DOI: 10.1111/prd.
12300
REVIEW ARTICLE
Periodontitis and rheumatoid arthritis: An update 2012‐2017
Peter Mark Bartold1 | Isabel Lopez‐Oliva2
1
Department of Dentistry, University of Adelaide, Adelaide, South Australia, Australia
2
Periodontology department, Queen Mary University London, London, UK
Correspondence
Peter Mark Bartold, Department of Dentistry, University of Adelaide, Adelaide, SA, Australia.
Email: mark.bartold@adelaide.edu.au
1 | I NTRO D U C TI O N
Rheumatoid arthritis and chronic periodontitis have been thought to
be interrelated diseases for many years.1 Despite this, the connection
has been considered unclear. Indeed, as recently as 2013, the pro‐
ceedings from a workshop jointly held by the European Federation
of Periodontology and American Academy of Periodontology in
2012 reported that epidemiological data on this relationship, includ‐
ing the National Health and Nutrition Examination Survey data set
and case‐control studies, were inconsistent. However, at this time,
there was good evidence in the literature from animal studies to
demonstrate biological plausibility for such a relationship. For exam‐
ple, Porphyromonas gingivalis can induce and exacerbate a rheuma‐
toid arthritis‐like condition in susceptible rodents. 2-4 Furthermore,
it had been demonstrated that antibodies against citrullinated pro‐
teins and peptides are often detected in the blood of rheumatoid
arthritis patients and similar citrullinated proteins can be found in in‐
flamed human gingiva.5,6 From this, it was concluded that there was
at least minimal evidence of an association between periodontitis
and rheumatoid arthritis.7 Since this workshop in 2012, considerable
work has been carried out to further study the relationship between
periodontitis and rheumatoid arthritis. The purpose of this review
is to consider what has been published since the 2012 workshop
and determine whether the evidence has moved from “minimal” to
“substantial.”
2 | PU B LI C ATI O N S 2 012‐2107
Since the consensus statement of the conjoint European Federation
of Periodontology and American Academy of Periodontology work‐
shop on periodontal and systemic interrelationships7 there have
been 152 papers published in the field of periodontal disease and
rheumatoid arthritis (Table 1; Figure 1). These papers include both
Periodontology 2000. 2020;83:189–212. wileyonlinelibrary.com/journal/prd
human and animal studies but exclude any in vitro studies. An analy‐
sis of all papers published in the field since 2000 demonstrates a
very significant increase in activity in this field since 2012 (Figure 1).
Apart from a very large number of reviews, the main areas these
publications have focused on over the period 2012‐2017 are animal
pathogenesis studies, citrullination and anti–citrullinated antibod‐
ies, cohort studies, effect of periodontal treatment on rheumatoid
arthritis, effect of rheumatoid arthritis treatments on periodontal
disease, investigating possible underlying molecular mechanisms of
the association, and the role of bacteria in the association (Table 2).
Accordingly, this review will focus on these areas as the basis for
determining the strength of an association between periodontal dis‐
ease and rheumatoid arthritis.
2.1 | Animal studies
Animal studies can provide a reasonably well‐controlled environ‐
ment to study specific diseases, as well as disease associations. Prior
to 2012, several seminal studies had been carried out demonstrating
a strong relationship between experimental periodontitis and ex‐
perimental arthritis.3,4,8 Interestingly, from these studies it became
apparent that this relationship was bidirectional in nature, in that
experimental periodontitis could result in joint changes without any
other induction of experimental arthritis and vice versa, in that ex‐
perimental arthritis could induce changes in the periodontium with‐
out any addition induction of experimental arthritis.
For the period 2012‐2017 there were 17 animal studies iden‐
tified as being of significance to the investigation into the rela‐
tionship between rheumatoid arthritis and periodontal disease
(Table 3).9 Some of these studies were confirmatory of earlier
studies and added further strength to the already documented
associations between these two diseases.9,10,13 The bidirectional
nature of the relationship was also confirmed in a study investigat‐
ing how chronic periodontal inflammation contributed to immune
© 2020 John Wiley & Sons A/S. | 189
Published by John Wiley & Sons Ltd
190 | BARTOLD and LOPEZ‐OLIVA

activation and associated joint inflammation. 20 A number of these
studies progressed the field significantly by beginning to unravel
the role of citrullination and peptidylarginine deiminase activity
in the periodontium in relation to subsequent arthritis develop‐
ment. Although these studies demonstrated that a peptidylargi‐
nine deiminase enzyme produced by P. gingivalis could have a role
in the association between rheumatoid arthritis and periodonti‐
tis, a number of questions remained unanswered. For example,
although infection with a peptidylarginine‐deiminase‐deficient
strain of P. gingivalis diminishes the severity of experimental ar‐
thritis compared with infection with wild‐type P. gingivalis,11 there
is still ongoing debate concerning asscarthritis. 21,22 Several key is‐
sues remain unresolved with regard to whether this effect is truly
related to P. gingivalis‐associated peptidylarginine deiminase, re‐
duced virulence of the mutant strain, a general feature of infection
by periodontal pathogens, or indeed unrelated to specific bacteria
and more related to levels of inflammation. The remaining import‐
ant issues are:
P. gingivalis virulence, resulting in more severe periodontitis.
Hence, the degree of periodontitis, rather than antigen citrulli‐
nation and anti–citrullinated protein antibody production, could
influence inflammatory arthritis severity.
• In this context, although many animal studies suggest that more
severe periodontal disease intensifies experimental arthritis, es‐
tablishing that aggravation of arthritis in this model is unique to
P. gingivalis–associated periodontal disease, but not observed with
other periodontal pathogens, is of great importance. Therefore,
studies investigating the roles of P. gingivalis and peptidylargi‐
nine deiminase as unique drivers of experimental arthritis will
provide a framework in which to address therapeutic questions.
Interestingly, studies are beginning to emerge demonstrating that
P. gingivalis is not the only bacteria that can be implicated in the
relationship between periodontal disease and rheumatoid arthri‐
tis, with Treponema denticola and Tannerella forsythia also being
demonstrated to play a potential role in the exacerbation of ex‐
perimental arthritis. 25

• Since peptidylarginine deiminase is a major virulence factor of The overall relevance of animal studies must be kept in context,
P. gingivalis, the finding that experimental periodontitis is mit‐ because no experimental model can fully replicate the human condi‐
igated when induced by strains deficient in peptidylarginine tion; nonetheless, the various animal models used for experimental
deiminase is not surprising. By catalyzing deimination of arginine, arthritis and periodontitis induction will allow us to study some of
peptidylarginine deiminase may convey a survival advantage to the mechanisms associated with citrullination and development of
P. gingivalis through the generation of ammonia. 23,24 Thus, pepti‐ arthritis. However, interpretation of any findings must be made in the
dylarginine deiminase function may directly, or indirectly, increase context that animal models do not completely reflect the complexi‐
ties of human disease for both periodontitis and rheumatoid arthritis.
a
TA B L E 1 Total number of publications published between
2000 and 2017 in reporting on the interrelationship between
2.2 | Cohort studies
periodontitis and rheumatoid arthritis
Prior to 2012 there had been many cohort studies published inves‐
Year of publication Number of publications
tigating the relationship between periodontal disease and rheuma‐
2000 3
toid arthritis.15 Over the last 20 years, many studies have identified
2001 1
an association between periodontitis, tooth loss, and rheumatoid
2002 0 arthritis. Of these, eight cross‐sectional studies were published be‐
2003 1 tween 2000 and 2012 that had study populations of more than 60
2004 0 subjects. 26-33 Only one of those studies reported negative results,
2005 3 and the remaining seven reported a higher risk and prevalence of
2006 4
2007 6
2008 6
2009 11
2010 18
2011 11
2012 17
2013 18
2014 22
2015 27
2016 33
2017 35
a
Search of papers in English in the Web of Science database using the F I G U R E 1 Number of publications published in the field of
search words “periodont* and rheumatoid.” periodontics and rheumatoid arthritis between 2000 and 2017
BARTOLD and LOPEZ‐OLIVA
TA B L E 2 Number of publications published between 2012 and
2017 in specific fields of study relating to the interrelationship
between periodontitis and rheumatoid arthritis
Number of
Topic of investigation publications
Reviews 37
Animal pathogenesis studies 12
Citrullination and anti–citrullinated antibodies 17
Cohort studies 18
Effect of periodontal treatment on rheumatoid 13
arthritis
Effect of rheumatoid arthritis treatments on peri‐ 12
odontal disease
Investigations into the possible underlying mo‐ 18
lecular mechanisms of the association between
rheumatoid arthritis and periodontal disease
Role of bacteria in the association 22
Genetic studies 3 One of the most studied periodontal bacteria in relation to rheu‐
periodontitis in rheumatoid arthritis patients and vice versa. From
this, it could have been concluded that, from these case‐control and
cross‐sectional studies, the evidence was very good to support a
relationship between periodontal disease and rheumatoid arthritis.
Nonetheless, in the period 2012‐2017, a further 18 cohort studies
were published (Table 4).34 These studies were based on a very wide
geographic spread of countries and included study populations rang‐
ing from 30 subjects to databases of over 1 000 000 individuals,
and only one study reported no relationship.46 Although the study
reporting negative results was based on 2740 rheumatoid arthritis
patients and 3924 matched controls, it seems the majority of studies
continue to confirm a significant relationship between periodontal
disease and rheumatoid arthritis. The most recent systematic review
with meta‐analysis considering the epidemiological evidence from
eight case‐control studies concluded that there is a strong and sig‐
nificant association between rheumatoid arthritis and periodontal
disease.52 In light of this, the need for any further case‐control cross‐
sectional studies is questioned, and there is now a need to delve fur‐
ther into the biologic processes associated with these relationships
and how they might arise and be managed.
2.3 | Role of bacteria in the association between
periodontitis and rheumatoid arthritis
For over 70 years there has been the concept that rheumatoid ar‐
thritis is an infectious disease through which bacterial infection of
the synovium may result in an immune response that could account
for some of the clinical features of rheumatoid arthritis.53 Therefore,
with the noted relationship between rheumatoid arthritis and perio‐
dontal disease, similar proposals were made,54 and so studies began
to focus on whether periodontal bacteria might be associated with,
or even cause, rheumatoid arthritis.
| 191
Early studies focused on the similarities between bacteria asso‐
ciated with periodontitis and those suspected to induce rheumatoid
arthritis in a genetically susceptible host. It was noted that periodon‐
tal bacteria are associated with a robust chronic inflammatory host
response within the periodontal tissues. Thus, it was proposed that
there was the potential for periodontal infection and to trigger, or ex‐
acerbate, rheumatoid arthritis.55 Prior to 2012, studies had demon‐
strated the presence of deoxyribonucleic acid in the synovium of
rheumatoid arthritis of a number of bacteria associated with peri‐
odontitis as well as of increased serum antibody levels against such
bacteria in these patients, including P. gingivalis, Prevotella interme‐
dia, Prevotella melaninogenica, T. forsythia, and Aggregatibacter acti‐
nomycetemcomitans.56-58 Taken together, these findings suggested
the possibility that periodontal bacteria (either whole or deoxyri‐
bonucleic acid) may translocate from the periodontal tissues to the
synovium where they could then exacerbate the inflammatory pro‐
cesses occurring within rheumatoid joints.
matoid arthritis has been P. gingivalis. The reason for this is because
of its unique characteristic for the expression of a peptidylarginine
deiminase, capable of citrullinating both host and bacterial pep‐
tides.59 Because peptidylarginine deiminase can only citrullinate
C‐terminal arginine and not internal arginine, in contrast to its ho‐
mologue human peptidylarginine deiminase‐2 and peptidylarginine
deiminase‐4, it can create citrullinated peptides that would not nor‐
mally occur in the absence of P. gingivalis, as human peptidylarginine
deiminase targets internal arginine substrates. It has been proposed
that P. gingivalis uses its gingipain enzyme to cleave peptides and
generate arginine residues that peptidylarginine deiminase would
then citrullinate.60 Furthermore, in opposition to human peptidy‐
larginine deiminase, P. gingivalis peptidylarginine deiminase is not
calcium dependent, and this enzyme is capable of auto‐citrullination,
becoming a citrullinated bacterial protein itself.61 This process, al‐
though not proven to occur in vivo, does provide a plausible pathway
in which, by presenting neoepitopes to the immune system, P. gin‐
givalis (in susceptible individuals, such as human leukocyte antigen
(HLA)‐DRB1 carriers) could break the tolerance to citrullinated pro‐
teins and lead to the consequent antigen response characteristic in
rheumatoid arthritis patients.62
Since 2012 there have been a further 22 studies published in‐
vestigating the role of periodontal bacteria in rheumatoid arthri‐
tis (Table 5). 57,63-83 Of these, 10 found no evidence for a role for
P. gingivalis in rheumatoid arthritis, eight studies confirmed a role
for P. gingivalis, and four reported equivocal results. In addition to
P. gingivalis, the following have all been implicated in the associa‐
tion between periodontitis and rheumatoid arthritis: A. actinomy‐
cetemcomitans, Filifactor alocis, Prevotella spp., Leptotrichia spp., and
P. intermedia.
A recent review has proposed that a close interplay between
microbiota and host can lead to the development of autoimmune
diseases such as rheumatoid arthritis.84 With the recent recog‐
nition that bacterial dysbiosis plays an important role in late‐
stage periodontitis,85,86 the potential for the oral microbiome and
192 | BARTOLD and LOPEZ‐OLIVA

