Journal of Human Hypertension (2014) 28, 165–169 & 2014 Macmillan Publishers Limited All rights reserved 0950-9240/14 www.nature.com/jhh ORIGINAL ARTICLE Infliximab, a TNF-a inhibitor, reduces 24-h ambulatory blood pressure in rheumatoid arthritis patients S Yoshida1, T Takeuchi1, T Kotani1, N Yamamoto1, K Hata1, K Nagai1, T Shoda1,STakai2, S Makino1 and T Hanafusa1 Tumour necrosis factor-alpha (TNF-a) is an important mediator in the pathogenesis of rheumatoid arthritis (RA) and hypertension. TNF-a inhibitors improve clinical symptoms and inhibit joint destruction in RA, but their effect on blood pressure (BP) has not been fully investigated. We measured 24-h BP using an ambulatory BP monitor in 16 RA patients treated with a TNF-a inhibitor, infliximab, to investigate its influence on BP and its association with the regulatory factors of BP and renin-angiotensin-aldosterone and sympathetic nervous systems. Infliximab significantly reduced the 24-h systolic BP (SBP) from 127.4±21.8 to 120.1±23.4 mm Hg (Po0.0001). Particularly, morning BP (0600–0800 h) decreased from 129.7±19.7 to 116.9±13.4 mm Hg (Po0.0001), and daytime BP decreased from 131.8±15.1 to 122.5±13.7 mm Hg (Po0.0001). Infliximab significantly reduced the plasma level of norepinephrine and plasma renin activity (PRA) (from 347.5±180.7 to 283.0±181.8 pg ml À 1 and 2.6±2.7 to 2.1±2.9 ng ml À 1 h À 1, respectively) but did not significantly reduce the plasma levels of dopamine and epinephrine. The reduction in morning SBP correlated with the reduction in the norepinephrine level (Po0.05) but not with that in PRA and inflammatory parameters related to RA. This study shows the effect of infliximab on ambulatory BP, especially daytime BP, which may be partly accounted for by the reduction of sympathetic nerve activity after infliximab treatment. Journal of Human Hypertension (2014) 28, 165–169; doi:10.1038/jhh.2013.80; published online 5 September 2013 Keywords: blood pressure; norepinephrine; renin–angiotensin system; rheumatoid arthritis; tumour necrosis factor INTRODUCTION that an improvement of the disease activity of RA by modified Rheumatoid arthritis (RA) is a systemic inflammatory disease anti-rheumatic drugs and infliximab is associated with a reduction characterised by polyarthritis. In RA patients, arteriosclerosis in BP. Moreover, an additional decrease in BP was observed in progresses in comparison with that in healthy individuals,1 and patients treated with infliximab, but its mechanism remains the prevalence of cardiovascular diseases is high,2,3 serving as unclear. an important prognostic factor for RA.2,4–6 Hypertension is an RA and its complications damage many organs, such as the lung important risk factor for cardiovascular disease,7 and its incidence and kidney, cause pain and stress and may exert effects on BP via among RA patients (about 70%) is higher than that among the sympathetic nervous system (SNS) and renin–angiotensin– healthy individuals.8 The disease activity of arthritis and the aldosterone (RAA) system directly or indirectly. In the present effects of drugs are considered to be RA-related factors influ- study, we measured the 24-h ambulatory BP in RA patients treated encing blood pressure (BP). Drugs for the treatment of RA have with infliximab, a TNF-a inhibitor, and investigated its influence on various influences on BP. Non-steroidal anti-inflammatory drugs BP as well as its association with the regulatory factors of BP and elevate BP,9 and leflunomide10 and cyclosporin11 also cause the SNS and RAA system. drug-induced hypertension. However, methotrexate12 and myco- phenolate mofetil13 were reported to lower BP and reduce morbidity and mortality from heart diseases among RA and MATERIALS AND METHODS psoriasis patients. Study population Tumour necrosis factor-alpha (TNF-a), an inflammatory cytokine The subjects of this study comprised 16 RA patients in whom treatment produced by macrophages, is an important factor involved in the 14 with infliximab was newly introduced at our hospital between July 2006 pathology of RA and is also associated with the pathology of and August 2008. All patients met the 1987 criteria of the American hypertension.15 The serum TNF-a level is elevated in hypertensive College of Rheumatology for RA.24 Hypertension was defined as a patients, similarly to that in RA patients,16 and a correlation repeatedly elevated BP exceeding 140 mm Hg of systolic BP (SBP) or between BP and the serum TNF-a level has been reported.17 TNF- 90 mm Hg of diastolic BP. No hypotensive drug was administered before a inhibitors have recently been used to treat RA and have been or during infliximab treatment to any patient. None of the patients shown to inhibit synovial inflammation and joint destruction.18 