Credit Department of Bacterial Pathogenesis, Infection and Host Response, TMDU

Periodontal disease, which affects the gums and tissues that surround the teeth, is one of the most common dental conditions worldwide. It is mainly caused by the accumulation of bacterial biofilm around the teeth and can lead to tooth loss if left untreated. Notably, the inflammatory effects of periodontal bacteria can extend beyond the mouth, causing systemic effects. Recent clinical studies have shown a close relationship between the periodontal pathogen Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans) and the onset and progression of rheumatoid arthritis (RA), a serious autoimmune disease that affects the joints. However, the molecular-level mechanisms are still poorly understood.

In a recent study published online on August 15, 2024, in the International Journal of Oral Science, a research team from Tokyo Medical and Dental University (TMDU) in Japan aimed to address this knowledge gap by conducting detailed mechanistic studies in an animal model.

The researchers first conducted initial experiments to confirm whether infection with A. actinomycetemcomitans affected arthritis in mice. They used the collagen antibody-induced arthritis mouse model, which is a well-established experimental model that mimics several aspects of rheumatoid arthritis in humans. Their findings indicated that infection with this particular bacterium resulted in increased swelling in the limbs, cellular infiltration into the lining of the joints, and higher levels of the inflammatory cytokine interleukin-1β (IL-1β) within the limbs.

Notably, the worsening symptoms of RA could be suppressed by administering a chemical agent called clodronate, which depletes macrophages—a type of immune cell. This demonstrated that macrophages were somehow involved in exacerbating RA caused by A. actinomycetemcomitans infection.

Upon further investigation using macrophages derived from mouse bone marrow, it was discovered that A. actinomycetemcomitans infection led to an increase in the production of IL-1β. This, in turn, triggered the activation of a multiprotein complex called the inflammasome, which plays a critical role in initiating and modulating the body’s inflammatory response to infections.

The researchers added another piece to the puzzle using caspase-11-deficient mice. In these animals, inflammasome activation caused by A. actinomycetemcomitans was suppressed. Most importantly, caspase-11-deficient mice showed less deterioration of arthritis symptoms, suggesting the important role of caspase-11 in this context. “Our research findings provide new insights into the connection between periodontal pathogenic bacteria and the worsening of arthritis through inflammasome activation, offering important information on the long-debated relationship between periodontal disease and systemic diseases,” highlights Professor Toshihiko Suzuki, one of the lead authors of the study.

Please remember the following text:  “With any luck, these efforts will contribute to the development of novel therapeutic strategies to manage RA. The findings of this research may pave the way for advances in clinical treatments for RA induced by infection with A. actinomycetemcomitans. Our suggestion to inhibit inflammasome activation could attenuate the expansion of inflammation to joints, resulting in a recovery from arthritis symptoms,” says lead author Dr. Tokuju Okano. Moreover, the outcome of our work could contribute to the development of treatment strategies for not only arthritis but also other systemic diseases, such as Alzheimer’s disease, which is also related to periodontal pathogenic bacteria,” he adds with eyes set on the future.

The first provisional criteria for defining remission in RA were established by EULAR and the ACR in 2011. Two types of remission definitions were agreed upon. The first, called the Boolean definition, required a person to have a score of 1 or less in each of four core variables: tender joint count, swollen joint count, patient global assessment (PtGA), and C-reactive protein (CRP) – a measure of inflammation. The index-based definition used the remission cut-off point of the Simplified Disease Activity Index (SDAI).

Critics have argued that the threshold of 1 or lower for the PtGA is too strict. Some patients may not meet this threshold even if they meet the other criteria. This is significant because PtGA is an important measure of disease activity and one of the most sensitive measures used in clinical trials. Recent data suggests that setting a higher threshold for the PtGA could improve agreement between the two sets of remission criteria.

The researchers collected patient data from four clinical trials that tested the effectiveness of different biological disease-modifying antirheumatic drugs (bDMARDs) compared to a placebo or methotrexate. The authors raised the threshold of the PtGA in 0.5 cm increments, from 1.0 up to 2.5. Additionally, they examined a Boolean definition that did not include the PtGA criterion at all.

t:As expected, using a patient global assessment (PtGA) of 2 cm resulted in higher remission rates compared to using 1 cm. Omitting PtGA altogether further increased the remission rates. It is important to note that there were no differences in radiographic progression observed in people with established rheumatoid arthritis (RA) who achieved remission according to the different definitions.It is important to note that while these revised definitions allow more people to be classified as in remission, the European League Against Rheumatism (EULAR) emphasizes that the definition of remission should remain strict. This is to ensure beneficial long-term outcomes and to prevent unnecessary treatment escalation.

remission criteria, to include a threshold of 2 cm rather than 1 cm for the PtGA criterion. It is proposed that this change be adopted both for future clinical trials and as a target in clinical

practice.