TA B L E 3 Animal studies published between 2012 and 2017 investigating the interrelationship between periodontitis and rheumatoid
arthritis

Study Aims of study Conclusions

Queiroz‐Junior To investigate whether chronic antigen‐in‐
et al (2012)9 duced arthritis influences infection‐induced
periodontitis in mice and whether periodon‐
tal disease modifies the clinical course of
antigen‐induced arthritis
Queiroz‐Junior To evaluate the effects of an anti–tumor ne‐
et al (2013)10 crosis factor‐alpha therapy with pentoxifyl‐
line in an experimental model of rheumatoid
arthritis–associated periodontal disease
Gully et al To study the role of peptidylarginine deimi‐
(2014)11 nase in the relationship between periodonti‐
tis and rheumatoid arthritis
Maresz et al To study the effect of Porphyromonas gingi‐
(2013)12 valis infection on collagen‐induced arthritis
Marchesan et al To determine the contribution of chronic
(2013)13 periodontal disease to immune activation
and development of joint inflammation using
the collagen‐induced arthritis model
Chukkapalli To investigate the role of periodontal bacteria
et al (2016)14 in the induction of joint inflammation in col‐
lagen‐induced arthritis
Correa et al To investigate if arthritis‐induced alveolar
(2016)15 bone loss is associated with modification in
oral microbiota
Eriksson et al To investigate the effect of preexisting
(2016)16 periodontitis on the development and the
immune/inflammatory response of pristane‐
induced arthritis
Sandal et al To explore immune mechanisms that may
(2016)17 connect periodontal disease and rheumatoid
arthritis
Yamakawa To determine the effects of Porphyromonas
(2016)18 gingivalis infection on the exacerbation of
rheumatoid arthritis in a mouse model
Jung et al Investigation of the pathogenic effects of
(2017)19 Porphyromonas gingivalis on autoimmune
arthritis in vivo
Correa et al To investigate the immunological features
(2017)20 associated with interleukin‐17 interaction
between experimental periodontitis and
arthritis
Exacerbation of infection‐induced periodontal disease by arthritis is associ‐
ated with an alteration in lymphocyte polarization pattern and increased
systemic immunoreactivity
Concomitantly with antigen‐induced arthritis, mice presented with alveolar
bone loss
A peptidylarginine deiminase–deficient strain of Porphyromonas gingivalis
was associated with reduced periodontitis and experimental arthritis
Ability of Porphyromonas gingivalis to exacerbate collagen‐induced arthritis
was dependent on expression of peptidylarginine deiminase
Chronic Porphyromonas gingivalis oral infection prior to arthritis induction
increased immune system activation and ultimately accelerated arthritis
development
Periodontal bacteria were identified in the synovial tissues. Collagen‐in‐
duced arthritis was exacerbated by presence of periodontal bacteria
(Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia)
Antigen‐induced arthritis is associated with changes in the composition of
the oral microbiota that might account for the alveolar bone loss observed
in antigen‐induced arthritis mice
Preexisting periodontitis induced antibodies against citrullinated peptide
derived from peptidylarginine deiminase in rats with pristane‐induced ar‐
thritis. There was no difference in the development of severity of pristane‐
induced arthritis between periodontitis‐challenged and periodontitis‐free
rats
Exposure of gingival tissues to Porphyromonas gingivalis has systemic effects
that can result in disease pathology in tissues that are spatially removed
from the initial site of infection. Elicitation of anti–citrullinated protein
antibody in a human leukocyte antigen DR1–restricted fashion by mice
exposed to Porphyromonas gingivalis provides support for the role of the
shared epitope in both periodontitis and rheumatoid arthritis. The ability of
Porphyromonas gingivalis to induce disease expression in arthritis‐resistant
mice provides support for the idea that periodontal infection may be able
to trigger autoimmunity if other disease‐elucidating factors are already
present
Porphyromonas gingivalis has the potential to exacerbate rheumatoid arthritis
Synovial inflammation and bone destruction were more severe in mice
infected with Porphyromonas gingivalis. Citrullination in synovial tissues was
greatest in Porphyromonas gingivalis–infected animals. The arthritogenic
effects of Porphyromonas gingivalis were, in part, dependent on the bacte‐
rial strain with or without fimbriae expression, route, and time of infection.
Porphyromonas gingivalis–induced citrullination may explain the possible
link between periodontal disease and rheumatoid arthritis
Interleukin‐17 was elevated in the presence of experimental arthritis ir‐
respective of the presence of periodontitis. Periodontitis increased levels
of rheumatoid factor and citrullinated proteins in the gingival tissues and
altered cytokine balance in arthritic rats. Arthritis was found to increase
periodontal destruction. These findings confirm the bidirectional interac‐
tion between periodontitis and arthritis
BARTOLD and LOPEZ‐OLIVA | 193

TA B L E 4 Cohort and population‐based studies between 2012 and 2017 investigating the interrelationship between periodontitis and
rheumatoid arthritis

Relationship
Study Study design Country Study sample found Conclusion

Potikuri et al Case‐control India Healthy controls = 93 Yes Periodontal disease is more frequent and
(2012)34 Rheumatoid arthritis = 91 severe in nonsmoking disease‐modify‐
ing antirheumatic drug–naïve rheuma‐
toid arthritis patients compared with
healthy controls
Periodontal disease in rheumatoid
arthritis patients was associated with
high titers of anti–citrullinated peptide
antibodies
Torkzaban et al Historical cohort Iran Nonrheumatoid arthritis = 53 Yes Rheumatoid arthritis had the potential to
(2012)35 study Rheumatoid arthritis = 53 affect periodontal indices
Susanto et al Case‐control Indonesia Healthy controls = 75 Yes Although prevalence and severity of
(2013)36 Rheumatoid arthritis = 75 periodontitis in rheumatoid arthritis
patients was comparable to controls,
gingival inflammation was greater in
rheumatoid arthritis as measured by
inflamed pocket epithelium surface area
Chen et al Population‐based Taiwan 1 000 000 individuals enrolled Yes Periodontal disease exposure was associ‐
(2014)37 retrospective in National Health Insurance ated with increased risk for rheumatoid
cohort study database arthritis
Khantisopon et Case series Thailand 196 rheumatoid arthritis Yes A high prevalence of periodontitis was
al (2014)38 patients with at least 20 teeth found in Thai patients with rheumatoid
arthritis
Chou et al Nationwide, pop‐ Taiwan Nonperiodontitis = 628 628 Yes Presence of periodontitis was associated
(2015)39 ulation‐based Periodontitis = 168 842 with an increased risk of rheumatoid
cohort study arthritis development
Ibanez et al Case series Chile 40 patients with rheumatoid Yes Periodontitis is common (87.5%) and
(2015) 40 arthritis severe in patients with rheumatoid
arthritis
Ozkan (2015) 41 Case‐control Turkey Healthy controls = 60 Yes There was a strong association between
Rheumatoid arthritis = 60 rheumatoid arthritis and periodontal
disease. The severity of periodontal
disease was significantly increased in
rheumatoid arthritis patients compared
to health controls
Pons‐Fuster et Case‐control Spain Healthy controls = 41 Yes Patients with rheumatoid arthritis
al (2015) 42 Rheumatoid arthritis = 44 suffered a higher risk of periodontal
disease
Vahabi et al Case‐control Iran Healthy controls = 30 Yes The severity of periodontal disease
(2015) 43 Rheumatoid arthritis = 30 increases in patients with rheumatoid
arthritis
Bello‐Gualtero Cross‐sectional Colombia Pre‐rheumatoid arthritis = 119 Yes Individuals with pre‐rheumatoid arthritis
et al (2016) 44 study Early rheumatoid arthritis = 48 have significant periodontal involve‐
Matched controls for both ment. Significant association with im‐
pre‐rheumatoid and early munoglobulin G against Porphyromonas
rheumatoid arthritis gingivalis noted
Choi et al Cross‐sectional Korea Rheumatoid arthritis Yes Prevalence of moderate or severe peri‐
(2016) 45 study patients = 264 odontitis was increased in rheumatoid
Age‐ and sex‐matched arthritis patients compared with
controls = 88 controls
Eriksson et al Case‐control Sweden Rheumatoid arthritis No No evidence of an increased prevalence
(2016) 46 patients = 2740 of periodontitis in patients with estab‐
Matched controls = 3942 lished rheumatoid arthritis

