Best Practice & Research Clinical Rheumatology xxx (2015) 1e13

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Best Practice & Research Clinical

Rheumatology
journal homepage: www.elsevierhealth.com/berh

The association between rheumatoid arthritis

and periodontitis
Michelle T. Leech, MBBS(Hons) FRACP PhD a, *,
P.M. Bartold, DDSc PhD b
a
b

Rheumatology, Monash Health, Faculty of Medicine, Monash University, Melbourne, Australia

Colgate-Dental Research Centre, University of Adelaide, Australia

a b s t r a c t
Keywords:
Rheumatoid arthritis (RA)
Periodontitis (PD)
Porphyromonas gingivalis
Citrullination
Peptidylarginine deiminase (PAD)

The relationship between rheumatoid arthritis and poor oral

health has been recognised for many decades. The association
between periodontal infection and the risk of developing RA has
been the subject of epidemiological, clinical and basic science
research in recent times. Converging and reproducible evidence
now makes a clear case for the role of specic periodontal infective
pathogens in initiating, amplifying and perpetuating rheumatoid
arthritis. The unique enzymatic properties of the periodontal
pathogen Porphyromonas gingivalis and its contribution to the
burden of citrullinated peptides is now well established. The
impact of localized infection such as periodontitis in shaping
specic anti-citrullinated peptide immune responses highlights a
key area for treatment, prevention and risk assessment in rheumatoid arthritis.
2015 Elsevier Ltd. All rights reserved.

Introduction
Rheumatoid arthritis (RA) is an autoimmune disease leading to synovial inammation and
destruction of cartilage and bone. RA, like many autoimmune diseases, is proposed to occur in
genetically at risk individuals, in response to a trigger or triggers. Viral or bacterial infections have long

* Corresponding author. Monash University Monash Health, Department of Rheumatology, Monash Medical Centre, Locked
Bag No 29, Clayton 3168, Melbourne, Australia. Tel.: 61 3 9594 3565; fax: 61 3 9594 6437.
E-mail address: Michelle.leech@monash.edu (M.T. Leech).
http://dx.doi.org/10.1016/j.berh.2015.03.001
1521-6942/ 2015 Elsevier Ltd. All rights reserved.

