1. 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

2. 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 2

3. 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 3

4. Question How is rheumatoid factor measurement used clinically at the present time? What are the main mechanisms for developing deep venous thrombosis? 4

5. 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 5

6. Question Does long-term freezing affect rheumatoid factor concentration measurements in plasma? 6

7. 7 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

8. 8 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

9. 9 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.

10. 10 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

11. 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? 11

12. 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 12

13. 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. 13

14. Editorial by Gregory Piazza & Paul M Ridker 14 Figure 5. Venous thromboembolism and atherothrombosis as chronic inflammatory diseases with shared risk factors and pathophysiology.

15. 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 15

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