(Continues)
194 | BARTOLD and LOPEZ‐OLIVA

TA B L E 4 (Continued)

Relationship
Study Study design Country Study sample found Conclusion

Silvestre et al Prospective com‐ Spain Rheumatoid arthritis = 73 Yes Patients with rheumatoid arthritis are
(2016) 47 parative study Controls = 73 more likely to present with periodontal
disease
Ayravainen et al Cross‐section Germany Rheumatoid arthritis = 168 Yes Patients with rheumatoid arthritis had
(2017) 48 Healthy controls = 168 (age, worse periodontal conditions
sex, and smoking matched) Relationship of bacteria unclear
Schmickler et al Prospective fol‐ Finland Rheumatoid arthritis (early dis‐ Yes Poorer periodontal condition in both
(2017) 49 low‐up study ease‐modifying antirheumatic rheumatoid arthritis groups. Association
drug) = 53 between antirheumatic drug treatment
Chronic rheumatoid arthritis and periodontal parameters
(insufficient response to dis‐
ease‐modifying antirheumatic
drug = 28
Controls (age, sex, and com‐
munity matched) = 43
Ouedraogo et al Case‐control Sub‐ Rheumatoid arthritis Yes Prevalence of periodontal disease was
(2017)50 Saharan patients = 43 twice as high among patients with rheu‐
Africa Controls = 86 matoid arthritis compared with controls
Unriza‐Puin et Case‐control 100 first‐degree relatives of Yes Periodontitis (diagnosis and severity) is
al (2017)51 rheumatoid arthritis patients a risk factor for rheumatoid arthritis in
200 matched healthy controls first‐degree relatives of patients with
rheumatoid arthritis. Presence of anti–
Porphyromonas gingivalis antibodies was
not a risk factor