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been considered as putative triggers for this disease. Periodontitis (PD), is also a chronic inammatory
condition initiated by bacterial accumulation on the interface between the teeth and gingiva and
modied by genetic, environments (eg smoking) and the host inammatory reaction. The similarities
between RA and PD were rst recognized by Snyderman and McCarty [1] and since then considerable
evidence has accumulated to support the concept of a strong interrelationship between these two
inammatory conditions.
The association between RA and periodontitis (PD) and the relationship of smoking to both conditions has become contextually relevant with the knowledge that immune responses to citrullinated
peptides are associated RA with and likely to be pathogenic. Smoking is known to increase levels of
citrullination via increases in the enzyme peptidylarginine deiminase (PAD). The opportunistic
infection that characterizes PD has become particularly relevant in this context. Porphyromonas gingivalis (P. gingivalis), the major pathogen in PD is the only bacterium known to express a PAD enzyme
(PPAD), and has been reported to be signicantly associated with RA [2,3]. The role of PPAD in
generating citrullinated bacterial and host proteins, the potential for these to interact with the host
immune system in genetically at-risk individuals, and the implications for treatment will be the main
focus of this review.
The link between rheumatoid arthritis and periodontitis
Rheumatoid arthritis (RA) is an autoimmune inammatory arthritis characterised by evidence of
serological autoimmunity and persistent synovial inammation. It has a prevalence of approximately
1% with a peak incidence in pre-menopausal women. Inammation of the synovial lining of joints
results in destruction of cartilage and erosion of bone, which, if unchecked, will lead to loss of function,
deformity and chronic pain. Periodontitis (PD) is the commonest described oral disease with highly
variable estimated prevalence rates of up to 50e60% in most populations [4]. Opportunistic infection
with bacteria within the sub-gingival biolm is associated with periodontal destruction, which can
lead to tooth loss and importantly create a signicant systemic inammatory burden. Virulence of the
colonizing bacteria as well as the intensity of the host immune response is thought to contribute to the
severity of the disease [5,6].
The increasing recognition of an epidemiological association between PD and RA must be considered in the context of the very high prevalence of PD in particular, the chronic nature of both conditions
and shared genetic and environmental risk factors [7]. Evidence supporting a causal link has emerged
from subsequent understanding of the pathogenic mechanisms underpinning both diseases, which
will be discussed in later in this review. Nevertheless a range of epidemiological data examining
presence and severity of both diseases as well as temporal relationships between the onset of RA and
PD has driven deeper inquiry into pathogenic links. Although PD is common, patients with longstanding active RA were shown to have increased incidence of PD compared with healthy non-RA
subjects [8,9]. Correspondingly RA prevalence is increased in patients with PD [10]. Indeed an increase in all systemic conditions including RA was reported in PD patients [11,12] In a study examining
shared risk factors for PD and RA, Mikuls et al., recently conrmed higher prevalence of PD in 277 RA
patients compared with 330 osteoarthritis controls using standardised periodontal examination [13].
The recent OSARA study examined oral health over time in outpatients with rheumatoid arthritis
and found that 94% of RA patients had PD. In 46 percent of RA patients PD was described as severe [14].
Odds ratio's of having both conditions are variably estimated as being between 2:1 and 8:1 [9]
depending on the criteria used to dene periodontitis. These odds ratios must be considered in the
context that RA has low but stable prevalence estimates whereas periodontitis prevalence estimates
are highly divergent. However it is compelling that in the large US population study NHANES III, more
than 50% of RA patients were edentulous [10].
Evidence supporting the association between periodontitis and RA
In addition to epidemiological data that supports the association between RA and PD, the shared
environmental associations as well as the underlying biology and local pathological outcomes is
striking. More than 100 genetic susceptibility loci have now been identied for RA [15]. The association
Please cite this article in press as: Leech MT, Bartold PM, The association between rheumatoid arthritis
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of a shared DRB1 locus with RA has been documented over many decades and has recently come into
sharp focus in the context of its relationship with seropositive RA specically Anti-Citrullinated Peptide
Antibody (ACPA)-positive RA. HLADR4 has also been associated with rapidly progressive PD [16]. A
higher frequency of the shared epitope in PD patients was observed compared with controls [17]. A
recent candidateegene association study genotyped a very large caseecontrol sample of aggressive PD.
Of 47 genes with genome wide signicance in RA and SLE, two genetic variants IRF5 and PRDM1 were
identied as shared susceptibility factors between RA and PD [18].
Environmental risks such as smoking are strongly associated with both PD and RA. In a study of
approximately 4500 patients, including three prospective cohorts, a clear doseeresponse effect of
smoking on the risk of developing RA was identied [19]. The epidemiological relationship between RA
and smoking which has been previously identied in large population studies, including the Nurses
Health Study, became a focus of intense interest when smoking was identied as a stimulus to citrullination of peptides via the induction of Peptidyl Arginine Deiminase (PAD) enzyme. Citrullination,
the process of enzymatic conversion of arginine to citrulline, is a physiological process that occurs in
the context of inammation and cell death. Citrullination via PAD activation requires the mobilization
of free intracellular calcium in mammalian systems. Such citrullinated peptides could drive ACPA responses. The subsequent epidemiological delineation of smoking as a risk factor for ACPA positive RA
rather than ACPA negative RA and the accumulating evidence that ACPA positivity is genetically
restricted has created a cogent link between specic genes and environmental triggers in driving
disease. These observations have equally formed the basis of exciting translational studies, which
