Improvement in Joint Inflammation is Accompanied by Reduction in Arterial Inflammation: Tocilizumab in Rheumatoid Arthritis

Graphical Abstract.

Study design and main results of the study.

Abbreviations: ¹⁸F-FDG-PET-MR^{: 18}F-fluorodeoxyglucose-positron emission tomographymagnetic resonance; L: left; R: right; RA: rheumatoid arthritis; SUV: standardized uptake value; TBR: target-to-background ratio.

Multiple lines of evidence have long demonstrated that individuals with rheumatoid arthritis (RA) are at a higher risk of atherosclerotic cardiovascular disease (CVD) events (1). The systemic inflammation present in this population is believed to contribute significantly to the heightened CVD risk. Further, disease-modifying therapies (DMARDs) used to manage RA are associated with lower CVD event rates (1). Notably, patients with RA have increased arterial ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) uptake measured by positron emission tomography (PET) (2), a surrogate marker of arterial inflammation that predicts CVD events (3). Recently, therapy with DMARDs, which are known to reduce RA-related joint inflammation and symptoms, was shown to lower arterial inflammation, suggesting a possible mechanism of CVD risk reduction (4). Additionally, tocilizumab is associated with improvements of arterial inflammation at ¹⁸F-FDG-PET in patients with giant cell arteritis (5). However, the relationship between changes in the signs and symptoms of articular inflammation and the change in arterial inflammation among rheumatoid arthritis patients remains unclear.

We hypothesized that improvements in RA articular symptoms and systemic inflammation following immunomodulatory therapy is accompanied by similar improvements in arterial inflammation. To test this hypothesis, we employed ¹⁸F-FDG-PET-magnetic resonance (¹⁸F-FDG-PET-MR) imaging to evaluate joints and arteries before and after treatment with tocilizumab, an interleukin-6 (IL-6) receptor inhibitor that improves RA symptoms (6). Nine subjects with an inadequate response to non-biologic DMARDs (e.g., methotrexate) and/or tumor necrosis factor (TNF) inhibitors (median age [IQR]: 60.5 [59.0-69.0] years, 66.7% females) were prospectively enrolled. They underwent ¹⁸F-FDG-PET-MR imaging prior to and after 12 weeks of treatment with tocilizumab 162 mg administered in weekly subcutaneous injections. PET image acquisition was performed 2 hours after ¹⁸F-FDG administration. One patient withdrew after developing pneumonia-related sepsis following the first tocilizumab dose. Arterial inflammation was assessed within the most diseased segment (the segment with the highest ¹⁸F-FDG uptake) of the index vessel (right or left carotid or ascending aorta) and reported as a ratio of the maximum arterial standardized uptake value (SUV) to the mean SUV of the blood background (internal jugular vein), yielding a target to background ratio (TBR), as previously described (4). Additionally, articular inflammation was determined as the ratio between the average bilateral wrist joint mean ¹⁸F-FDG uptake to that of blood background. A sensitivity analysis using the mean ¹⁸F-FDG uptake of the most diseased joint (the highest ¹⁸F-FDG uptake among hip, shoulder, or wrist) was performed. Clinical disease activity index (CDAI), which considers the number of tender and swollen joints in addition to patient and physician’s global assessments of disease activity, was used to assess clinical RA disease activity (6). The CDAI score, which does not include levels of C-reactive protein (CRP), ranges between 0 and 76, with higher scores denoting higher disease activity [≤2.8 (disease remission), >2.8 and ≤10 (low disease activity); >10 and ≤ 22 (moderate disease activity), and >22 (high disease activity)]. The Mass General Brigham Institutional Review Board approved this study; all individuals provided written informed consent. Data were analyzed using the Wilcoxon rank-sum test and Spearman’s rank correlation coefficient (R_s).

Tocilizumab therapy was associated with significant improvement in CDAI scores (median [IQR]: 24.5 [21.0-35.2] at baseline vs. 7.5 [3.7-17.5] at week 12; p=0.018). Individual patient changes in arterial ¹⁸F-FDG uptake, most diseased joint ¹⁸F-FDG uptake and CDAI scores are reported in Figure 1. The reduction in the CDAI scores correlated with reductions in arterial ¹⁸F-FDG uptake (Rs=0.73; p=0.040) and wrist joint ¹⁸F-FDG uptake (R_s=0.94; p=0.002). Reductions in wrist joint ¹⁸F-FDG uptake also positively correlated with reductions in arterial ¹⁸F-FDG uptake (Rs=0.79; p=0.036). Also, reductions in most diseased joint ¹⁸F-FDG uptake correlated with reductions in arterial ¹⁸F-FDG uptake (R_s=0.79; p=0.021). Furthermore, declines in CRP levels correlated with reductions in arterial ¹⁸F-FDG uptake (R_s=0.76; p=0.028), CDAI (R_s= 0.96; p<0.001) and wrist joint ¹⁸F-FDG uptake (R_s=0.89; p=0.007). Arterial ¹⁸F-FDG uptake decreased in 6 of 8 (75%) patients, but this reduction did not reach statistical significance (median [IQR]: 2.03 [1.8-2.3] at baseline vs. 1.9 [1.6-2.7] at week 12; p=0.263).

Figure 1. Individual patients levels of arterial inflammation, joint inflammation and CDAI before and after therapy with tocilizumab.

Individual values of arterial inflammation [as most diseased segment of the index vessel (MDS) tissue-to-background ratio (TBR)], joint inflammation (as most diseased joint TBR) and Clinical Disease Activity (CDAI Score) are reported, at baseline and after 12-weeks therapy with tocilizumab (follow up). For each measure, median values are reported both at baseline and at follow up (red points connected by red dotted line). Abbreviations: CDAI: clinical disease activity index; TBR: tissue-to-background ratio.

In this hypothesis-generating pilot study, using advanced multi-modality imaging we showed that tocilizumab-induced changes in joint inflammation and symptoms were accompanied by reductions in arterial inflammation. As expected, tocilizumab was associated with significant symptomatic improvement. While we did not observe a significant decrease in arterial inflammation in this small pilot study, larger studies, such as TARGET, have recently demonstrated that immunomodulatory therapies reduce arterial inflammation in RA(4). Additionally, tocilizumab has been shown to reduce arterial inflammation in patients with giant cell arteritis (5). Studies in larger cohorts, spanning a longer duration of time, using a randomized placebo-controlled design and assessing the effect on arterial inflammation in relation to subsequent cardiovascular events, are therefore needed. Moreover, the effects of tocilizumab could be tested with novel techniques of molecular imaging which are able to capture arterial inflammation better than ¹⁸F-FDG arterial uptake (7). In the meantime, our preliminary findings support the hypothesis that among patients with RA, as articular symptoms and inflammation abate, arterial inflammation and cardiovascular risk may similarly improve.

New Knowledge Gained.

• Among patients with rheumatoid arthritis, improvement of joint inflammation and symptoms associates with improvement in arterial inflammation after therapy with tocilizumab.

Clinical Implications:

• As patients with rheumatoid arthritis experience significant improvements in inflammatory joint symptoms following therapy with tocilizumab, they also experience decreases in arterial inflammation, which associates with a reduced risk of cardiovascular disease events.

Abbreviations:

¹⁸F-FDG-PET-MR

¹⁸F-FDG-PET-magnetic resonance

CDAI

clinical disease activity index

CVD

cardiovascular disease

IL-6

interleukin-6

RA

rheumatoid arthritis