disease‐associated dysbiosis may play a role in breaking immune
tolerance and subsequent development of rheumatoid arthritis.
This concept is in keeping with current concepts linking the meta‐
bolic role of the gut microbiota in health and rheumatoid arthritis.87
Interestingly, of the two next‐generation sequencing studies carried
out to date that have investigated the oral microbiome in rheumatoid
arthritis, both found no evidence for association between P. gingi‐
63,69
valis or its peptidylarginine deiminase and rheumatoid arthritis.
Further research is now needed to determine whether it is the pri‐
mary periodontal infection and specific bacteria of the associated
inflammation that is the principal linking mechanism between peri‐
odontitis and rheumatoid arthritis.
2.4 | Posttranslational protein modification and
autoantibody production
2.4.1 | Citrullinated proteins and autoimmunity
Recognition that rheumatoid arthritis may be an autoimmune
disease, manifested by development of disease‐specific autoan‐
tibodies to citrullinated protein antigens, has been an important
development. 88 Citrullinated proteins are produced by peptidy‐
larginine deiminase enzymes. 88 The anti–citrullinated protein an‐
tibodies in rheumatoid arthritis are specific for certain citrullinated
proteins (including alpha‐enolase, vimentin, and fibrinogen). Of
the five known mammalian peptidylarginine deiminases, pepti‐
dylarginine deiminase‐2 and ‐4 are associated with citrullinated
proteins in rheumatoid arthritis. Accumulation of proteins such as
fibrin within the synovium and their prolonged degradation, which
includes citrullination, leads to exposure of new epitopes to im‐
munocompetent cells within the synovium. As already noted, anti–
citrullinated protein antibodies have a high predictive value for the
onset of rheumatoid arthritis several years before it is evident clini‐
cally and are also associated with more severe and worse clinical
outcomes. 89,90
2.4.2 | Gingival tissue as an extra‐articular source of
citrullination
Recent studies have confirmed a potential role for the inflamed
periodontal tissues in the pathophysiology of rheumatoid arthri‐
tis with the identification of citrullinated proteins and peptidy‐
larginine deiminase‐2 and peptidylarginine deiminase‐4 in such
tissues. 5,6 Furthermore, the obligate anaerobe P. gingivalis (signifi‐
cantly implicated in the development of periodontal inflammation)
produces a peptidylarginine deiminase capable of citrullinating
proteins as well as undergoing autocitrullination. 62,90 Even more
intriguing is that P. gingivalis also expresses cell‐surface enolase,
which, when citrullinated, results in antibodies that cross‐react
with antibodies to alpha‐enolase found in some rheumatoid arthri‐
tis patients.91 Thus, there is considerable potential for significant
citrullination to occur within inflamed periodontal tissues, and this
in turn may prime susceptible individuals to a heightened anti–cit‐
rullinated protein antibody reaction during the later development
of rheumatoid arthritis.
BARTOLD and LOPEZ‐OLIVA
TA B L E 5 Studies 2012‐2017 investigating the microbiology associated with the interrelationship between periodontitis and rheumatoid
arthritis
Study Aims
Scher et al Pyrosequencing used to pro‐
(2012) 63 file the abundance and the
oral microbiota in new‐onset
rheumatoid arthritis
Mikuls et al To examine the relationship of
(2012)57 Porphyromonas gingivalis to
the presence of autoantibod‐
ies in individuals at risk of
rheumatoid arthritis
de Smit To compare the host immune
(2012) 65 responses in rheumatoid
arthritis patients with and
without periodontitis in
relation to the presence of
cultivable Porphyromonas
gingivalis in subgingival
plaque
Totaro et al To evaluate the presence of
(2013)65 Porphyromonas gingivalis
deoxyribonucleic acid in
synovial‐tissue biopsies
Arvikar et al To examine Porphyromonas
(2013)66 gingivalis antibody responses
and their clinical associa‐
tions in patients with early
rheumatoid arthritis prior to
and after disease‐modifying
antirheumatic drug therapy
Population
31 subjects with new‐onset
rheumatoid arthritis
34 chronic rheumatoid
arthritis patients
18 controls with similar peri‐
odontitis but no rheumatoid
arthritis
171 autoantibody negative
113 autoantibody positive
38 autoantibody‐positive
and high‐risk subjects
95 rheumatoid arthritis
subjects
32 rheumatoid arthritis
subjects
37 subjects with “other”
arthritides
50 subjects with early rheu‐
matoid arthritis and not
receiving disease‐modifying
antirheumatic drug therapy
43 late‐onset rheumatoid
arthritis and other con‐
nective‐tissue diseases
receiving disease‐modifying
antirheumatic drug therapy
| 195
Role for
Porphyromonas
Conclusions gingivalis
Patients with new‐onset rheumatoid arthritis No
had a high prevalence of periodontal disease.
The subgingival microbiota profile of new‐
onset subjects was similar to subjects with
chronic rheumatoid arthritis and periodontal
disease of similar severity but no rheumatoid
arthritis. Overall exposure to Porphyromonas
gingivalis was similar among all groups
Immunity to Porphyromonas gingivalis, but Yes
not Prevotella intermedia or Fusobacterium
nucleatum, is significantly associated with
the presence of rheumatoid arthritis–related
autoantibodies in individuals at risk of rheu‐
matoid arthritis. Supports the hypothesis
that infection with Porphyromonas gingivalis
may play a central role in the early loss of
tolerance to self‐antigens during the patho‐
genesis of rheumatoid arthritis
Severity of periodontitis is related to sever‐ Equivocal
ity of rheumatoid arthritis. Rheumatoid
arthritis patients with severe periodontitis
had a more robust antibody response to
Porphyromonas gingivalis than nonrheuma‐
toid arthritis controls. Not all rheumatoid ar‐
thritis patients had cultivable Porphyromonas
gingivalis
Subjects with rheumatoid arthritis showed Yes
higher positivity for Porphyromonas gingivalis
deoxyribonucleic acid in synovial tissue
compared with the controls. Subjects with
the HLA‐DRB1*04 allele showed a higher
positivity for Porphyromonas gingivalis
deoxyribonucleic acid in synovial tissue
compared with those negative for the al‐
lele. Presence of Porphyromonas gingivalis
did not influence disease activity, disease
disability, or positivity for autoantibodies.
Porphyromonas gingivalis deoxyribonucleic
acid was detected in synovial tissue
Not all early‐onset rheumatoid arthritis Yes
subjects have positive Porphyromonas
gingivalis antibody responses. There was
a trend toward greater disease activity in
Porphyromonas gingivalis–positive subjects
(Continues)
196 | BARTOLD and LOPEZ‐OLIVA
TA B L E 5 (Continued)
Study Aims
Mikuls et al To examine the degree to
(2014)67 which shared risk factors
explain the relationship
between periodontitis
and rheumatoid arthritis
and to determine associa‐
tions of periodontics and
Porphyromonas gingivalis
with pathologic features of
rheumatoid arthritis
de Smit et al To investigate whether anti–
(2014)68 Porphyromonas gingivalis
antibody levels are prog‐
nostic for development of
rheumatoid arthritis
Zhang et al A metagenome‐wide associa‐
(2015)69 tion study of fecal, dental,
and salivary samples of
individuals with rheumatoid
arthritis and healthy controls
Seror et al To investigate the possible
(2015)70 link between Porphyromonas
gingivalis infection and rheu‐
matoid arthritis
Lee et al To measure levels of
(2015)71 serum antibodies against
Porphyromonas gingivalis and
human alpha‐enolase‐1 in
patients with rheumatoid
arthritis and determine the
association with severity of
periodontitis or rheumatoid
arthritis
Kimura et al To investigate the role of peri‐
(2015)72 odontal pathogens in rheu‐
matoid arthritis remission
Hashimoto To determine whether the
et al presence of periodontitis
(2015)73 and Porphyromonas gingivalis
in subgingival biofilm associ‐
ates with the development of
rheumatoid arthritis
Kobayashi To determine whether serum
et al antibodies to peptidylar‐
(2016)74 ginine deiminase affect
the clinical response to
disease‐modifying antirheu‐
matic drugs in patients with
rheumatoid arthritis
Population
287 patients with rheuma‐
toid arthritis
330 patients with osteoar‐
thritis (control)
298 at‐risk patients for rheu‐
matoid arthritis
694 subjects with early
rheumatoid arthritis not
exposed to steroids or
disease‐modifying antirheu‐
matic drugs
248 subjects with rheuma‐
toid arthritis
85 age‐ and sex‐matched
healthy controls
21 subjects with active rheu‐
matoid arthritis
70 subject in clinical
remission
72 subjects with arthralgia
who had never received
any antirheumatic drugs or
glucocorticoids
60 subjects with rheumatoid
arthritis and treated with
disease‐modifying antirheu‐
matic drugs
Role for
Porphyromonas
Conclusions gingivalis
Periodontitis was more common in anti– Yes
citrullinated protein antibody–positive
rheumatoid arthritis patients. No difference
between rheumatoid arthritis patients and
controls in the levels of Porphyromonas
gingivalis or anti–Porphyromonas gingivalis
antibodies. Weak association between
anti–Porphyromonas gingivalis antibodies
and anti–citrullinated protein antibody and
rheumatoid factor. Both periodontitis and
Porphyromonas gingivalis appear to shape the
autoreactivity of rheumatoid arthritis
Porphyromonas gingivalis antibody levels were No
not prognostic for development of rheuma‐
toid arthritis
Dysbiosis was noted on the oral microbiome
of rheumatoid arthritis subjects, and this
was partially resolved after rheumatoid
arthritis treatment
No association between anti–Porphyromonas No
gingivalis antibodies with rheumatoid ar‐
thritis or anti–citrullinated protein antibody
status
Anti–Porphyromonas gingivalis and anti–alpha‐ Equivocal
enolase antibody titers were correlated
with severity of periodontitis in rheumatoid
arthritis subjects. Porphyromonas gingivalis
antibody titers not associated with rheuma‐
toid arthritis disease activity
Persistent synovitis was associated with No
Prevotella intermedia
Advanced periodontics was associated with No
higher arthritis activity. The presence of
Porphyromonas gingivalis was not associated
with arthritis activity
Patients with low anti–peptidylarginine Yes
deiminase titers had a greater decrease
in clinical markers of rheumatoid arthritis
disease activity compared with patients
with high anti–peptidylarginine deiminase
titers. The serum immunoglobulin G levels to
peptidylarginine deiminase appear to affect
the clinical response to disease‐modifying
antirheumatic drugs treatment in patients
with rheumatoid arthritis
(Continues)
BARTOLD and LOPEZ‐OLIVA
TA B L E 5 (Continued)
Study Aims
Santegoets To determine the differ‐
et al ences in the innate immune
(2016)75 response to Porphyromonas
gingivalis between healthy
controls and rheumatoid
arthritis patients
Kharlamova To investigate the role of
et al Porphyromonas gingivalis
(2016)76 in the etiology of rheuma‐
toid arthritis by analyz‐
ing antibody response to
Porphyromonas gingivalis
arginine gingipain type B
Johansson To investigate whether anti–
et al Porphyromonas gingivalis
(2016)77 antibodies predate symptom
onset and anti–citrullinated
protein antibody production
Goh et al To investigate the association
(2016)78 between elevated serum
levels of immunoglobulin G
antibodies to 19 periodontal
bacteria and the prevalence
of rheumatic factor
Ghotaslou To investigate the relation‐
et al ship between the presence
(2016)79 of Porphyromonas gingivalis
deoxyribonucleic acid in
synovial fluid of rheumatoid
arthritis patients
Bender et al Systematic review of studies
(2017) 80 investigating serum antibody
levels in patients with and
without rheumatoid arthritis
Cheng et al To characterize the subgin‐
(2017) 81 gival microbiomes from
periodontitis and health in
individuals with/without
rheumatoid arthritis and at
risk of rheumatoid arthritis
Martu et al To detect bacterial deoxyribo‐
(2017) 82 nucleic acid from subgingival
plaque and serum in patients
affected by rheumatoid
arthritis and refractory
periodontitis
Martinez‐ To evaluate the relationship
Rivera et al of salivary ammonia and the
(2017) 83 presence of bacteria with
rheumatoid arthritis
Population
35 rheumatoid arthritis
subjects
65 subjects with
periodontitis
59 nonperiodontitis subjects
1974 rheumatoid arthritis
subjects
377 nonrheumatoid arthritis
subjects
251 rheumatoid arthritis
subjects
198 healthy controls
2461 subjects nonrheuma‐
toid arthritis subjects with
positive immunoglobulin G
antibodies to 19 periodon‐
tal bacteria and rheumatoid
factor
22 subjects with rheumatoid
arthritis
20 subjects without rheuma‐
toid arthritis
114 articles identified and
13 met the inclusion criteria
and included studies from
the years 1995‐2015
45 anti–citrullinated protein
antibody–positive nonrheu‐
matoid arthritis subjects
31 healthy controls
30 anti–citrullinated protein
antibody–positive rheuma‐
toid arthritis subjects
19 patients with peri‐
odontitis and refractory
periodontitis
No controls
132 consecutive rheumatoid
arthritis patients
| 197
Role for
Porphyromonas
Conclusions gingivalis
A reduced immune response to Equivocal
Porphyromonas gingivalis in rheumatoid
arthritis subjects was noted. Proposed to re‐
sult in prolonged exposure to Porphyromonas
gingivalis and possible autoantibody produc‐
tion, but not proven
Porphyromonas gingivalis is a credible candi‐ Yes
date for triggering and/or driving autoim‐
munity and autoimmune disease in a subset
of rheumatoid arthritis patients
Anti–Porphyromonas gingivalis antibody con‐ Yes
centrations were significantly increased in
rheumatoid arthritis patients compared with
controls and were detectable years before
the onset of rheumatoid arthritis symptoms
Elevated levels of immunoglobulin G anti‐ No
bodies to periodontal bacteria are mostly
unassociated with rheumatoid factor
seropositivity
Porphyromonas gingivalis deoxyribonucleic No
acid was detected in 13.6% of subjects with
rheumatoid arthritis. There was no signifi‐
cant relationship between Porphyromonas
gingivalis deoxyribonucleic acid and rheuma‐
toid arthritis
Meta‐analysis revealed a statistically higher Yes
antibody titer against Porphyromonas gin‐
givalis in patients with rheumatoid arthritis
than in healthy controls
Levels of Porphyromonas gingivalis were high No
in anti–citrullinated protein antibody–posi‐
tive nonrheumatoid arthritis subjects
Aggregatibacter actinomycetemcomitans was
detected at similar frequency in all groups.
Bacteria implicated in periodontitis and/
or autoantibody generation were Filifactor
alocis, Prevotella spp. and Leptotrichia spp.
Serum and subgingival plaque from pa‐ No
tients with rheumatoid arthritis contain
Porphyromonas gingivalis, Tannerella forsythia,
and Prevotella intermedia
Note: invalid conclusion due to absence of
any controls
Rheumatoid arthritis activity is associated No
with high salivary ammonia and the pres‐
ence of Tannerella forsythia
198 | BARTOLD and LOPEZ‐OLIVA
Since 2012 there have been 17 papers published that focused
specifically on citrullination and anti–citrullinated protein anti‐
body production in periodontitis and rheumatoid arthritis subjects
(Table 6).3,4,11,22,92-104 Of these, seven studies concluded that inflam‐
mation was the principal driver of gingival citrullination, five focused
solely on bacteria, and in particular P. gingivalis, as being the driver
of gingival citrullination, two studies concluded the process was a
combination of both inflammation and bacterial infection, and the
remaining two studies were unclear in what the driving force behind
gingival citrullination was.
Future research will need to continue to probe the role of gingi‐
val inflammation and infection as an extra‐articular source of protein
citrullination and production of anti–citrullinated protein antibody.
Importantly, the roles of P. gingivalis and its unique peptidylarginine
deiminase in this process need to be determined. To date, P. gingi‐
valis and peptidylarginine deiminase are thought to be critical to the
relationship between periodontal disease and rheumatoid arthritis.
However, peptidylarginine deiminase has not been identified in in‐
flamed periodontal tissues, and good evidence for peptidylarginine
deiminase activity in situ has also not been demonstrated. Thus,
with gingival inflammation, much like lung inflammation in smokers,
evidence is accruing to support that it is the initial inflammatory hit
and not the presence of P. gingivalis that is the critical factor in gin‐
gival citrullination and initial production of anti–citrullinated protein
antibody.
Based on these findings, it has been proposed that human and
bacterial peptidylarginine deiminases could be important targets for
therapy in the management of rheumatoid arthritis.105-107 Moreover,
it has been hypothesized that periodontal therapy could decrease
the load of P. gingivalis and peptidylarginine deiminase in the gingival
pocket and that by reducing gingival inflammation the expression of
human peptidylarginine deiminases could be reduced, and therefore
lessen endogenous and bacterial citrullination and weaken the auto‐
immune response.
2.4.3 | Carbamylation and malondialdehyde‐
acetaldehyde adducts
As detailed earlier, posttranslational modification of proteins can
lead to the production of autoantibodies and loss of immune tol‐
erance. Apart from citrullination, several other posttranslational
modifications of proteins have been associated with rheumatoid ar‐
thritis. Of these, malondialdehyde‐acetaldehyde adducts and car‐
bamylated proteins are receiving particular attention.108 A recent
study identified immunohistochemical evidence of the presence of
malondialdehyde‐acetaldehyde adducts and citrullinated and car‐
bamylated proteins in inflamed human gingival tissue biopsies but
not in biopsies of healthy, noninflamed gingiva.109 Identification of
such modified proteins in inflamed gingiva may explain, in part, how
inflammation of the periodontal tissues may influence the develop‐
