Association of different immunosuppressive medications with periodontal condition
in patients with rheumatoid arthritis – results from a cross-sectional study
Dr. Dirk Ziebolz1
*, Annegret Rupprecht1
*, Dr. Jan Schmickler*, Laura Bothmann†
Juliane Krämer‡
, Prof. Dr. Daniel Patschan§
, Prof. Dr. Gerhard A Müller‖
, Prof. Dr. Rainer F.
, Dr. Jana Schmidt*, Dr. Gerhard Schmalz*, Dr. Susann Patschan‖
* Dept. of Cariology, Endodontology, and Periodontology, University Leipzig, Germany
† Dental Practice Dr. Frank Paschereit, Northeim, Germany
‡ Dental Practice Rümenapp & Kollegen, Northeim, Germany
§ Dept. of Cardiology, Pulmonology, Angiology and Nephrology, Brandenburg Medical
School, University Hospital Brandenburg, Brandenburg, Germany
‖ Dept. of Nephrology and Rheumatology, University Medical Center Goettingen, Goettingen,
¶ Dept. of Preventive Dentistry, Periodontology, and Cariology, University Medical Center
Goettingen, Goettingen, Germany
1) These authors contributed equally to this work as first authors.
Corresponding author:
PD Dr. Dirk Ziebolz, M.Sc.
University Leipzig
Dept. of Cariology, Endodontology, and Periodontology
Liebigstraße 12
D-04103 Leipzig
Tel.: +49 (0) 341-9721211
Fax: +49 (0) 341-9721219
E-mail address: [email protected]
words: 2779
number of figures: 0
number of tables: 3
number of references: 40
Running title: periodontal inflammation and RA medication
One-sentence summary
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Different immunosuppressive medications for patients with RA are associated with the pa￾tients’ degree of gingival and periodontal inflammation, but not with the severity of periodon￾tal disease.
Background: The aim of this cross-sectional study was to investigate clinical periodontal
findings as well as prevalence of selected potentially periodontal pathogenic bacteria in pa￾tients with rheumatoid arthritis (RA) treated with different immunosuppressive rheumatic
Methods: 168 patients with RA undergoing different immunosuppressive medications were
included and divided into subgroups according to their medication, which was taken in the
past six months, in detail I) non-steroidal anti-inflammatory drugs (NSAID) and glucocorti￾coids combined, and II-VII) different disease modifying anti-rheumatic drugs (DMARDs): II)
Methotrexate (MTX), III) Leflunomide , IV) MTX and TNF-α antagonists combined, V) Inter￾leukin-6 (IL-6) antagonist, VI) MTX and Rituximab combined, and VII) combination therapies
of more than two of these DMARDs. Periodontal examination consisted of papilla bleeding
index (PBI), periodontal status with periodontal probing depth (PD), bleeding on probing
(BOP) and clinical attachment loss (AL). Periodontitis was classified as none/mild, moderate
or severe. Samples obtained from gingival crevicular fluid were analyzed for presence of
eleven periodontal pathogenic bacteria.
Results: Patients with MTX + TNF-α antagonists therapy showed higher PBI and BOP val￾ues compared to Leflunomide (pi<0.01) and higher BOP than MTX + Rituximab (p=0.02).
Porphyromonas gingivalis (p<0.01), Treponema denticola (p<0.01), Fusobacterium nodatum
(p=0.02) and Capnocytophaga species (p=0.05) was associated with medication subgroup,
whereby post hoc testing confirmed singular differences for several medication subgroups.
Conclusions: RA medication is associated with periodontal inflammation, without differ￾ences in periodontal disease severity. Thereby, combination of MTX + TNF-α shows an in-
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creased potential to periodontal inflammation. Additionally, several differences in prevalence
of selected bacteria were detected.
rheumatoid arthritis, periodontitis, immunosuppression, inflammation, microbiology
An interrelationship between periodontitis and rheumatoid arthritis (RA) has been previously
described in several studies.
1-4 Both diseases exhibit multifactorial characteristics and are
characterized by episodes of progression and stagnation, respectively.
5-7 Accordingly, the
underlying pathological mechanisms of the interaction between both diseases are of interest.
A key role of several potentially periodontal pathogenic bacteria has been described, particu￾larly for Porphyromonas gingivalis.
8-10 Nevertheless, several clinical cross-sectional studies
have been unable to confirm the key role for Porphyromonas gingivalis in the interrelation￾ship between periodontitis and RA.
