Periodontitis and rheumatoid arthritis (RA) are two common chronic inflammatory diseases sharing a similar hostmediated pathogenesis [1]. Periodontitis is characterized by soft and hard tissue destruction around teeth, ultimately leading to tooth loss [2], while RA is characterized by destruction of cartilage andbone in the joints, mediated by similar boneresorptive cytokines and proteinases [1, 3]. Both diseases lead to significant morbidity, with periodontitis ultimately leading to tooth loss and loss of masticatory function, and RA leading to loss of joint function and loss of mobility

2. • By
• Romissaa Aly Esmail
• Assistant lecturer of Oral Medicine,
Periodontology, Diagnosis and Dental
Radiology (Al-Azhar University)
Periodontitis and Rheumatoid
Arthritis

3. • Contents:
• Introduction
• Etiology of Periodontitis and Rheumatoid
Arthritis
• Periodontal Pathogens may Be Involved in the
Development of RA
• Role of Genetics in RA and in Periodontitis
• Mechanism Linking Periodontitis to RA
• Common Pathogenesis—Common Treatment

4. Periodontitis and rheumatoid arthritis (RA) are two common chronic
inflammatory diseases sharing a similar hostmediated pathogenesis [1].
Periodontitis is characterized by soft and hard tissue destruction around
teeth, ultimately leading to tooth loss [2],
while RA is characterized by destruction of cartilage and bone in the
joints, mediated by similar boneresorptive cytokines and proteinases [1,
3].
Both diseases lead to significant morbidity, with periodontitis ultimately
leading to tooth loss and loss of masticatory function, and RA leading to
loss of joint function and loss of mobility

7. Two‐hit working model for the interplay between gingival
inflammation and subsequent inflammatory joint disease.
(1) Initial inflammation and subsequent Porphyromonas
gingivalis infection leads to (2) citrullination and (3, 4, 5)
subsequent antibody production.
A later event in the joints (6) leads to joint inflammation (7);
localized citrullination; (8) exacerbated antibody response with
amplification of joint inflammation (ACPA, anti–citrullinated
peptide antibody; B, B cell; CPA, citrullinated peptide antibody;
Mϕ, macrophage; PAD, peptidylarginine deiminase; RA,
rheumatoid arthritis; T, T cell; TNF, tumor necrosis factor; Y,
antibody

9. • Figure 2. The
pathogenesis of the
periodontal disease

11. Fig. 1. P. gingivalis is a periodontopathogenic bacterium that secretes two prominent enzymes, gingipains (Rgp and Kgp) and
PPAD. Gingipain endopeptidases cleave proteins in some Arg (Rgp) or Lys (Kgp) sites, leading to producing peptides by Lys or
Arg C-terminal.
Gingipains also convert fibrinogens to fibrins and fibrins into some peptides (part C). In addition, fibrin (ogen) and α-enolase could
also be degraded and converted to peptides by Arg in C-terminal via P. gingivalis gingipains.
The resulted peptides are the preferential substrates for PPAD which turns them into citrulline (part D and A). PPAD can also
citrullinate intact proteins such as fibrin, vimentin, α-enolase, and type II collagens (part C and G). Gingipains degrade IgG in its Fc
regions and convert them to immunogenic RF antigens (part F).
P. gingivalis gingipains increase C5a concentration in periodontal sites by its C5 convertase activity. These bacteria can attract
macrophages and neutrophils to periodontal sites

14. Key: CCP Cyclic
citrullinated peptide,
CRP C-reactive
protein, DAS28
Disease Activity Score
(28 joints), ESR
Erythrocyte
sedimentation rate,
HAQ Health
Assessment
Questionnaire, OHI
Oral hygiene
instructions, RF
Rheumatoid factor,
SRP Scaling and root
planing, TNF-α Tumor
necrosis factor-α

