Why are people with severe gum disease more at risk of diabetes, heart disease and death?

Research is examining the risk posed by periodontitis and looking beyond to the health economics of early treatment in patients with other non-communicable diseases.

“If you fractured your arm and the bone was sticking out through your skin, and then you left it untreated, you would end up with a severe infection and lose the limb. In your mouth there are around 28 teeth, each in essence a small bone doing just that, protruding through the skin.”

Professor Iain Chapple conjures a striking image when introducing the significance of oral health and the dangers of periodontitis – severe inflammation of the gums. He continues to outline the added difficulty that comes from having those multiple protrusions in contact with the microbiome of the mouth, second only in complexity in the human body to the gastrointestinal tract microbiome.

“You have almost a thousand different species of bugs in direct contact with these protruding bones. Fortunately, our gums form a specialist barrier that seals the tooth and protects the unmitigated access for those bugs to our bloodstream. But what people perhaps forget is that teeth cannot replace themselves by shedding their surface like skin does, there is no natural bug-removal process. As bacteria start to grow on teeth, so does the challenge for the gums. They become inflamed as the immune system goes into overdrive trying to kill the bugs. The gums start to ulcerate under the surface and the first people notice it is when they brush their teeth and find some blood in their saliva.”

It is estimated that between 80-90 per cent of adults will have some form of gingivitis, the early form of periodontitis. But, as oral health deteriorates, the periodontitis becomes more severe. The blood that appears in saliva is the result of small microscopic ulcers forming between the gums and teeth that allow blood to enter the mouth. The great risk, however, is that the micro-ulcers are a doorway or two-way street, and bacteria are also pushed into the bloodstream when we eat and drink. The result is “bacteraemia” – the presence of bacteria in blood – which is most severe in people with the most severe periodontitis.

Periodontitis is a chronic non-communicable disease, and in its most severe form is the sixth most prevalent human disease, affecting 11.2% of the world’s population.

 Beyond managing the local threat to oral health such as tooth loss, abscesses and receding gums, periodontal research has tended to focus on one of two avenues; oral health as a window to what is happening in the body, and as a risk factor for comorbidity with other non-communicable diseases.

“We talk about the mouth being a window to the body,” says Professor Chapple. “You can understand a lot about an individual through their mouth, whether that is levels of bacterial colonisation, or efficacy of an immune response. As a diagnostic tool it is both highly accessible and incredibly useful.”

“But perhaps more importantly, and something that is garnering more and more attention nowadays, is the very real and highly significant impact that inflammation of periodontal tissues can have on the body as a whole. Our group is continuing to investigate this and to quantify exactly how much of a risk it poses, particularly when observed in combination with other non-communicable diseases- this is called co-morbidity.”

Shock waves

Having joined the University of Birmingham in 1990, Professor Chapple was quick to set up the periodontal research group. As a young lecturer, he saw the opportunity to work in a field that connected with multiple disciplines - biology, immunology, microbiology, pharmacology, medicine, surgery and many more. 

“The periodontal area did just that,” explains Professor Chapple. “More importantly, periodontitis is both an inflammatory-immune disease and an infectious-immune disease, so you are immediately able to draw parallels with research into other infectious diseases and also other non-communicable diseases;  cardiovascular disease, diabetes, rheumatoid arthritis, chronic kidney disease. Birmingham is a great place to explore those parallels as the research groups here are very open to collaboration. We want to work with them, and they want to work with us. Being able to draw on that expertise helps us to understand the true impact of periodontitis on general health.”

Studies investigating the comorbid impact have been undertaken since the 1960s, but a 1998 paper (Garcia et al) in Annals of Periodontology sparked significant debate in the field. A longitudinal study of over 800 US veterans found that, after 25 years of observation, those with moderate to severe periodontal bone loss disease at the start of the study had significantly higher mortality 25-years later. 

As stated in the paper ‘The increase in risk attributable to periodontal status was found to be similar in magnitude to, and independent of, that attributable to cigarette smoking in this cohort.’ 

“That paper created shock waves,” explains Professor Chapple. “It really outlined how poor oral health and periodontitis could be a contributing factor to mortality. Not just a diagnostic window, not just a threat to your oral health, but a contributing factor to people dying earlier.”

In the twenty years since that paper, the Chapple group at Birmingham have made strides in making sense of that risk through research into different patient groups.

Dentistry hospital

The Birmingham Dental Hospital and School of Dentistry opened its doors to students and patients in April 2016.

Cumulative risk 

“For a number of years we have been looking at what bacteria do when they enter the bloodstream to the white blood cells,” says Professor Chapple. “In particular, how do neutrophils react?”

When looking at white blood cell activity in the peripheral blood of people with periodontitis, the team have found neutrophils in a constant state of stress and on high alert.