11,12 A further approach may be immunological in nature;
a recent study by this working group demonstrated a potential imbalance of innate immunity
in patients with RA and periodontitis.
Although these potential approaches explaining the interrelationships between periodontitis
and RA are reasonable and are of potential interest, clear evidence of underlying (causative)
pathobiological mechanisms for periodontal disease influencing RA development is still lack￾ing. As previously described in the literature, this may be due to the heterogeneity of patients
with RA, particularly with regard to their multifarious medication.11,12 Consistent with this find￾ing, different anti-inflammatory and/or immunosuppressive drugs might influence both RA
and periodontal inflammation. In this context, a recent cohort study reported that different
pharmacological treatment regimens for RA could influence both diseases; clinical and mi￾crobiological symptoms observed in periodontal disease patients.14 Several studies have
addressed the effect of different RA-related medications on periodontal disease severity and
periodontal inflammation.
15-20 Specifically, tumor necrosis factor alpha (TNF-α) antagonists
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have been well examined, and have been reported to potentially demonstrate positive ef￾fects on periodontal condition.
15-17 This finding highlights the potential relevance of RA￾related medications to periodontal disease severity in RA-patients. However, until recently
no systematic investigation of different medications and their association with different perio￾dontal disease related parameters have been performed. Previously, neither clinical nor mi￾crobiological characteristics have been analyzed in relation to individual treatment strategies.
Thus, the aim of this study was to investigate periodontal findings as well as the prevalence
of potentially pathogenic bacteria in a cohort of patients with RA treated with different immu￾nosuppressive (rheumatic) medications. We hypothesized that differences in RA-medication
would affect the periodontal condition in patients with RA.
Materials and Methods
This clinical, monocentric, and cross-sectional study was reviewed and approved by the lo￾cal ethics committee of the medical faculty of the Georg-August-University Goettingen, Ger￾many (application No. 14/2/13). All participants were informed verbally and in writing about
the study and provided their written informed consent for participation in the study.
The study participants were originally enrolled in a related, parent study investigating clinical
periodontal and microbiological findings and their association with rheumatologic disease
parameters in patients with RA.11 Exclusively, patients with RA from the previous study were
considered in the current study and divided into subgroups according to their medication,
which was taken for the past six months, in detail group I) non-steroidal anti-inflammatory
drugs (NSAID) and glucocorticoids, and groups II-VII) with different disease modifying anti￾rheumatic drugs (DMARDs): II) Methotrexate (MTX), III) Leflunomide, IV) MTX and TNF-α
antagonists combined, V) Interleukin 6 (IL-6) antagonist, VI) MTX and Rituximab combined,
and VII) combination therapies of more than two of these DMARDs.
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Sample size calculation: The primary endpoint clinical attachment loss (AL) under considera￾tion of different immunosuppressive therapies of patients with RA (expected difference: AL
>1.5 mm, standard deviation: 0.5 to 1.5 mm) was used for case number estimation; 1.5-mm
AL can be seen as a clinically relevant difference. Thus, a statistical power of 80% was de￾sired, and a minimum sample size of 17 patients per subgroup was required.
A total of 168 participants was included and divided into the subgroups as follows: I) NSAID
and glucocorticoids (n=17), II) MTX (n=41), III) Leflunomide (n=28), IV) MTX + TNF-α antag￾onists combined (n=27), V) IL-6 antagonist (n=16), VI) MTX + Rituximab combined (n=19),
and VII) combined DMARDs (n=20). Between the subgroups, no differences in age (p=0.21),
gender (p=0.63), smoking habits (p=0.76), DAS-28-ESR (p=0.41), aCCP (p=0.12), and RF
(p=0.99) were found (table 1).
Patients with RA undergoing their routine appointment at the Dept. of Nephrology and
Rheumatology of the University Medical Center Goettingen, between January 2013 and
January 2014, were asked for their voluntary participation. The underlying inclusion criteria
were an age of 18-70 years with RA diagnosis by a rheumatologist according to the Ameri￾can College of Rheumatology and European League Against Rheumatism (ACR/EULAR).21
The exclusion criteria were as follows: severe systemic disease in addition to RA (e.g. diabe￾tes mellitus, chronic heart diseases, endocarditis, delicate controlled hypertension, renal
disorders), infectious diseases (HIV/AIDS, hepatitis, tuberculosis), neuropathy, additional
immunosuppressive medication aside from RA therapy (e.g., due to organ transplantation),
pregnancy, and limited mobility according to the function class IV ACR. Moreover, antibiotic
therapy during the last three months was an exclusion criterion. From the patients’ medical
records, general parameters including age, gender, smoking status as smoker/non-smoker
(non-smoker defined as never smoking or no smoking for at least one year) as well as recent
RA medication and current RA specific parameters “Disease Activity Score” (DAS28-ESR)22
antibodies against cyclic citrullinated peptide (aCCP) and rheumatic factor (RF) were rec￾orded.