15. Rheumatoid arthritis (RA) is an
autoimmune disease characterized by
chronic inflammation of the joints,
particularly the small joints of the hands
and feet, with progressive destruction
resulting in variable degrees of
deformity and functional disability.
Inflammation plays a key role in the
origin of RA
Rheumatoid arthritis was first described
clinically in an 1800 doctoral thesis by
Landre-Beauvais, a French medical
student who called it the “primary
aesthetic gout”.
Later in 1859, Sir Alfred
Garred established the
distinction between
rheumatoid arthritis and gout
and he called the condition as
rheumatoid arthritis

16. Periodontitis is also a chronic
inflammatory condition initiated by
bacterial accumulation on the
interface between the teeth and
gingiva and modified by genetics,
environments (e.g. smoking) and the
host inflammatory reaction.
The similarities between RA and
periodontitis were first recognized by
Snyderman and McCarty in 1982, and
since then, considerable evidence has
accumulated to support the concept
of a strong interrelationship between
these two inflammatory conditions

20. Table 1 The 2010 American
College of Rheumatology/
European League Against
Rheumatism classification
criteria for RA

22. Etiology of Periodontitis and
Rheumatoid Arthritis

23. Etiology of Periodontitis
Periodontitis results from microbial imbalance
of the oral microbiota especially due to “red
complex”, which includes Porphyromonas
gingivalis, Treponema denticola and Tannerella
forsythia.
The bacteria of the red complex, along with
Aggregatibacter actinomycetemcomitans, are
unwanted visitors in the heterogenous
microbiome which is present on the tooth
surface.

24. Due to this, the pathogens are
resistant to attack by phagocytes and
bactericidal proteins, peptides and
reactive oxygen species, and are thus
difficult to eradicate, leading to the
development of a chronic
inflammatory reaction
which causes periodontal
tissue damage and the
erosion of tooth-supporting
structures due to
dysregulation of innate
immune response against
the bacteria.
The consequences of
periodontal
inflammation in the
form of overactive
neutrophils and high
levels of inflammatory
molecules (such as
cytokines and CRP),
can be detected in the
blood of patients with
periodontitis

25. • RA is a systemic autoimmune disease of joints characterized by chronic, painful
inflammation of joints, disability and increased mortality which affects up to 0.5–
1.0% of the global population
• Though the cause of RA is still ill-defined, however, it is thought to be triggered
by a combination of genetic and environmental factors that lead to the collapse
of immune tolerance at mucosal surfaces, specifically the lungs, gut and
periodontium.

26. The autoimmune response is characterized by the
production of rheumatoid factor and ACPAs [11] which
bind to citrullinated epitopes in the joints and lead to
the formation of immune complexes containing
rheumatoid factor which promotes tissue damage by
activation of synovial macrophages and dendritic cells,
and the release of proinflammatory cytokines and
tissue-degrading enzymes
Also, peptidylarginine deiminases (PADs) which are
released from neutrophils during necrosis or during
the production of eutrophil extracellular traps
citrullinate proteins in the joints which results in a self-
sustained local immune reaction

27. Citrullination occurs
naturally in vivo and
has an important role
in the normal
functioning of the
immune system and in
physiological processes
such as skin
keratinization, the
insulation of neuronal
axons, maintaining
plasticity in the central
nervous system and in
gene regulation via
chromatin remodelling.
The post-translational
modification of
proteins by the
enzymatic deimination
of arginine residues
converts these
positively charged
remnants into a neutral
citrulline residue
Moreover,
deimination of
arginine residues
can occur under
pathologic
inflammatory
conditions
associated with
apoptosis and
necrosis of
neutrophils

28. Periodontal Pathogens Involved in the
Development of RA

29. Periodontal pathogens are organized in a
biofilm with the other groups of bacteria
and may be able to incite a chronic
continuous infection.
The suspected periodontal pathogens have
been shown repeatedly to be present in most
individuals suffering from various forms of
periodontal disease.

