Periodontal disease

Question 1

what are examples of periodontal diseases (PD)?

Answer 1

PD: gum diseases
- tends to refer to periodontitis

Gingivitis - inflmmation of gums (gingi)
Periodontitis

Question 2

what is periodontitis/PD?

Answer 2

Chronic inflammatory disease
- most common inflammatory disease, affecting over a third of the population
- loss of periodontal ligament - attachment loss
- loss of alveolar bone - bone loss
- root surfaces exposed with gingival recession due to destruction of connective tissue attachment - red and swollen gums gums
- large spaces between lower teeth - signs of drifting due to bone loss
- Destruction of attachment system and neighboring bone loss due to chronic inflammation

Question 3

how does bone loss occur in PD?

Answer 3

can be seen by radiographs:
- Roots and teeth in tact in no PD – healthy bone between roots - marginal bone levels are consistent
- PD: significant bone loss, teeth move and fall out due to no attachment - resorption of 50-60% of bone in mandible. marginal bone levels are reduced

Question 4

what does PD lead to?

Answer 4

PD is a major cause of tooth loss if left untreated
affects:
- functional and esthetic sequelae
- dietary quality
- nutrient intake
- quality of life
- can lead to complete tooth loss

Question 5

how does the tooth root surface section change with PD in a micrograph?

Answer 5

Gum attached to the tooth
- Gum/gingival epithelium
- Left = tooth root surface - calculus forms
- Calculus = plaque
- periodontal pocket - space formed between gum and tooth surface
- an ulcerated pocket forms in the gingival epithelium
- Chronic infiltration of cells near ulcerated pocket in the subepithelial connective tissue – inflammation below the ulcer

Question 6

how does PD affect systemic inflammation?

Answer 6

area of ulceration in gingival epithelium is an area as large as 8-20cm2 inside the mouth, depending on severity
- very large
- Each ulceration can be colonised by 1 million to 10 billion bugs per site
- In mouth of PD patient, over >500 ulcer sites
- Massive lesion and inflammation
- PD complex can impact systemic inflammation

Question 7

is PD linked to increased mortality?

Answer 7

Association between gum and heart disease and mortality
- flossing and dental hygiene is crucial in PD management
- PD is the most prevalent chronic inflammatory disease

Question 8

how prevalent is PD and what can it cause?

Answer 8

most prevalent chronic inflammatory disease, >30% of older adults affected in the UK
- people with PD are more likely to have other systemic diseases: CVD and stroke, chronic kidney disease, COPD, RA
- evidence indicates that this association in part may be causal

Question 9

why is the link between RA and PD important?

Answer 9

• an association between PD and RA is important from a clinical and public health perspective
• PD may be part of a causal pathway in RA pathogenesis
• a significant proportion of RA incidence and mortality attributed to PD
• PD could represent a modifiable risk factor for RA
• even if association is non-causal, PD would contribute to RA morbidity

Question 10

what is the association between RA and PD? what are the limitations of these studies?

Answer 10

meta-analysis summarises evidence
- Positive association between RA and PD

Question 11

how may the meta-analysis be limited?

Answer 11

the meta-analysis included small case-control studies (patients recruited from dental clinics, whereas controls were healthy volunteers working in the clinics - no age or sex matching) - leads to selection bias which could over/underestimate the true association
- need larger sample
- used studies which had widespread methods/design/ setting and different definitions of RA (some used self-reported symptoms, others used a criteria/clinical score ACR)
- wide variation in assessment of PD, no consistent definition criteria - some studies used serological markers e.g. antibodies to pathogens, but these don’t correlate with clinical phenotype
- some studies used self-reported markers of PD which lack validity

Question 12

what have population-based studies shown about PD and RA associattion?