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Clinical examination
In accordance with a previous study11
all patients were examined once under standardized
conditions by two experienced, blinded and calibrated dentists (JS, AR, kappa ≥0.8). During
clinical dental examination, the Decayed-, Missing- and Filled-teeth index (DMF-T) were as￾sessed. Teeth with a reasonable cavitation of tooth surface (D-T), as well as missing teeth
(M-T) and filled or crowned teeth (F-T) were documented.
23 To detect gingival inflammation,
the Papilla bleeding index (PBI) was performed using a periodontal probe#
as described by
Lange et al.24 The periodontal condition was assessed by measurement of periodontal prob￾ing depth (PD), bleeding on probing (BOP), and clinical attachment loss (AL) on six meas￾urement points per tooth using a millimeter-scaled periodontal probe#
. Based on the defini￾tion of the AAP/CDC, the severity of periodontitis was classified into none/mild (neither se￾vere nor moderate periodontitis), moderate (≥2 interproximal sites with AL ≥4 mm [not on
same tooth] or ≥2 interproximal sites with PD ≥5 mm) or severe periodontitis (≥ 2 interproxi￾mal sites with AL ≥6 mm [not on the same tooth] and ≥1 interproximal site with PD ≥5 mm)
Microbiological analysis
As described in a previous study11
, subgingival biofilm samples were obtained from the five
deepest periodontal pockets using sterile paper tips. Before sample collection, careful su￾pragingival plaque removal was performed. For the microbiological analysis, a commercial
polymerase chain reaction (PCR) based test system was applied**. During the analysis,
which was performed in the clinical laboratory of the Dept. of Preventive Dentistry, Periodon￾tology, and Cariology Goettingen, following potentially periodontal pathogens were detected:
(detection threshold: >102
): Aggregatibacter actinomycetemcomitans (Aa), (detection
threshold >10³): Porphyromonas gingivalis (Pg), Tannerella forsythia (Tf), Treponema denti￾cola (Td), Prevotella intermedia (Pi), Parvimonas micra (Pm), Fusobacterium nucleatum
PCP 15; Hu-Friedy, Chicago, IL, USA
** Micro-IDentplus-Test, HainLifescience, Nehren, Germany
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(Fn), Campylobacter rectus (Cr), Eubacterium nodatum (En), Eikenella corrodens (Ec) and
Capnocytophaga species (Csp).
Statistical analysis
Statistical analyses were performed using a statistical software package††
. Metric data were
examined according to their normal distribution using the Kolmogorov-Smirnov test. The
comparison of normally distributed samples was performed using t-test or univariate ANO￾VA, and non-normally distributed data were compared using the Mann-Whitney U test or H
test according to Kruskal and Wallis. The categorical/nominal data were compared using the
chi-square test and Fisher´s exact test. In cases of significant results, post hoc testing with a
Bonferroni-test with multiple t-testing or standardized residuals for categorized data were
applied. For standardized residuals, values < -2 or > 2 were interpreted as an important
group difference. A p-value of 0.05 was considered statistically significant.
Clinical oral findings
Between subgroups, several differences could be detected regarding dental (DMF-T) and
periodontal findings (PD, BOP, AL) and severity of periodontal disease (table 2). A signifi￾cantly higher PBI was detected for patients with MTX + TNF-α antagonists compared to
Leflunomide (0.97 ± 0.95 vs. 0.21 ± 0.32, p<0.01; table 2). In BOP values, patients with MTX
+ TNF-α antagonists demonstrated higher BOP compared to Leflunomide (43.74 ± 19.72 vs.
24.47 ± 12.40, p<0.01) and compared to MTX + Rituximab (43.74 ± 19.72 vs. 25.75 ± 19.96,
p= 0.02; table 2). Regarding periodontal disease severity, standardized residuals in post hoc
testing were between -1.6 and 1.2 (cut off: <-2 and >2).