ment of rheumatoid arthritis through the production of modified
proteins that have the potential to produce autoimmune responses
that can later influence alterations in inflamed rheumatoid joints.
It was concluded that the potential for these posttranslational
modifications of proteins to play a role in autoimmunity in a mul‐
tisystem inflammatory syndromic disease model now needs to be
determined.
2.5 | Immunogenetics
In multifactorial diseases such as periodontitis and rheumatoid ar‐
thritis, genetics is of considerable importance, because a proportion
of the clinical variance of these diseases can be attributed to genetic
factors. In particular, genes controlling the expression of interleukin‐1,
tumor necrosis factor, and prostaglandin E2 are crucial to the patho‐
logic processes associated with periodontitis and rheumatoid arthritis.
Many of the genes that regulate the cytokine expression have
been mapped to the HLA‐DR region of chromosome 5 in the area
of the interleukin‐1 and tumor necrosis factor‐alpha genes.110 The
HLA genes appear to confer the strongest genetic associations for
rheumatoid arthritis.111 The disease‐conferring portion is confined
to a short sequence within the third hypervariable region of the
HLA‐DRB1 gene.112 For rheumatoid arthritis, the HLA genes and
gender constitute about 30% of the genetic risk, with other ge‐
netic factors such as germline genes, T‐cell receptors, and cytokine
genes also accounting for some of the genetic risk for rheumatoid
arthritis.113 The HLA‐DR phenotype has also been reported to be
an important component for genetic susceptibility in some forms
of periodontitis.114 However, although the HLA‐DR4 epitope has
been found to be associated with both rheumatoid arthritis and
periodontitis, it is believed that this shared genetic epitope is not
enough to explain the association between rheumatoid arthritis
and periodontitis. 31
Only three reports have been published since 2012 investigating
the role of genetic correlations between both rheumatoid arthritis
and periodontitis, with the focus moving away from the HLA‐DR
gene and focusing more on cytokine expression.115-118 From these
studies, it has been concluded that interleukin‐1 and interleukin‐10
gene polymorphisms have some, albeit small, correlations between
periodontitis and rheumatoid arthritis.
2.6 | Studies investigating possible underlying
molecular mechanisms of the association between
rheumatoid arthritis and periodontitis
With it becoming increasingly apparent that nearly all the popula‐
tion‐based studies have confirmed the association between peri‐
odontal disease and rheumatoid arthritis, it is now time to move
the field from pure observation studies to one of dissecting out
the possible mechanisms that might be responsible for such an
association.
In rheumatoid arthritis, there is considerable dysregulation of the
major inflammatory cytokine networks118 in a manner similar to that
seen in periodontitis.119 The imbalance between proinflammatory
and anti‐inflammatory cytokines and growth factors in periodontitis
and rheumatoid arthritis is comparable. Both conditions demonstrate
BARTOLD and LOPEZ‐OLIVA
TA B L E 6 Studies 2012‐2017 investigating the role of citrullination in the interrelationship between periodontitis and rheumatoid arthritis
Study Aims of study
Nesse et al To determine the presence and location
(2012)3 of citrullinated proteins in periodontitis
tissue and synovial tissue of rheumatoid
arthritis patients
Harvey et al To determine the presence of peptidylar‐
(2013) 4 ginine deiminase‐2 and ‐4 in periodontal
tissues and levels of anti–citrullinated
protein antibody in gingival crevicular
fluid from inflamed and noninflamed
periodontal sites
Quirke et al To study the immune response to pepti‐
(2014)92 dylarginine deiminase in patients with
rheumatoid arthritis, periodontitis and
controls (no arthritis); determine pepti‐
dylarginine deiminase autocitrullination
Gully et al To study the role of peptidylarginine
(2014)11 deiminase in the relationship between
periodontitis and rheumatoid arthritis
de Pablo et al To determine whether periodontitis is as‐
(2014)93 sociated with autoantibodies character‐
istic of rheumatoid arthritis
Reichert et al To investigate, in generalized aggressive
(2015)94 periodontics and generalized chronic
periodontitis, the presence of anti–cyclic
citrullinated peptide and citrullinated
alpha‐enolase peptide 1 compared with
nonrheumatoid arthritis/nonperiodonti‐
tis controls
Konig et al To define the citrullination status and
(2015)22 biology of peptidylarginine deiminase
and to characterize the anti–peptidylar‐
ginine deiminase response in rheumatoid
arthritis and associated periodontal
disease
Janssen et al Determine the presence of rheumatoid
(2015)95 arthritis–associated autoantibod‐
ies in patients without rheumatoid
arthritis who had oral or lung mucosal
inflammation
Gonzalez et al To assess alveolar bone loss in anti–cit‐
(2015)96 rullinated protein antibody–positive
rheumatoid arthritis patients compared
with osteoarthritis control patients
Gabarrini et al To assess peptidylarginine deiminase
(2015)97 gene expression and citrullination pat‐
terns in Porphyromonas gingivalis isolates
from periodontitis patients with and
without rheumatoid arthritis
| 199
Role for inflamma‐
Conclusions tion or bacteria
Within the periodontium, citrullination is a physiologic Inflammation
process in healthy tissues and increased during perio‐
dontal inflammation. Periodontitis‐induced citrullination
may play a role in the etiology of rheumatoid arthritis
Peptidylarginine deiminase‐2 and ‐4 and citrullinated Inflammation
proteins were present in inflamed but not healthy peri‐
odontal tissues. Presence of anti–citrullinated protein
antibody in gingival crevicular fluid was mainly associ‐
ated with the presence of periodontitis
Evidence was presented to demonstrate peptidylargi‐ Bacteria
nine deiminase autocitrullination. This supports the
hypothesis that, as a bacterial antigen, citrullinated
peptidylarginine deiminase may break immune tolerance
in rheumatoid arthritis
A peptidylarginine deiminase–deficient strain of Bacteria
Porphyromonas gingivalis was associated with reduced
periodontitis and experimental arthritis
The antibody response seen in periodontitis patients is Inflammation
generally targeted against uncitrullinated autoantigens
associated with rheumatoid arthritis. Such loss of toler‐
ance could lead to epitope spreading to citrullinated
epitopes as the autoimmune response in periodontitis
evolves into presymptomatic rheumatoid arthritis
peptides
Generalized aggressive periodontitis and generalized Unknown
chronic periodontitis and the presence of periodonto‐
pathic bacteria are not associated with increased risk for
occurrence of anti–cyclic citrullinated peptide
Peptidylarginine deiminase autocitrullination is not the Inflammation
underlying mechanism linking periodontal disease and
rheumatoid arthritis. Peptidylarginine deiminase may be
protected from autocitrullination. Anti–peptidylarginine
deiminase antibodies could have a protective role in the
development of periodontitis
Rheumatoid arthritis–associated autoantibodies were Inflammation
associated with lung mucosal inflammation and also may
be associated with periodontal inflammation
Greater alveolar bone loss was associated with higher Not determined
anti–citrullinated protein antibody titers
Peptidylarginine deiminase is ubiquitous to Unclear, but
Porphyromonas gingivalis but absent in other related mitigates
species. No significant difference was found in the against a role for
composition and expression of the peptidylarginine peptidylarginine
deiminase gene regardless of the presence of rheuma‐ deiminase
toid arthritis or periodontal disease. Thus, it is unclear
whether Porphyromonas gingivalis plays a role in rheuma‐
toid arthritis; and if it does, it is unlikely to arise due to a
variation in peptidylarginine deiminase gene expression
(Continues)
200 | BARTOLD and LOPEZ‐OLIVA
TA B L E 6 (Continued)
Study Aims of study
Fisher et al To determine the relation of peptidylar‐
(2015)98 ginine deiminase and smoking as risk
factors for rheumatoid arthritis
Shimada et al To evaluate the serum levels of anti–
(2016)99 citrullinated protein antibody and to
peptidylarginine deiminase as well as the
endogenous expression of peptidylargi‐
nine deiminase‐4 in individuals with and
without rheumatoid arthritis before and
after periodontal treatment
Li et al To determine whether circulating plasma‐
(2016)100 blasts from rheumatoid arthritis patients
produce anti–citrullinated protein
antibody and whether Porphyromonas
gingivalis facilitates the generation of
anti–citrullinated protein antibody
Laugisch et al To assess human and bacterial peptidy‐
(2016)101 larginine deiminase activity on gingival
crevicular fluid
Konig et al To define the microbiological composition
(2016)102 and antigenic repertoire of gingival cre‐
vicular fluid in patients with periodontal
disease and healthy controls
Schwenzer et al To determine the mechanism by which
(2017)103 periodontal disease could induce anti–
citrullinated protein antibody
Janssen et al To determine the presence of citrullinated
(2017)104 histones in inflamed periodontal tissue
and determine the presence of anti–cit‐
rullinated histone autoantibodies in sera
from rheumatoid arthritis patients
levels of interleukin‐6 and tumor necrosis factor‐alpha systemically
and locally, which are known to activate the inflammatory response,
and lower levels of interleukin‐10 and transforming growth factor‐
beta, which are known to have anti‐inflammatory effects.120
Identifying the cytokine networks operational in rheumatoid
arthritis has resulted in the development of new therapeutic ap‐
121
proaches for the management of this disease. Of special impor‐
tance is the proinflammatory cytokine tumor necrosis factor‐alpha,
as it plays a key role in the immune response for both rheumatoid ar‐
thritis and periodontitis. Tumor necrosis factor‐alpha modulates the
inflammatory response as it can increase the inflammatory response
by binding to the receptor p55 (T receptor type 1; CD120a), whereas
binding to receptor p75 (tumor necrosis factor receptor type 2;
CD120b) attenuates the inflammatory response.122 In periodontitis,
tumor necrosis factor‐alpha has been associated with the breakdown
of connective tissue attachment and bone.123 Rheumatoid arthri‐
tis patients suffering with periodontitis have higher levels of tumor
Role for inflamma‐
Conclusions tion or bacteria
Smoking is a risk factor for rheumatoid arthritis before Inflammation
it develops clinically. Porphyromonas gingivalis was not
associated with pre‐rheumatoid arthritis autoimmunity
or risk of rheumatoid arthritis. Antibodies to peptidy‐
larginine deiminase peptides are not an early feature of
anti–citrullinated protein antibody ontogeny
There is a possible association between anti–pepti‐ Bacteria
dylarginine deiminase immunoglobulin G and anti–
citrullinated protein antibody implicating a role for
peptidylarginine deiminase in protein citrullination in
patients with rheumatoid arthritis and periodontitis
Circulating plasmacytes can produce anti–citrullinated Bacteria
protein antibody, and this process can be facilitated by
anti–Porphyromonas gingivalis immune responses
Peptidylarginine deiminase and peptidylarginine deimi‐ Both bacteria and
nase activities were elevated in rheumatoid arthritis and inflammation
nonrheumatoid arthritis patients with periodontitis
The citrullinome in periodontitis was similar to the hy‐ Both bacteria and
percitrullination observed in inflamed joints implicating inflammation
the periodontium in the pathogenesis of rheumatoid
arthritis. Aggregatibacter actinomycetemcomitans was
associated with hypercitrullination in host neutrophils
Two citrullinated peptides were elevated in gingival cre‐ Bacteria
vicular fluid of rheumatoid arthritis subjects and these
were associated with antibodies to Prevotella intermedia
but not Porphyromonas gingivalis arginine gingipains
Citrullinated histone H3 can be identified in inflamed Inflammation
periodontal tissues and is targeted by autoantibodies in
the sera of rheumatoid arthritis subjects. This supports
the role of periodontitis in the generation of antigens
targeted by autoantibodies against citrullinated proteins
necrosis factor‐alpha than those without periodontitis, and these
levels are positively correlated with rheumatoid arthritis severity.120
Since 2012 there have been 24 studies published beginning to
address these issues (Table 7).51,124-137,139,140 All of these studies have
considered possible molecular pathological processes that are either
common to both conditions or responsible for driving similar patho‐
logical processes in both conditions. Specifically, these studies have
considered the role of various inflammatory cytokines (including
interleukin‐1, interleukin‐4, interleukin‐6, interleukin‐17, and tumor
necrosis factor‐alpha), how oxidative stress may play a role in both
conditions, effects of altered serum protein profiles, environmen‐
tal factors, such as obesity and smoking, and extracellular enzyme
activity (including cathepsins, matrix metalloproteinases, and plas‐
minogen activator). To date, it is too early to determine which, if any,
of these processes are important; but it is an important beginning,
and further studies are required. Given that both diseases represent
a significant dysregulation of the inflammatory response, it seems
BARTOLD and LOPEZ‐OLIVA
TA B L E 7 Studies 2012‐2017 investigating the possible molecular mechanisms involved in the interrelationship between periodontitis and
rheumatoid arthritis
Study
Inflammatory cytokines
Ishida et al (2012)124
Guzeldemir et al (2013)125
Javed et al (2014)126
de Aquino (2017)127
Tumor necrosis factor studies
Gumus et al (2013)128
Kojima et al (2016)129
Oxidative stress
Esen et al (2012)130
Sezer et al (2013)131
Environmental studies
Unriza‐Puin et al (2017)51
Huang et al (2017)132
Serum proteins
Yokoyama et al (2014)133
Redman et al (2016)134
Enzymes
Silosi et al (2015)135
Aims
To determine deoxyribonucleic acid methylation pro‐
file of interleukin‐6 gene promoter in patients with
rheumatoid arthritis and periodontitis
To determine whether the proinflammatory and anti‐
inflammatory cytokine levels in gingival crevicular
fluid can distinguish between rheumatoid arthritis
and periodontitis patients
A review of the literature to assess cytokine levels in
gingival crevicular fluid of rheumatoid arthritis and
periodontitis patients
To determine whether the Th17/Th17 signaling path‐
way is involved in Porphyromonas gingivalis–induced
experimental arthritis
To assess gingival crevicular fluid levels of a prolifera‐
tion‐inducing ligand and B‐cell‐activating factor in
patients with rheumatoid arthritis and periodontitis
and compare with tumor necrosis factor levels
To evaluate the methylation profile of the tumor ne‐
crosis factor‐alpha gene in patients with rheumatoid
arthritis and periodontitis
To evaluate the relationship between rheumatoid
arthritis and periodontitis with regard to antioxidant
and oxidant status
To investigate the impact of periodontitis on oxidative
stress in rheumatoid arthritis patients
To investigate body mass index and anti–Porphy‐
romonas gingivalis antibodies in first‐degree relatives
of rheumatoid arthritis patients
To identify environmental factors associated with
rheumatoid arthritis and gingival disease
To evaluate serum protein profiles specific for patients
with rheumatoid arthritis and periodontitis
To investigate serum procalcitonin and C‐reactive pro‐
tein levels in serum of rheumatoid arthritis patients
and correlate this with periodontitis
To determine gingival crevicular fluid and serum
matrix metalloproteinase‐9 as a biomarker for rheu‐
matoid arthritis and periodontitis
| 201
Conclusions
Hypomethylation of the interleukin‐6 promoter region
may lead to increased levels of serum interleukin‐6
No consistent patterns were identified
Interleukin‐1beta, interleukin‐4, interleukin‐10, matrix
metalloproteinase‐8, matrix metalloproteinase‐13, and
tumor necrosis factor‐alpha were found to be higher
in patients with rheumatoid arthritis than in healthy
controls without periodontitis
Development of Porphyromonas gingivalis experimental
arthritis was dependent on the Th17 axis, leading to
increased neutrophil infiltration of the joints
Tumor necrosis factor and B‐cell‐activating factor levels
were higher in rheumatoid arthritis patients than in
periodontitis patients, suggesting an overproduction of
these mediators in rheumatoid arthritis
Hypermethylation of tumor necrosis factor‐alpha gene
promoter may be unique to patients with both rheuma‐
toid arthritis and periodontitis
The presence of rheumatoid arthritis did not af‐
fect the local oxidative stress index in patients with
periodontitis
Increased oxidative stress was noted in both rheumatoid
arthritis and periodontitis patients, but the relationship
was weak
Obesity and presence of periodontics was positively cor‐
related with rheumatoid arthritis
Male gender and vitamin C intake and vitamin D levels
were found to be correlated with elevated gingival
disease in rheumatoid arthritis patients
Complement component 3, complement factor H, and
ceruloplasmin were found to be elevated in patients
with rheumatoid arthritis and periodontitis
Circulating procalcitonin is a more discriminative bio‐
marker than serum C‐reactive protein for periodontitis
in patients with rheumatoid arthritis
Serum levels of matrix metalloproteinase‐9 were similar
between rheumatoid arthritis only and rheumatoid
arthritis/periodontitis patients. Gingival crevicular fluid
levels of matrix metalloproteinase‐9 were increased
in patients with rheumatoid arthritis and periodontitis
compared with periodontitis alone
(Continues)
202 | BARTOLD and LOPEZ‐OLIVA

