Abstract
The prevalence of periodontitis is increased in patients with rheumatoid arthritis (RA) and periodontopathic bacteria can citrullinate proteins. Periodontitis may, therefore, be an initiator of RA and a target for prevention. Periodontal disease and periodontal bacteria have not been investigated in at-risk individuals with RA autoimmunity but no arthritis. To examine periodontal disease and periodontopathic bacteria in anti-cyclic citrullinated protein (anti-CCP) antibody-positive at-risk individuals without arthritis. This cross-sectional study took place at a teaching hospital from April 27, 2015, to May 8, 2017. Forty-eight anti-CCP-positive individuals without arthritis (CCP+ at-risk) were recruited nationally. Twenty-six patients with early RA (ERA) and 32 healthy control individuals were recruited locally. Data were analyzed between June 1, 2017, and December 1, 2017. Periodontal assessment and examination of joints using ultrasonography. Prevalence of diseased periodontal sites, clinical periodontitis, and periodontal inflamed surface area in CCP+ at-risk individuals compared with patients with ERA and healthy individuals matched for age and smoking. Paired-end sequencing of DNA from subgingival plaque from diseased and healthy periodontal sites was performed and DNA was profiled and analyzed. A total of 48 CCP+ at-risk individuals (mean [SD] age, 51.9 [11.4] years; 31 [65%] female), 26 patients with ERA (mean [SD] age, 54.4 [16.7] years; 14 [54%] female), and 32 healthy individuals (mean [SD] age, 49.4 [15.3] years; 19 [59%] female) were recruited. Of 48 CCP+ at-risk individuals, 46 had no joint inflammation on ultrasonography. Thirty-five CCP+ at-risk individuals (73%), 12 healthy individuals (38%), and 14 patients with ERA (54%) had clinical periodontitis. The median (interquartile range) percentage of periodontal sites with disease was greater in CCP+ at-risk individuals compared with healthy individuals (3.3% [0%-11.3%] vs 0% [0%-0.7%]) and similar to patients with ERA (1.1% [0%-13.1%]). Median (interquartile range) periodontal inflamed surface area was higher in CCP+ at-risk individuals compared with healthy individuals (221 mm2 [81-504 mm2] vs 40 mm2 [12-205 mm2]). Patients with CCP+ at-risk had increased relative abundance of Porphyromonas gingivalis (but not Aggregatibacter actinomycetemcomitans) at healthy periodontal sites compared with healthy individuals (effect size, 3.00; 95% CI, 1.71-4.29) and patients with ERA (effect size, 2.14; 95% CI, 0.77-3.52). This study found increased prevalence of periodontitis and P gingivalis in CCP+ at-risk individuals. This suggests periodontitis and P gingivalis are associated with disease initiation and could be targets for preventive interventions in RA.
Highlights
Autoantibodies associated with rheumatoid arthritis (RA) can be detected in the serum years before patients develop joint inflammation,1-3 suggesting the joints may be a target rather than the primary cause of this disease
The median percentage of periodontal sites with disease was greater in cyclic citrullinated peptide (CCP)+ at-risk individuals compared with healthy individuals (3.3% [0%-11.3%] vs 0% [0%-0.7%]) and similar to patients with early RA (ERA) (1.1% [0%-13.1%])
Median periodontal inflamed surface area was higher in CCP+ at-risk individuals compared with healthy individuals (221 mm2 [81-504 mm2] vs 40 mm2 [12-205 mm2])
Summary
Autoantibodies associated with rheumatoid arthritis (RA) can be detected in the serum years before patients develop joint inflammation, suggesting the joints may be a target rather than the primary cause of this disease. Such observations suggest a preclinical phase of RA and, importantly, raise the possibility of disease prevention. The enrichment of serum IgA anticitrullinated protein antibodies (ACPA) in individuals at risk of RA suggests mucosal sites (eg, oral mucosa) may be important in the earliest phase of RA.. In a putative etiological model, virulent strains of P gingivalis at inflamed periodontal sites generate novel citrullinated antigens that trigger a mucosal immune response in certain individuals, possibly those with genetic predispositions.. The enrichment of serum IgA anticitrullinated protein antibodies (ACPA) in individuals at risk of RA suggests mucosal sites (eg, oral mucosa) may be important in the earliest phase of RA. There is good evidence that periodontitis and RA are clinically associated. periodontitis is associated with a specific bacterial signature characterized by the increased abundance of the pathogenic organism Porphyromonas gingivalis alongside a community of other, predominantly anaerobic, organisms. Porphyromonas gingivalis is capable of citrullinating local antigens by virtue of its peptidylarginine deiminase enzyme. In a putative etiological model, virulent strains of P gingivalis at inflamed periodontal sites generate novel citrullinated antigens that trigger a mucosal immune response in certain individuals, possibly those with genetic predispositions. Recent data suggest the periodontopathic bacterium Aggregatibacter actinomycetemcomitans may directly induce neutrophil citrullination at the periodontium and potentially initiate ACPA
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