Microbiological findings
Different associations between medication subgroups and different potentially periodontal
pathogenic bacteria were detected. The prevalence of Pg was significantly associated with
†† SPSS Statistics 22.0, SPSS Inc., Chicago, IL, USA
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medication subgroup (p<0.01), which was confirmed by standardized residuals for Lefluno￾mide (2.8) and IL-6 antagonist (4.2). Furthermore, a significant association between Td and
medication subgroup was found (p<0.01), which has been confirmed by standardized resid￾uals for NSAID and glucocorticoids (2.7) and MTX (2.4). The prevalence of Fn was also as￾sociated with the medication subgroup (p=0.02), which has been confirmed by standardized
residuals for MTX + Rituximab (3.8). Moreover, Csp showed an association with medication
subgroups, which was confirmed by standardized residuals for IL-6 antagonist (2.6). Further
associations were not found (Table 3).
Main results: Patients with MTX + TNF-α antagonists showed higher PBI and BOP values
compared to Leflunomide as well as higher BOP than the MTX + Rituximab group. The
prevalence of Pg, Td, Fn and Csp was associated with the medication subgroup.
Interpretation with the available literature: The current study aimed to investigate periodontal
findings and prevalence of potentially pathogenic periodontal bacteria in a cohort of patients
with RA. The periodontal and microbiological findings of the total cohort have been previous￾ly analyzed and discussed.10 Accordingly, the current study focused on the separation into
different medication-related subgroups.
In general, the prevalence of periodontitis was very high in the study cohort. This situation
has been previously well described in the literature and an association between RA and per￾iodontal disease severity appears evident.3,4,26,27 This finding might also be caused by motor
restrictions, which resulted in reduced oral health abilities.
28 Moreover, general disease bur￾den, quality of life and the enormous impairment on daily life might also be an additional
causative factor for the insufficient periodontal situation.29 The current study did not assess
any oral hygiene parameters. However, the effect of medication on oral hygiene ability is
unclear and was thus not within the scope of the current study, which assessed potential
associations between medication and periodontal condition.
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Furthermore, subgroups were comparable regarding their disease activity (DAS-28-ESR)
and aCCP. It appears feasible that some participants in this cross-sectional study were on
certain medication combinations due to the severity of their presenting symptoms and/or the
duration of their illness, resulting in reduced disease activity. Therefore, different combina￾tions and monotherapy of immunosuppressive drugs were considered within this investiga￾tion. The comparability of disease activity between subgroups must thereby seen as a man￾datory condition for analysis of associations between medication and periodontal condition.
More than half of the patients with RA received MTX as a monotherapy or in combination
with other drugs. MTX modifies autoimmunological inflammatory processes during RA via
multiple mechanisms, including adenosine mediated anti-inflammatory effects, increased
apoptosis of T cells and reduction of cell proliferation.30,31 Due to its excellent benefit-to￾toxicity ratio and substantial anti-progressive effects, MTX is one of the preferred drugs for
RA treatment.32,33 MTX combined with TNF-α antagonists was associated with the highest
degree of gingival and periodontal inflammation in the current study, which was significantly
higher compared to Leflunomide, and for periodontal inflammation, to MTX + Rituximab.
TNF-α antagonists has been well established in the management of RA.34 TNF-α is an im￾portant mediator in inflammatory processes and is thus involved in inflammation during RA
and periodontitis.
35,36 Accordingly, inhibition of the cytokine might positively affect RA and
periodontitis, which has been previously described in several studies.
17,19,20 However, this
finding is contradictory to the findings of the current study with a higher degree of inflamma￾tion in the TNF-α antagonists medication subgroup. This finding is supported by findings
obtained by Pers et al. 2008, which found increased gingival and periodontal inflammation
following the application of TNF-α antagonists.
15 No reasonable hypothesis can be formed
for this effect, but it seems that the positive effect of TNF-α antagonists therapy is conversely
related if the drugs were administered in combination with MTX. Furthermore, it was con￾spicuous that exclusively periodontal inflammation, but not periodontal disease severity
(presence of moderate or severe periodontitis) was associated with different medication
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subgroups. This may be influenced by the fact that the patients needed to take the medica￾tion for at least six months, but it was not considered which medication was taken before.
However, differences in medication might only affect recent inflammation, but not the de￾struction of bone. This finding is consistent with the assumption made by Pers et al. 2008,
that inflammation and destruction is interrelated but separate components of periodontal
condition in patients with RA.
15 Summarized, this fact cannot be clarified with the current
study’s findings.
An additional aspect for consideration were differences in the prevalence of selected bacte￾ria between the investigated subgroups. Only limited data on this topic have been published
so far. In a previous study of this working group no significant influence of different immuno￾suppressive rheumatic medications on finding of periodontal pathogenic bacteria could be
determined.37 In another study an association between medication and periodontal bacteria
could be found, such that Td was particularly prevalent if TNF-α antagonists was applied.
