Increase in circulating Th17 cells during anti-TNF therapy is associated with ultrasonographic improvement of synovitis in rheumatoid arthritis

Dobrina N Hull, Helen Cooksley, Shilpa Chokshi, Richard O Williams, Sonya Abraham, Peter C Taylor, Dobrina N Hull, Helen Cooksley, Shilpa Chokshi, Richard O Williams, Sonya Abraham, Peter C Taylor

Abstract

Background: Anti-TNF agents have revolutionised rheumatoid arthritis (RA) treatment; however, a third of patients fail to achieve therapeutic responses. Unexpectedly, studies in murine and human arthritis have indicated that anti-TNF treatment can increase circulating T helper 17 (Th17) cells, but the relationship to treatment response is unclear. To identify immune correlates of anti-TNF treatment response, we conducted a longitudinal study using clinical, ultrasound and T cell assessments.

Methods: Patients with RA (n = 25) were studied at protocol visits during the initial 12 weeks of anti-TNF treatment. Improvement in the disease activity score of 28 joints (DAS28) >1.2 defined treatment responders (n = 16) and non-responders (n = 9). Changes in synovial thickening and vascularity of 10 metacarpophalangeal joints were quantitatively assessed by grey scale and power Doppler ultrasound. The frequency of circulating Th17 cells was determined by IL17 enzyme-linked immunospot assay (Elispot) and flow cytometry (fluorescence-activated cell sorting (FACS)).

Results: The frequency of circulating IL17-producing cells increased significantly 12 weeks after anti-TNF initiation (Elispot median (range) specific spot forming cells (spSFC)/106 360 (280-645) vs 632 (367 - 1167), p = 0.003). The increase in CD4 + IL17+ cells at 12 weeks was confirmed by FACS (median (range) %, 0.7 (0.5-0.9) vs 1.05 (0.6-1.3); p = 0.01). The increase in circulating Th17 cells inversely correlated with reduction in synovial vascularity (r = -0.68, p = 0.007) and thickening (r = -0.39; p = 0.04). Higher frequencies of circulating Th17 cells at baseline were associated with poorer anti-TNF treatment response defined by ultrasonographic measures.

Conclusions: These results demonstrate a link between changes in circulating Th17 cells with resolution of ultrasonographic features of synovial inflammation and vascularity during anti-TNF treatment. The findings may reflect redistribution of Th17 cells from inflamed joints or TNF-driven regulation of Th17 cell production.

Trial registration: ClinicalTrials.gov: NCT01060098 . Registered 29 January 2010.

Keywords: Ankylosing spondylitis; Anti-TNF; Psoriatic arthritis; Rheumatoid arthritis; T cells.

Figures

Fig. 1
Fig. 1
Differences between anti-TNF responders and non-responders in improvement in synovial thickening and vascularity. Representative ultrasound images of changes in synovial thickening (a and b) and synovial vascularity (c and d) in a metacarpophalangeal joint of a good responder (a and c) and poor responder (b and d) to anti-TNF therapy
Fig. 2
Fig. 2
Anti-TNF treatment increases frequency of circulating T helper (Th)17 cells. Change in numbers of IL17-producing peripheral blood mononuclear cells during anti-TNF treatment determined by IL17 enzyme-linked immunospot (Elispot) assay (a) and representative IL17 Elispot experimental wells (b). PBMC (n = 200,000) were seeded in triplicate in each experiment and stimulated with 1 mg/ml anti-CD3 antibody for 20 hours and the numbers of cytokine-producing cells were enumerated. Change in the frequency of circulating CD4 + IL17+ cells in the peripheral blood of patients with rheumatoid arthritis (RA) determined by flow cytometry (c) and representative dot plots (d). Bars represent median and interquartile range; *p < 0.05, **p < 0.01 versus baseline visit (Wilcoxon matched pairs test). spSFC/106, specific spot-forming cells per million PBMC
Fig. 3
Fig. 3
Increase in circulating T helper (Th)17 cells during anti-TNF treatment correlates with improvement in joint inflammation. Negative correlation is shown between the change in frequency of IL17-positive cells (determined by IL17 enzyme-linked immunospot (Elispot) assay) from baseline to week 12 on treatment and the change in quantitative ultrasound scores for synovial thickening (Trans STA) and vascularity (Trans PDA) from baseline to week 12 in patients with rheumatoid arthritis (RA). Correlation was tested using the Spearman’s rank method. 10 MCP Trans PDA composite transverse power Doppler area score for synovial vascularity of ten metacarpophalangeal joints, 10 MCP Trans STA composite transverse synovial thickness area score of ten metacarpophalangeal joints. a Synovial thickening. b Synovial vascularity
Fig. 4
Fig. 4
Higher frequency of T helper (Th17) cells at baseline associated with poorer response to anti-TNF treatment. Positive correlation between the frequency of circulating IL17-producing cells (determined by IL17 enzyme-linked immunospot (Elispot) assay) at baseline and the change in quantitative score for synovial vascularity (composite transverse synovial thickness area score of ten metacarpophalangeal joints (10 MCP Trans PDA score) from baseline to week 1 on treatment (a) in patients with rheumatoid arthritis (RA) with presence of power Doppler signal at baseline (n = 19). Positive correlation is shown between the frequency of circulating IL17-producing cells (determined by IL17 Elispot assay) at baseline and the change in quantitative score for synovial thickening (10 MCP Trans STA score) from baseline to week 1 (b), from baseline to week 4 (c) and from baseline to week 12 (d) on treatment in the whole RA cohort. Correlation was tested using Spearman’s rank method. spSFC/106 specific spot forming cells per 106, 10 MCP Trans PDA composite transverse power Doppler area score for synovial vascularity of ten metacarpophalangeal joints

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