Protection from articular damage by passive or active anti‐tumour necrosis factor ( TNF)‐ α immunotherapy in human TNF‐ α transgenic mice depends on anti‐ TNF‐ α antibody levels

Summary Active anti‐tumour necrosis factor ( TNF)‐α immunization with the kinoid of TNF‐α ( TNF ‐ K ) induces polyclonal anti‐ TNF‐α antibodies and ameliorates arthritis in human TNF‐α ( hTNF‐α ) transgenic mice ( TTg ). We compared the efficacy of TNF ‐ K to that of infliximab (IFX) and of TNF ‐ K and IFX co‐administration, and evaluated whether the titres of anti‐hTNF‐α antibodies induced by immunization were a determinant of TNF ‐ K efficacy. Forty‐eight TTg mice received one of the following treatments: TNF ‐ K immunization ( TNF ‐ K group); weekly IFX throughout the study duration ( IFXw0 –15); TNF ‐ K plus weekly IFX for 4 weeks ( TNF ‐ K  +  IFX ); and weekly IFX for 4 weeks ( IFXw0 –4); PBS . Animals were killed at week 16. Anti‐ hTNF‐α antibody titres and clinical and histological scores were compared. All TNF ‐ K immunized mice ( TNF ‐ K and TNF ‐ K  +  IFX ) produced anti‐ hTNF‐α antibodies. Titres were higher in TNF ‐ K   versus   TNF ‐ K  +  IFX ( P  < 0·001) and correlated inversely with histological inflammation ( R  = −0·78; P  = 0·0001) and destruction ( R  = −0·67; P  = 0·001). TNF ‐ K  +  IFX had higher histological inflammation and destruction versus   TNF ‐ K ( P  < 0·05). A receiver operating characteristic ( ROC) analysis of anti‐ hTNF‐α antibody titres identified the criterion cut‐off value to discriminate most effectively between the TNF ‐ K and TNF ‐ K  +  IFX groups. Mice with high versus low titres had less histological inflammation and destruction ( P  < 0·05). In a model of TNF‐α ‐dependent arthritis, protection from articular damage by TNF ‐ K correlates with the titres of induced anti‐ hTNF‐α antibodies. The co‐administration of TNF ‐ K and a short course of infliximab does not result in less articular damage versus solely TNF ‐ K , due probably to lower anti‐ hTNF‐α antibody production. These results are relevant for future development of active anti‐ TNF‐α immunization in human disease.