The current study found differences in the prevalence of periodontal bacteria between sub￾groups, but could not confirm these results. However, none of the investigated medications
appeared to cause strong microbiological changes, but only singular differences were found.
This finding is consistent with the comparable clinical periodontal disease severity between
subgroups. Comparable results were also found by another study, which determined, that
subgingival microbiota of patients with new-onset rheumatoid arthritis (absence of any
treatment with DMARD or steroids) is similar to patients with chronic RA under immunosup￾pressive therapy with different DMARDs.38 Future clinical studies with a prospective design,
including an untreated control group would be necessary, to draw meaningful conclusions.
Thereby, changes in periodontal biofilm and clinical periodontal parameters should be as￾sessed longitudinally.
On the other hand, several studies have suggested a link between oral (pathogenic) bacte￾ria, periodontal diseases and RA.26,27,39
In this context it has to be considered, that certain
potential periodontal pathogenic bacteria (e.g. Porphyromonas gingivalis and Aggregatibac-
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ter actinomycetemcomitans) may contribute to RA pathogenesis through a direct influence
on burden of citrullinated peptides.40 Thus, an association between periodontitis and/or peri￾odontal pathogenic bacteria and disease progression or severity of RA appears possible.
Accordingly, the presence of periodontal pathogenic bacteria could lead to counteract the
immunotherapy of RA. For this reason, in the future treatment of periodontitis may be includ￾ed as an adjunct to conventional RA therapy or as part of a preventive strategy.40
Strengths and limitations: This is the first systematic investigation of associations between
RA medication and recent clinical as well as microbiological findings in patients with RA. An
additional strength of this study was the inclusion of homogenous groups with comparable
age, gender, smoking habits as well as rheumatoid parameters. Moreover, the examinations
were standardized and performed in a blind manner. Moreover, a power calculation was
performed, and a reasonable sample size compared to other studies could be achieved.
Nevertheless, due to correction for multiple comparisons, the power might be negatively in￾fluenced. Due to multiple testing, the probability of producing false negatives might be in￾creased, reducing statistical power and thus the power calculation may not be accurate un￾less it also accounted for these additional corrections. This must be considered in the inter￾pretation of the results. Several further limitations must be addressed. The patients took the
medication for at least six months, but previous medication as well as the duration of the
medication was not considered. Moreover, no untreated patients with RA were investigated,
which makes impossible to derive a robust conclusion regarding the association between
medication and periodontitis severity in general. In addition, the high prevalence of periodon￾tal disease must be taken into account when interpreting the findings. Differences in perio￾dontal disease severity might not be detected due to high prevalence. Furthermore, the
cross-sectional design does not provide any conclusions about the effect of the medication
on clinical and/or bacterial findings. In principle, a longitudinal study design, beginning with
the diagnosis, would be necessary to draw strong conclusions; however, a very long investi￾gation period would be necessary, as relevant changes in periodontal tissue will require
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time. Moreover, change in medication during therapy is not rare, which makes the situation
very complex and difficult to assess. Furthermore, the PCR-based test system used in this
study only requires a low proportion of the complex subgingival microbiota.
Within the limitations of this cross-sectional study, RA medication is associated with perio￾dontal inflammation, without differences in periodontal disease severity. Patients treated with
MTX + TNF-α antagonists showed the highest degree of inflammation. Only marginal differ￾ences in the prevalence of select potentially pathogenic bacteria were detected between
different RA medications.
Key messages
Based upon their mechanisms of action and efficacy on overall reduction of the systemic
inflammation associated with RA-related medications, they have varying effects
on periodontal inflammation. Better understanding of the effects of these medications on the
overall periodontal presentation is critical to the optimal oral and systemic care of patients
with RA.
We would like to thank Dr. C. Kossack and S. Fresmann‡‡ for providing the documentation
software‡‡ of the periodontal findings. Moreover, the authors would like to thank M. Hoch of
the Dept. of Preventive Dentistry, Periodontology, and Cariology, University Medical Center
Goettingen, Germany, for support in the laboratory microbiological analysis and Dr. T. Kott￾mann of the Clinical Research Organisation, Hamm, Germany, for performing the statistical
‡‡ “Parostatus.de”, Berlin, Germany
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Conflict of interest statement
The authors certify that they have no affiliations with or involvement in any organization or
entity with any financial interest or non-financial interest in the subject matter or materials
discussed in this manuscript.
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