Incomplete response of inflammatory arthritis to TNFα blockade is associated with the Th17 pathway

Objectives To establish if changes in Th1/Th17 cell populations previously reported in experimental arthritis occur in patients with rheumatoid arthritis (RA) treated with anti-tumour necrosis factor a (TNF alpha) agents, and whether the therapeutic response to anti-TNF alpha is compromised in patients and mice because of elevated Th17/IL-17 levels. Finally, to assess the efficacy of combined blockade of anti-TNF alpha and anti-IL-17 in experimental arthritis. Methods A longitudinal study of two independent cohorts (cohort 1, n = 24; cohort 2, n = 19) of patients with RA treated with anti-TNF alpha biological agents was carried out to assess their Th17/IL-17 levels before and after the start of anti-TNFa therapy. IL-12/23p40 production was assessed in plasma Peripheral blood lymphocytes (PBLs) and monocytes. Mice with collagen-induced arthritis (CIA) were treated with anti-TNF alpha alone, anti-IL17 alone or a combination of the two. Efficacy of treatment and response was assessed from changes in Disease Activity Score 28-erythrocyte sedimentation rate scores in patients, and in clinical scores and histological analysis in CIA. Results Significant increases in circulating Th17 cells were observed in patients after anti-TNF alpha therapy and this was accompanied by increased production of IL-12/23p40. There was an inverse relationship between baseline Th17 levels and the subsequent response of patients with RA to anti-TNFa therapy. In addition, PBLs from non-responder patients showed evidence of increased IL-17 production. Similarly, in anti-TNF alpha-treated mice, there was a strong correlation between IL-17 production and clinical score. Finally combined blockade of TNFa and IL-17 in CIA was more effective than monotherapy, particularly with respect to the duration of the therapeutic effect. Conclusions These findings, which need to be confirmed in a larger cohort, suggest that a Th17-targeted therapeutic approach may be useful for anti-TNF alpha non-responder patients or as an adjunct to anti-TNF alpha therapy, provided that safety concerns can be addressed.