30. • The biofilm in periodontitis serves as an abundant supply of
lipopolysaccharides (LPS), thereby easily fulfilling the fourth
requirement of chronic LPS exposure.
• Furthermore, the local production of IgA and IgM in periodontal
disease has been demonstrated although the ability of the LPS from
the periodontal biofilm to cross-react with the cartilage to cause an
anti-cartilage response has not been demonstrated, it is logically
possible

31. Role of Genetics in RA and in
Periodontitis

32. Of these, IL-1, TNF-α and PGE2 have been found to be
under quite strong genetic control.
Studies focusing on overproduction of “hyper-responsive
monocyte genetic traits” have shown common genetic
origin that influence the susceptibility to inflammatory
diseases especially the proinflammatory mediators such
as IL-1β, TNF-α and PGE2 which are typically seen in
patients with aggressive periodontitis.

33. • The concept of a monocytic hypersecretory
state has also been described for rheumatoid
arthritis patients .
• Many of the genes that regulate the cytokine
profiles and responses of monocytes have been
mapped to the human leukocyte antigen D–
related (HLA-DR) region of chromosome 5 in the
area of the TNF-β genes.

34. Mechanism Linking Periodontitis to
RA

35. Involvement of P. gingivalis and A. actinomycetemcomitans as
microflora in gut and gums are major contributing factors in
progression of RA and periodontitis [10].
In RA, increased immune responses to P. gingivalis and ACPA levels in
healthy individuals who go on to develop RA at a later date (so-called
pre-RA) have been noticed [34, 36].
This theory was supported by Nagahama in 2015, who reported a
correlation between ACPAs and periodontitis parameters (such as
the number of missing teeth, community periodontal index and
clinical attachment loss) in 9554 healthy adults

36. • The immuno-pathogenesis of periodontitis involves both
innate and adaptive immune systems.
• P. gingivalis acts as the antagonist in disrupting the
homeostatic balance between the subgingival commensal
microflora and the host defense system. Lipopolysaccharide
(LPS), the cell surface protein of P. gingivalis and A.
actinomycetemcomitans, is recognized by toll-like receptors
(TLRs) found on resident cells including epithelial cells and
mast cells.
• The activated resident cells release IL-8, creating a
chemotactic gradient that drives the trans-endothelial
migration of neutrophils towards the infection site (gingival
sulcus) to phagocytose the microbes.
• Neutrophils can also kill microbes by releasing neutrophil
extracellular traps (NETs), during which lysosomal enzymes i.e.
myeloperoxidase and matrix metalloproteinase (MMP) are
aborted to destroy the microbial colony

37. P. gingivalis affects the
inflammatory status of the joints
by deregulating the local immune
responses in the periodontium. A.
actinomycetemcomitans,
bacterially secreted leukotoxin,
is directly responsible for releasing the
hypercitrullinated cargo from neutrophils
at sites of periodontitis, and these titres
of antibodies which are specific for the
bacterium (and the toxin itself) are
strongly associated with the presence of
ACPA and rheumatoid factor in patients
with RA

38. Current evidence suggests that a combination of genetic
and environmental risk factors are involved in the
pathogenesis of RA.
Certain environmental triggers such as stress, smoking and infectious
agents can precipitate post-translational modification of proteins as a
physiological process, but the modified proteins may break the
immune tolerance in genetically susceptible individuals, leading to
autoantibody production.
The circulating autoantibodies form immune complexes with
autoantigens, and in the event of trauma or infection, the immune
complexes gain access to the synovial space through dilated vessels. As
a result, the classical complement pathway is activated and leukocyte
recruitment is stimulated.
The pro-infl ammatory cytokines generated by immune cells alters the
metabolism of fi broblast-like synoviocytes (FLS).
Instead of synthesizing extracellular matrix components, FLS secrete
matrix metalloproteinases and cytokines that degrade the cartilage
tissue and induce osteoclastogenesis.

