OP0104 RHEUMATOID FACTOR, ANTI-CITRULLINATED PEPTIDE ANTIBODIES, AND SHARED EPITOPE AS PREDICTORS OF CLINICAL RESPONSE TO TREATMENT IN PATIENTS WITH EARLY RHEUMATOID ARTHRITIS: A STUDY BASED ON A RANDOMIZED CONTROLLED TRIAL (NORD-STAR)
Authors: K. Lend, G. Wolbink, T. Rispens, L. Padyukov, G. Frazzei, J. Christiaans, J. Lampa, M. Lund Hetland, M. S. Heiberg, D. Nordström, M. Nurmohamed, A. Rudin, M. Østergaard, E. A. Haavardsholm, K. Hørslev-Petersen, T. Uhlig, B. Gudbjornsson, G. Grondal, J. W. R. Twisk, R. F. Van Vollenhoven
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Previous studies have suggested that rheumatoid factor (RF) and/or anti-citrullinated protein antibodies (ACPA) positivity selectively associates with better responses to abatacept treatment in early rheumatoid arthritis (RA). <h3>Objectives:</h3> To investigate whether RF, ACPA, and shared epitope (SE) alone or in combination predict treatment response to the initial treatment with abatacept as well as with certolizumab-pegol or tocilizumab versus active conventional treatment. <h3>Methods:</h3> This analysis included treatment-naïve early RA patients who were randomized (1:1:1:1) in the NORD-STAR trial to receive methotrexate in combination with active conventional treatment, certolizumab-pegol, abatacept or tocilizumab [1, 2]. ACPA positivity was defined as a concentration greater than 10 U/mL using the CCP2 EliA (Phadia), and RF positivity was defined as greater than 5 IU/mL using the IgM RF EliA (Phadia). Participants were genotyped for HLA-DRB1 alleles and classified as SE positive (≥1 SE allele) or SE-negative (no SE alleles). Clinical Disease Activity Index remission (CDAI ≤2.8) was analyzed longitudinally (4, 8, 12, 16, 24, 32, 40 and 48 weeks) with logistic generalized estimating equations (GEE) analysis. The treatment effect across subgroups, based on RF, ACPA and SE status individually and in combinations, were assessed with interaction terms, using active conventional treatment as the reference. Analyses were adjusted for sex, country, age, BMI, DAS28-CRP and smoking status at baseline. The treatment effects were analyzed after 24 and 48 weeks. Results are presented as adjusted average marginal differences in CDAI remission rates with 95% CIs. <h3>Results:</h3> A total of 812 patients underwent randomization, whereof 795 were in the primary analysis population [1, 2]. Of the 795 patients, serum samples were available for 770 patients and whole blood samples for 703 patients. Overall, 604/770 (78%) were RF positive, 633/770 (82%) were ACPA positive, 554/703 (79%) were shared epitope positive, and 431/695 (62%) were positive for all three biomarkers. At baseline, measures of disease activity were lower in seropositive (positive for either RF, ACPA or both) compared with seronegative patients. Patient characteristics stratified by treatment group are shown in Table 1. Table 2 shows the adjusted marginal differences in CDAI remission rates. With active conventional treatment as the reference, RF and/or ACPA positivity at baseline predicted a better response to abatacept at 24 weeks but not at 48 weeks. Combining RF/ACPA with SE did not yield better prediction (p <sub>interaction</sub> =0.86; p <sub>interaction</sub> =0.75, respectively). Efficacy in triple-positive patients was similar at 24 weeks and at 48 weeks in the certolizumab-pegol treatment group (p <sub>interaction</sub> =0.27; p <sub>interaction</sub> =0.27, respectively), while significantly poorer efficacy was observed at 24 weeks, but not at 48 weeks in the tocilizumab treatment group (p <sub>interaction</sub> =0.03; p <sub>interaction</sub> =0.31, respectively). Thus, at 48 weeks we found no evidence of heterogeneity of treatment effect based on RF, ACPA, and SE status individually or in combination in any of the biologic treatment groups compared with active conventional treatment. <h3>Conclusion:</h3> Based on this large randomized controlled trial, we confirm that rheumatoid factor and/or ACPA positivity are associated with a better response to abatacept at 24 weeks. However, there was no association with response at 48 weeks, and the addition of SE did not improve prediction of response. Moreover, ACPA, RF and shared epitope did not, alone or in combination, predict clinical responses of importance in any of the treatment groups. <h3>REFERENCES:</h3> [1] Hetland ML et al, BMJ 2020;371:m4328. [2] Østergaard M et al, Annals of the Rheumatic Diseases 2023;82:1286-1295. <h3>Acknowledgements:</h3> We express our gratitude to the patients, study nurses, investigators, joint assessors, data management, and study teams who were involved in the NORD-STAR trial. <h3>Disclosure of Interests:</h3> Kristina Lend: None declared, Gertjan Wolbink: None declared, Theo Rispens Novartis, Genmab, Leonid Padyukov: None declared, Giulia Frazzei: None declared, Jeroen Christiaans: None declared, Jon Lampa: None declared, Merete Lund Hetland Medac, Novartis, Pfizer, Sandoz, AbbVie, BMS, Eli Lilly, MSD, Pfizer, Sandoz, Novartis, Marte S Heiberg: None declared, Dan Nordström Pfizer, Novartis, BMS, Lilly, MSD, Novartis, Pfizer, UCB, MSD, Michael Nurmohamed: None declared, Anna Rudin: None declared, Mikkel Østergaard AbbVie, BMS, Boehringer Ingelheim, Celgene, Eli Lilly, Galapagos, Gilead, Hospira, Janssen, MEDAC, Merck, Novartis, Novo Nordisk, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi, and UCB, AbbVie, BMS, Boehringer Ingelheim, Celgene, Eli Lilly, Galapagos, Gilead, Hospira, Janssen, MEDAC, Merck, Novartis, Novo Nordisk, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi, and UCB, AbbVie, Amgen Inc., BMS, Merck, Celgene, and Novartis, Espen A Haavardsholm Abbvie, Pfizer, Eli Lilly, UCB Pharma, Novartis, Kim Hørslev-Petersen: None declared, Till Uhlig Galapagos, Pfizer, UCB, Lilly, Bjorn Gudbjornsson Novartis and Nordic-Pharma, Novartis, Gerdur Grondal: None declared, Jos W.R. Twisk: None declared, Ronald F. van Vollenhoven AbbVie, AstraZeneca, Biogen, BMS, Galapagos, GSK, Janssen, Pfizer, RemeGen, UCB, AbbVie, AstraZeneca, Biogen, BMS, Galapagos, GSK, Janssen, Pfizer, RemeGen, UCB, AstraZeneca, BMS, Galapagos, MSD, Novartis, Pfizer, Roche, Sanofi, UCB.