“They are hyperactive and hyper-reactive, chucking out lots of toxic species – oxygen radicals in particular. So you have this low-grade inflammatory process happening in the bloodstream for however long you have that disease for. The consequences of that for patients who already have a chronic non-communicable disease can be really quite troubling.” 

neurophil-net-min

Active neutrophil extracellular traps (NETs) - neutrophils release NETs as they die and trap bugs

 Chronic non-communicable diseases are increasingly prevalent, partly as a result of our ageing population, but also due to an increase in sedentary lifestyles and refined diets. Their impact upon the global disease burden and healthcare economy is significant, and evidence suggests that 92% of older adults have at least one non-communicable disease.

Professor Chapple provides the example of patients with rheumatoid arthritis, an autoimmune disease that affects around 25 million people worldwide. Specific antibodies directed against the joint structures are elevated in patients with rheumatoid arthritis. Those antibodies are also found in the bloodstream of people with periodontitis who have not yet developed rheumatoid arthritis.

“Imagine then, if the antibodies first form in the periodontal tissues due to the inflammation that is present there – there is strong evidence for this - you then have a secondary event in a joint that directs those antibodies against the joint and further increases the antibodies. This may well lead to the development of signs and symptoms of rheumatoid arthritis in some people.”

“A different example is in heart disease where an increase in the acute-phase reactant, C-reactive protein (CRP) occurs. CRP is also elevated in periodontitis from the immune response to periodontal disease. On its own in an otherwise perfectly healthy patient, you would detect it. But it is that additional burden that comes with periodontitis that we have started to see - the comorbidity.”

The periodontal research group continue to investigate the risk of cumulative risk and comorbidity with other diseases. In 2015, Dr Praveen Sharma led the publication of a paper in the Journal of Clinical Periodontology that linked periodontitis to a higher mortality rate in patients with chronic kidney disease.

Data from 13,734 participants were analysed to show that individuals with both periodontitis and chronic kidney disease had an all-cause mortality rate of 41% at 10 years, compared to 32% for those with chronic kidney disease alone.

To put this into context, the increase in 10 year mortality associated with diabetes in patients with chronic kidney disease, independent of periodontitis, is from 32% in non-diabetics to 43% in people with diabetes.

Through multiple epidemiological and mechanistic studies the group have also shown that periodontitis is a significant independent risk factor for cardiovascular mortality, rheumatoid arthritis and type 2 diabetes.

“What Praveen showed in the study of the US data set was the comorbid effect in a specific population,” explains Professor Chapple. “Periodontal disease added to kidney disease significantly increased mortality, supporting the growing evidence base for the cumulative effect of inflammation from different sources. Put simply, if you have severe gum disease you are more likely to die. The real question now is why is that?”

The team are now working with the RIISC (Renal Insufficiency In Secondary Care) cohort to identify if the link between periodontitis and chronic kidney disease could be a causal link. If that is the case, improving oral health across the population becomes even more important.

Towards better oral health

Professor Chapple believes that the importance of oral health is receiving greater recognition from healthcare specialists.

In 2017 the team co-organised a workshop that brought together the International Diabetes Federation and European Federation of Periodontology. By systematically reviewing all of the available research on the relationship between periodontitis and diabetes, they produced a set of guidelines for medical and dental teams, as well as patients, for detecting and managing periodontal diseases in people with diabetes.

“It is an important step, but there does need to be further dissemination into the public and at the moment that is somewhat country-specific,” states Professor Chapple. He knows something about the crucial aspect of communicating research directly to the public, having been featured in a prime time TV documentary, ‘The Truth About Your Teeth’ on BBC. 

 

The focus for the team now is twofold. Firstly, to mirror their progress with other groups such as patients with cardiovascular disease, and in February 2019 a similar joint workshop will take place between the European Federation of Periodontology and the World Heart Federation. But for the diabetes patients, the drive is to answer some of the big questions on how to best understand the practicalities of changing practice for physicians and dentists. What are the health economics of properly treating periodontitis in diabetes patients? Can dentists be used to help in the early detection of diabetes risk?

Early signs are promising. Working with NHS England, the group have been engaged in a health economic analysis which has shown that treating periodontitis well in diabetes patients would save about £128m per annum, and the early detection of diabetes risk by dentists could lead to £48m in annual savings. It is a sizeable sum that, when aligned with the significant benefit to individual patients, has become the backbone of a commissioning standard, for oral health and diabetes.

“In the next ten to fifteen years, you can see a pathway to dentists being expected to assess risk of diabetes in periodontitis patients in their chair,” predicts Professor Chapple. “But it is a journey. Our job, alongside presenting the evidence base for building our understanding of periodontitis and risk, is to help healthcare providers to carefully manage that journey without putting undue pressure elsewhere in the healthcare system due to inappropriate referrals or other such issues.”

“It is a huge opportunity to help practitioners and patients alike. In the UK, people tend to only visit their GP when they are not feeling well whereas the majority of patients see their dentist on a more regular basis and when they are well. This allows dental teams to practice prevention rather than just cure. The World Health Organisation already sees that interaction as crucial for giving patient guidance on risk factors such as weight loss, smoking, sleep, so it is not much of a departure from that. It would be a real marker for how we see good oral health as being essential for healthy living.”

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