identify the structural interaction with citrullinated peptides, and the HLADRB1 (shared epitope)encoded structurally modied antigen-binding pocket [20]. In an elegant proof of concept study,
mice, which overexpress the human shared epitope, develop orid arthritis in response to citrullinated
brinogen but not in response to unmodied brinogen [21]. This molecular and in vivo evidence that
specic genetic risk can predispose to more effective binding of citrullinated peptides and drive more
intense T-cell responses to these citrullinated peptides will be particularly relevant to understanding
possible causal links between PD and RA, discussed later in this review.
Interestingly PAD-2 and PAD-4, citrullinated proteins and ACPA have been identied in inamed
human periodontal tissues [22,23]. This could provide another source of extra-articular citrullination
and serve as a link between PD and RA. The role of periodontal citrullination and RA is still in its
formative stages and any link to RA and shared HLA epitopes will be important to establish.
Periodontitis, P. gingivalis and citrullination
An additional pathway by which proteins may be citrullinated in periodontal tissues is through
PPAD produced by P gingivalis. The relationship between the infection which characterises PD and its
relationship to ACPA positivity, RA development and/or exacerbation is the principal focus of this review and will therefore be discussed in detail in this section.
Periodontitis and bacterial infection
In periodontitis predominantly gram-negative anaerobic bacteria are located within a bacterial
biolm on the tooth surface in a sub-gingival location. Bacterial and host factors drive local inammation and tissue destruction. Osteoclast activation results in alveolar bone loss in a process, which
closely resembles cytokine-driven osteoclast activation, and bone erosion in RA. Among the micro ora
associated with PD, one of the best studied is P. gingivalis.
Periodontitis and systemic inammation
Pathogenic bacteria are able to participate in a complex interaction with resident bacteria. These
pathogenic bacteria are protected from host defense by virtue of this co-operation, the biolm, and
sub-gingival location [24]. P. gingivalis has been shown to promote dysbiosis by down-regulating
complement and TLR signaling [25]. Another study demonstrated differential suppression of macrophage subsets by P. gingivalis favouring persistent carriage [26]. Notwithstanding this protection,
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chronic bacterial infection in PD leads to the release of bacterial toxins that can stimulate the immune
system [27]. Evidence for activation of inammatory cytokines, integrins, complement and prominent
local activation of neutrophils is well established [28]. Given this evidence of chronic immune activation, it is not surprising that chronic PD has recently been associated with elevations in high
sensitivity CRP (hs-CRP), both locally and systemically [29,30]. In this way the chronic bacterial burden
itself and associated immune response may mimic the effect of adjuvant, which boosts immune responses in a range of animal models of inammatory disease most notably experimental arthritis. Over
400 bacterial species have been identied within the periodontal microbiota and recent reports
indicate this is likely to increase as more sophisticated microbiome techniques are used to probe for as
yet unidentied periodontal pathogens [31]. The possible contribution of these to augmentation of
immune responses relevant to RA is beyond the scope of this review. P. gingivalis has been the subject of
intense investigation in the last decade for reasons relating to its unique properties discussed in the
section that follows.
P. gingivalis infection, PPAD and citrullination
The virulence of P. gingivalis has been attributed to the production of proteolytic enzymes known as
gingipains, which contribute to local tissue destruction and direct apoptosis of gingival cells, as well as
overriding host defense mechanisms including complement. Of key relevance to this review, P. gingivalis remains the only known bacterium which can produce the enzyme Peptidyl Arginine Deiminase
(PAD) [2]. This enzyme was subsequently named P. gingivalis peptidyl arginine deiminase (PPAD).
Following this observation, it was proposed that PPAD could be a link between PD, citrullination and RA
[32]. This enzyme, like human PAD, converts arginine to citrulline resulting in post-translational
structural protein modication. This structural modication is believed to generate a range of neoantigens including citrullinated laggrin, vimentin, collagen and enolase. Although P. gingivalis PAD
(PPAD) is not fully homologous to human PAD, it has been clearly shown to citrullinate both host and
bacterial peptides [33]. In strong support of this, the titre of antibodies to P. gingivalis has been shown
to positively correlate with circulating levels of ACPA in RA [13].
PPAD is distinct from mammalian PAD in having no requirement for calcium ux to activate enzyme
activity [2]. Gingipains co-operate with PPAD by generating arginine-containing residues through
proteolytic cleavage. PPAD unlike human PAD can deiminate free arginine as well as C-terminal arginine
residues [2]. Underscoring this co-operation is evidence that P. gingivalis mutants lacking argininegingipain proteolytic cleavage function cannot facilitate citrullination in spite of fully functional PAD
[33]. Evidence that PPAD citrullinates peptides generated by gingipain degradation of brinogen and
alpha-enolase is of particular interest. This is in the context of increasing evidence that antibodies to
citrullinated enolase peptides (CEP) have higher specicity in RA than other ACPA species [34].
These demonstrated biological propensities of PPAD become very meaningful in the context of
studies, which examine the temporal relationship between periodontitis and RA in humans and the
possible causal relationships in animal models.
Patients with new onset RA have been observed to have a higher prevalence of PD; out of keeping
with their young age and smoking status [35]. Evidence that P. gingivalis infection precedes RA in
humans has been complemented by animal studies supporting a causal relationship. For example, mice
with pre-existing periodontitis developed earlier and more severe arthritis [36]. P. gingivalis infection
appeared to sensitise animals to early arthritis development. The developing arthritis in these animals
was characterised by more dramatic bone and cartilage destruction and a more rapid clinical course. Of
