Circulating Th17 cells and joint inflammation during anti-tumour necrosis factor therapy in rheumatoid arthritis

Abstract

BackgroundAnti-tumour necrosis factor (TNF) agents have revolutionised the treatment of rheumatoid arthritis, although a substantial proportion of patients respond inadequately. Studies in murine and human arthritis have paradoxically shown that anti-TNF treatment can increase circulating interleukin-17-producing T helper (Th17) cells but the association of these changes with treatment responses remains unclear. To investigate immune correlates of anti-TNF treatment response in patients with rheumatoid arthritis we did a longitudinal study using serial clinical, ultrasonographic, and T-cell immunological assessments. Methods25 patients with rheumatoid arthritis naive to biological therapy were followed at four predetermined protocol visits during the first 12 weeks of anti-TNF-alpha treatment. 16 patients were treatment responders, as defined by improvement in disease activity score in 28 joints (DAS28) by more than 1·2 from baseline. Nine patients were non-responders (change in DAS28 score <1·2 from baseline). Changes in synovial thickening and vascularity of metacarpophalangeal joints were quantitatively assessed by power Doppler ultrasonography (PDUS). Changes in the frequency of circulating Th17 cells were evaluated by ELISPOT and intracellular cytokine staining of peripheral blood mononuclar cells. Statistical analysis included Wilcoxon signed rank matched pairs test and Spearman's rank correlation. Written informed consent was obtained from study participants, and ethics approval was obtained from the local ethics committee. This study is registered with ClinicalTrials.gov, number NCT01060098. FindingsELISPOT analysis showed a significant increase in circulating IL17-producing cells 12 weeks after anti-TNF initiation (baseline vs 12 weeks: mean 466 spSFC/106 [SD 277] vs 759 [510]; p=0·003). Fluorescence-activated cell sorting analysis confirmed significant increase in CD4+IL17+ cells at treatment week 12 (baseline vs 12 weeks: mean 0·78% [0·5] vs 1·1 [0·5]; p=0·01). The dynamics of changes in circulating Th17 cells during anti-TNF-alpha treatment were the same in treatment responders and non-responders and in patients treated with different types of anti-TNF alpha agents, suggesting a class effect. The increase in circulating Th17 cells during treatment correlated with reduction in synovial vascularity (r=−0·68, p=0·007) and synovial thickening (r=−0·39; p=0·04) as determined by PDUS. Higher numbers of circulating Th17 cells at baseline were associated with poorer response to anti-TNF-alpha treatment as defined by DAS28 score and ultrasonographic measures. InterpretationThis is the first study, to our knowledge, that links changes in circulating Th17 cells evaluated by cellular assays with resolution of ultrasonographic features of synovitis during anti-TNF treatment. The findings could mean that Th17 cells are redistributed from inflamed joints during treatment or that TNFα could have a role in the regulation of Th17 cell production. FundingThe Kennedy Trust for Rheumatology Research, Imperial College Healthcare Charity, UK Medical Research Council.