Infliximab, a TNF-Α Inhibitor, Reduces 24-H Ambulatory

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 mycophenolate 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. X25% of the total readings were excluded from the study. Infliximab-induced changes in the SNS and RAA system Statistical methods Pre- versus post-treatment haematological values were as À 1 À 1 The differences in clinical and laboratory findings between pre- and post- follows: plasma renin activity, 2.6±2.7 vs 2.1±2.9 ng ml h ; infliximab treatment were evaluated using the Wilcoxon rank sum test. A norepinephrine, 347.5±180.7 vs 283.0±181.8 pg ml-1;dopa- two-way-layout analysis of variance was used to compare the pre- and mine, 15.75±8.66 vs 14.19±11.92 pg ml À 1; and epinephrine, post-treatment 24-h ambulatory BP values. The BP at each time point was 30.94±28.34 vs 22.06±18.71 pg ml À 1 (Table 2). The reductions evaluated using the t-test. Spearman’s rank correlation test was also used in plasma renin activity and the level of norepinephrine were to investigate the association between BP reduction and other parameters. significant (P ¼ 0.0159 and P ¼ 0.0182, respectively). A P-value of o0.05 was regarded as significant. A statistical analysis was performed using JMP ver. 8.0 statistical software programme (SAS Institute, Cary, NC, USA). Relation between variations in morning SBP and other parameters The association between the SNS or RAA system and the infliximab-induced reductions of the daytime SBP—particularly RESULTS the morning SBP—was investigated. The rate of morning SBP Baseline characteristics Patient baseline characteristics are shown in Table 1. There were 10 women and 6 men (mean age: 56.6±12.3 years), and the mean Table 2. Changes in clinical and laboratory findings pre- and post- infliximab treatment

Table 1. Baseline characteristics Before 2 weeks after P-value treatment treatment Patients (n)16 Age (years) 56.6±12.32 DAS28-CRP 4.68±0.64 2.67±1.12 o0.0001 Sex (female/male) 10/6 CRP (mg dl À 1) 2.55±2.24 0.50±0.71 o0.0001 Disease duration (months) 39.5±36.86 MMP-3 (ng ml À 1) 245.2±166.4 133.9±120.9 o0.0001 BMI (kg m À 2)22±3.72 ESR (mm h À 1) 43.7±29.1 25.9±29.7 0.0016 HbA1c 5.8±0.797 RF (IU ml À 1) 202.1±304.9 157.7±242.7 0.0002 Hypertension (n)7PRA (ng ml À 1 h À 1) 2.6±2.7 2.1±2.9 0.0159 Diabetes mellitus (n)2Norepinephrine (pg ml À 1) 347.5±180.7 283±181.8 0.0182 Hyperlipidemia (n)2Dopamine (pg ml À 1) 15.75±8.66 14.19±11.92 0.246 Smoking (n)4Epinephrine (pg ml À 1) 30.94±28.34 22.06±18.71 0.0916 MTX (n)1624-h systolic BP (mm Hg) 127.4±21.8 120.1±23.4 o0.0001 Average dose (mg per week) 7.6±2.64 24-h diastolic BP (mm Hg) 75.2±9.2 71.6±10.1 0.240 Prednisolone (n)1024-h heart rate 73.4±9.8 67.1±7.1 0.085 Average dose (mg per day) 6.2±5.92 NSAIDs (n)12Abbreviations: BP, blood pressure; CRP, C-reactive protein; DAS28-CRP, disease activity score 28-C-reactive protein; ESR, erythrocyte sedimentation Abbreviations: BMI, body mass index; HbA1c, hemoglobin A1c; MTX, rate; MMP-3, matrix metalloproteinase-3; PRA, plasma renin activity; methotrexate; NSAIDs, non-steroidal anti-inﬂammatory drugs. RF, rheumatoid factor.

