Validity of ultrasound as a surrogate marker of serum inflammatory cytokines after tocilizumab introduction in rheumatoid arthritis patients

Abstract

Abstract Background Rheumatoid arthritis (RA) is characterized by persistent synovitis, which is evaluated using ultrasound. Ultrasound-based global assessment of the joints is correlated with serum cytokine levels. This correlation was validated in cross-sectional but not in prospective studies. We aimed to verify this validity in a prospective study of RA patients treated with the interleukin (IL)-6 receptor inhibitor tocilizumab. Methods Twenty-four consecutive RA patients started on tocilizumab treatment were prospectively enrolled. Serum levels of 27 cytokines/chemokines were measured using a multiplex immunoassay (Bio-Plex assay). Clinical examination and comprehensive ultrasound assessment of joints were conducted at baseline and 24 weeks. Results Clinical and ultrasound global scores showed significant improvements at 24 weeks (Disease Activity Score 28-joint count-erythrocyte sedimentation rate: p = 0.001, ultrasound power Doppler global score with 40 joints [PD40]: p = 0.028); however, there was no significant improvement in the inflammatory cytokine levels (IL-6: p = 0.93, vascular endothelial growth factor [VEGF]: p = 0.79, tumor necrosis factor [TNF]: p = 0.85). Before tocilizumab introduction, PD40 showed a significant correlation with multiple serum cytokines, including IL-6 (r = 0.584, p = 0.045), VEGF (r = 0.582, p = 0.047), TNF-α (r = 0.695, p = 0.012), and interferon gamma-induced protein-10 [IP-10] (r = 0.827, p = 0.001); this correlation was lost after 24 weeks. IL-6-associated cytokines (IL-8, IP-10, monocyte chemoattractant protein-1, macrophage inflammatory protein-1a) and growth factors (VEGF, platelet-derived growth factor-bb, fibroblast growth factor-basic) altered > 50% of the correlated partner-cytokines after tocilizumab introduction. Conclusions The ultrasound global score is not a reliable surrogate marker of multiple inflammatory cytokine statuses during tocilizumab treatment. Thus, it should not be a rationale to determine tocilizumab discontinuation in RA patients.