critical importance, only viable P. gingivalis inoculation produced this effect. Other Porphyromonal
pathogens such as P intermedia were not able to mediate this exacerbation of arthritis. This animal data
reconnects with observations in humans in which circulating antibodies to P. gingivalis, but not other
Porphyromonal species, correlated with ACPA positivity and titre [13]. Mice infected with wild-type P.
gingivalis in the context of collagen-induced experimental arthritis develop antibodies to citrullinated
peptides including enolase [37]. Recombinant human a-enolase and P. gingivalis enolase, either citrullinated or uncitrullinated, were used to immunise DR4-IE-transgenic mice and control mice. Mice
immunised with either citrullinated P. gingivalis enolase or human enolase developed arthritis. This
study has important and broad implications given that it demonstrates that the human shared epitope
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mediates increased MHC class II binding of citrullinated peptides of both human and bacterial origin. It
additionally demonstrates that the specic immune response that ensues is arthritogenic.
P. gingivalis oral infection has been shown to increase the release of a range of cytokines including
RA-relevant monokines IL-1, IL-6 and TNF [38]. In the same study P. gingivalis increased Th17 responses
and IL-23 production.
However, a critical nding that a PPAD decient strain of P. gingivalis lacks pathogenic potential in
terms of both PD and RA, indicates that the citrullination function of P. gingivalis is of paramount
importance [39]. In this study the genetically modied PAD-decient strain of P. gingivalis was associated with reduced development of PD, and importantly decreased clinical arthritis, bone erosion and
circulating ACPA levels compared with animals inoculated with wild-type P. gingivalis.
Auto-citrullination of PPAD and associations with RA
An additional layer of complexity relates to the recognition that the PPAD enzyme itself can be
citrullinated in a process referred to as auto-citrullination [40]. The Cit-PPAD, which is generated may
then, itself, act as a neo-antigen. Evidence for immunogenicity of PPAD is emerging from both human
and animal studies. Circulating anti-PPAD antibodies are reported in RA [41]. Evidence of elevated levels
of anti-PPAD in RA serum also point to the capacity of a bacterial protein to break tolerance. In contrast
to this, in a recent study [40], patients with RA and healthy controls were assayed for IgG antibodies to
citrullinated recombinant PPAD (rPPAD) and unmodied rPPAD. Anti-PPAD antibodies did not correlate
with ACPA and were decreased in RA patients with PD, leading the authors to propose that anti-PPAD
antibodies may have a protective role for the development of PD in patients with RA. Whilst both PD
and P. gingivalis constitute an inammatory burden and may shape auto-reactivity in RA, the overwhelming evidence converging from human and animal studies supports a specic role for the unique
PPAD enzymatic function of P. gingivalis. Gingival PPAD activity, in conjunction with the constitutive
citrullination occurring as a result of the gingival inammation, provide a continuous and evolving
range of citrullinated host and possibly bacterial peptides leading to progressive loss of tolerance
initially locally and then systemically. Physiological citrullination in the synovium in the context of cell
death, inammation or repair, may then direct this primed immune system to attack joint tissues.
Immune responses carbamylated peptides: anti-CarP Ab and RA
An emerging literature points to evidence of immune responses to other post-translationally
modied peptides that may predate ACPA responses. Carbamylation is the non-enzymatic modication of molecules containing primary amine or thiol groups. Anti-Carbamylated protein antibodies
(Anti-CarP) have been described in patients with RA but also in those with arthralgia or pre-arthritis
[42]. In this context, anti-CarP antibodies are associated both with increased risk of developing RA, and
increased risk of erosive RA. Anti-CarP antibodies have been detected in 20% of ACPA negative RA
patients [43]. In contrast to ACPA, the lack of association of Anti-CarP Ab with HLA-DRB1 alleles, other
known risk genes or smoking [42] point to distinct biological mechanisms underlying their formation.
A striking observation is that mice with CIA do not develop reliable ACPA responses, except after
inoculation with P. gingivalis. In a recent study, however, in a mouse CIA model, mice developed antiCarP antibodies before the onset of arthritis [44]. As arthritis developed the anti-CarP Ab response
intensied. This study suggests that breaking tolerance to Carbamylated peptides is perhaps an earlier
and easier step than loss of tolerance to citrullinated peptides. Whilst P. gingivalis, through gingipain
activity, is able to mediate proteolysis, there are no direct links as yet published between PD, P. gingivalis and carbamylation. However, a recent publication has proposed a role for carbamylation within
inamed periodontal tissues in the RA/PD axis and this was substantiated by immunohistochemical
demonstration of carbamylated proteins within inamed human periodontal tissues.
Dysbiosis and dysregulated immunity: chicken or egg?
Much of the above review aims to highlight increasing evidence, which supports a causal or
aetiopathogenic relationship between chronic gingival inammation and P. gingivalis infection with
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RA. However, this must be balanced by examining the complexity surrounding the interaction between
dysregulated microbiota and the immune system. A return to what is known about shared genetic risks
in PD and RA may be relevant. Shared susceptibility genes in PD and RA are critically involved in
shaping antigen recognition, tight binding and hence subsequent T-cell responses. It is therefore
conceivable, and indeed has been suggested, that these same factors may shape the host inammatory
and immune response, which occurs as gingivitis is developing. The progression of periodontitis and
the survival of particular bacteria such as P. gingivalis may therefore be favoured by certain host immune factors. The evolution and composition of resident microbial populations in all mucosal surfaces
is thought to be critically important in triggering a range of immune and inammatory diseases [45].
Whilst the initial focus has related to the consequences of host immune responses to this microbiota,
there is increasing interest in the role of local mucosal immunity and dysregulation of this in driving a
particular microbiota composition which favours chronic inammation or immune activation.
