Host Modulation and Treatment of Periodontal Disease

Abstract

Periodontitis is the sixth-most prevalent disease in the world and the first cause for tooth loss in adults. With focus shifted to the inflammatory/immune response in the pathogenesis of periodontitis, there is a critical need to evaluate host modulatory agents. Synthetic and biological disease-modifying antirheumatic drugs are a cornerstone for the treatment of inflammatory diseases. Recent prospective cohort studies showed that synthetic disease-modifying antirheumatic drugs improved periodontal clinical parameters following nonsurgical periodontal treatment in patients with rheumatoid arthritis. Treatment with recombinant humanized monoclonal antibodies against CD20 (rituximab) and IL-6 receptor (tocilizumab), the latter also in clinical trials for the treatment of COVID-19 pneumonia, resulted in decreased periodontal inflammation and improved periodontal status. Studies on the effect of TNF-α inhibitors in patients with periodontitis yielded inconsistent results. Recent data suggest that probiotics provide anti-inflammatory clinical benefit, as do nutritional supplements, such as n-3 fatty acids, when combined with periodontal therapy. Probiotics reduce the production of proinflammatory cytokines/chemokines by suppressing NF-κB pathways and promote the accumulation of T regulatory cells. Statins, like aspirin, have been shown to exhibit anti-inflammatory and bone-preserving actions by upregulating production of Specialized Proresolving Mediators (SPMs). Currently, there is insufficient scientific support for the topical delivery of statins or bisphosphonates as adjuncts to periodontal therapy. Here, we present a critical review of the most recent host modulatory agents applied in humans and the key immune pathways that they target. Emerging evidence from novel drug candidates, including SPMs and complement inhibitors as previously studied in animal models and currently in human clinical trials, suggests future availability of adjunctive therapeutic strategies for the management of periodontitis.

Keywords: bone resorption; cytokines; immune system; inflammation; periodontitis; therapeutics.

Figure 1.

Immune regulation by host modulatory agents in periodontitis. The host immune/inflammatory response to the microbial challenge triggers the self-degradation of periodontal tissues and drives the pathogenic process in periodontitis. Recent preclinical and human trials revealed promising host modulatory agents in periodontitis that inhibit destructive aspects of inflammation and upregulate anti-inflammatory and regenerative mechanisms promoting a favorable environment for the return to periodontal tissue homeostasis. MMP, metalloproteinase; PDLSC, periodontal ligament stem cell; PMN, polymorphonuclear neutrophil; n-3 PUFA, omega-3 polyunsaturated fatty acid.

Figure 2.

Cellular targets of host modulation agents in periodontitis. Conventional synthetic and biological disease-modifying antirheumatic drugs (DMARDs) are currently being prescribed for the treatment of rheumatoid arthritis. Biological DMARDs inhibit the expression of key proinflammatory markers in periodontitis, such as IL-17 and IL-6, and suppress the proliferation of CD4+ T cells. Rituximab is a monoclonal antibody targeting CD20 that results in the depletion of B cells. Bisphosphonates disrupt osteoclastic activity, inhibit bone degradation, and promote osteoblastic activity. Omega-3 (n-3) polyunsaturated fatty acids (PUFAs) regulate fatty acid metabolites of inflammatory cells, suppress proinflammatory gene expression by inhibiting proinflammatory pathways, and decrease the production of inflammatory mediators. n-3 PUFAs are the substrates for the generation of specialized proresolving lipid mediators (SPMs), including resolvins, maresins, and protectins, which orchestrate the active resolution of inflammation. Statins exert their anti-inflammatory and bone-preserving actions by modulating the ERK, MAPK, PI3-Akt, and NF-κB pathways. They also induce the upregulation of SPMs, namely 15-epi-LXA4 and 13-series resolvins, via the LOX-5 and COX-2 enzymatic pathways, respectively, especially when combined with aspirin. Complement inhibitors such as Cp40 suppress osteoclastogenesis and bone loss and decrease IL-17 and the RANKL/OPG ratio in nonhuman primates. Probiotics reduce the production of proinflammatory cytokines by inhibiting the NF-kB pathway and promote the accumulation of Tregs by inhibiting histone deacetylases. SPMs downregulate cytokines/chemokines and promote bone regeneration. D-resolvins antagonize IL-17, induce the expression of the endothelial anti-inflammatory marker Del-1 through the GSK-3b-C/EBPb pathway, and decrease CD4+ cells. SPMs restore viability, proliferation, and migration of human PDLSCs and enhance differentiation of cementoblasts/osteoblasts. IL, interleukin; PDLSC, periodontal ligament stem cell.