongs to a large panel of antigens recognized by those of IgA class. While IgG or IgA ACa-Fib positivity at baseline does not appear to have an impact on RA activity, we show that double IgG anti-CCP/ACa-Fib positivity is associated with a significantly more severe structural prognosis at 2 years compared with anti-CCP alone (p-value=0.01). We also highlight the prognostic value of IgG and IgA ACa-Fib, with a higher percentage of patients with rapid radiological progression when they have double anti-CCP/ACa-Fib positivity, compared with anti-CCP alone (42% for IgG anti-CCP+/ACa-Fib+ patients compared with 27% for ACPA+; 50% for IgA anti-CCP+/ACa-Fib+ patients compared with 31% for ACPA+ patients).

Conclusion: Fibrinogen is a major antigen of the anti-carbamylated response of IgG class in anti-CCP- patients. While ACa-Fib IgG/IgA have prognostic value in anti-CCP+ patients, constituting an additional factor of severity, both Ab seem to have a different clinical relevance since ACa-Fib of IgG isotype behave as RF and those of IgA class as ACPA-like.

REFERENCES: [1] Brevet P, Lattard C, Guillou C, Rottenberg P, Fardellone P, Le-Loët X, et al. Anti-Carbamylated Fibrinogen Antibodies Might Be Associated With a Specific Rheumatoid Phenotype and Include a Subset Recognizing In Vivo Epitopes of Its γ Chain One of Which Is Not Cross Reactive With Anti-Citrullinated Protein Antibodies. Front Immunol 2021;12:733511.

[2] Truchetet M-E, Dublanc S, Barnetche T, Vittecoq O, Mariette X, Richez C, et al. Association of the Presence of Anti-Carbamylated Protein Antibodies in Early Arthritis With a Poorer Clinical and Radiologic Outcome: Data From the French ESPOIR Cohort. Arthritis & Rheumatology (Hoboken, NJ) 2017;69:2292–302.

[3] Combe B, Rincheval N. Early lessons from the recent-onset rheumatoid arthritis cohort ESPOIR. Joint Bone Spine. 2015 Jan;82(1):13-7. doi: 10.1016.

Acknowledgements: Acknowledgement: An unrestricted grant from Merck Sharp and Dohme (MSD) was allocated for the first 5 years. Two additional grants from INSERM were obtained to support part of the biological database. The French Society of Rheumatology, Pfizer, Abbvie, Lilly, and more recently Fresenius and Biogen also supported the ESPOIR cohort study. We also wish to thank Nathalie Rincheval (Montpellier) who did expert monitoring and data management and all the investigators who recruited and followed the patients (F. Berenbaum, Paris-Saint Antoine, MC. Boissier, Paris-Bobigny, A. Cantagrel, Toulouse, B. Combe, Montpellier, M. Dougados, Paris-Cochin, P. Fardellone et P. Boumier Amiens, B. Fautrel, Paris-La Pitié, RM. Flipo, Lille, Ph. Goupille, Tours, F. Liote, Paris- Lariboisière, O. Vittecoq, Rouen, X. Mariette, Paris Bicetre, P. Dieude, Paris Bichat, A. Saraux, Brest, T. Schaeverbeke, Bordeaux, J. Sibilia, Strasbourg).

Disclosure of Interests: None declared.

© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.