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

Journal article

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 α (TNFα) agents, and whether the therapeutic response to anti-TNFα is compromised in patients and mice because of elevated Th17/IL-17 levels. Finally, to assess the efficacy of combined blockade of anti-TNFα 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-TNFα biological agents was carried out to assess their Th17/IL-17 levels before and after the start of anti-TNFá 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-TNFα 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-TNFα 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-TNFα therapy. In addition, PBLs from non-responder patients showed evidence of increased IL-17 production. Similarly, in anti-TNFα-treated mice, there was a strong correlation between IL-17 production and clinical score. Finally combined blockade of TNFα 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-TNFα nonresponder patients or as an adjunct to anti-TNFα therapy, provided that safety concerns can be addressed.

Authors: Alzabin, S; Abraham, S; Taher, T; Palfreeman, A; Hull, D

• Publication status: Published
• Journal: ANNALS OF THE RHEUMATIC DISEASES
• Volume: 71
• Issue: 10
• Pages: 1741-1748
• Publication date: 2012-10-01
• DOI: 10.1136/annrheumdis-2011-201024
• EISSN: 1468-2060
• ISSN: 0003-4967
• Language: English