Journal of Human Hypertension (2014) 165 – 169 & 2014 Macmillan Publishers Limited Anti-TNF-a therapy reduces BP in RA patients S Yoshida et al 167 Before treatment 180 After treatment † † † † † Before treatment †† † (127.4±21.8mmHg)

140

100

After treatment (120.1±23.4mmHg) 60 00 00 00 00 00 00 1:00 3:00 5:00 7:00 9:00 11:00 13: 15: 17: 19: 21: 23: Figure 1. Comparison of 24-h SBP measurements between pre- and post-infliximab treatment (n ¼ 16). BP was significantly reduced after infliximab treatment (*Po0.0001 by two-way layout analysis of variance, 95% confidence interval [-9.7-4.9] for 24-h ambulatory BP before vs after infliximab treatment), particularly the BP measured in the morning and on awakening (wPo0.05, wwPo0.01 by paired t-test for 24-h ambulatory BP before vs after infliximab treatment).

P=0.03

R 2=0.28, P<0.05 900 0 800 20 700 10

600 0 500 -300 -200 -100 100 200 400 -10 300 -20 200 -30 100 Improvement of SBP(mmHg) -40 0 Before After -50 Norepinephrine (pg/ml) Improvement in norepinephrine (pg/ml) Figure 2. Relation between norepinephrine level and morning SBP measurements pre- and post-infliximab treatment. The norepinephrine level decreased significantly after infliximab treatment, and a significant positive correlation was observed between the improvement in morning SBP (0700 h) and the norepinephrine level. A full colour version of this figure is available at the Journal of Human Hypertension journal online.

(0700 h) reduction correlated with that of norepinephrine SBP, especially the morning SBP. ABPM of all patients in this study reduction (Po0.05) but not with that of plasma renin activity was performed during hospital admission, which restricted the reduction (Figure 2). The rate of daytime SBP reduction had no daily activities of the patients. This may have resulted in the correlation with that of other parameters, such as CRP, erythrocyte improvement of reproducibility of ABPM. sedimentation rate, matrix metalloproteinase-3, DAS28-CRP and Morning BP surge is a physiological reaction, but a marked its components. surge is a risk for hypertensive organ disorders and cardiovascular events.29–31 Variations in morning BP surge and the morning BP are correlated with thickening of the tunica intima32 and DISCUSSION myocardial weight30,33 and are involved in both direct pressure Inhibition of BP elevation by the TNF-a inhibitor etanercept in a rat load on the blood vessels and mechanical stress on plaques.34,35 hypertensive model has been reported,19 but its influence on The incidence of cardiovascular events is higher in RA patients humans has not been fully elucidated. BP elevation occurring than in healthy subjects2,3 and is reduced by a TNF-a inhibitor.36 immediately after etanercept administration has been reported,26 Insulin resistance37 and improvement of lipid abnormality38 are but BP remained unchanged after TNF-a inhibitor administration considered as the mechanisms. Our data suggest that infliximab- in another report.27 Recently, Klarenbeek et al. have reported a induced reduction of the daytime SBP, especially of morning SBP, decrease in BP in patients with lower disease activity and is a possible mechanism of this inhibitory effect on cardiovascular an additional decrease in patients treated with infliximab, but events. the mechanism of these reductions remains unclear.23 The Hypertension results from abnormal BP control. The SNS and discrepancy between these previous reports may result from the RAA system are important regulatory factors of BP39–41 and are measurement of casual BP, which varies widely within a single day involved in morning BP surge.42–44 Inflammatory cytokines, or between days. Also, the intra-individual reproducibility of ABPM including TNF-a, excite the SNS,45,46 and TNF-a induces the has been shown to be poor because of the differences of daily expression of angiotensin 1-receptor and angiotensin II in mice.46 activities.28 The present study showed the influence of a TNF-a However, influences of TNF-a inhibitors on the SNS or RAA system inhibitor, infliximab, on 24-h BP. Infliximab reduced the daytime have not been reported previously. The present study showed