As with RA, many of the hundreds of risk genes for inammatory bowel disease relate to immune
function [46]. Genetic factors which lead to altered innate immune surveillance may predispose to
increased mucosal translocation of bacteria. In mice the NOD2 genotype was shown to lead to instability in the composition of microbiota that could promote colon inammation. Genotype dependent
disease could be transferred via maternally transmitted microbiota to NOD2 decient and wild type
hosts [47]. Variation in host susceptibility to P. gingivalis has been shown in mouse models [48]. In this
study the Balb-CJ mouse strain was highly susceptible to PD development after P. gingivalis inoculation
compared with ve other strains. In humans, genetic variants associated with neutrophil function were
associated with more aggressive periodontitis. Fc Gamma receptor and IL-6 polymorphisms have been
associated with increased odds of identifying pathogenic bacteria including P. gingivalis in PD patients
[49]. Class II HLA polymorphisms in the DQ locus have been described, which are associated with
susceptibility to, as well as protection from, PD [50]. In another study, certain HLA variants were
negatively associated with colonisation by PD-related microorganisms [51].
Whilst HLA association studies in the last decade have identied relationships between HLA
polymorphisms and PD, the hypothesis that upregulated immune responses to local bacteria have
driven more aggressive PD, has been favoured. However, evolving theories especially from examination
of gut dysbiosis, suggest that genetically determined unbalanced, or inefcient local mucosal immunity, along with environmental factors, may favour the persistence of pathogenic bacteria. Known
genetic associations of PD may, therefore, be mechanistically linked via predisposition to the persistence of pathogenic bacteria including P. gingivalis. The precise ways in which these genetic risks may
modify oral mucosal immunity to support infection and persistence of pathogenic bacteria will have
important implications for both PD and RA.
Enormous progress in the understanding of the pathogenesis of RA and PD has, and will continue to
have impact on treatment of both diseases, as well as the new goal of disease prediction and prevention. The management of rheumatoid arthritis has evolved rapidly in the last three decades and the
treatment approaches directly reect an understanding of the underpinning biology. In the section that
follows, the implications for treatment of RA, which are raised by specic aspects of this review, will be
discussed in more detail.
RA and periodontitis: implications for treatment
Over the last two decades, RA treatment has transitioned from symptom control to disease control.
The amelioration of severe joint damage and disability afforded by disease control could be attributed
in the rst instance to global immune suppressing drugs described as disease modifying antirheumatic drugs (DMARD). These oral agents including Methotrexate and more recently Leunomide could be described as having a blanket or generalised immunosuppressive effect. A highly
favourable risk:benet ratio has supported the persistence of these anchor oral agents well into the
biologic era. The development of therapies, mostly large biologic molecule parenteral agents, which
are designed to target specic aspects of the immune response, has further improved treatment responses in a subset of patients with severe disease.
The identication of ACPA positive patients has also suggested a possible treatment stratication,
wherein evidence of increased immune responses to citrullinated peptides as a disease driver, may
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point to the utility of biologic therapies which specically down regulate T-cell responses or delete B
cells, such as abatacept (CTLA4-Ig) and Mabthera (anti-CD20 monoclonal antibody). In practice,
however, all biologic therapies including, but not limited to these, such as anti-TNF, anti-IL-6 receptor
Ab are comparably effective in ACPA-positive RA. There is some evidence that a more favourable
response to therapy with Abatacept or Mabthera is seen in ACPA-positive compared with the same
agents in ACPA-negative RA [52]. In general, most of the current treatment approaches for RA,
acknowledge activation of the immune system and seek to down-regulate the immune-inammatory
network globally or by targeting specic aspects of the immune system with the same net effect. None
of the current approaches specically take into account the increasing understanding of the contribution of PD, P. gingivalis, PAD, PPAD and smoking as possible drivers of disease. Equally, none of the
current approved therapies particularly take into account the evolving understanding of the role of
citrullinated and modied peptides in RA. The challenge for evolving therapies will be to translate the
vast knowledge regarding key citrullinated peptides into a rational therapeutic approach. Equally, there
is now the opportunity to predict risk and intervene to prevent disease in RA probands at a time when
serological loss of tolerance has not yet crossed the threshold into disease.
Antigen-specic therapy: down-regulation of immune responses to citrullinated peptides
In addition to broad targeting of aspects of the immune system involved in antigen presentation or
shaping antibody responses, the recognition of expanding immune responses specically to citrullinated peptides may highlight treatment approaches. Therapies that augment T-regulatory (Treg)
function to restore tolerance are under investigation and development. It is postulated that existing
therapies down-regulate immunity and inammation but do not address the specic antigenic
drivers or ampliers of disease. Antigen-specic immunotherapy, which induces tolerance, is
emerging. It has been shown that dendritic cells, in which NFkB family member RelB is inhibited
during antigen exposure, will induce a tolerising or antigen-specic Treg response. This has been
translated into a phase I trial in humans in which autologous ex-vivo DC, tolerised to a citrullinated
peptide, were re-introduced [53]. Increasing understanding of the interaction between PD and RA,
specically PPAD generated citrullinated host and bacterial peptides will further inform this
approach. Moreover, further understanding of structural and physicochemical interactions between
the MHC class II molecule, and the particular citrullinated peptides and anking amino acids, will
narrow the focus to specic citrullinated peptides with eminent arthritogenic potential. The diversity
