It has been well recognized that both periodontitis and RA are associated with persistent high levels of pro-inflammatory cytokines including TNF-α, IL-1, and IL-6 [
4,
5,
36‐
39]. This leads to the hypothesis that pro-inflammatory cytokine-targeted pharmacologic treatment may reduce systemic and local levels of these cytokines, and concomitantly improve periodontal inflammatory condition. Novel therapeutic strategies based on TNF-α and IL-6 blockade have been developed, and are currently used for the treatment of RA [
72•,
73]. To date, there have been several studies evaluating in vitro and in vivo efficacy of TNF-α- and IL-6R-targeted therapies in the treatment of periodontitis.
Significant inhibitory effects of IL-1 and TNF antagonists on periodontal inflammatory and destructive responses have been demonstrated in a
Macaca fascicularis primate model of experimental periodontitis [
74]. The results indicated that injection of soluble receptors to IL-1 and TNF inhibited by approximately 80 % the recruitment of inflammatory cells in close proximity to bone, and also reduced the formation of osteoclasts by 67 % and the amount of bone loss by 60 %, respectively [
74]. Likewise, blockade of IL-1 and TNF resulted in an inhibitory effects on the progression of inflammatory cell infiltration toward alveolar bone in the same animal model [
75]. In addition, the histomorphometric analysis indicated that IL-1 and TNF antagonists reduced the loss of connective tissue attachment by approximately 51 % and the loss of alveolar bone height by almost 91 % in the same experimental periodonttiis model [
76]. However, the effects of local injection of IL-1 and TNF soluble receptors proved different between the early and late phases of periodontal wound healing in a non-human primate model [
77]. Short-term blockade of IL-1 and TNF may facilitate periodontal wound healing, whereas the prolonged blockade may have adverse effects [
77]. Furthermore, recent studies showed that anti-TNF-α antibody treatment improved the host response to
Porphyromonas gingivalis and was related to reduced serum levels of TNF-α and IL-6 in mice [
78,
79].
The effect of cytokine-targeted therapy on periodontal condition in patients with RA has been reported in several studies [
80‐
85,
86••]. A summary of study methods and results obtained from each study are presented in a chronological order (Table
1). First, Pers et al. evaluated periodontal condition in 20 French patients with RA who had received infliximab (IFX, a chimeric mouse/human anti-TNF-α monoclonal antibody) every 6 weeks for more than 22 months and 20 race-, age-, gender-, and smoking status-balanced patients with RA who had not received IFX medication [
80]. Of 20 patients in the control group, nine were subjected to assessment before and after IFX therapy. The results showed that IFX increased modified gingival and papillary bleeding indices and decreased attachment loss, but did not affect PD [
80]. The second comparative clinical study conducted by Oritz et al. reported that medication of TNF inhibitors including IFX, etanercept (ETN, a recombinant fusion protein linked to human type II TNF receptor-Fc portion), or adalimumab (ADA, a fully humanized anti-TNF-α monoclonal antibody) resulted in an improvement of gingival index (GI), BOP, PD, and CAL, which is only shown with periodontal therapy [
81]. Mayer et al. indicated that patients with RA who received IFX had lower periodontal indices and GCF TNF-α levels [
82,
83]. In addition, Üstün et al. showed that TNF inhibitors such as IFX and ADA decreased periodontal inflammatory indices, and also lowered GCF levels of IL-1 β and IL-8, and saliva levels of IL-8 and monocyte chemoattractant protein-1 [
84]. Recently, Kobayashi et al. demonstrated a beneficial effect of ADA therapy on periodontal inflammatory condition in patients with RA [
85]. It was proposed that this might be related to decrease in serum levels of CRP, matrix metalloproteinase-3 (MMP-3), IL-6, TNF-α, and acute phase proteins [
85]. On the other hand, there has been only one study assessing IL-6R inhibition therapy with tocilizumab (TCZ, a humanized monoclonal anti-human IL-6R antibody with specificity for the soluble and membrane-expressed IL-6R) on periodontal condition in patients with RA and CP [
86••]. The results showed that the patients with RA who received TCZ exhibited a greater decrease in GI, BOP, PD, CAL, and serum levels of IL-6 and MMP-3 than the control patients [
86••].