Answer 12

> 4000 patients aged over 65
- RA based on ACR, PD based on dental exam measures (attachment loss and probing depth)
- outcome: looked at dental health status and grouped: dentate with no PD (healthy control), dentate with PD, edentate (loss of all teeth)

People with RA had 4x increased risk of PD and over 3x more likely to have complete tooth loss
- Independent of age, gender, race, smoking etc

Stratified for RF seropositivity in RA patients:
- RF+ RA more likely to have PD and edentate compared to RF-
- complete tooth loss highly likely in those with RF+ RA
- independent of age, sex, race, smoking

Question 13

what possible pathways can occur in the association between PD and RA?

Answer 13

• PD can be causal factor in RA pathogenesis through various pathways
• susceptibility to chronic inflammatory diseases e.g. PD, RA can be determined by environmental exposures, genetic factors which can be common for both diseases
• also, RA may predispose to PD
• dental treatment preferences may be different in RA patients which may result in increased tooth loss
• comorbidity of RA with sjorgen’s can lead to dental cavity and decay and may result in tooth loss if untreated
• poor oral hygiene related to reduced dexterity of RA patients could lead to tooth decay and PD
• low bone mineral density/osteoporosis can be associated with RA itself and RA medications like GCC, which can be related to PD, and the drugs may improve PD
• socioeconomic factors pose risk

Question 14

how can RA treatments impact PD?

Answer 14

the RA drugs may actually improve PD

OR

RA medication can suppress the immune system, so bacteria in gums persist

also GCCs can affect the bone in mouth and lead to resorption

Question 15

what are the key PD pathogens?

Answer 15

periodontal pathogens may explain link between RA and PD, as they play a role in breaking immune tolerance to citrullinated antigens, leading to RA development

e.g.:
- porphyromonas gingivalis (Pg)
- Aggregatibacter actinomycetemcomitans (Aa)
- oral microbiome as a whole has been implicated

Question 16

what is the citrullination process?

Answer 16

citrullination is a normal process across multiple tissues: e.g. NETosis response of neutrophils can trigger CCP production
- Netosis in gums or joint can lead to ACPA
- post-translational modifications to arginine by peptidylarginine deaminases (PADs), which replace arginine side chain with citrulline
Citrullination is a molecular mechanism that generates citrullinated neo/autoantigens that drive immune response in RA
- these modified peptides can cause development of ACPAs

Question 17

what are ACPAs?

Answer 17

Anti-citrullinated peptide antibodies
- highly specific for RA (98%)
- biomarkers of disease severity and progression
- may appear up to 14 years prior to RA onset
- risk factors for ACPA+ RA: HLA-DRB1 shared epitope, PTPN22, smoking
- smoking is an important risk factor for both PD and RA

Question 18

what is the ACR RA classification critera?

Answer 18

Early RA identification is important, so ACR is used:
- no. and site of involved joints
- increased acute phase response e.g. CRP, ESR
- symptom duration
- autoantibodies: RF, ACPA

Question 19

what is the etiological hypothesis linking PD to RA?

Answer 19

• loss of tolerance to citrullinated antigens is an early event that precedes the onset of RA
• factors that dysregulate citrullination in presymptomatic stage of RA can include PD
• PD and oral pathogens (Pg and Aa) have been associated with production of citrullinated antigens in RA
• Pg has a bacterial PAD enzyme (PPAD) which citrullinates proteins
• Aa has a different citrullination mechanism, where it secretes lymphotoxin A, a pore forming toxin that induces neutrophil death, leading to leukotoxic hypercitrullination mediated by host PADs
• hypothesised that citrullination/hypercitrullination leads to amino acid chains being recognised as autoantigens, leading to ACPA production and autoimmune damage in RA

Question 20

what evidence supports the etiological hypothesis linking PD to RA?

Answer 20

• citrullinated proteins are present in gums of PD patients
• ACPA and RF are present in PD patients

Question 21

how was the model of RA and PD studied?

Answer 21

to understand the etiological model of RA and PD pathogens, they tested ACPAs and their uncitrullinated controls in a sample of patients without RA who had been diagnosed with PD, and compared them with non-PD healthy controls

Question 22

what were the key autoantigens tested in the etiological model looking at differences in antibody titres?

