Background Immunogenicity, a formation of anti-drug antibodies (ADA) against a biologic agent, has also been reported in patients with rheumatoid arthritis (RA) receiving anti-TNF antibody (Ab) treatment. In case of infliximab (IFX), immunogenicity is strongly linked to subtherapeutic serum drug levels and a lack of clinical response . On the other hand, autoimmune phenomena, such as lupus-like syndrome or auto-Ab productions, are frequently observed in RA patients receiving TNF inhibitors, and some of these patients also show insufficient clinical response . However, the association between immunogenicity and autoimmunity has not been fully elucidated.
Objectives In RA patients treated with IFX, ADA-predicting factors such as patient background and auto Ab production are examined and a better management for ADA-mediated insufficient response is investigated.
Methods Fifty-seven Japanese RA patients (female 79%; 55.2 years old; disease duration 7.2 years) treated with IFX from 2004 to 2013 were retrospectively examined. Serum IFX trough levels and ADA against IFX were measured by ELISA and radioimmunoassay (RIA), respectively . Anti-nuclear antibodies (ANA) and anti-DNA Abs were measured by semi-quantitative indirect fluorescence assay and RIA, respectively. Both anti-single-stranded (ss) and double-stranded (ds) DNA Abs were measured by ELISA.
Results Twenty-one RA patients (36.8%) developed ADA after the IFX administration and their serum IFX trough levels were significantly lower compared to those in ADA-negative group (0.09±0.04 vs. 2.48±0.33 μg/mL, p <0.0001). There were no significant differences in age, sex, disease duration, RA stage, DAS28 score, and concomitant use of oral prednisolone (PSL) and MTX between the groups. Anti-DNA Abs (RIA) were more frequently recognized in ADA-positive group at the last observation (57% vs 22%, p =0.011). In addition, ADA-positive group showed significantly higher serum levels of anti-DNA (1.53±0.43 to 26.5±19.7 IU/mL, p =0.003) and anti-ssDNA Ab (13.6±1.09 to 34.8±12.2 AU/mL, p =0.038) along with the development of ADA. There also was a positive correlation of serum ADA levels with ANA (r =0.273, p =0.0002), anti-DNA (r =0.229, p =0.0014) or anti-ssDNA Ab (r =0.155, p =0.0258) levels. Although ADA-positive patients had a higher cumulative IFX withdrawal rate (p =0.047), preceding intravenous (IV)-PSL administration was significantly associated with higher sustained IFX treatment rate in the group (p =0.0008).
Conclusions The development of ADA against IFX is linked to lupus-like autoimmunity and subsequent insufficient clinical response against IFX. Therefore, it may be useful to monitor serum ANA and anti-DNA Abs as predicting factors of ADA in RA patients treated with IFX. In addition, IV-PSL might be effective to restore the ADA-mediated insufficient response.
van Schouwenburg PA, et al. Nat Rev Rheumatol. 2013 Mar; 9:164-172.
Yukawa N, et al. Arthritis Res Ther. 2011; 13:R213.
Acknowledgements The authors thank Dr. D. van der Kleij and Dr. G. J. Wolbink for the measurements of serum levels of IFX and anti-IFX Abs.
Disclosure of Interest None declared