Response to Letter Regarding Article, “Angiotensin-Converting Enzyme Inhibition Improves Vascular Function in Rheumatoid Arthritis”
We would like to thank Drs Popa and Netea for their interest in our study1 and their comments.
It is a prerequisite of clinical studies investigating endothelial function that patients remain clinically stable throughout the course of the study to allow the assessment of the potential impact of the study drug. Clinically stable patients, however, present with low disease activity and demonstrate low markers of inflammation, thus explaining the relatively low levels of interleukin-1, interleukin-6, CD40, myeloperoxidase, and tumor necrosis factor (TNF)-α in our study. The average serum concentration of TNF-α in the present study was 1.74±1.82 pg/mL. The manufacturer gives a minimal detection limit of 0.03 pg/mL for the high-sensitivity assay kit, which is 15-fold more sensitive than the older Quantikine kit and allows measurement further down into the physiological range of plasma TNF-α levels.
Although we concur with Drs Popa and Netea that “therapeutic TNF neutralization on its own also is able to improve endothelial function,” it is somewhat surprising that they cite an article published in 2004 because the first evidence was provided by our group in 2002 in this journal.2 Importantly, the effects of angiotensin-converting enzyme inhibition on endothelial function were observed in patients on stable background therapy, including TNF-α antagonists. Hence, it is unlikely that the concomitant therapy, which remained unchanged throughout the study, affected the study results. It is of note that the improvement in endothelial function in the present study showed a moderate inverse correlation with TNF-α levels even after the 3 patients treated with TNF antagonists were excluded (r=−0.46, P=0.02).
Finally, although we appreciate that Drs Popa and Netea agree with our conclusion that further exploration of angiotensin-converting enzyme inhibitory strategies in rheumatoid arthritis is extremely important, only large-scale prospective randomized clinical trials will provide evidence that the improvements in vascular function with angiotensin-converting enzyme inhibitors,1 antiinflammatory strategies,2 and statins3 translate into a reduction in the cardiovascular burden of our patients with rheumatoid arthritis.
Dr Ruschitzka received an unrestricted research grant from Sanofi-Aventis. Dr Nussberger received a research grant from Sanofi-Aventis and was co-winner of the Sanofi-Aventis Heart Prize 2007. The other authors report no conflicts.
Flammer AJ, Sudano I, Hermann F, Gay S, Forster A, Neidhart M, Kunzler P, Enseleit F, Periat D, Hermann M, Nussberger J, Lüscher TF, Corti R, Noll G, Ruschitzka F. Angiotensin-converting enzyme inhibition improves vascular function in rheumatoid arthritis. Circulation. 2008; 117: 2262–2269.
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