Angiotensin Converting Enzyme Activity in Anti-TNF-Treated Rheumatoid Arthritis and Ankylosing Spondylitis Patients

Boglárka Soós; Miklós Fagyas; Ágnes Horváth; Edit Végh; Anita Pusztai; Monika Czókolyová; Alexandra Csongrádi; Attila Hamar; Zsófia Pethő; Nóra Bodnár; György Kerekes; Katalin Hodosi; Éva Szekanecz; Szilvia Szamosi; Sándor Szántó; Gabriella Szűcs; Zoltán Papp; Zoltán Szekanecz

doi:10.3389/fmed.2021.785744

Angiotensin Converting Enzyme Activity in Anti-TNF-Treated Rheumatoid Arthritis and Ankylosing Spondylitis Patients

Front Med (Lausanne). 2022 Jan 27:8:785744. doi: 10.3389/fmed.2021.785744. eCollection 2021.

Authors

Boglárka Soós¹, Miklós Fagyas², Ágnes Horváth¹, Edit Végh¹, Anita Pusztai¹, Monika Czókolyová¹, Alexandra Csongrádi², Attila Hamar¹, Zsófia Pethő¹, Nóra Bodnár¹, György Kerekes³, Katalin Hodosi¹, Éva Szekanecz⁴, Szilvia Szamosi¹, Sándor Szántó^{1

5}, Gabriella Szűcs¹, Zoltán Papp², Zoltán Szekanecz¹

Affiliations

¹ Division of Rheumatology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
² Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
³ Intensive Care Unit, Department of Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
⁴ Department of Oncology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
⁵ Department of Sports Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.

Abstract

Introduction: Angiotensin-converting enzyme (ACE) and ACE2 have been implicated in the regulation of vascular physiology. Elevated synovial and decreased or normal ACE or ACE2 levels have been found in rheumatoid arthritis (RA). Very little is known about the effects of tumor necrosis factor α (TNF-α) inhibition on ACE or ACE2 homeostasis. In this study, we assessed the effects of one-year anti-TNF therapy on ACE and ACE2 production in RA and ankylosing spondylitis (AS) in association with other biomarkers.

Patients and methods: Forty patients including 24 RA patients treated with either etanercept (ETN) or certolizumab pegol (CZP) and 16 AS patients treated with ETN were included in a 12-month follow-up study. Serum ACE levels were determined by commercial ELISA, while serum ACE2 activity was assessed using a specific quenched fluorescent substrate. Ultrasonography was performed to determine flow-mediated vasodilation (FMD), common carotid intima-media thickness (ccIMT) and arterial pulse-wave velocity (PWV) in all patients. In addition, CRP, rheumatoid factor (RF) and ACPA were also measured. All assessments were performed at baseline and 6 and 12 months after treatment initiation.

Results: Anti-TNF therapy increased ACE levels in the full cohort, as well as in the RA and AS subsets. ACE2 activity increased in the full cohort, while the ACE/ACE2 ratio increased in the full cohort and in the RA subset (p < 0.05). Uni- and multivariable regression analyses determined associations between ACE or ACE/ACE2 ratios at different time points and disease duration, CRP, RF, FMD and IMT (p < 0.05). ACE2 activity correlated with CRP. The changes of ACE or ACE2 over 12 months were determined by treatment together with either RF or FMD (p < 0.05).

Conclusions: Anti-TNF treatment may increase ACE and ACE2 in the sera of RA and AS patients. ACE and ACE2 may be associated with disease duration, markers of inflammation and vascular pathophysiology. The effects of TNF inhibition on ACE and ACE2 may reflect, in part, the effects of these biologics on the cardiovascular system.

Keywords: angiotensin converting enzyme; ankylosing spondylitis; anti-TNF therapy; biologics; rheumatoid arthritis; vascular disease.