TA B L E 7 (Continued)

Study Aims Conclusions

136
Hao et al (2015)
Kirchner et al (2017)137
Kim et al (2017)138
Miscellaneous
Montero‐Melendez et al
(2014)139
Gittaboyina et al (2017)140
To study the effect of cathepsin K deficiency on ex‐
perimental rheumatoid arthritis and periodontitis
To determine levels of active matrix metalloprotein‐
ase‐8 and periodontal bacteria in gingival crevicu‐
lar fluid of patients with rheumatoid arthritis and
periodontitis
To explore the role of nicotinamide phosphoribo‐
syltransferase in periodontal inflammation during
arthritis pathogenesis
To investigate the relationship between periodontitis,
the melanocortin receptor, and rheumatoid arthritis
To investigate the relationship between
Porphyromonas gingivalis and pentraxin‐3 levels in
patients with rheumatoid arthritis and periodontitis
Deficiency of cathepsin K caused a significant reduction
in rheumatoid arthritis associated inflammation and
gingival inflammation
No difference in periodontal bacteria noted. Matrix met‐
alloproteinase‐8 levels were increased in the rheuma‐
toid arthritis/periodontitis group
Inhibition of nicotinamide phosphoribosyltransferase
was found to play an important role in the pathogen‐
esis of rheumatoid arthritis–mediated periodontal
inflammation
A melatocortin agonist was found to protect against joint
and periodontal damage in an animal model of peri‐
odontitis and arthritis
A positive association between Porphyromonas gingivalis
and pentraxin‐3 levels in patients with rheumatoid
arthritis and periodontitis was noted

