Background Immunogenicity, a formation of anti-drug antibodies (ADA) against a biologic agent, has had an impact in patients with rheumatoid arthritis (RA) receiving anti-TNF antibody (Ab) treatment because it is strongly linked to sub-therapeutic serum drug levels and a lack of clinical response . We previously reported the association between immunogenicity and lupus-like autoimmune phenomena in RA patients treated with infliximab (IFX), which included increased levels of serum anti-nuclear Ab (ANA) or anti-DNA Ab and was also associated with insufficient clinical response (EULAR 2014 poster, FRI0288). The underlying mechanism of these phenomena, however, has never been fully elucidated.
Objectives We investigated if immunogenicity and lupus-like autoimmune phenomena were associated with kinetics of specific cytokines, which might explain the underling immunological mechanisms of these two phenomena.
Methods We measured serum levels of various cytokines including IL-6, IFN-γ, and IFN-α in the stock sera obtained from the same patients who were enrolled in the previous study. The patients were 57 Japanese RA patients treated with IFX between 2004 and 2013. We used multiplex assay kits to measure the cytokine levels in sera obtained before and after the initiation of IFX treatment. The sera used were same as those used for the detections of ADA, ANA, and anti-DNA Abs.
Results Twenty-one RA patients (36.8%) developed ADA after the IFX administration, and ANAs (57.1% and 33.3%, p=0.100) and anti-DNA Abs (57.1% and 22.2%, p=0.0107) were more frequently recognized in ADA-positive patients. There were no significant differences in any cytokine profiles between ADA-positive and -negative patients before the initiation of IFX treatment. However, ADA-positive patients (from 248±102 to 467±135 pg/mL, p=0.0353) developed higher IFN-α levels after the initiation of IFX treatment compared to ADA-negative patients (from 232±107 to 221±138 pg/mL, p=0.134). IL-6 was significantly decreased in ADA-negative patients after IFX treatment (from 211±149 to 10.4±3.6 pg/mL, p<0.0001), whereas it remained high levels in ADA-positive patients (from 58.3±14.3 to 63.5±12.5 pg/mL, p=0.595). The same trends were also observed in serum IFN-γ levels (from 27.0±10.5 to 14.8±3.9 pg/mL, p=0.778 in ADA-negative patients; from 28.8±9.7 to 34.5±10.8 pg/mL, p=0.658 in ADA-positive patients). The difference between ADA-positive and -negative patients in the latter two cytokine levels seemed to reflect inadequate responses for IFX treatment, but might indicate underlying aberrant cytokine milieu associated with both immunogenicity and lupus-like phenomena induced by IFX treatment.
Conclusions The present study suggests that both immunogenicity and lupus-like autoantibodies induced by IFX treatment in RA patients could be explained by aberrant cytokine milieu especially type I IFN. Further study to dissect the precise molecular mechanisms of these clinically important events can be expected.
van Schouwenburg PA., et al. Nat Rev Rheumatol. 2013; 9(3):164-172.
Acknowledgements The authors thank Desiree van der Kleij and Geritt Jan Wolbink for the measurements of serum levels of IFX and anti-IFX Abs.
Disclosure of Interest Y. Ishikawa: None declared, T. Fujii Grant/research support from: Pfizer Japan Inc., S. Kondo-Ishikawa: None declared, M. Hashimoto: None declared, M. Furu: None declared, H. Ito: None declared, Y. Imura: None declared, N. Yukawa: None declared, H. Yoshifuji: None declared, K. Ohmura Grant/research support from: Pfizer Japan Inc., T. Mimori: None declared