Journal Club

Increased Rheumatoid Factor and Deep Venous Thrombosis: 2 Cohort Studies of 54,628 Individuals from the General Population

C.L. Meyer-Olesen, S.F. Nielsen, and B.G. Nordestgaard

February 2015

www.clinchem.org/content/61/2/349.full

© Copyright 2015 by the American Association for Clinical Chemistry

Introduction

• The risk of deep venous thrombosis is increased in patients with rheumatoid arthritis

• In patients with rheumatoid arthritis, increased rheumatoid factor is associated with markers of inflammation and disease activity

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Hypothesis

• Increased concentrations of rheumatoid factor are associated with increased risk of deep venous thrombosis in individuals without autoimmune rheumatic disease in the general population

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Question

• How is rheumatoid factor measurement used clinically at the present time?

• What are the main mechanisms for developing deep venous thrombosis?

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Materials and methods

• Plasma IgM rheumatoid factor was measured The Copenhagen City Heart Study (n=9,657)

• 9657 samples drawn in 1981-83 and frozen at -20°C until 2009-10

The Copenhagen General Population Study (n= 44,971) • 12,211 samples drawn in 2004-06 and frozen at -80°C

until 2009-10 • 32,760 samples drawn in 2008-12 and measured fresh

immediately after sampling Turbidimetry (Konelab) with an interassay CV of 2%

• Over the course of 32 years of follow-up, 670 individuals developed deep venous thrombosis

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Question

• Does long-term freezing affect rheumatoid factor concentration measurements in plasma?

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Figure 1. Risk of deep venous thrombosis comparing individuals with a rheumatoid factor concentration above or equal to a cut point versus below, as a function of different cutpoint values

One-year risk of deep venous thrombosis

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Cumulative incidence of deep venous thrombosis

Figure 2. Fine-Gray cumulative incidences of deep venous thrombosis by five categories of baseline concentrations of rheumatoid factor as a function of age

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0.1

0.2

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Cum

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inci

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f DV

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30 40 50 60 70 80 90 100Age (years)

12060-11930-5915-29<15

Rheumatoid factor level (IU/mL)

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Risk of deep venous thrombosis

Figure 3. Risk of deep venous thrombosis by five categories of baseline concentrations of rheumatoid factor. P is for trend.

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Figure 4. Absolute five-year risks of deep venous thrombosis as a function of rheumatoid factor concentration, sex, age, and obesity

Absolute 5-year risks of deep venous thrombosis

Questions

• What are the potential confounders in the association between high rheumatoid factor concentrations and risk of deep venous thrombosis?

• Which type of studies could further clarify the relationship between rheumatoid factor, inflammation, and deep venous thrombosis?

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Discussion

• We observed an increased risk of deep venous thrombosis in individuals with increased concentrations of rheumatoid factor

• Potential limitations: white individuals only and risk of diagnostic misclassification

• Strengths: up to 32 years of follow-up without losses, adjustment for major risk factors, and consistent results within 2 separate cohorts and in all sensitivity analyses

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Editorial by Gregory Piazza and Paul M Ridker• The current study adds to the body of evidence

supporting inflammation as a critical component in the pathophysiology of venous thrombosis

• Ongoing randomized trials will specifically evaluate the impact of inflammatory modulation on venous thromboembolism

• Should these trials demonstrate a reduction in the rate of venous thromboembolism this condition could be considered a chronic disorder requiring long-term anti-inflammatory therapy

Editorial: Piazza G and Ridker PM. Is Venous Thromboembolism a Chronic Inflammatory Disease? Clin Chem 2015;61:313-16.

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Editorial by Gregory Piazza &

Paul M Ridker

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Figure 5. Venous thromboembolism and atherothrombosis as chronic inflammatory diseases with shared risk factors andpathophysiology.

Conclusion

• Increased rheumatoid factor in the general population was associated with up to 3-fold increased long-term risk and up to 9-fold increased one-year risk of deep venous thrombosis

• This suggests that severely increased rheumatoid factor could be considered as a thrombophilic condition

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