Comment on: Venous thrombotic events are not increased in patients with rheumatoid arthritis treated with anti-TNF therapy

Kosei Kawakami, Assistant professor,
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Other Contributors:

August 10, 2011

Dear Editor,

We read with interest the recent article by Davies et al. [1] reporting on venous thrombotic events (VTEs) in patients with rheumatoid arthritis (RA) treated with antitumour necrosis factor (anti-TNF). They suggest that anti-TNF therapy is not associated with an increased risk of VTEs in RA patients, although, until the present time, retrospective studies looking at VTEs in anti-TNF-treated RA patients have produced conflicting results.[2] We previously reported that anti-TNF drugs were a likely cause of VTE development in RA patients following major orthopaedic surgery.[3] Because of these contradictory results, the effects of anti-TNF therapy on the risk of VTEs after orthopaedic intervention remain unclear.

Orthopedic procedures, including total joint arthroplasties (TJAs) such as total knee arthroplasty (TKA) and total hip arthroplasty (THA), have substantially improved overall patient function and quality of life. However, complications after surgery, especially postoperative VTEs, can pose serious functional and psychological challenges. Therefore, more data are needed on the effects of non-biological and biological disease- modifying antirheumatic drugs (DMARDs) after surgical intervention. The aim of this study was to identify risk factors for acute VTEs after TJAs.

This was a retrospective study of 500 consecutive patients undergoing TJAs during a 5-year period from January 2005 to December 2009. All RA patients fulfilled the 1987 revised American College of Rheumatology criteria for RA and/or the 2010 RA classification criteria.[4, 5]
The timing of surgical intervention for patients treated with biological DMARDs was based on guidelines from the British Society for Rheumatology and the Japan College of Rheumatology.[6, 7] VTEs of the lower extremities were diagnosed using venous ultrasonography by three experienced medical technologists who were blinded to which patients were taking biological DMARD therapy. Twenty-three patients with preoperative VTEs were excluded.

Multivariate logistic regression analysis was performed to determine the risk factors for postoperative VTEs. A p-value of <0.05 was considered statistically significant. All analyses were performed using R-2.9.1 statistical software.

There were 130 patients who developed postoperative VTE. Multivariate logistic regression analysis showed that age (p=0.0012, odds ratio [OR]=1.04 [1.01-1.06]), use of biological DMARDs (p=0.0048, OR=2.72 [1.36-5.45]), past history of VTEs (p=0.033, OR=2.48 [1.07-5.70]), and TKA (vs. THA) (p=0.000083, OR=4.32 [2.09-8.96]) were risk factors for VTE.

Case reports [8] and basic research have shown that TNF-alpha decreases platelet activation and inhibits thrombus formation, and that TNF-alpha blocking by a biological DMARD may lead to thrombus formation.[9] The results of our study also suggest that biological DMARDs may cause the occurrence of VTE in RA patients after TJA.
However, this study had several limitations. Among RA-related surgeries, TJA was designated high risk surgery for the development of VTEs by the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.[10] Moreover, VTEs of the lower extremities were identified using venous ultrasonography, and the sample size was not large enough to investigate complications after joint surgery in RA patients treated with biological DMARDs.

Therefore, to confirm the risks for VTEs after TJA in RA patients treated with anti-TNF, additional prospective studies are necessary.


1. Davies R, Galloway JB, Watson KD, et al. Venous thrombotic events are not increased in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the British Society for Rheumatology Biologics Register. Ann Rheum Dis. (Online first)

2. Petitpain N, Gambier N, Wahl D, et al. Arterial and venous thromboembolic events during anti-TNF therapy: a study of 85 spontaneous reports in the period 2000-2006. Biomed Mater Eng 2009;19(4-5):355-64.

3. Kawakami K, Ikari K, Kawamura K, et al. Complications and features after joint surgery in rheumatoid arthritis patients treated with tumour necrosis factor-alpha blockers: perioperative interruption of tumour necrosis factor-alpha blockers decreases complications? Rheumatology (Oxford) 2010;49(2):341-7.

4. Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31(3):315-24.

5. Aletaha D, Neogi T, Silman AJ, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis 2010;69(9):1580-8.

6. Ledingham J, Deighton C. Update on the British Society for Rheumatology guidelines for prescribing TNFalpha blockers in adults with rheumatoid arthritis (update of previous guidelines of April 2001). Rheumatology (Oxford) 2005;44(2):157-63.

7. Koike R, Takeuchi T, Eguchi K, et al. Update on the Japanese guidelines for the use of infliximab and etanercept in rheumatoid arthritis. Mod Rheumatol 2007;17(6):451-8.

8. Grange L, Nissen MJ, Garambois K, et al. Infliximab-induced cerebral thrombophlebitis. Rheumatology (Oxford) 2005;44(2):260-1.

9. Cambien B, Bergmeier W, Saffaripour S, et al. Antithrombotic activity of TNF-alpha. J Clin Invest 2003;112(10):1589-96.

10. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008;133(6 Suppl):381S-453S.

Conflict of Interest

None declared