Associations Of Periodontitis (PD) With Established Seropositive Rheumatoid Arthritis are Independent of Smoking and Other Risk Factors

Ted R. Mikuls¹, Jeffrey Payne², Fang Yu³, Geoffrey M. Thiele⁴, Richard J. Reynolds⁵, Grant W. Cannon⁶, Jeffrey Markt⁷, David McGowan⁸, Gail S. Kerr⁹, Robert Redman¹⁰, Andreas M. Reimold¹¹, Garth Griffiths¹², Mark Beatty², Shawneen Gonzalez², Debra Bergman¹³, Bartlett C. Hamilton III¹⁴, Alan R. Erickson¹ and James R. O'Dell¹⁵, ¹Omaha VA Medical Center and University of Nebraska Medical Center, Omaha, NE, ²College of Dentistry, University of Nebraska Medical Center, Lincoln, NE, ³University of Nebraska Medical Center, Omaha, NE, ⁴Int Med/Sec of Rheum/Immun, Univ of Nebraska Med Ctr, Omaha, NE, ⁵Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL, ⁶Division of Rheumatology, Salt Lake City VA and University of Utah, Salt Lake City, UT, ⁷Otol-Head and Neck Surgery, University of Nebraska Medical Center, Omaha, NE, ⁸Dentistry, George E. Wahlen VA Medical Center, Salt Lake City, UT, ⁹Rheumatology, Washington DC VAMC, Georgetown and Howard University, Washington, DC, ¹⁰Dentistry, Washington DC VA, Georgetown and Howard University, Washington, DC, ¹¹Rheumatology, Dallas VA and University of Texas Southwestern, Dallas, TX, ¹²Dentistry, Dallas VA and University of Texas Southwestern, Dallas, TX, ¹³Internal Medicine, University of Nebraska Medical Center, Omaha, NE, ¹⁴University of Nebraska Medical Center and Omaha VA Medical Center, Omaha, NE, ¹⁵Dept of Internal Medicine, University of Nebraska Medical Center, Omaha, NE

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: Osteoarthritis, P. Gingivalis, Periodontitis, rheumatoid arthritis (RA) and risk assessment

Session Information

Title: Rheumatoid Arthritis - Human Etiology and Pathogenesis

Session Type: Abstract Submissions (ACR)

Background/Purpose:

Periodontitis (PD) has been proposed as a risk factor in RA. Reports have suggested that this association may be due to confounding from smoking , sicca syndrome, impaired oral hygiene, and HLA-DRB1 alleles (increased in rare forms of PD). Recent speculation has focused on the role of P. gingivalis (Pg), an oral pathogen with the unique capacity of citrullinating protein. We sought to examine the degree to which shared risk factors might explain or confound the relationship of PD with established RA.

Methods:

RA cases (N=287) and osteoarthritis controls (N=330) underwent a standardized exam with PD defined using the criteria of Machtei et al (J Periodontol, 1990). The percentage of sites with supragingival plaque served as a measure of oral hygiene. HLA-DRB1 SE containing alleles were imputed using SNPs from the extended MHC. Anti-Pg antibody to outer membrane antigen (OMA) was measured using ELISA. Subgingival plaque was assessed for the presence of Pg using PCR. Anti-cyclic citrullinated protein (aCCP) antibody and RF were measured by ELISA and nephelometry, respectively. Associations of PD with RA (and aCCP positive RA) were examined using multivariable regression.

Results:

Cases and controls were similar in all demographics assessed. PD was more common in RA (35%, p = 0.022) and aCCP positive RA (n=240; 37%; p = 0.006) vs. controls (26%). There were no RA-control differences in anti-Pg or the frequency of Pg positivity by PCR. Anti-Pg antibody showed weak but statistically significant associations with both aCCP (r=0.14, p=0.022) and RF (r=0.19, p=0.001). PD was associated with increased RA disease severity based on swollen joint count (p=0.004), DAS-28-CRP (p=0.045), total Sharp score (p=0.015), aCCP (p=0.011), and RF (p<0.001) levels. Associations of PD with established aCCP positive RA were independent of all covariates examined (with similar, albeit non-significant ORs observed in never smokers). In models not shown, associations were also independent of anti-Pg and Pg PCR status.

Table: Multivariable associations of PD with RA (Odds Ratios and 95% CIs)

Full Cohort

Analysis Limited to Never Smokers

All RA

aCCP pos. RA

All RA

aCCP pos. RA

Periodontitis

1.36 (0.89, 20.6)

P = 0.153

1.59 (1.01, 2.49)

P = 0.043

1.37 (0.65, 29.1)

P = 0.409

1.87 (0.82, 4.25)

P = 0.157

HLA-DRB1 SE pos.

3.95 (2.68, 5.83)

P < 0.001

5.32 (3.44, 8.22)

P < 0.001

4.71 (2.55, 8.71)

P < 0.001

7.01 (3.43, 14.32)

P < 0.001

Ever smoking

1.93 (1.31, 2.83)

P = 0.001

1.97 (1.29, 2.99)

P = 0.002

—-

*Full models not shown; covariates included age, gender, race, BMI, diabetes, marital status, oral dryness, oral hygiene, and education; MV models limited to participants reporting either Caucasian or African American race/ethnicity

Conclusion: The relationship of PD with established aCCP positive RA does not appear to be driven by the prevalence of shared risk factors such as smoking or HLA-DRB1 SE nor does this relationship appear to be dependent on evidence of Pg infection. Defining the precise role that Pg plays in early disease evolution and mechanisms linking PD with more severe RA remain important knowledge gaps for future research.

Disclosure:

T. R. Mikuls,

Roche/Genentech and Biogen IDEC Inc.,

J. Payne,
None;

F. Yu,
None;

G. M. Thiele,
None;

R. J. Reynolds,
None;

G. W. Cannon,
None;

J. Markt,
None;

D. McGowan,
None;

G. S. Kerr,

Amgen, Abbott,

R. Redman,
None;

A. M. Reimold,

UCB,

Janssen Pharmaceutica Product, L.P.,

Ardea,

Novartis,

Lilly,

Pfizer,

G. Griffiths,
None;

M. Beatty,
None;

S. Gonzalez,
None;

D. Bergman,
None;

B. C. Hamilton III,
None;

A. R. Erickson,
None;

J. R. O’Dell,
None.

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