39. • Recent investigations into the relationship between
osteoclast activation and vascular damage have suggested
a common pathway in the development of periodontitis
and rheumatoid arthritis.
• It has been hypothesized that both rheumatoid arthritis
and periodontitis share common molecular pathways
within the receptor activator of nuclear factor kappa β
(RANK)/ osteoprotegerin (OPG)/tumour necrosis factor–
related apoptosis-inducing ligand (TRAIL) axis, whereby a
decrease in OPG leads to reduced vascular protection

40. • Fig. 1
• A hypothetical “two-hit” model of induction of
chronic destructive periodontitis. The first “hit” involves
the periodontopathic subgingival biofilm and its
microbial products, such as endotoxin.
• The second “hit” involves a medical systemic
disease, such as (but not limited to) rheumatoid
arthritis and post-menopausal osteoporosis, which
increases biomarkers of systemic inflammation in the
circulation, including C-reactive protein (CRP),
cytokines (e.g. IL6), prostanoids (e.g. PGE2) and
matrix metalloproteinases (e.g. MMP-9). CVD,
cardiovascular disease

41. Among periodontal pathogens, P. gingivalis
possesses a diverse range of PAMPs, including
LPS, fimbriae and gingipains which ensure the
activation of a broad range of immune
receptors such as TLR2, TLR4, nucleotide-
binding oligomerization domain–containing
protein 2 (NOD2) and proteinase-activated
receptor 2 (PAR2), and explain the dominant
role of P. gingivalis in the development of
inflammation [48].
Dysregulation of the cytokine network
and aberrant activation of leukocytes
participating in the innate immune
response to periodontal pathogens
could therefore be another explanation
for the clinical and epidemiological link
between periodontitis and RA.

43. Chronic inflammation impairs
the immune system and thus
creates an environment that is
ideally suitable for the
breakdown of immune
tolerance.
Increased amounts of damage to cells
in inflamed tissue, along with high
concentrations of calcium ions,
promote the activity of PADs.
This enzyme activity, along with the
release of intracellular proteins, results in
the rapid and uncontrolled generation of
citrullinated epitopes, which trigger the
autoimmune responses via the binding of
ACPAs

44. • The citrullination of autoantigens in synovial
tissue and at other mucosal sites, such as the
inflamed gingiva, is a prerequisite for the initiation
and maintenance of autoimmune reactions in
patients with RA.
• Since the generation of citrullinated epitopes
depends upon PADs, their importance in the
generation of the autoantigens that drive
autoimmunity in RA is unquestionable

52. Common Pathogenesis—Common Treatment

53. Currently, the mainstream “first-line” modes of treatment
for RA remain the NSAIDs such as aspirin, naproxen,
diclofenac and ibuprofen. Their mechanism of action
through the inhibition of cyclooxygenase (COX) synthesis
produces both analgesic and antipyretic properties.
While these medications are effective in reducing the pain
symptoms in RA, they do not significantly alter its course [67].

54. • Corticosteroids are more potent anti-inflammatory medications
compared with NSAIDs; however, they come with greater side
effects.
• For this reason, they are only indicated for a short period of time
at low dosages, during exacerbations or flares of rheumatoid
arthritis.
• Intra-articular (IA) injections of corticosteroid can be used for local
symptoms of inflammation [70].
• They work by preventing phospholipid release and decreasing actions
of eosinophils, therefore decreasing inflammation. Their side effects
include bone thinning, weight gain, diabetes and immunosuppression. A

55. • In contrast to the NSAIDS, which do not significantly
alter the course of RA, a newer family of medications
designated as disease-modifying anti-rheumatic drugs
(DMARDs) has been developed.
• To be classified as a DMARD, the medication
must demonstrate an ability to change the
course of RA for at least 1 year as evidenced by
sustained improvement in function, decreased synovitis
and prevention of further joint damage.
• Examples of these medications include parenteral gold
salts, methotrexate, sulfasalazine, hydroxychloroquine
(antimalarial drug), penicillamine, azathioprine and
leflunomide.

56. Biological disease-modifying anti-rheumatic drugs
(bDMARDs) are very much effective in retarding the
progression of joint damage caused by rheumatoid
arthritis.
Though it is the most “direct, defined and targeted”
method of treatment, it has some serious side effects,
such as increased risk of infections and neurologic
disease similar to multiple sclerosis and lymphoma

57. For example, blocking the IL1 receptor and using gene therapy to
deliver IL-1 receptor antagonist are two strategies under investigation
to modulate the effect of elevated IL-1 in inflamed tissues.
Control of cytokines and their
receptors is also emerging as a
field of considerable promise.

