Periodontitis and ACPA positive Arthralgia*s; a link by protein citrullination

Patients with inflammatory arthralgia*s who have antibodies to citrullinated
proteins (ACPA) and/or rheumatoid factor (RF) have a 50-70% chance to develop
of RA within 5 years. The prevalence of RA varies from 0.5-1.1%.
Genetic and environmental factors cause an immunological response with the
production of ACPA and /or RF, and an inflammatory response characterized by an
elevated CRP and ESR.
ACPA are directed to peptides post-translationally modified by the conversion
of arginine to citrulline by the enzyme peptidyl arginine deiminase (PAD) and
are specific serological markers for a subset of patients with rheumatoid
arthritis (approximately 60%). The occurrence of these anti-citrullinated
protein antibodies (ACPA) is seen several years before the onset of disease4.
The association of HLA-DRB1 alleles is seen exclusively for the ACPA-positive
subset of disease. These antibodies exist in around 2% of normal populations
and are rare in other inflammatory conditions.
Independent of ethnicity, 10%-15% of an adult population will develop severe
periodontitis. Microbial plaque accumulates in the subgingival area and causes
an inflammatory response with destruction of the surrounding bone and soft
tissue of the teeth. Bacteria are essential but not sufficient to cause the
disease. By eliciting bacteraemia systemic inflammatory responses or
cross-reactivity leading to auto-immune reactions periodontitis causes an
inflammatory burden with damage far beyond the oral cavity. Several studies
described a strong link between the presence of periodontitis and RA.
The incidence of the periodontal pathogen Porphyromonas gingivalis in severe
adult periodontitis is 70%. P.gingivalis expresses peptidyl arginine deiminase
(PAD), the enzyme responsible for citrullination of peptide antigens on
arginine residues. Microbial PAD citrullinates arginine in fibrin found in
periodontal tissue. The immune system in patients with periodontitis is exposed
to citrullinated antigens that might become systemic immunogens. Autoantigens
modified by citrullination through exposure to periodontal pathogens might
induce the ACPA response in the context of untreated periodontitis. The levels
of antibodies against P. gingivalis have been correlated with levels of ACPAs
in patients with RA. Citrullinated *-enolase is an immuno-dominant epitope
showing sequence similarity and cross-reactivity with enolase from P.
gingivalis. This could indicate a role for infection with P. gingivalis in
priming the autoimmune response towards ACPA production.
In order to understand molecular events that occur before the onset of RA, in
particular related to adaptive immunity, we want to investigate ACPA and/or RF
positive patients with arthralgia*s who are at risk for the development of RA.
The investigation will have two arms:
1. Investigation of periodontitis as a risk factor for the development of RA
2. Investigation of the role of cellular immune responses in the development of
RA
Investigating risk factors for the development of RA on both a clinical
(periodontitis) and immunological level may result in new opportunities for
intervention and maybe even prevention of the development of RA.

.

Primary Objective: To investigate the presence of periodontitis in ACPA and or
RF positive patients with arthralgia*s.
Secondary Objective: to unravel the role of the cellular immune response in
ACPA positive persons with arthralgia*s who are at risk for the development of
RA

Study design: observational cohort study.

Data to be collected at baseline:
Age, sex, ethnic group, body weight and height, smoking habits, profession or
activities of daily living. A health assessment questionnaire (HAQ) (attachment
1) and a SF-36 (attachment 2).
Clinical examination: DAS44 and periodontal screening including a panoramic
radiograph.
Sample taking: peripheral blood (5 tubes), gingivocrevicular fluid (GCF),
subgingival plaque.
Synovial fluid (SF) will be drawn when applicable. When patients are eligible
for periodontal or orthopaedic surgery tissue will be obtained

There are no risks associated with participation. The potential benefit to
participants will be detection of periodontitis.