likely that investigations into underlying common cytokine path‐
ways will be particularly important. To date, interesting advances are
being made in identifying common genes and gene polymorphisms,
particularly with regard to interleukin‐1 and interleukin‐6.117,124
2.7 | Effect of periodontal treatment on
rheumatoid arthritis
Owing to its high prevalence, periodontitis may represent an im‐
portant modifiable factor for rheumatoid arthritis incidence and
severity. If this is proven, treatment of periodontitis could present
an inexpensive and safe nonpharmacological treatment with direct
benefit for patients with rheumatoid arthritis.
Prior to 2012, a number of small clinical studies evaluating the
effect of nonsurgical periodontal therapy on rheumatoid arthritis
concluded that treatment of periodontitis may have a significant
positive effect on rheumatoid arthritis severity. As a result, the joint
European Federation of Periodontology and the American Academy
of Periodontology workshop held in 2013 concluded that more rig‐
orous clinical controlled trials and research were needed in the field.7
Since 2012 there have been a further 19 studies published con‐
cerning the effect of periodontal treatment on rheumatoid arthritis
patients (Table 8).47,117,141-151 Three recent systematic reviews have
concluded that nonsurgical periodontal treatment in individuals with
periodontitis and rheumatoid arthritis could lead to improvements
in markers of disease activity in rheumatoid arthritis. However, all
of the studies included in the systematic reviews had low subject
numbers, with the periods of intervention no longer than 6 months.
It was concluded that larger studies are required to explore the
effect of nonsurgical periodontal treatment on clinical indicators
of rheumatoid arthritis, using more rigorous biochemical and clini‐
cal outcome measures, as well as giving consideration to potential
confounding factors of comorbidity.47,117,141-151 Since the review
by Caldeloro et al149 in 2017, which covered the literature up to
December 2014, there have been a further two studies published
investigating the influence of periodontal treatment on rheumatoid
arthritis.150,151 Unfortunately, both of those studies also suffer from
very low subject numbers. Nonetheless, both studies reported a
beneficial outcome in terms of clinical markers of rheumatoid ar‐
thritis activity through a reduction in disease activity score‐28 and
erythrocyte sedimentation rate. Thus, it is clear, as concluded from
the first systematic review published in 2014, that larger studies are
required to explore the effect of nonsurgical periodontal treatment
on clinical indicators of rheumatoid arthritis.
2.8 | Effect of rheumatoid arthritis treatments on
periodontal disease
Given that a bidirectional association has been observed in animal
models, it stands to reason that treatments for rheumatoid arthritis
should have some potential to influence the clinical manifestation of
periodontitis. This is particularly important since most treatments
for rheumatoid arthritis involve the use of host‐modifying drugs. In
particular, the medications known as disease‐modifying antirheu‐
matic arthritis drugs are of particular assistance in managing severe
forms of rheumatoid arthritis and used as a higher level of clinical
intervention if conventional drugs such as nonsteroidal anti‐inflam‐
matory drugs are having little effect. Interestingly, host modulation
treatments are beginning to emerge as an important area of investi‐
gation for the adjunct treatment of periodontitis.152
Since 2012 there have been 12 studies published investigating
the effect of various treatments for rheumatoid arthritis on peri‐
odontitis (Table 9).117,153-163 Of these, the majority have focused
on the effect of tumor necrosis factor‐alpha inhibitors, with most
BARTOLD and LOPEZ‐OLIVA
TA B L E 8 Studies 2012‐2017 investigating the effect of treatments for periodontitis on rheumatoid arthritis parameters
Study Study aims
141
Okada et al (2013) To evaluate whether periodontal treatment may affect
serum antibodies to Porphyromonas gingivalis and citrul‐
line levels in relation to disease activity of rheumatoid
arthritis
Erciyas et al (2013)142 To evaluate the effects of nonsurgical periodontal
treatment on clinical periodontal measurements and
systemic inflammatory mediator levels in low or moder‐
ate to highly active rheumatoid arthritis patients with
periodontitis
Biyikoglu et al To evaluate the clinical outcomes and effects of nonsurgi‐
(2013)143 cal periodontal therapy on serum, gingival crevicular
fluid interleukin‐1 levels in chronic periodontitis patients
with/without rheumatoid arthritis
Kaur et al (2014)144 Systematic review of literature up to September 2013.
Five studies included from 2005 to 2013
Jeffcoat et al (2014)145 To estimate the effects of periodontal therapy in medical
costs and hospitalizations among individuals diagnosed
with a number of systemic conditions, including rheuma‐
toid arthritis
Roman‐Torres et al To evaluate the efficacy of periodontal scaling and oral
(2015)146 hygiene instruction for patients with mild chronic peri‐
odontitis and rheumatoid arthritis through clinical peri‐
odontal parameters and laboratory tests for C‐reactive
protein and erythrocyte sedimentation rate
Silvestre et al (2016) 47 A systematic review up to February 2015. Eight studies
included from 2005 to 2013
Khare et al (2016)147 To examine the effect of nonsurgical periodontal therapy
on the clinical parameters of rheumatoid arthritis.
Case‐control study of 30 controls (nontreated chronic
periodontitis with rheumatoid arthritis) and 30 cases
(treated chronic periodontitis with rheumatoid arthritis)
Kurgan et al (2016)148 To evaluate the effect of nonsurgical treatment on gingi‐
val crevicular fluid levels of matrix metalloproteinase‐8,
prostaglandin E2, and interleukin‐6 levels in patients
with periodontitis with or without rheumatoid arthritis;
27 subjects with periodontitis and rheumatoid arthritis,
26 patients with gingivitis or periodontitis only, and 13
healthy controls
Calderaro et al A systematic review up to December 2014. Four studies
(2017)149 included from 2005 to 2013
Kurgan et al (2017)150 To evaluate the effect of nonsurgical treatment on gingi‐
val crevicular fluid levels of plasminogen activator‐2 in
patients with periodontitis with or without rheumatoid
arthritis; 15 subjects with periodontitis and rheumatoid
arthritis, 15 patients with periodontitis only, and 15
healthy controls
Balci Yuce et al To evaluate inflammatory cytokine and vitamin D levels in
(2017)151 healthy, rheumatoid arthritis, and periodontitis patients
before and after nonsurgical treatment
| 203
Conclusions
Supragingival scaling decreased the disease activity
score‐28–C‐reactive protein and the serum levels of im‐
munoglobulin G to Porphyromonas gingivalis and citrulline
in patients with rheumatoid arthritis
Nonsurgical periodontal treatment may prove beneficial
in reducing rheumatoid arthritis severity as measured
by erythrocyte sedimentation rate, C‐reactive protein,
tumor necrosis factor‐alpha levels in serum, and disease
activity score‐28 in low or moderate to highly active
rheumatoid arthritis patients with chronic periodontitis
Significant decreases in disease activity Score‐28 and gin‐
gival crevicular fluid interleukin‐1 amounts were noted
after periodontal treatment, suggesting that periodontal
therapy synergizes with systemic rheumatoid arthritis
therapy to improve rheumatoid arthritis status
Nonsurgical periodontal treatment in individuals with
periodontitis and rheumatoid arthritis could lead to im‐
provements in markers of disease activity in rheumatoid
arthritis
No treatment effect was noted for rheumatoid arthritis
Periodontal therapy in patients with rheumatoid arthritis
and mild chronic periodontitis showed an improvement
in the periodontal parameters and laboratory tests that
were evaluated
Nonsurgical periodontal therapy improved the periodon‐
tal conditions of patients with rheumatoid arthritis with
beneficial effects on the disease activity score‐28 and
erythrocyte sedimentation rate scores
Nonsurgical periodontal therapy may contribute to reduc‐
tion in severity and symptoms of rheumatoid arthritis
Nonsurgical treatment in patients with rheumatoid
arthritis and periodontitis may reduce gingival crevicular
fluid levels of matrix metalloproteinase‐8, prostaglandin
E2, and interleukin‐6. No effect on rheumatoid arthritis
parameters noted
Reduction in disease activity score‐28 in patients with
rheumatoid arthritis after periodontal treatment sug‐
gested that the improvement in periodontal condition is
beneficial to rheumatoid arthritis patients
In patients with rheumatoid arthritis, nonsurgical peri‐
odontal treatment reduced plasminogen activator‐2
levels. No effect on rheumatoid arthritis
Elevated vitamin D levels in rheumatoid arthritis patients
decreased following periodontal treatment
204 | BARTOLD and LOPEZ‐OLIVA

TA B L E 9 Studies 2012‐2017 investigating the effect of treatments for rheumatoid arthritis on periodontal parameters

Study Aims Conclusions

Han and Reynolds To determine the relative effect of antirheumatic
(2012)153 agents on the levels of inflammatory biomarkers and
periodontal inflammation in rheumatoid arthritis pa‐
tients with periodontitis. Systematic review including
13 studies published between 2000 and 2011
Savioli et al (2012)154 To evaluate the influence and the evolution of
periodontal disease in rheumatoid arthritis patients
submitted to anti–tumor necrosis factor therapy
Mayer et al (2013)155 To evaluate the effect of autoimmune diseases (in‐
cluding rheumatoid arthritis) and anti–tumor necrosis
factor‐alpha therapy on the clinical and immunologic
parameters of the periodontium
Ustun et al (2013)156 To evaluate the effects of host modulation therapy on
periodontal and biochemical parameters
Kobayashi et al To assess interleukin‐6 receptor inhibition treatment
(2014)157 on the periodontal condition of patients with rheu‐
matoid arthritis and periodontitis
Kobayashi et al To assess the effect of anti–tumor necrosis factor‐
(2014)158 alpha antibody on periodontal condition of rheuma‐
toid arthritis patients and compare serum protein
profiles before and after treatment
Fabri et al (2015)159 To evaluate effect of anti–tumor necrosis factor ther‐
apy on periodontal status in patients with ankylosing
spondylitis and rheumatoid arthritis
Kobayashi et al To compare the periodontal condition in patients with
(2015)160 rheumatoid arthritis and periodontitis before and
after interleukin‐6 receptor inhibition therapy
Coat et al (2015)161 To assess the potential effect of anti–B lymphocyte
(rituximab) therapy on the periodontal status of
patients with rheumatoid arthritis
Kadkhoda et al To investigate the effect of anti–tumor necrosis
(2016)162 factor‐alpha blockade on periodontal conditions in
patients with active rheumatoid arthritis
Ancuta et al (2017)163 To evaluate the periodontal status with and with‐
out tumor necrosis factor inhibitors in rheumatoid
arthritis patients
Dominguez‐Perez et To assess the effect of anti–tumor necrosis factor‐
al (2017)117 alpha antibody on the periodontal condition of pa‐
tients with rheumatoid arthritis and compare serum
protein profiles before and after treatment
There are limited data to suggest that anti–tumor necrosis
factor‐alpha agents can reduce local production of inflamma‐
tory cytokines and periodontal inflammation in rheumatoid
arthritis patients with periodontitis
Periodontal disease may affect tumor necrosis factor blocker
efficacy in patients with rheumatoid arthritis. Sustained
gingival inflammation may hamper treatment response in
rheumatoid arthritis
Patients with autoimmune diseases (including rheumatoid
arthritis) had higher periodontal indices and higher tumor ne‐
crosis factor‐alpha levels in the gingival crevicular fluid than
controls did. Anti–tumor necrosis factor‐alpha treatment
appeared to reverse this phenomenon
Tumor necrosis factor blockers may significantly modify host
responses in terms of biochemical parameters of the peri‐
odontium and may mask significant associations reported
between periodontitis and rheumatoid arthritis
Anti–interleukin‐6 treatment resulted in decreases in gingival
bleeding index, bleeding on probing, pocket depth at‐
tachment levels, serum interleukin‐6, and serum matrix
metalloproteinase‐3
Anti–tumor necrosis factor‐alpha treatment had a beneficial
effect on the periodontal tissues of rheumatoid arthritis
patients. Changes in unidentified serum proteins were noted
No improvement in periodontal parameters noted after
anti–tumor necrosis factor treatment in rheumatoid arthritis
patients
There was a beneficial effect of tocilizumab therapy on levels
of periodontal inflammation in patients with rheumatoid
arthritis and periodontitis
Anti–B lymphocyte therapy improved periodontal outcomes
in periodontitis patients with rheumatoid arthritis
Anti–tumor necrosis factor‐alpha therapy may have a benefi‐
cial effect on periodontal conditions and reduce the tumor
necrosis factor‐alpha levels in the gingival crevicular fluid of
periodontitis patients with rheumatoid arthritis
There was a significant improvement in both rheumatoid
arthritis–related characteristics and periodontal status after
6 months of anti–tumor necrosis factor therapy
Anti–tumor necrosis factor‐alpha treatment had a beneficial
effect on the periodontal condition of rheumatoid arthritis
patients. Changes in unidentified serum proteins were noted
after treatment

