Abstract
BackgroundAnti-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.MethodsPatients 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)).ResultsThe 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.ConclusionsThese 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 RegistrationClinicalTrials.gov: NCT01060098. Registered 29 January 2010.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1197-5) contains supplementary material, which is available to authorized users.
Highlights
Anti-TNF agents have revolutionised rheumatoid arthritis (RA) treatment; a third of patients fail to achieve therapeutic responses
We have previously reported an increase in peripheral blood T helper 17 (Th17) cell numbers by fluorescenceactivated cell sorting (FACS) and an increase in IL17producing cells by enzyme-linked immunospot assay (Elispot) after anti-TNF treatment in patients with ankylosing spondylitis, psoriatic arthritis and RA [26]
Two other studies point to an association between higher baseline levels of interleukin 17 (IL17) or a higher frequency of Th17 cells and poor anti-TNF treatment response in RA; in these studies this relationship has been investigated using clinical measures of disease activity only and at a single time point on treatment, rather than longitudinally [25, 41]. We investigated this hypothesis by exploring relationships between ultrasonographic and T cell immunological changes during anti-TNF therapy to determine if a higher frequency of IL17-producing cells at baseline was associated with poor treatment response
Summary
Anti-TNF agents have revolutionised rheumatoid arthritis (RA) treatment; a third of patients fail to achieve therapeutic responses. 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. Th17 cells are a highly pro-inflammatory T helper (Th) cell subset, which have been shown to contribute to arthritis pathogenesis [1, 2] Their signature cytokine, interleukin 17 (IL-17), has pleiotropic effects on effector cells of the immune system and can induce production of other pro-inflammatory cytokines [1], contribute to cartilage damage by promoting release of matrix metalloproteinases, increase osteoclast differentiation leading to bony erosions and mediate angiogenesis in inflamed joints [2,3,4,5]. Synovial tissue IL17 mRNA has been shown to be associated with increased progression of joint damage in RA in a 2-year prospective study [10]
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