Biomarkers of inflammation and development of rheumatoid arthritis in women from two prospective cohort studies

Abstract

Objective: To examine the association of biomarkers of inflammation with preclinical rheumatoid arthritis (RA).

Methods: A nested case-control study was performed using samples from 2 large, prospectively studied cohorts of women (the Women's Health Study [WHS] and the Nurses' Health Study [NHS]). Blood samples obtained prior to symptom onset in women who later developed RA were selected as incident RA cases, and 3 controls per case were randomly chosen, matched for age, menopausal status, postmenopausal hormone use, and day, time, and fasting status at the time of collection. Plasma was tested for levels of interleukin-6 (IL-6), soluble tumor necrosis factor receptor II (sTNFRII) (as a proxy for TNFalpha), and high-sensitivity C-reactive protein. Relationships between biomarkers and RA were assessed using conditional logistic regression models, adjusting for age, body mass index, smoking habits, ethnicity, and reproductive factors.

Results: In 93 incident cases in the NHS and 77 incident cases in the WHS, the mean time between blood collection and the onset of RA symptoms was 5.2 years (range 0.3-12 years). Median IL-6 and sTNFRII levels were significantly higher in preclinical RA cases compared with matched controls in the NHS (P = 0.03 and P = 0.003, respectively) though not in the WHS. Pooled analysis of the NHS and WHS cohorts demonstrated significant association of sTNFRII with RA (relative risk 2.0 [95% confidence interval 1.1-3.6], P for trend = 0.004), and a modest association of IL-6 with RA (relative risk 1.4 [95% confidence interval 0.8-2.5], P for trend = 0.06).

Conclusion: Levels of sTNFRII, a biomarker typically associated with active RA, were elevated up to 12 years prior to the development of RA symptoms and were positively associated with incident RA in these nested case-control studies. Studies with repeated assessments of biomarkers prior to RA development may provide further insight into the timing of biomarker elevation in preclinical RA.

Figure 1

Prevalence of elevated preclinical biomarker levels for RA cases diagnosed 0.3 – 4 years, 4–8 years, and 8–12 years after blood collection in the Nurses’ Health Study (1989–2002), Nurses’ Health Study II (1993–2003), and Women’s Health Study (1992–2002). IL-6 and sTNFR2 include WHS and NHS data, anti-CCP and hs-CRP include only NHS data. Thresholds were anti-CCP > 5 U/ml, IL-6 ≥ 2.21 mg/dl, sTNFR2 ≥ 2442.1 mg/dl and hsCRP ≥ 3.14 mg/dl.