58. • Fig. 2 Proposed mechanisms underlying the links between periodontal
disease and the pathogenesis of rheumatoid arthritis [25]. a In response to
Porphyromonas gingivalis infection, neutrophils can release neutrophil
extracellular traps (NETs), structures characterized by active proteases and
peptidylarginine deiminases (PADs). The concomitant action of these enzymes
generates citrullinated epitomes and triggers the synthesis of anti-citrullinated
protein antibodies (ACPAs).
• The production of citrullinated epitomes is accelerated by the synergistic
action of gingipains and P. gingivalis peptidylarginine deiminase (PPAD), both of
which are unique to P. gingivalis. Molecular mimicry by some bacterial proteins
(such as bacterial enolase with human α-enoase) is also involved in the
breakdown of immune tolerance to host molecules.
• A secondary signal directed against citrullinated epitopes in the joints leads
to increased production of rheumatoid factor and ACPAs, leading to
accumulation of immune complexes. b Neutrophils attractive to the gingival
crevice undergo necrosis, thereby releasing damage-associated molecular
patterns (DAMPs), which accelerate local and systematic inflammation.
• c In the infected periodontium, virulence factors expressed by P.
gingivalis, such as lipopolysaccharide, fimbriae, gingipains and lipoproteins,
are recognized by Toll-like receptors, protease-activated receptors and/or
nucleotide-binding oligomerization domain–containing 2 (NOD2) receptors
on gingival epithelial cells and phagocytes, such as dendritic cells

59. • Tumour necrosis factor (TNF) is one of the
messenger proteins that promotes inflammation in
joints. Biologic medications such as etanercept
(Enbrel), infliximab (Remicade), adalimumab (Humira),
golimumab (Simponi) and certolizumab pegol (Cimzia)
are all TNF inhibitors.
• These inhibitors mainly prevent the recruitment of
cells that cause inflammation and thus cause rapid
symptom relief. These medications are often used in
combination with other DMARDs, especially
methotrexate.
• TNF inhibitors are contraindicated in patients with
congestive heart failure of demyelinating diseases

60. Anakinra (Kineret) is a drug that is injected
subcutaneously daily and works by binding to
interleukin 1 (IL-1), another chemical messenger of
inflammation.
It can be used in combination with other DMARDs or as
monotherapy, but as the drug has a lower response rate than
other biologics, it is not used as frequently .
Another drug rituximab (Rituxan) is
useful in RA because it depletes B
cells, responsible for inflammation
and production of abnormal
antibodies.

61. Abatacept (Orencia) another biologic medication works by blocking activation of T cell. Mainly given
by intravenous infusion once a month or subcutaneously once a week, it is used in patients who
were not effectively treated with traditional DMARD medications [83].
Tocilizumab (Actemra) is another biologic that works by blocking interleukin 6 (IL-6).
It is administered via intravenous infusion given monthly or via weekly subcutaneous injections. It is
also used for patients who have not been effectively treated with traditional DMARD medications
[84].
Lastly, tofacitinib (Xeljanz) is a JAK inhibitor works by blocking Janus kinases within cells, which are
enzymes of inflammation.

62. Another emerging area of potential
for host modulation in periodontitis
and rheumatoid arthritis is control of
the matrix metalloproteinases
(MMPs) that are important mediators of
connective tissue breakdown in both hard
and soft tissues.
In this regard, tetracyclines and various
chemical analogues have been found to
inhibit MMP activity by a mechanism that
is independent of their antimicrobial
property
A number of clinical trials using low-
dose tetracycline to modify
periodontitis have been carried out,
with the most recent data indicating
that low-dose doxycycline is safe and
significantly effective

63. With the emerging understanding
that RA and periodontitis are
multifactorial diseases,
combination therapies that target
multiple disease outcomes are also
emerging.
For example, in an animal study, it
was reported that the
administration of a combination of
a chemically modified tetracycline
(CMT-1) plus an NSAID, such as
flurbiprofen or tenidap,
synergistically inhibited severe
bone destruction in arthritic rats,
with the suppression of MMP
activity in the joints.
Similar encouraging results have
been reported for periodontitis in
humans [