Tocilizumab, a Potent Interleukin-6 Receptor Inhibitor, Decreases Bone Resorption and Increases the Rate of Bacterial Infection After Tooth Extraction in Rats

Abstract

Purpose Our objective was to evaluate the influence of pretreatment with tocilizumab (TCZ) in bone healing after tooth extraction in rats. Methods Wistar male rats were equally divided into sham (ie, nonoperated), saline (both treated with 0.1 ml/kg saline), and six TCZ groups treated with 1, 2, 4, 8, 16, and 32 mg/kg TCZ (TCZ1 to TCZ32, respectively). Twenty-four hours after administration of vehicle or TCZ, exodontia of the first lower left molar was performed, and the animals were euthanized three days later for hematological analysis and organ (liver, spleen, and kidney mass indexes, and histological evaluation), gingiva (myeloperoxidase [MPO] assay), and mandible (radiographic, histomorphometric analysis, and IL-6 immunostaining) evaluation. Analysis of variance/Bonferroni test (statistical significance, P < .05) was performed using GraphPad Prism version 5.0 (GraphPad Inc, San Diego, CA, USA). Results There was no difference in radiographic results; however, leukopenia ( P = .039) and neutropenia ( P < .001) were statistically significant in the TCZ16 and TCZ32 groups. Weight loss ( P < .001) and reduced liver index ( P = .001) were significantly dose-dependent; however, no histological alterations were observed in the other organs. Osteoclast counts were reduced in groups TCZ4 to TCZ32 ( P < .001), and IL-6 immunostaining increased in the TCZ8 to TCZ32 groups ( P < .001). Alveolar infection rates increased in groups TCZ4 to TCZ32 ( P < .001), and MPO had a biphasic response, exhibiting a reduction in groups TCZ2 and TCZ4, and an increase in group TCZ32 ( P = .004). Conclusion TCZ-induced immunosuppression led to a reduction in osteoclast function, an increase in alveolar infection, and compensatory neutrophil infiltration.

Tocilizumab: Another medication related to osteonecrosis of the jaws? A case report and literature review

“…In summary, considering the nature of case reports like ours and the current lack of prospective studies, we can only assume causality between interleukin-6 inhibitors such as tocilizumab and MRONJ. With the promising future perspectives of tocilizumab use in immunoinflammatory diseases and in COVID-19 treatment, our clinical report as well as the research of Imaculada de Queiroz Rodrigues et al [ 31 ] and previous case reports showed that in the clinical setting, surgeons need to pay attention to side effects of tocilizumab, especially due to increased risk of postsurgical infection. This clinical case recommends a dental examination before prescribing tocilizumab as well as periodic dental checkups during treatment.…”

“…Recent scientific reports declare the intravenous administration of tocilizumab in the treatment of the COVID-19 related acute respiratory insufficiency with encouraging results [ 30 ], [ 31 ], [ 21 ], [ 22 ]. Due to an overproduction of proinflammatory cytokines and especially IL-6, a large number of COVID-19 affected patients in critical situation experience a “cytokine storm” [ 31 ]. This storm contributes to increased disease severity as well as aggravation of prognosis, and tocilizumab contributes to symptom improvement by reducing the IL-6 expression associated inflammation [ 31 ].…”

“…Due to an overproduction of proinflammatory cytokines and especially IL-6, a large number of COVID-19 affected patients in critical situation experience a “cytokine storm” [ 31 ]. This storm contributes to increased disease severity as well as aggravation of prognosis, and tocilizumab contributes to symptom improvement by reducing the IL-6 expression associated inflammation [ 31 ]. However, further studies are needed to validate the ability of tocilizumab to restore T cell counts in COVID-19 patients.…”

“…Based on the expanded therapeutic potential of tocilizumab due to the current COVID-19 pandemic and regarding its clinical relevance in oral surgery procedures according to the above mentioned clinical reports, Imaculada de Queiroz Rodrigues et al evaluated the effect of pretreatment with tocilizumab on bone remodeling in rats after tooth extraction [ 31 ]. In this study, the mandible of 48 rats was clinically and histomorphologically evaluated after intravenous administration of tocilizumab and extraction of the first lower left molar.…”

“…According to its results, reduced osteoclast count, increased histological signs of infection, myeloid suppression and induction of response in neutrophil infiltration of the alveolar mucosa were demonstrated. The suppression of IL-6 in rats is likely to contribute significantly to inflammatory alveolar bone destruction [ 31 ].…”