Periodontitis and the oral pathogens involved in the inflammatory disease may be environmental factors contributing to the development of anticyclic citrullinated peptide (CCP) antibody-positive disease in juvenile idiopathic arthritis (JIA), an association study found.

Antibodies to Porphyromonas gingivalis were significantly higher in children with CCP-positive JIA than in those with seronegative JIA, with median levels of 9.04 μg/mL versus 5.69 μg/mL (P<0.001), according to Sampath Prahalad, MD, of Emory University in Atlanta, and colleagues.

The CCP-positive JIA group also had a greater frequency of tender or bleeding gums (43% vs 23%, P=0.017), the researchers reported online in Pediatric Rheumatology.

Environmental factors such as exposure to cigarette smoke and microbes associated with periodontal disease have been strongly implicated in adult rheumatoid arthritis. In adult disease, "a prevailing hypothesis suggests that in genetically susceptible individuals, citrullinated peptides produced by Porphyromonas gingivalis may disrupt the immune system's acceptance of endogenous citrullinated antigens, leading to a robust immune response to both self- and non-self citrullinated antigens," Prahalad and colleagues explained.

The disease in about 5% of children with JIA resembles adult rheumatoid arthritis, with chronic joint inflammation and seropositivity for anti-CCP antibodies or rheumatoid factor (RF). However, it has not been determined whether this subgroup of patients also is influenced by similar environmental exposures.



To examine this possibility, the investigators enrolled 77 children with CCP-positive JIA and 124 with seronegative disease. Among the CCP-positive group, 65 were also positive for RF, and all CCP-negative children were negative for both autoantibodies.

The cohort's mean age at diagnosis ranged from 6 to 10.4 years and at the time of sample collection, from 9.7 to 13.3 years. Children with CCP-positive JIA were significantly more likely to be female (89.6% versus 65.2%, P<0.001), older at diagnosis (10.4 versus 6 years, P<0.001), and non-Caucasian (42.9% versus 6.3%, P<0.001).

Environmental factors such as smoke exposure and oral health history were analyzed in 37 CCP-positive and 121 CCP-negative children.

After controlling for age at collection, the odds of having tender or bleeding gums were 2.2 times higher in the CCP-positive group (95% CI 0.98-4.83, P=0.056).

CCP-positive patients also had a higher prevalence of red and swollen gums compared to their CCP-negative counterparts (35.1% versus 19.8%, P=0.055). Pain on chewing was present in 24.3% of CCP-positives versus 13.2% of negatives (P=0.105).

As with P. gingivalis, serum levels of antibodies to Prevotella intermedia also were higher in the CCP-positive group (5.4 μg/mL versus 4.9 μg/mL, P<0.005).

These two oral pathogens may act synergistically, increasing periodontitis risk by almost six-fold, the researchers noted. Most previous research on JIA and oral health has compared JIA patients with healthy controls and has yielded conflicting results. In one study that included 32 JIA cases and 24 healthy controls, JIA patients had more periodontal clinical attachment loss than controls, in spite of similar levels of dental plaque and marginal bleeding.

Another study reported higher frequencies in JIA patients than controls of sites with plaque, bleeding on probing, and probing depths of 2 mm. Yet another case-control investigation concluded that JIA was not a risk factor for periodontitis after adjustment for microbial plaque as a surrogate for oral hygiene status. Those studies, however, did not differentiate between CCP-positive and CCP-negative JIA.

"The unique aspect of this study was that the comparison group was not healthy children but children with JIA polyarticular RF disease," said Daniel J. Lovell, MD, MPH, University of Cincinnati Children's Hospital Medical Center. "It showed that the JIA polyarticular RF-positive category of patients were statistically more likely to have clinical symptoms and physical exam finding of periodontal disease than JIA poly RF-negative patients."

Calling the study "very interesting and well done," Lovell said it provides even more evidence linking JIA polyarticular RF-positive disease with adult RA. He noted that the RF-positive patients were almost always also CCP-positive, as has been shown in adults and other JIA studies.

A limitation of the study was that it did not evaluate gingival health through full periodontal exams. Nor did it administer oral health questionnaires to all CCP-positive JIA cases tested for antibody responses; given the rarity of CCP-positive JIA, it relied on some stored serum samples from CCP-positive patients to increase its power. The authors also noted that some observed differences might have been due to differences in age, although the association between CCP-positive JIA and antibody responses to P. gingivalis persisted despite correcting for age at time of sample collection.

"In the future, a careful oral examination by periodontists or other qualified oral health professionals, and the simultaneous ascertainment of antibody responses to oral pathogens, as well as next-generation sequencing of the subgingival microbiome on an inception cohort of children with CCP-positive JIA, would allow us to better characterize the etiopathology of this disease," they wrote.

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