of autoantigens identied to date in RA may, in the rst instance, seem to limit this therapeutic
approach. However, it has been shown that antigen specic Tregs are able to regulate broader
specicity T-effector responses [54].
Managing P. gingivalis infection: antibiotics and RA
Long before the appreciation of any relationship between periodontal infection and RA, antibiotics,
as a treatment approach in RA, were under examination. Early last century, in the 1930s, sulfonamides
were trialed for the treatment of RA [55]. Of note, sulphonamides, which are effective against gramnegative and gram-positive bacteria, were also used in the 1940s to treat PD [56]. The development
of sulphasalazine for RA treatment was based on this observation of early efcacy of sulpha-based
antibiotics and the subsequent publication of the benets of sulfamethoxazole lend weight to a
contribution of antibacterial action of sulphasalazine in RA [57].
There are a number of studies examining the efcacy of tetracyclines in RA. Randomised control
trials comparing minocycline with placebo have demonstrated efcacy in RA. Tetracyclines are known
to have efcacy against periodontal pathogens [58]. Macrolide antibiotics including clarithromycin and
roxithromycin have been used in the treatment of RA. Azithromycin has gained signicant attention in
recent years as an adjunct to the treatment of PD [59]. Increased clinical responses to clarithromycin
compared with placebo were observed in a six month randomised controlled trial [60]. In a one-year
study, the addition of clarithromycin to methotrexate and low dose corticosteroids produced additional clinical efcacy [61]. In patients failing at least one DMARD, response rates to roxithromycin in a
six-month double blind RCT, were signicantly higher than placebo [62]. The uoroquinolone
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antibiotic levooxacin, when added to methotrexate, reduced swollen and painful joints at six months,
compared with the addition of placebo [63].
The observation that antimicrobial approaches have some efcacy in RA raises the possibility of
infection as a driver. It is important to consider, however, that antibiotics may have other non-specic
anti-inammatory effects. Minocycline, for example, has been shown to have both anti-inammatory
and anti-apoptotic effects [64]. Recently, Azithromycin was shown to suppress gingival broblast
cytokine production in response to P. gingivalis LPS [65]. The increasing link between PD and RA now
also raises the possibility that antibiotics may act to decrease the burden of gingival bacteria, which
particularly, via PPAD, may be driving loss of tolerance. The timing of clinical effect, within 6 months, in
established RA does, however, raise the question as to whether established ACPA responses could be
diminished in this time frame. Decreasing the continual drive to citrullination by bacterial PPAD may,
however, prevent further expansion of ACPA specicities and diminish the augmentation of immune
responses.
Another important consideration is the actual efcacy of antibiotics against gingival pathogens.
Although the pathogens are described to be sensitive to the antibiotics reviewed above, organisms like
P. gingivalis can evade antibiotic action as a function of their sub-gingival location and maintenance of
biolms, and is known to be viable in the face of high antibiotic concentrations. The extent to which
organisms like P. gingivalis are eradicated in RA patients in trials examining antibiotic efcacy has not
yet been examined. The dependence of RA response in these studies on antibiotic treatment of PD
cannot, therefore, be extrapolated.
PAD and PPAD as targets in RA treatment
The evidence that P. gingivalis lacking the PPAD enzyme can not exacerbate experimental arthritis,
and the association between P. gingivalis burden and systemic ACPA in humans, raises the possibility of
targeting PPAD, itself, to switch off one driver to autoimmunity. PAD polymorphisms have been
described in RA in some populations [66]. The contribution of human PAD driving local citrullination in
joint tissues also highlights a way to reduce the generation of citrullinated peptides which may be
perpetuating local inammation and immune attack. PAD2 and PAD4 enzymes have been detected in
rheumatoid synovium and synovial uid [67] and in human gingiva [22] [23]. Human PAD enzymes do,
however, have diverse physiologic roles and the toxicity of proposed interventions would require a
detailed examination. Interestingly, minocycline and other tetracycline derivatives have been shown,
in one screening study, to have a direct inhibitory effect on PAD4 [68]. In an experimental mouse
model, Cl-Amide, a PAD4 inhibitor, decreased clinical arthritis and epitope spreading, especially to
citrullinated antigens [69]. Calcium modulation/chelation to modify PAD activity and citrullination has
been utilised in a model of astrocyte injury [70]. The recognition of the pathogenic role of protein
deimination in hypoxic neuronal injury and vascular damage, has driven the development and testing
of PAD4 inhibitors in other disease contexts [71]. Dreyton et al. have recently described the development and optimisation of a pan-protein arginine deiminase inhibitor [72]. Stable and selective inhibitors of PAD continue to be examined and optimised [73].
PPAD in contrast, is non-homologous with human PAD at the protein level, and this is reected in
specic differences in its optimal activity requirements and actions. This highlights an opportunity for
therapy that may have minimal impact on the eukaryotic host. Nevertheless approaches targeting
PPAD may need to take into account that, by the time of RA diagnosis, tolerance to citrullinated
peptides has already been breached. However, it is known that further epitope spreading can occur
after disease onset, and progressive and increasing loss of tolerance may exacerbate or perpetuate
disease. Information regarding structure and enzymatic function of PPAD is less developed than for
human PAD. Cysteine-protease inhibitors such as leupeptin have been demonstrated in vitro to inhibit
PPAD [2].
Although PAD has a clearly dened role in normal physiological processes, the increasing identication for a role for PAD in contributing to tissue damage in vascular, hypoxic and inammatory
settings, has informed the development of PAD inhibitors for use in a spectrum of human diseases. The
information presented in this review highlights a rationale for their possible utility in RA as a novel or
complementary approach to modulating immune responses in RA.
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Smoking cessation: periodontitis and RA