was previously diagnosed with heart disease. Disease-modifying anti- TNF-a inhibitors have been reported to reduce BP in mice.19 It has rheumatic drugs, non-steroidal anti-inflammatory drugs and thera- peutic drugs for diabetes and hyperlipidemia remained unchanged been controversial whether TNF-a inhibitors lead to a reduction of throughout the study period. Informed consent was obtained from BP in humans. Several reports showed that TNF-a inhibitors all patients after the study was explained to them. Study protocols reduced the aortic stiffness concomitant with the disease activity were approved by the institutional review board of Osaka Medical of RA, but not BP.20–22 Recently, Klarenbeek et al.23 have shown College. 1Department of Internal Medicine (I), Osaka Medical College, Takatsuki, Japan and 2Department of Pharmacology, Osaka Medical College, Takatsuki, Japan. Correspondence: Professor T Takeuchi, Department of Internal Medicine (I), Osaka Medical College, 2-7 Daigaku-Machi, Takatsuki, Osaka 569-8686, Japan. E-mail: [email protected] Received 21 November 2012; revised 9 July 2013; accepted 17 July 2013; published online 5 September 2013 Anti-TNF-a therapy reduces BP in RA patients S Yoshida et al 166 Study design disease duration was 39.5±36.9 months. Their RA disease activity All patients received infliximab (3 mg kg À 1) on weeks 0 (on the initiation level was high, as indicated by a DAS28-CRP value of 43.2. day), 2 and 6 and every 8 weeks thereafter. Physical examination, Seven patients had been diagnosed as having hypertension, haematological evaluations and ambulatory BP monitoring (ABPM) were and two patients each had been diagnosed as having diabetes performed before and after the first 2 weeks of the treatment with and hyperlipidemia. Four patients had a smoking habit. All infliximab during the hospital admission. The disease activity of RA was patients were treated with methotrexate; 12 were treated evaluated with the help of the Disease Activity Score-C reactive protein with non-steroidal anti-inflammatory drugs; and 10 were treated (DAS28-CRP), which was calculated using the following components: tender joint counts, swollen joint counts, CRP and patient global with prednisolone. assessment.25 Rheumatoid factor, erythrocyte sedimentation rate and matrix metalloproteinase-3 values were measured. Plasma samples were Infliximab-induced changes in RA disease activity obtained from the patients, who rested in a recumbent position for 30 min Pre- and post-treatment test results of infliximab treatment are 1 in the morning (from 0630 to 0700 h), and were stored at À 80 C until shown in Table 2. The mean values of pre- verus post-treatment analysis. The plasma renin activity was measured using the ± ± radioimmunoassay-2 antibody method (TFB Inc., Tokyo, Japan), and test results were as follows: DAS28-CRP, 4.68 0.64 vs 2.67 1.12, Po0.0001; CRP, 2.55±2.24 vs 0.50±0.71 mg dl À 1, Po0.0001; and epinephrine, norepinephrine and dopamine levels were measured using À 1 a catecholamine test (Tosoh Co., Tokyo, Japan) and high-performance matrix metalloproteinase-3, 254.2±166.4 vs 133.9±120.9 ngml , liquid chromatography (Tosoh Co.). Po0.0001. All measurements were significantly reduced, indicating that the disease activity was reduced. Twenty-four-hour ABPM Twenty-four-hour ABPM was performed before and after the first 2 weeks Infliximab-induced changes in 24-h BP and pulse of the treatment with infliximab using a TM-2025 ambulatory BP monitor The 24-h BP and heart rate values between pre- and post- (A&D Co., Tokyo, Japan). An appropriately sized cuff was placed around the infliximab treatment are shown in Table 2 and Figure 1. The pre- nondominant arm. Monitoring was initiated after confirming that the treatment values were significantly higher than the post-treatment difference between the monitored BP value and that measured values (127.4±21.8 vs 120.1±23.4 mm Hg, Po0.0001). The simultaneously using the auscultatory method was within 5 mm Hg. The pre- versus post-treatment morning SBP (129.7±19.7 vs 116.9± measurement interval was set at 1 h. SBP, diastolic BP and heart rate were 13.4 mm Hg, Po0.0001) and mean daytime SBP (131.8±15.1 vs recorded. The patients were instructed to avoid moving their arm during ± BP measurement. All patients woke up at 0600 h and went to bed at 2100 h 122.5 13.7 mm Hg, Po0.0001) were both reduced. However, the during ABPM. BPs measured between 2100 and 0600 h, 0600 and 2100 h, pre- versus post-treatment mean sleep SBP remained unchanged and 0600 and 0800 h were defined as sleep, daytime and morning BP, (119.5±11.9 vs 115.0±12.4 mm Hg, P40.05) as did the 24-h respectively. Those patients whose recordings showed an error rate of diastolic BP and heart rate.