finding a beneficial effect on the periodontium and only one re‐
port demonstrating no improvement in periodontal parameters
noted after anti–tumor necrosis factor treatment in rheumatoid
arthritis patients.159 Other disease‐modifying antirheumatic drugs
investigated included interleukin‐6 receptor inhibitor and anti–B
lymphocyte therapy, both of which also demonstrated a beneficial
effect on the periodontal tissues of rheumatoid arthritis patients
taking these medications.160,161 Only one systematic review on
this subject area has been published, and it reviewed the litera‐
ture up to 2011.153 This systematic review concluded that there
were limited data to suggest that anti–tumor necrosis factor‐alpha
agents can reduce local production of inflammatory cytokines and
periodontal inflammation in rheumatoid arthritis patients with
periodontitis. This is an important area of investigation that needs
further larger studies. One issue of importance is whether peri‐
odontal inflammation and infection can influence the efficacy of
BARTOLD and LOPEZ‐OLIVA
disease‐modifying antirheumatic drugs in the management of rheu‐
matoid arthritis, since there is potential for significant suppression
of basic biologic defense mechanisms to allow the periodontal in‐
fection to worsen as the host loses a considerable portion of its
host defense capacity. One study has demonstrated that such a
situation is possible, in that periodontal disease may affect tumor
necrosis factor blocker efficacy in patients with rheumatoid ar‐
thritis whereby sustained gingival inflammation and infection may
hamper treatment response in rheumatoid arthritis.154
3 | A U N I F Y I N G H Y P OTH E S I S
From the evidence to date, it is clear that periodontitis and rheu‐
matoid arthritis, in a subset of hitherto unidentified patients, is
associated. The evidence for this is clear, in that, though associa‐
tions can be shown, not all periodontitis patients have rheuma‐
toid arthritis and, conversely, not all rheumatoid arthritis patients
have periodontitis. However, in a subset of individuals (most likely
with common genetic and environmental risk factors), rheumatoid
arthritis and periodontitis are intimately interrelated. The impor‐
tant question now is to identify these subsets and determine how
these associations occur. Over the years, a number of hypotheses
have been put forward as to how these associations might occur;
these include host‐mediated osteoclast activation and vascular
damage mediated through common receptor activator of nuclear
F I G U R E 2 Concept proposals for the interplay between periodontitis and rheumatoid arthritis. A, How gingival citrullination may interact
with subsequent citrullination in joints to modify rheumatoid arthritis. B, Common inflammatory pathways between periodontitis and
rheumatoid arthritis (NF, nuclear factor; TNF, tumor necrosis factor). C, Two‐hit model, whereby inflammatory changes in the periodontium
can exacerbate subsequent inflammatory process in the joints
| 205
factor kappa‐Β ligand pathways, bacterial infection, viral infection
and the “two‐hit” model (Figure 2). Of these, the two‐hit model, as
originally proposed by Golub et al in 2006,164 is the most attrac‐
tive as it allows either inflammation or infection, or indeed both,
to play central roles in the development of rheumatoid arthritis
in susceptible individuals (Figure 3). In this model, the possibility
exists that priming anti–cyclic citrullinated peptide antibodies may
be produced during the development of periodontitis. If a later
event, such as joint inflammation, results in citrullination then, in
a primed individual, the subsequent antibody response could be
very robust. Such a response is in keeping with recent observa‐
tions that experimental animals with a preexisting chronic infec‐
tion or periodontitis develop experimental arthritis at a faster and
more pronounced rate than nonprimed animals.7,8
4 | W H AT A R E TH E I N CO N S I S TE N C I E S
I N TH E A S S O C I ATI O N B E T W E E N
PE R I O D O NTITI S A N D R H EU M ATO I D
A RTH R ITI S ?
Notwithstanding the strong evidence to support an association be‐
tween periodontitis and rheumatoid arthritis, a number of inconsist‐
encies still exist that have not been fully explored or explained.
206 | BARTOLD and LOPEZ‐OLIVA

F I G U R E 3 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)

4.1 | Incidence and gender frequencies of
periodontitis and rheumatoid arthritis
The most striking and confounding difference between periodon‐
titis and rheumatoid arthritis is their different gender frequencies.
Rheumatoid arthritis occurs worldwide, affecting approximately
1%‐2% of the population in a female:male ratio of 3:1 and has a peak
165
onset in the fourth and fifth decades of life. Periodontitis is also
a global condition, with up to 95% of the population suffering from
gingivitis and up to 50% having some form of chronic periodonti‐
tis. Approximately 5%‐15% of the population appear to suffer from
166,167
advanced and aggressive periodontitis. Most studies have re‐
ported that periodontitis (both prevalence and severity) in males is
higher than in females.168 The phenomena of incidence disparity and
gender frequency has not been investigated in any detail to date and
remains a significant issue with regard to the association between
periodontitis and rheumatoid arthritis.
4.2 | Rheumatoid arthritis is a relatively modern
disease. Is peridontitis?
Although rheumatoid arthritis was reported by Hippocrates, there is
some doubt as to whether this was a true case of rheumatoid arthri‐
tis.169 Today, it is generally considered that rheumatoid arthritis was
not documented in Europe until the 1800s, around the time of the
Industrial Revolution, indicating that this condition may have been a
by‐product of the industrial age.169 Based on the identification of six
skeletons in ancient (Late Archaic Culture Period, 3000 to 5000 years
ago) burial sites in Alabama with lesions suggestive of rheumatoid ar‐
thritis, it was proposed that rheumatoid arthritis may have been pre‐
sent in the pre‐Columbus New World and subsequently translocated
to the old world of Europe through pathogens or allergens originally
native to the New World.170 Nonetheless, the antiquity of rheuma‐
toid arthritis remains controversial. A review of all reported rheuma‐
toid arthritis cases from ancient Egypt revealed that none of them
represent real rheumatoid arthritis, instead being either examples
BARTOLD and LOPEZ‐OLIVA
of changing naming conventions or of imprecise diagnostic criteria.
Most cases represented osteoarthritis or spondyloarthropathies.171
Though there is little doubt periodontitis affected ancient civiliza‐
tions, some doubt has been cast as to its prevalence and severity in
those populations.171-174 More recently, studies have emerged indicat‐
ing that the incidence and severity of moderate to severe periodon‐
titis in ancient populations was markedly decreased when compared
with the prevalence in modern populations.175 This highlights the po‐
tential importance of modern‐day risk factors such as smoking and
diabetes in determining susceptibility to progressive periodontitis in
modern populations. From these studies, it seems that although peri‐
odontitis was present in ancient civilizations its exacerbation in the
post‐Industrial Revolution era does give it some similarity with rheu‐
matoid arthritis. Nonetheless, the obvious discrepancy of rheumatoid
arthritis being a post‐Industrial Revolution disease and periodontitis
being an ancient disease needs further investigation.
4.3 | There is no evidence that peptidylarginine
deiminase is present and active in situ in
periodontal tissues
Despite the claims that P. gingivalis and its peptidylarginine deiminase
are central to the periodontitis/rheumatoid arthritis association story, a
number of critical issues remain to be resolved: importantly, anti–P. gin‐
givalis antibodies or the frequency of P. gingivalis between rheumatoid
67
arthritis patients and osteoarthritis controls. Furthermore, another
study reported that the frequency of anti–P. gingivalis antibody titers
and subgingival presence of P. gingivalis were no different between
rheumatoid arthritis patients with and without periodontitis. A num‐
ber of other periodontal bacteria also appear to be present at the same
level between rheumatoid arthritis and control patients. Together,
these findings argue strongly against a central role for this bacterium in
rheumatoid arthritis. The role for peptidylarginine deiminase has also
been exaggerated. Until such time that peptidylarginine deiminase can
be demonstrated to be present and active in periodontal tissues, a cen‐
tral role for the bacteria‐derived enzyme should be questioned.
4.4 | Absence of peptidylarginine
deiminase decreases both experimental
periodontitis and arthritis
In animal studies, it has been noted that when infected with strains of
P. gingivalis deficient in the expression of peptidylarginine deiminase
the rheumatoid arthritis experience is diminished. However, impor‐
tantly, in these animals exposed to the peptidylarginine deiminase–de‐
ficient P. gingivalis, the degree of periodontal disease is also diminished.
Thus, the interpretation that absence of peptidylarginine deiminase is
the driving force behind better arthritis outcomes may be incorrect, as
it may well be that the reduction of periodontal inflammation in ani‐
mals exposed to peptidylarginine deiminase–negative P. gingivalis may
be the cause of the diminished arthritic response. This is an important
matter that needs to be resolved through carefully planned experi‐
ments to account for all permutations of experimental outcomes.
| 207
4.5 | Not everyone with rheumatoid arthritis has
periodontal disease, and vice versa
One of the most important observations in any association studies is
that the disease relationship is not 100%. In the case of periodontitis
and rheumatoid arthritis, not everyone who has rheumatoid arthritis
manifests periodontitis, and not everyone with periodontitis manifests
with rheumatoid arthritis. However, there is a subset of individuals for
whom this is true; and it is these individuals who should be targeted and
identified, as they will be the individuals who most likely will benefit
greatly for periodontal or rheumatoid arthritis treatment interventions.
5 | CO N C LU S I O N S
A biologic link between periodontitis and rheumatoid arthritis
was first postulated in 1982.1 Since then, a considerable amount
of work in the field has been carried out, particularly in the last
5 years. It now seems that we can say with confidence that there
is a very strong relationship between these two chronic inflam‐
matory conditions. However, none of the proposals put forward
to date can adequately explain this relationship. Though it seems
that there is an epidemiological relation between the two condi‐
tions, it is not clear whether this is coincidental or due to common
risk factors. At present, a causal relationship between these two
conditions would seem unlikely, and it would be more feasible that
the relationship is one of an association in a subset of susceptible
rheumatoid arthritis patients, perhaps even in a syndromic relation‐
ship through linked hyperinflammation and other dysregulated in‐
flammatory mechanisms. There is clear need for further research,
but more cohort studies and population‐based studies considering
case‐control relationships should now be considered redundant,
and more biologically focused approaches need to be utilized. In
addition, larger studies are required to determine, with certainty,
whether periodontitis prevention and therapy could ameliorate
both the onset and progression of rheumatoid arthritis in yet to be
defined patient groups. If proven, periodontal therapy could be an
inexpensive, nonpharmaceutical way of improving rheumatoid ar‐
thritis in addition to the known local and systemic benefits of main‐
taining periodontal health. Notwithstanding this, population‐based
studies have provided sufficient evidence to recommend that all
patients diagnosed with rheumatoid arthritis should undergo a
periodontal assessment, as they may have a higher risk of suffering
from chronic periodontitis than the rest of the adult population.
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How to cite this article: Bartold PM, Lopez‐Oliva I.
Periodontitis and rheumatoid arthritis: An update 2012‐2017.
Periodontol 2000. 2020;83:189–212. https​://doi.org/10.1111/
prd.12300​