title: Incomplete response of inflammatory arthritis to TNFα blockade is associated with the Th17 pathway.
abstract: OBJECTIVE
  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-TNFα 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 non-responder patients or as an adjunct to anti-TNFα therapy, provided that safety concerns can be addressed.
authors.affiliation: Correspondence to Saba Alzabin, University of Oxford, Kennedy Institute of Rheumatology, London W6 8LH, UK. s.alzabin@epistem.co.uk
authors.forename: Saba
authors.initials: S
authors.lastname: Alzabin
authors.forename: Sonya M
authors.initials: SM
authors.lastname: Abraham
authors.forename: Taher E
authors.initials: TE
authors.lastname: Taher
authors.forename: Andrew
authors.initials: A
authors.lastname: Palfreeman
authors.forename: Dobrina
authors.initials: D
authors.lastname: Hull
authors.forename: Kay
authors.initials: K
authors.lastname: McNamee
authors.forename: Ali
authors.initials: A
authors.lastname: Jawad
authors.forename: Ejaz
authors.initials: E
authors.lastname: Pathan
authors.forename: Anne
authors.initials: A
authors.lastname: Kinderlerer
authors.forename: Peter C
authors.initials: PC
authors.lastname: Taylor
authors.forename: Richard
authors.initials: R
authors.lastname: Williams
authors.forename: Rizgar
authors.initials: R
authors.lastname: Mageed
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology*; D004351:Drug Resistance / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D020381:Interleukin-17 / Q000276:immunology*; D008137:Longitudinal Studies; D008297:Male; D051379:Mice; D008875:Middle Aged; D060888:Real-Time Polymerase Chain Reaction; D058504:Th17 Cells / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
chemical_list: D018501:Antirheumatic Agents; D020381:Interleukin-17; D014409:Tumor Necrosis Factor-alpha