& 2014 Macmillan Publishers Limited Journal of Human Hypertension (2014) 165 – 169 Anti-TNF-a therapy reduces BP in RA patients S Yoshida et al 168 that infliximab reduced the level of norepinephrine and plasma 8 Panoulas VF, Douglas KM, Milionis HJ, Stavropoulos-Kalinglou A, Nightingale P, renin activity, suggesting that the drug inhibited activities of the Kita MD et al. Prevalence and associations of hypertension and its control in SNS and RAA system. Particularly, the reduction in norepinephrine patients with rheumatoid arthritis. Rheumatology (Oxford) 2007; 46: 1477–1482. level correlated with the reduction in morning SBP, indicating that 9 Morrison A, Ramey DR, van Adelsberg J, Watson DJ. Systematic review of trials of the inhibitory effect of infliximab on morning SBP may involve the the effect of continued use of oral non-selective NSAIDs on blood pressure and SNS. There is a possibility that an improvement of clinical hypertension. Curr Med Res Opin 2007; 23: 2395–2404. symptoms (for example, pain relief) by infliximab treatment is 10 Rozman B, Praprotnik S, Logar D, Tomsic M, Hojnik M, Kos-Golja M et al. Leflu- associated with a reduction of serum norepinephrine levels as well nomide and hypertension. Ann Rheum Dis 2002; 61: 567–569. 11 Kvien TK, Zeidler HK, Hannonen P, Wollheim FA, Førre O, Hafstro¨mIet al. Long as daytime BP in the present study. However, we did not observe term efficacy and safety of cyclosporin versus parenteral gold in early rheumatoid associations of the improvement of RA activity with the reduction arthritis: a three year study of radiographic progression, renal function, and of serum norepinephrine levels and daytime BP. arterial hypertension. Ann Rheum Dis 2002; 61: 511–516. This study had several limitations. It was a single-arm trial; 12 Choi HK, Hernań MA, Seeger JD, Robins JM, Wolfe F. Methotrexate and mortality the number of patients studied was small; the patients were in patients with rheumatoid arthritis: a prospective study. Lancet 2002; 359: followed only for a short period; and the influence of long-term 1173–1177. administration of infliximab on BP was not investigated. Other 13 Herrera J, Ferrebuz A, MacGregor EG, Rodriguez-Iturbe B. Mycophenolate mofetil TNF-a inhibitors were not investigated. Moreover, circulating treatment improves hypertension in patients with psoriasis and rheumatoid norepinephrine is not a precise method for evaluating sympa- arthritis. J Am Soc Nephrol 2006; 17: S218–S225. 14 Choy EH, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid thetic nerve activity. Further studies are needed to show the arthritis. N Engl J Med 2001; 344: 907–916. influence of anti-inflammatory drugs on BP, its mechanism and 15 Kim KI, Lee JH, Chang HJ, Cho YS, Youn TJ, Chung WY et al. Association between the associations between anti-inflammatory drugs and the blood pressure variability and inflammatory marker in hypertensive patients. regulatory factors of BP. Circ J 2008; 72: 293–298. 16 Do¨ rffel Y, La¨tsch C, Stuhlmu¨ller B, Schreiber S, Scholze S, Burmester GR et al. Preactivated peripheral blood monocytes in patients with essential hypertension. Hypertension 1999; 34: 113–117. 17 Zinman B, Hanley AJ, Harris SB, Kwan J, Fantus IG. Circulating tumor necrosis What is known about this topic factor-alpha concentrations in a native Canadian population with high rates of Hypertension is an important risk factor for cardiovascular disease, type 2 diabetes mellitus. J Clin Endocrinol Metab 1999; 84: 272–278. and its incidence in patients with rheumatoid arthritis (RA) is higher 18 Elliott MJ, Maini RN, Feldmann M, Long-Fox A, Charles P, Katsikis P et al. 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& 2014 Macmillan Publishers Limited Journal of Human Hypertension (2014) 165 – 169