Smoking is a common risk factor for both RA and PD. In RA, the link between specic genetic risks
and smoking as a trigger to disease is perhaps more clearly delineated. Smoking appears to drive ACPApositive RA in genetically susceptible individuals. There is a range of studies that examine the effect of
smoking on response to RA treatments, as well as the chances of being in remission. The efcacy of
standard DMARD such as methotrexate is diminished in smokers, and in all biologic registries, smokers
are more likely to fail biologic therapies including anti-TNF drugs [74]. The likelihood of relapse after
drug-free remission in the Best study was associated with smoking. When mice that overexpress
human susceptibility genes (the shared epitope), were exposed to cigarette smoke in an arthritis
model, enhanced immune responses to citrullinated collagen and vimentin were observed. Smoking
was identied as an important covariate in determining disease activity in response to treatment.
Current smokers took longer than previous or non-smokers to achieve steady disease state (approximately 50 weeks).
Given that this review is focused on the relationship between periodontitis and associated P. gingivalis infection as a trigger to initiate or perpetuate RA, the impact of smoking cessation on periodontitis will be examined here. Smoking cessation was additive to the benet of non-surgical
periodontal therapy after 24 months and a recent review concluded that smoking cessation was an
important component of periodontal therapy [75].
Effect of periodontitis treatment on RA
A recent systematic review to examine the impact of PD treatment on RA serological and clinical
parameters was able to include ve studies. All of the included studies were small and of only six
months duration. Nevertheless, non-surgical periodontitis treatment was associated with decreased
erythrocyte sedimentation rate and a trend to decreased TNF and disease activity scores. No changes in
IL-6, CRP, anti-CCP (ACPA) or rheumatoid factor were observed. Larger studies with a longer duration
are warranted particularly to examine impact of this intervention on ACPA titre and specicities.
RA prevention in at risk individuals
The substantial progress in damage prevention strategies in RA has led to progressively more
ambitious goals. The identication of a sub-clinical serological phase, and the study of seropositive
rst-degree relatives with arthralgia, are exciting new developments. An NIH funded RCT in 2014
examines the utility of a personalised risk estimator in rst-degree relatives of RA patients. The
importance of the relationship between RA and PD is exemplied by the inclusion of poor oral health,
along with smoking, as behavioural factors for modication in at-risk individuals [76]. The outcomes of
this study will inform the management of pre-RA in a high-risk group. ACPA responses have been
detected in at-risk individuals up to 15 years before disease onset [77]. Whilst there are studies using
pharmacotherapy such as methotrexate and abatacept (CTLA4) inhibition in pre-RA or early RA, many
aspects of this review highlight the opportunity for simple or non-pharmacological interventions to
circumvent disease.
Conclusion
The possible role of infection as a trigger for disease development in RA has been the subject of
intense investigation in the last fty years. Denite evidence of a consistent relationship between
particular systemic viral or bacterial infections and RA has been elusive. The recognition that genetically determined immune responses to citrullinated peptides are strongly associated with, and likely
pathogenic in RA, has converged with evidence that chronic periodontal infection provides a continuous drive to both immune activation and the production of citrullinated peptides. Animal and human
studies provide robust support for the idea that P. gingivalis PPAD enzymes can lead to the generation of
citrullinated autoantigens and citrullinated bacterial peptides relevant to human RA. The identication
Please cite this article in press as: Leech MT, Bartold PM, The association between rheumatoid arthritis
and periodontitis, Best Practice & Research Clinical Rheumatology (2015), http://dx.doi.org/10.1016/
j.berh.2015.03.001

