Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.

Smoking and Periodontal Status Are Associated with ACPA Fine Specificity and Levels of Inflammatory Cytokines in Rheumatoid Arthritis: The ARIC Study.

Bromberg1,  Reuven, Sokolove1,  Jeremy, Lahey1,  Lauren J., Alonso2,  Alvaro, Wener3,  Mark H., Gersuk4,  Vivian H., Buckner4,  Jane Hoyt

Stanford University, Palo Alto, CA
University of Washington, Seattle, WA
Benaroya Research Institute, Seattle, WA
Chapel Hill, NC
Minneapolis, MN
Stanford Univ School of Med, Stanford, CA
Univ of MN MMC108, Minneapolis, MN


Environmental factors predisposing to the development of rheumatoid arthritis (RA) include tobacco exposure (TE) and possibly periodontal disease (PD). Only TE has been clearly associated with risk for anti-citrullinated protein antibodies (ACPA). We sought (i) to determine whether periodontal disease (PD) was associated with an increased risk for development of APCA, (ii) to assess for interaction between TE and PD in the development of APCA, and (iii) whether this interaction was affected by presence of the HLA-DR4 shared epitope (SE).


We performed serum profiling of 16 putative RA-associated autoantibodies and 47 cytokines in 44 participants of the Atherosclerosis Risk in Communities (ARIC) study with a hospital discharge diagnosis of RA. Participants underwent detailed periodontal assessment (PD status: none or mild; moderate or severe). We evaluated levels of anti-cyclic citrullinated peptide antibodies by a second generation assay (CCP2) as well as breadth, amplitude, and specificity of ACPA targeted by RA patients with current or prior TE; moderate to severe PD; TE with PD; or neither TE or PD.


The average number of ACPA subtypes closely paralleled the average CCP2 value and was higher among RA participants with TE and concurrent PD (Table 1). Small numbers particularly in non-smokers without PD (n=1), limited assessments to qualitative analysis.

Table 1.

 Average CCP2 titer (AU)Average # ACPA subtypesn
Tobacco exposure (TE)7.551.111
Periodontal disease (PD)53.42.012
TE and PD224.311.520

Evaluation of individual ACPAs again suggested an interaction among smokers with PD as demonstrated by much higher levels of most ACPA subtypes among those with TE and PD compared with subjects with TE or PD alone. In most cases there were minimal differences between subgroups with TE or PD alone. An exception was anti-cit-fibrinogen autoantibodies which were elevated in both the TE and PD subgroups; with levels among those with TE approaching average levels of those with TE and PD combined. Among subjects positive for both TE and PD, HLA-DR4 status (7 positive, 12 negative) was associated with ACPA targeting citrullinated enolase, clusterin, and histone 2B.

Levels of 18 serum cytokines including TNFa, IL1b, IFN-g followed a similar pattern to ACPA and were markedly elevated in the subgroup with combined TE and PD compared with TE or PD alone.


The presence of PD and TE was associated with increased breadth and amplitude of ACPA subtypes. This suggests a possible interaction between the presence of both TE and PD resulting in further increase in CCP2 titer, number of ACPA subtypes represented, and level of most individual ACPA subtypes. HLA-DR4 SE status appears to further influence the development of only a subgroup of ACPA subtypes. The relative lack of a combined effect between smoking and PD for anti-citrullinated fibrinogen antibodies supports a model in which these autoantibodies are formed in response to airway inflammation-induced citrullination of fibrinogen predisposing to autoantibody formation.

To cite this abstract, please use the following information:
Bromberg, Reuven, Sokolove, Jeremy, Lahey, Lauren J., Alonso, Alvaro, Wener, Mark H., Gersuk, Vivian H., et al; Smoking and Periodontal Status Are Associated with ACPA Fine Specificity and Levels of Inflammatory Cytokines in Rheumatoid Arthritis: The ARIC Study. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :2170

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