Answer 22

citrullinated-vimentin (cit-vim)
vimentin (vim)

CEP-1 (citrullinated amylase)
REP-1 (amylase)

citrullinated fibrinogen (cit-fib)
fibrinogen (fib)

Question 23

how do antibody titres compare in patients with or without PD

Answer 23

In people with PD compared without PD, looked at % difference in antibody titres
- These patients didn’t have RA
- Citrullinated antibodies and arginine controls
- PD patients all had higher levels of ACPA and antibodies to uncitrullinated arginine controls

univariate analysis: serum antibody titers were higher for antibodies against cit-vim, vim, CEP1, REP1, fib

Light blue = multivariate response – accounts for factors that affect results e.g. as we age we have more autoantibodies, sex as women more likely to have AI, smoking as it can cause RA and PD
- Even with this, ACPAs are significantly increased in PD compared to those without PD for the same autoantigens, particularly CEP1, REP1, fib

Question 24

how does stratification for smoking affect antibody titres in PD vs non-PD patients? include summary

Answer 24

• there is a significant interaction with smoking and anti-vim and anti-CEP1 ACPAs compared to non-smokers
• % difference in antibody titres are higher among non-smokers compared to smokers
• non-smokers had higher titrers of antibodies against CEP1, REP1 and vim, independent of age and sex
• anti-fib was elevated in both groups compared to healthy controls

summary:
- in patients withut RA, PD is associated with higher titres of antibodies to both citrullinated and uncitrullinated peptides
- this suggests that tolerance breakdown in non-smokers with PD may be initiated with uncitrullinated peptides, with spreading to citrullinated epitopes as the autoimmune response evolves into pre-symptomatic RA

Question 25

are antibodies against arginine-containing peptides present in pre-RA states?

Answer 25

Antibodies against arginine-containing peptides from RA autoantigens were present in a population-based study sample of 386 patients with pre-RA - Looked at antibodies in people who didn’t have RA but got RA years later - Citrullinated measure and arg control of same peptide - Seropositivity to citrullinated peptides were higher in pre-RA than control, with frequency between 4-21%, but some seropositivity arginine peptides are elevated too, varying between 1-11% - frequency of positivity for citrullinated peptides higher compared to arginine peptides, which was lower except for anti-vim

Question 26

do antibodies to uncitrullinated peptides occur before corresponding ACPA development?

Answer 26

Years before disease onset: - anti-arginine antibodies were detected 14 years before onset - significantly earlier compared to antibodies corresponding to citrullinated peptides - e.g. anti-REP1 detected 12 years before RA diagnosis, whereas anti-CEP1 detected 5 years before onset Antibodies against uncitrullinated peptides seem to occur prior to antibodies against corresponding citrullinated peptides - arginine antibodies predate citrullinated antibodies, which appear closer to onset of symptoms

Question 27

what do the results of antibody seropositivity in RA show?

Answer 27

suggests that there are 2 stages of ACPA development: 1. antibodies against arginine peptide appear 2. antibodies against citrullinated peptides develop we can only speculate that PD has contributed to increased autoantibody seropositivity in pre-RA sample, as the sample wasn't examined for PD - PD is a common disease, prevelance of about >30% among 40 year olds in sweden, so may drive the antibody changes

Question 28

how do these results affect the etiological hypothesis linking PD to RA?

Answer 28

- in inflammatory context of PD, ctrullinated antigens are produced, to which the immune system mounts humoural response with production of autoantibodies against uncitrullinated peptides first, then against citrullinated peptides (ACPAs against autoantigens) - inflammation-induced citrullination by PAD in the gums may occur in relation to microbiome dysbiosis, bacteria and netosis - inflammation in joint leads to activation of PAD and citrullination of host proteins - ACPA binds citrullinated proteins which causes molecular mimicry in smokers/genetic predisposed people, leading to epitope spreading and sustained immune response with high affinity antibodies to citrullinated proteins in ACPA+ RA Disease progression from asymptomatic – exposure to gum disease and smoking drive ACPA – develop symptoms and inflammation - RA

Question 29

how can PD be tested as a causal factor for RA?

