The dynamics of Th17 and Th1 cells during anti-TNF therapy in patients with inflammatory arthritis and relationship with treatment response

Anti-TNF agents have revolutionised the treatment of rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA), however a significant proportion of patients respond inadequately. Studies in murine and human arthritis have paradoxically shown that anti-TNF treatment can increase circulating Th17 and Th1 cells but the relationship of these changes to treatment response remains unclear. The aim of the work in this thesis was to conduct a prospective, longitudinal investigation of patients with inflammatory arthritis during anti-TNF treatment and using clinical, ultrasound and immunological assessments to gain an understanding of the immune correlates of treatment response. Patients with RA (n=25), AS (n=15) and PsA (n=8) were recruited and followed over the first 12 weeks of treatment. Improvement in validated disease activity scores defined treatment responders and non-responders. Power Doppler ultrasound (PDUS) provided a quantitative assessment of changes in synovial thickening and vascularity during treatment, with synovial vascularity showing faster and greater reduction with treatment than synovial thickening. PBMCs testing using IL17 and IFNy ELISpot assays and flow cytometry consistently showed increased frequencies of circulating Th1 and Th17 cells in all three disease groups during anti-TNF therapy. Multiplex cytokine testing demonstrated a decrease in serum levels of proinflammatory cytokines and chemokines. Analyses of relationships between clinical, ultrasonographic and T-cell immunological changes revealed significant negative correlations between the increased frequency of Th1 and Th17 cells and reduction in synovial thickening and vascularity from baseline to 12 weeks on treatment in the RA group. Higher numbers of circulating Th17 cells at baseline in the RA group were associated with poorer anti-TNFa treatment response as defined by DAS28 score and ultrasonographic measures. This is the first study to link changes in T-cell immunopathology evaluated by cellular assays with morphological changes in arthritis assessed by PDUS during anti-TNFa treatment.Open Acces