ANTI INFLIXIMAB ANTIBODIES DETECTED BY A DRUG TOLERANT ASSAY ARE FREQUENT BUT, IN MANY CASES, WITHOUT RELEVANT CLINICAL SIGNIFICANCE

Background: Infliximab (Ifx) has proven effective in treating rheumatoid arthritis (RA) and spondyloarthropathies (SpA), although around 40% of cases fails, mainly due to immunogenicity. Formation of immunocomplexes between antibodies to Ifx (ATI) and Ifx can increase drug clearance, leading to treatment failure. Standard ELISA assays which are drug -sensitive are frequently used, being able to detect only free ATI. Interest in drug-tolerant assays to measure total ATI (free and complexed) is increasing. Objectives: To compare the development of ATI using both drug-tolerant and drug-sensitive assays at early stages of Ifx therapy. To analyse the relationship of ATI detected by both assays with the drop-out of treatment. Methods: This is a prospective observational study including 45 patients with RA and 61 with axial-SpA treated with standard doses of Ifx (3mg/kg and 5mg/kg, respectively) enrolled at Biological Therapy Unit of Hospital La Paz. Serum samples were obtained at 2, 6, 12 and 22 weeks (W) after Ifx initiation. The data about discontinuation for inefficacy was obtained from the database. ATI presence was evaluated by a drug-sensitive in-house two-site (bridging) ELISA (bELISA) and a drug-tolerant commercial ELISA assay (Immundiagnostik®,IDK). All comparisons were performed throughout non-parametrical test. In SpA group, due to the low number of ATI+ patients at W12 by bELISA the statistical analysis to compare both assays were not performed. Results: ATI detection by both assays at early stages (≤22 W) of treatment is shown in Table 1a . ATI were always detected earlier by IDK than bELISA and also in RA than in SpA patients probably reflecting the effect of lower Ifx doses. Three out of 106 (3%) vs 0 (0%) patients had ATI at W 2 and 62 (58%) vs 20 (18%) patients at W22, by IDK and bELISA, respectively. Table 1. Patient characteristics of all included patients W2 W6 W12 W22 AR SpA AR SpA AR SpA AR SpA a) ATI+ patients (n, %) at early stages bELISA 0 0 3(7%) 0 10(22%) 1(2%) 13(29%) 7(12%) IDK 1(2%) 2(3%) 7(16%) 2(3%) 16(36%) 16(26%) 28(62%) 34(56%) b) Patients who discontinued (n, %) Ifx therapy considering ATI status at early stages bELISA+ 9(90%)* 1(100%)* 12(92%) 4(57%) bELISA - 23(66%) 22(37%) 20(63%) 19(35%) IDK+ 15(94%)* 7(44%) 24(86%) 13(38%) IDK - 17(59%) 11(24%) 13(77%) 10(27%) *p<0.05 comparing between ATI+ vs ATI- in each assay. Once ATIs appeared, regardless both methods, they persisted throughout the follow-up, indicating that immunogenicity was not transient. At W22, only 13/28 (46%) and 7/34 (21%) patients with ATI detected by IDK were also positive by bELISA in RA and SpA, respectively. ATI levels by IDK were higher in ATI+ by bELISA than in ATI- patients at early stages: ATI levels by IDK at W12: 91[74-348] ng/ml ATI+ vs 21.7[15-59.5] ng/ml ATI- (p<0.01) and at W22: 132 [89-372] ng/ml ATI+ vs 23[13-66] ng/ml ATI- (p<0.001). However, only in 4% (2/45) patients with RA and in 13% (8/61) patients with SpA the detection by IDK was earlier than by bELISA at W12. Free IFX in serum was not detected in bELISA ATI+ patients. In IDK ATI+ patients low circulating Ifx levels were present as compare to ATI- since W6 to the end of follow-up (p<0.01). More ATI+ patients dropped out Ifx at W12 and W22 regardless de assay ( Table 1 .b), being statistically significant for both assays in patients with RA and only for bELISA in patients with SpA. Conclusion: ATI measured by a drug-tolerant assay are always detected earlier than ATI detected by bELISA, indicating that immunogenicity, at least with Ifx, is usually an early event. High levels of ATI by IDK are associated with an earlier detection by bELISA in case of RA patients. ATI detected only by drug tolerant assays are associated with low levels of circulating Ifx but not with a complete drug neutralization and may do not have clinical relevance compared to ATI detected by bELISA. Many patients have low levels of ATI which can only be detected by drug tolerant assays after long-term of follow-up. The reasons why ATI levels rise rapidly in some patients while in others remain low are currently unknown but may be relevant if the clinical effect of immunogenicity is to be minimized. Acknowledgements: We are grateful to all the rheumatologists and nurses of the Daycare Department for Biologics and to the laboratory technicians of the Immunological Unit Disclosure of Interests: ANA MARTÍNEZ-FEITO: None declared, Borja Hernández-Breijo: None declared, Marta Novella-Navarro: None declared, Victoria Navarro-Compán Grant/research support from: AbbVie, Janssen, Lilly, Novartis, Pfizer, and UCB, Cristina Diego: None declared, Irene Monjo: None declared, Laura Nuño: None declared, Alejandro Villalva: None declared, Diana Peiteado: None declared, DORA PASCUAL-SALCEDO: None declared, Pilar Nozal: None declared, Alejandro Balsa Grant/research support from: Abbvie, Pfizer, Novartis, Roche.Amgen, Sandoz, Lilly, UCB. Personal fees and non- financial support from BMS. Grants, personal fees and non- financial support from Nordic., Chamaida Plasencia Grant/research support from: AbbVie, Lilly, Novartis, Pfizer,Sanofi, Biogen and UCB. Citation: Ann Rheum Dis, volume 80, supplement 1, year 2021, page 546Session: Rheumatoid arthritis - biological DMARDs (POSTERS only)