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M.T. Leech, P.M. Bartold / Best Practice & Research Clinical Rheumatology xxx (2015) 1e13

of these causal links and the recognition that smoking is a shared risk factor for both conditions, has
very important implications for RA stratication, personalised management and prevention.

Practice Points
 Periodontal infection with P. gingivalis may be involved in initiation and perpetuation of
inflammation in Rheumatoid arthritis.
 Surgical and non-surgical periodontal care is important in RA patients
 Asymptomatic relatives of RA patients who carry genetic risk for RA may reduce this risk by
both smoking cessation and periodontal care.

Research Agenda
 Establishing increased evidence of immune response to citrullinated bacterial peptides
including evidence of molecular HLADR4 interaction with citrullinated bacterial peptides will
further strengthen the postulate that citrullinated non-host peptides can drive disease.
 Examining the contribution of PD infection to Carbamylation of peptides and anti-CarP Ab
formation may help identify which PD patients are at risk of RA even before anti-CCP responses are evident.
 Well-designed and larger studies examining the impact of periodontal treatment on RA
disease activity and breadth of anti-CCP responses will guide a more systematic response to
PD intervention in RA.

Conict of interest
The authors have no nancial and personal relationships with other people or organisations that
could inappropriately inuence (bias) the content of this article.
Competing interests
None to declare.
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