Smoking Status Is Associated with Inflammatory Cytokine Profile and Disease Activity in Anti-Citrullinated Protein Antibody Positive Rheumatoid Arthritis: Decreased Inflammation and Disease Improvement with Smoking Cessation?

Catriona Cramb¹, Jeremy Sokolove², Geoffrey M. Thiele³, Gail S. Kerr⁴, Grant W. Cannon⁵, Andreas M. Reimold⁶, Ted R. Mikuls⁷ and William H. Robinson⁸, ¹VA Palo Alto Heatlh Care System and Stanford University, Palo Alto, CA, ²Medicine, VA Palo Alto Health Care System and Stanford University, Palo Alto, CA, ³Int Med/Sec of Rheum/Immun, Univ of Nebraska Med Ctr, Omaha, NE, ⁴Rheumatology, Washington DC VAMC, Georgetown and Howard University, Washington, DC, ⁵Division of Rheumatology, Salt Lake City VA and University of Utah, Salt Lake City, UT, ⁶Rheumatology, Dallas VA and University of Texas Southwestern, Dallas, TX, ⁷Omaha VA Medical Center and University of Nebraska Medical Center, Omaha, NE, ⁸Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: anti-citrullinated protein/peptide antibodies (ACPA), cytokines, pathogenesis and tobacco use, rheumatoid arthritis

Session Information

Title: Rheumamtoid Arthritis - Human Etiology and Pathogenesis

Session Type: Abstract Submissions (ACR)

Background/Purpose: Smoking is a major risk factor for rheumatoid arthritis (RA) and has been associated with increased disease severity and lower rates disease remission. We hypothesized that levels of disease activity would be associated with smoking status and this would be related to levels of anti-citrullinated protein antibodies (ACPA) and/or serum cytokines.

Methods: The Veterans Affairs RA (VARA) registry was initiated in 2003 with routine collection of clinical demographics including disease activity score (DAS28) as well as baseline serum sampling. 1468 veterans with RA were included in the current study (76.9% anti-CCP2+, 90.7% male, mean age median age 63 (IQR 57-72), Median disease duration 8.45 years (IQR 2.8-18). Baseline serum samples were evaluated for levels of 19 distinct ACPA and 17 cytokines using the BioPlex platform on the Luminex 200 instrument. Smoking status was recorded as current, former, or never smokers. We evaluated the association of smoking status with disease activity (DAS28) by ANOVA and with levels of ACPA and cytokines using significance analysis of microarray (SAM) and output sorted based on false discovery rates (FRDs) in order to identify cytokines or autoantibodies with the greatest difference between different categories of smoking status.

Results: RA disease activity was significantly higher among current compared with former or never smokers (P<0.01). Among anti-CCP2 positive patients, levels of several cytokines associated with RA pathogenesis including TNFα, IL-17, IFNγ, GM-CSF, MCP-1, IL-2, and IL-7 were found to be significantly higher among current smokers compared with both former and non-smokers (FDR (q-value) <0.1%). Cytokine levels were similar between former and never smokers. Notably, levels of many ACPA were higher among current compared with never smokers, but similar between current and former smokers. Though number of subjects was smaller, the effect of smoking status on cytokine profile was not observed in the anti-CCP2 negative population.

Conclusion: Among anti-CCP2 positive RA patients, current smoking status is strongly associated with increased RA disease activity as well as elevation in several serum cytokines. This effect does not seem to be related to level of ACPA. The observation that higher levels of DAS28 and serum cytokines was only seen in current, and not former, smokers suggests that the effect of smoking may be minimized by smoking cessation. The effect of smoking cessation on RA disease activity should be evaluated in a prospective manner and multiplex cytokine profiling may provide a surrogate endpoint for efficacy of this intervention.

Disclosure:

C. Cramb,
None;

J. Sokolove,
None;

G. M. Thiele,
None;

G. S. Kerr,
None;

G. W. Cannon,
None;

A. M. Reimold,
None;

T. R. Mikuls,
None;

W. H. Robinson,
None.

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