Unexpected arterial wall and cellular inflammation in patients with rheumatoid arthritis in remission using biological therapy: a cross-sectional study

Abstract

Background: Increasing numbers of patients (up to 40 %) with rheumatoid arthritis (RA) achieve remission, yet it remains to be elucidated whether this also normalizes their cardiovascular risk. Short-term treatment with TNF inhibitors lowers arterial wall inflammation, but not to levels of healthy controls. We investigated whether RA patients in long-term remission are characterized by normalized inflammatory activity of the arterial wall and if this is dependent on type of medication used (TNF-inhibitor versus nonbiological disease-modifying antirheumatic drugs (DMARDs)).

Methods: Arterial wall inflammation, bone marrow and splenic activity (index of progenitor cell activity) was assessed with (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT) in RA patients in remission (disease activity score (DAS28) <2.6 for >6 months) and healthy controls. We performed ex vivo characterization of monocytes using flow cytometry and a transendothelial migration assay.

Results: Overall, arterial wall inflammation was comparable in RA patients (n = 23) in long-term remission and controls (n = 17). However, RA subjects using current anti-TNF therapy (n = 13, disease activity score 1.98[1.8-2.2]) have an almost 1.2-fold higher (18)F-FDG uptake in the arterial wall compared to those using DMARDs (but with previous anti-TNF therapy) (n = 10, disease activity score 2.24[1.3-2.5]), which seemed to be predominantly explained by longer duration of their rheumatic disease in a multivariate linear regression analysis. This coincided with increased expression of pro-adhesive (CCR2) and migratory (CD11c, CD18) surface markers on monocytes and a concomitant increased migratory capacity. Finally, we found increased activity in bone marrow and spleen in RA patients using anti-TNF therapy compared to those with DMARDs and controls.

Conclusions: A subset of patients with RA in clinical remission have activated monocytes and increased inflammation in the arterial wall, despite the use of potent TNF blocking therapies. In these subjects, RA disease duration was the most important contributor to the level of arterial wall inflammation. This increased inflammatory state implies higher cardiovascular risk in these patients, who thus may require more stringent CV risk management.

Keywords: Cardiovascular disease; Imaging; Inflammation; Rheumatoid arthritis.

Fig. 1

Increased arterial TBR in RA patients on anti-TNF therapy. Quantification of the ¹⁸F-FDG uptake as the maximum target-to-background ratio (TBR) (a, c) and TBR in the most diseased section (MDS) (b, d) in the ascending aorta revealed that RA subjects in stable remission have levels of arterial wall inflammation comparable to healthy controls (a, b). However, we found increased uptake in RA patients with anti-TNF treatment (n = 13) versus RA subjects on DMARDs (n = 10) and controls (n = 17). p values are adjusted for age, gender, BMI, current smoking and systolic blood pressure, * = p < 0.05, ** = p < 0.01. DMARD disease-modifying antirheumatic drug, MDS most diseased segment, RA rheumatoid arthritis, TBR target-to-background ratio, TNF tumor necrosis factor

Fig. 2

Ex vivo monocyte adhesive and migratory properties. Increased expression (represented as fold change of delta median fluorescent intensity) of monocyte surface markers CCR2, CD11c and CD18 in RA subjects with anti-TNF treatment (n = 20) versus RA patients with DMARDs (n = 16) and controls (n = 20) (a). Assessment of transendothelial migratory capacity showed a concomitant increase in number of transmigrated cells (represented as a white arrow in (b)) (c). Data are means + SEM (for each subject, transmigrated cells are calculated of independent counts of five frames of view). * = p < 0.05, ** = p < 0.01. DMARD disease-modifying antirheumatic drug, MFI median fluorescence intensity, RA rheumatoid arthritis, TNF tumor necrosis factor

Fig. 3

Bone marrow and splenic activity in RA patients. Cross-sectional ¹⁸F-FDG PET/CT images representing ¹⁸F-FDG uptake (red) in the aorta, bone marrow (top and bottom) and spleen (bottom) in a RA patient without (a) or with anti-TNF treatment (b). Quantification of maximum standard uptake values (SUV_max) showed increased activity in both bone marrow (c) and spleen (d) of RA patients with continued anti-TNF treatment versus RA patients without anti-TNF treatment and controls. * = p < 0.05, ** = p < 0.01. DMARD disease-modifying antirheumatic drug, RA rheumatoid arthritis, SUV standardized uptake values, TNF tumor necrosis factor