Answer 29

Test intervention compared to no intervention group - intervention trials are critical to explore PD and RA relationship - Take RA patients and treat for PD to see if their symptoms improve - If they get better, then PD causes RA - if the association is causal, successful PD therapy will attenuate/reduce RA disease activity

Question 30

is there much evidence showing causal relationship of PD and RA?

Answer 30

no, few small studies - effect of PD treatment in patients with RA and PD - beneficial effect on ESR, TNFa - DAS (disease activity score) improvement - lower DAS28 score, symptoms and signs improved, decreased severity driven by inflammation markers limitations: treatment of PD reduces inflammation markers anyway

Question 31

what is the OPERA trial?

Answer 31

outcomes of periodontal therapy in RA - pilot study, randomised controlled trial - primary outcomes: feasibility of trial, recruitment and retention rates, acceptable study design - looked at proportion of patients with RA - secondary outcomes: pilot data on efficacy and safety of the intervention to reduce disease activity - endpoints: PD pain endpoints to assess severity of PD, DAS28, tender and swollen joint counts, ESR, CRP, global disease activity assessment, EULAR, musculoskeletal ultrasound Dental exam to obtain fluid and plaque - Assess PD And used Musculo-skeletal ultrasound to monitor RA - Gives objective image to see difference that isn’t invasive - Better than self-reported measure of joitn pain Use probe to see how deep it goes in gum – indicates bone loss - DAS for RA – number of damaged joints, inflammatory markers, symptoms – number – high number = severe

Question 31

what did patients need to present with to be included in OPERA trial?

Answer 31

active RA - DAS28 score needs to reflect active disease - previously treated with DMARD PD: moderate to severe PD - clinical attachment loss - cumulative probing death Needed to have both conditions - Used over 600 RA patients - Over half consented to dental exam - 100 didn't meet PD criteria - Screened 200 people - Randomised 60 to treatment or control - overall 6 month follow up of only 18%

Question 32

what were the stratifications in the OPERA trial?

Answer 32

stratified randomisation based on gender, age and ACPA - treatment group: non-surgically treated for PD straight away, oral hygiene - control group: oral hygiene only, delayed PD treatment for 6 months

Question 33

how did PD treatment affect periodontal inflammation surface area (PISA) in OPERA trial?

Answer 33

PISA = size of ulcerated surface in PD pocket in patients - PISA similar at baseline in both groups - Treatment reduces size of ulcer significantly and much faster than control, at both 3 and 6 month follow ups

Question 34

how did PD treatment affect the RA DAS28-CRP score in OPERA trial?

Answer 34

For RA, treatment does decrease DAS for RA in 3 months - significant reduction in DAS in treatment group compared to control group at 3 and 6 months - But at 6 months DAS does worsen – this could be due to flare up, other driver of disease, but mainly due to treatment of gum disease requiring patient compliance to go to the dentist, brush teeth, floss – patients may not do this properly after 3 months, so RA symptoms may get worse

Question 35

how did PD treatment affect the ultrasound measures of synovitis in OPERA trial?

Answer 35

Ultrasound - Left = greyscale measure of synovitis and synovial hypertrophy – bone with joint space - Right = measures active inflammation and angiogenesis in joint Treatment is effective in reducing synovitis at first in 3 months but reverts to synovitis at 6 months, similar to previous response

Question 36

what were the key results from the OPERA trial?

Answer 36

PD treatment improves probing depth and PISA, but no complete resolution in PD inflammation achieved, and depends on patient compliance with instructions PD treatment improves patient global RA disease activity (DAS28-CRP) and ultrasound synovitis - definitive trial of PD treatment in RA is worthwhile