Background Oxidative stress induced by reactive oxygen species (ROS) is also an important mechanism that underlies destructive and proliferative synovitis in rheumatoid arthritis (RA). Abundant amounts of reactive oxygen species have been detected in the synovial fluid of inflamed rheumatoid joints. It is reported that drugs that block tumor necrosis factor (TNF) reduce the oxidative stress marker levels in patients with RA [1,2]. Then, it is plausible to consider that interleukin-6 (IL-6)-blocking drug also reduce ROS levels in RA cases.

Objectives The influence of not only TNF-blocking drug, but also IL-6-blocking drug on the serum level of oxidative stress marker were evaluated.

Methods In this study, we measured reactive oxygen species (ROM: reactive oxygen metabolites) using a free radical analytical system (FRAS4, Wismarl, Italy) in 140 patients with RA treated with disease-modifying anti rheumatic drugs (DMARDs) (n=91), TNF-blocking drugs (infliximab, etanercept) (n=8), and an interleukin-6 (IL-6)-blocking drug (tocilizumab) (n=26). As a control, patients suffering from osteoarthritis (OA) were selected (n=15). Of these 26 patients treated with tocilizumab, 3 cases were followed longitudinally. Serum level of ROM was measured before administration of tocilizumab, 1 week after administration, 3 and 4 months after administration. Inflammatory makers (CRP: C-reactive protein, WBC: white blood cell) and matrix metalloproteinase-3 (MMP-3) were also measured.

Results Patients with OA showed 375.5 ± 72.5 Carr U of ROM, which is significantly lower (p<0.05) level than that of patients with RA treated with DMARDs: 464.2 ± 112.3 Carr U of ROM. While, serum levels of ROM in patients treated with TNF-blocking therapy showed 377.1 ± 53.7 Carr U of ROM, a level similar to that in the OA group, suggesting that anti-TNF biologics therapy effectively reduces oxidative stress in patients with RA. Finally, serum levels of ROM in patients treated with IL-6 blocking therapy showed 239.2 ± 73.7 Carr U of ROM which is dramatically and significantly lower (p<0.01) than that of OA and DMARDs group [3]. In addition, of 3 cases confirmed longitudinally, all cases showed smooth reduction of serum ROM after tocilizumab administration, however one case showed increase of WBC count (before: 8110, 4 months after: 10810) and MMP-3 levels (before: 224, 4 months after: 674). There may be some independent pathway between reduction of ROS and control of joint inflammation.

Conclusions Serum level of oxidative stress markers is dramatically low and smoothly reduced in patients with RA treated with tocilizumab, suggesting that IL-6 blocking therapy reduces not only joint damage, but also extra-articular manifestations caused by oxidative stress, including vascular degeneration in patients with RA. We believe that this drastic effect may reduce the incidence of cardiovascular events and mortality in patients with RA.

References

1. Kageyama Y, Takahashi M, Nagano A et al. Clin Exp Rheumatol. 2008

2. Kageyama Y, Takahashi M, Nagano A et al. Rheumatol Int. 2008

3. Hirao M, Yamasaki N, Hashimoto J et al. Rheumatol Int. 2012

Disclosure of Interest None Declared