Effect of tofacitinib therapy on angiotensin converting enzyme activity in rheumatoid arthritis

Dorottya Kacsándi; Miklós Fagyas; Ágnes Horváth; Edit Végh; Anita Pusztai; Monika Czókolyová; Boglárka Soós; Attila Ádám Szabó; Attila Hamar; Zsófia Pethő; Nóra Bodnár; György Kerekes; Katalin Hodosi; Szilvia Szamosi; Gabriella Szűcs; Zoltán Papp; Zoltán Szekanecz

doi:10.3389/fmed.2023.1226760

Effect of tofacitinib therapy on angiotensin converting enzyme activity in rheumatoid arthritis

Front Med (Lausanne). 2023 Oct 9:10:1226760. doi: 10.3389/fmed.2023.1226760. eCollection 2023.

Authors

Dorottya Kacsándi¹, Miklós Fagyas², Ágnes Horváth¹, Edit Végh¹, Anita Pusztai¹, Monika Czókolyová¹, Boglárka Soós¹, Attila Ádám Szabó^{2

3}, Attila Hamar¹, Zsófia Pethő¹, Nóra Bodnár¹, György Kerekes⁴, Katalin Hodosi¹, Szilvia Szamosi¹, Gabriella Szűcs¹, Zoltán Papp², Zoltán Szekanecz¹

Affiliations

¹ Department 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 Kálmán Laki Doctoral School of Biomedical and Clinical Sciences, University of Debrecen, Debrecen, Hungary.
⁴ Intensive Care Unit, Department of Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.

Abstract

Introduction: The Renin-Angiotensin-Aldosterone system (RAAS) has been implicated in the regulation of the cardiovascular system and linked to rheumatoid arthritis (RA). Little information has become available on the effects of Janus kinase (JAK) inhibition on RAAS. Here we studied the effects of 12-month tofacitinib treatment on angiotensin converting enzyme (ACE), ACE2 production and ACE/ACE2 ratios in RA along with numerous other biomarkers.

Patients and methods: Thirty RA patients were treated with tofacitinib in this prospective study. Serum ACE concentrations were assessed by ELISA. ACE2 activity was determined by a specific quenched fluorescent substrate. ACE/ACE2 ratios were calculated. We also determined common carotid intima-media thickness (ccIMT), brachial artery flow-mediated vasodilation (FMD) and carotid-femoral pulse-wave velocity (cfPWV) by ultrasound. C-reactive protein (CRP), rheumatoid factor (RF) and anti-citrullinated protein autoantibodies (ACPA) were also determined. All measurements were performed at baseline, as well as after 6 and 12 months of tofacitinib treatment.

Results: After the dropout of 4 patients, 26 completed the study. Tofacitinib treatment increased ACE levels after 6 and 12 months, while ACE2 activity only transiently increased at 6 months. The ACE/ACE2 ratio increased after 1 year of therapy (p < 0.05). Logistic regression analyses identified correlations between ACE, ACE2 or ACE/ACE2 ratios and RF at various time points. Baseline disease duration also correlated with erythrocyte sedimentation rate (ESR) (p < 0.05). One-year changes of ACE or ACE2 were determined by tofacitinib treatment plus ACPA or RF, respectively (p < 0.05).

Conclusion: JAK inhibition increases serum ACE and ACE/ACE2 ratio in RA. Baseline inflammation (ESR), disease duration and ACPA, as well as RF levels at various time points can be coupled to the regulation of ACE/ACE2 ratio. The effect of tofacitinib on RAAS provides a plausible explanation for the cardiovascular effects of JAK inhibition in RA.

Keywords: JAK inhibition; angiotensin converting enzyme; rheumatoid arthritis; targeted therapy; tofacitinib; vascular disease.

Grants and funding

This study received funding from the European Union and the State of Hungary and co-financed by the European Social Fund in the framework of TAMOP-4.2.4.A/2-11/1-2012*0001 ‘National Excellence Program’ (ZS), European Union grant GINOP-2.3.2-15-2016-00050 (ZS), and Pfizer Investigator Initiated Research Grant no. WI188341 (ZS). MF and AS were supported by the ÚNKP-22-5-DE-408 and ÚNKP-22-3-I-DE-248 New National Excellence Program of The Ministry for Innovation and Technology. This paper was supported by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences (BO/00069/21/5). The funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.