BA20 - Rheumatoid Arthritis in the WHI

This page provides study documentation for BA20. For description of the specimen results, see Specimen Results Description (open to public). Data sets of the specimen results are included in the existing WHI datasets located on the WHI Data on this site (sign in and a completed Data Distribution Agreement are required; see details on the Data site).

Investigator Names and Contact Information

Larry W. Moreland, MD, Chief, Division of Rheumatology and Clinical Immunology, University of Pittsburgh


The overall objectives of this proposal are to investigate the meaning of self-reported RA and to determine whether autoimmunity and inflammatory factors associated with RA are risks for CVD, and at what time point during the evolution of disease  these events are relevant. More importantly, this study provides a unique opportunity to dissect what specific aspects of inflammation and/or thrombogenesis are associated with CVD in RA patients.
The Women's Health Initiative (WHI) cohort provides a unique opportunity to explore potential mechanisms involved in higher total mortality and CVD incidence in women with Rheumatoid arthritis (RA). The study of RA provides a specific and unique opportunity to evaluate the independent role of inflammation in coronary heart disease (CHD) risk, especially how markers of inflammation such as cytokines and measures of endothelial function and activation of thrombogenesis and fibrinolysis contribute to the risk of CHD in association with traditional CV risk factors. The large sample size, ethnic variation, and excellent follow up makes the WHI a unique resource. Unfortunately, the self-reported RA in the WHI is inaccurate, making it of very limited value at present. A new test, anti-cyclic citrullinated peptide (anti-CCP) has been shown to have both a high sensitivity and specificity for identifying patients with RA. The sensitivity is close to 80% and the specificity between 95-98%. The addition of measurement of rheumatoid factor (RF) can improve the sensitivity of identifying women who report RA.  We are proposing to test several hypotheses about the etiology of excess mortality and CHD in participants who report RA. These hypotheses can be tested in the WHI cohort by identifying subjects with probable RA and non-RA controls, and testing CVD-related biomarkers, especially inflammation, thrombosis and fibrinolysis, and both CHD and total mortality outcomes. A major goal of the study will be to determine how many of the participants who report RA have anti-CCP autoantibodies or RF. The group with anti-CCP and RF can then be further subclassed by their HLA DR status/high-risk shared epitopes. We will be able to determine whether women who report RA and have anti-CCP antibodies and/or RF have a different distribution of inflammatory markers and risk factors than those that do not have anti-CCP antibody or RF and presumably do not have RA, even though they report such a disease. We will be able to determine whether the women with anti-CCP antibodies and RF have an increased risk of CHD and total mortality, and to evaluate whether increased mortality is secondary to inflammation and activation of thrombogenesis (i.e., higher levels of D-dimer, fibrinogen, soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular adhesion molecule-1 (sVCAM-1) as well as relationship to lipoproteins, such as the number and distribution of LDL and HDL particles.)  This study provides an opportunity to dissect what specific aspects of inflammation and/or thrombogenesis are associated with both CHD and total mortality in patients with probable RA and will greatly enhance our understanding of women’s health.
Specific objectives
1:  Determine the prevalence of anti-CCP(+) antibodies among postmenopausal women who self-report RA at baseline or followup    (Anti-CCP positivity has high sensitivity and specificity for actual cases of RA.) 
2:  Validate the anti-CCP+ diagnosis of RA in a subset of WHI participants who self-report a diagnosis of RA, verifying this diagnosis with antibody testing (RF and CCP) and clinical evaluation (1987 ACR Classification Criteria
3:  Evaluate cytokines, chemokines, CVD risk factors and HLA-DRB epitopes as determinants of true clinical RA (as identified by anti-CCP+) 
4:  Evaluate the risk of CVD and total mortality among women who reported RA and several comparison groups.
5:  Determine whether RA and pre-RA diagnosis autoantibody/inflammatory markers are associated with CVD-related biomarker abnormalities and with incident CVD.
9,988 reported RA
U of Colorado
(Holers Lab)
     Anti-CCP, RF, ANA ab
Subset of 1
600 participants=
300 anti CCP(+)
(150 CHD/150
300 anti CCP(-)
(150 CHD/150
    Cytokines: IL-1a, IL-1b, IL-6, IL-12p40, IL-12p70, IL-15, IL-17, IP-10, MCP-1, TNF, FGF-2, Eotaxin, GM-CSF
U Vermont
(Tracy Lab)
     hsCRP, sVCAM1, sICAM, D-Dimer, fibrinogen
     NMR Lipoproteins
Subset of 1
3,724 participants =
1,862 anti CCP (+)
1,862 anti CCP (-)
     Cytokines: IL-1a, IL-1b, IL-6, IL-12p40, IL-12p70, IL-15, IL-17, Eotaxin, FGF-2, TNF, IP-10, MCP-1, GM-CSF
Subset of
3,724 participants =
1862 anti CCP (+)
1862 anti CCP (-)
U Pitt
(Trucco Lab)
     HLA-DR typing (lab confirmed DNA requirements via email on 2/4/10-JK)
*Estimate numbers for subsets 2, 3 and 4. Adjustments to the numbers within the subsets will be made after completion of Set 1.


See publications: 1701.  WHI publications by study lists published WHI papers that have been generated by ancillary studies. A complete list of WHI papers is available in the Bibliography section of this website.