Objective To evaluate the effect of disease activity and antirheumatic treatment on blood pressure (BP) in patients with recent-onset rheumatoid arthritis (RA).
Methods 508 patients with RA were randomised to receive (1) sequential monotherapy, (2) step-up combination therapy, (3) initial combination with prednisone or (4) with infliximab. Systolic and diastolic BP (SBP, DBP), disease activity score (DAS) and body mass index (BMI) were evaluated every 3 months. A linear mixed model was used to model SBP and DBP in each treatment group during year 1, adjusting for baseline BP, changes in BMI, DAS and cardiovascular medication.
Results In all groups, mean SBP and DBP were lower for patients with DAS ≤2.4 than for patients with DAS >2.4. In addition, patients initially treated with infliximab (group 4) had a larger decrease in SBP and DBP over time than patients in groups 1–3. The decrease in BP was also observed in patients treated with infliximab after failure on conventional disease-modifying antirheumatic drugs in groups 1–3. The decrease in BP associated with treatment with infliximab occurred irrespective of the DAS response.
Conclusion A lower DAS is associated with lower BP. An additional decrease in BP was observed in patients treated with infliximab. Further research is needed to confirm the effect of infliximab on BP.
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Rheumatoid arthritis (RA) is a systemic inflammatory disease which is associated with a higher prevalence of cardiovascular morbidity and mortality, possibly through effects on blood vessels that resemble the pathophysiology of atherosclerosis.1 2 Antirheumatic treatment aims at diminishing disease activity and thereby probably decreases cardiovascular risk.3 Various antirheumatic drugs may have other favourable and/or unfavourable effects on cardiovascular risk.4,–,13
Because cardiovascular diseases account for a considerable burden of morbidity and mortality in patients with RA, the effect on cardiovascular risk should be considered when choosing a treatment strategy. Hypertension, a risk factor for developing cardiovascular disease, is highly prevalent in patients with RA.14 We analysed the relationship between disease activity and blood pressure (BP) and the effect of four different RA treatment strategies on BP during the first 2 years of treatment.
Patients and methods
The BeSt study is a multicentre randomised clinical trial in disease-modifying antirheumatic drug (DMARD)-naïve patients with active RA (disease duration ≤2 years) comparing four different treatment strategies: sequential monotherapy (group 1, n=126), step-up combination therapy (group 2, n=121), initial combination therapy with prednisone (group 3, n=133) and initial combination therapy with methotrexate and the tumour necrosis factor α (TNFα) inhibitor infliximab (group 4, n=128). Details of the study, including data about the antirheumatic treatment in the four treatment arms, have been published previously (see appendix 1 in online supplement).15 16
Treatment was adjusted based on 3-monthly disease activity score (DAS) measurements (DAS44).17 If a patient had a DAS >2.4, treatment was adjusted according to the predefined protocol for each group. If the DAS was ≤2.4 (low disease activity (LDA)) for at least 6 months, medication was tapered to a maintenance dose. Every 3 months, as part of a vital signs check, single measurements of systolic and diastolic BP (SBP and DBP, respectively) were performed by trained nurses, blind to the treatment allocation. BP was measured according to local clinical standards: in 16 centres a sphygmomanometer plus stethoscope was used and in four centres electronic devices were used. For each patient, the measurement method was the same during the study period. BP readings were performed at least 1 h before or 4 weeks after administration of infliximab (infliximab infusions every 8 weeks). Patients were classified into four DAS categories at each 3-monthly visit: remission (DAS <1.6), LDA (DAS ≥1.6 but ≤2.4), moderate disease activity (MDA, DAS >2.4 but ≤3.7) and high disease activity (HDA, DAS >3.7). Patients with a DAS <1.6 from 6 to 24 months (one DAS ≥1.6 allowed) were classified as ‘continuous remission’. Patients with a DAS >2.4 from 6 to 24 months (one DAS ≤2.4 allowed) were classified as ‘continuous clinical failure’.
The SPSS 16.0 software package was used. Baseline characteristics were analysed using one-way analysis of variance, the Kruskal–Wallis test and the χ2 test. Two different linear mixed model (LMM) analyses were performed for SBP and DBP, all with the unstructured covariance matrix. The first LMM was performed to compare SBP and DBP among the different DAS categories based on all nine BP measurements per patient, corrected for age, gender, body mass index (BMI), the use of antihypertensive medication at baseline and the use of non-steroidal anti-inflammatory drugs (NSAIDs)/cyclo-oxygenase-2 inhibitors (COXIBs) at baseline and during follow-up. Then LMM was used to model SBP and DBP during the first year of follow-up because, from the protocol, it follows that patients who were initially treated with infliximab or prednisone used it for at least 7.5–9 months. SBP and DBP at the four follow-up visits of year 1 were used as outcomes, with time (as factor) and baseline SBP or DBP, randomisation, age, gender, NSAID/COXIB use at baseline and during each follow-up visit, antihypertensive drug use at baseline, δDAS and δBMI (both for each visit compared with baseline) as fixed effects and a random patient effect.
The baseline characteristics of the four treatment groups were comparable.15 Mean (SD) BP (mm Hg) at baseline was high to normal in all groups: 138 (20)/84 (10), 140 (21)/85 (12), 136 (21)/85 (12) and 136 (20)/84 (11) for groups 1–4, respectively. At baseline, mean (SD) DAS was 4.4 (0.9), 34% smoked and mean (SD) BMI was 26 (5) kg/m2. Of all patients, 22% had a medical history of cardiovascular disease, comprising mainly hypertension (31%), peripheral vascular disease (26%) and acute coronary syndrome (19%). In groups 1–4, 14%, 17%, 14% and 7% of patients were on antihypertensive medication at baseline, whereas 87%, 80%, 89% and 87% used NSAIDs or COXIBs. Detailed baseline characteristics and cardiovascular co-medication at baseline are shown in appendix 2 in the online supplement. During the 2 years of the study, 27 patients were lost to follow-up.
Mean DAS improved earlier in patients in treatment groups 3–4 than in groups 1–2. From year 1 onwards, disease activity was comparable and stable in all groups16 (see appendix 3 in online supplement). Patients with LDA (DAS ≤2.4) had, on average, lower SBP and DBP than patients with MDA/HDA (DAS >2.4) (LMM, figure 1), also after correction for age, gender, BMI and the use of antihypertensive medication and NSAIDs/COXIBs at baseline and during follow-up. A similar effect was observed for the mean DBP values.
Figure 2 shows the progression of SBP and DBP in the four treatment groups over time. After correction for the change in DAS from baseline, baseline SBP, age, gender, NSAID/COXIB use at baseline and during follow-up, antihypertensive drug use at baseline and δBMI, longitudinal data analysis of the first year (LMM) showed that initial combination treatment with infliximab was associated with a reduction in SBP of 4.8 mm Hg compared with sequential monotherapy (p=0.001), 3.0 mm Hg compared with step-up combination therapy (p=0.04) and 4.5 mm Hg compared with initial combination treatment with prednisone (p=0.002). Patients in group 4 also had lower DBP than patients in the other groups, although this was less pronounced and partly non-significant (table 1). No statistically significant differences were found between the other treatment groups, with the exception of a decrease in DBP of 2.0 in group 3 compared with group 1 (table 1). Unadjusted LMM results are shown in appendix 4 in the online supplement. Study centre and the use of leflunomide or ciclosporin did not influence the association between treatment and BP and were therefore omitted from the analysis.
In group 4, 22 patients (17%) were classified as ‘continuous clinical remission’ and 11 (9%) as ‘continuous clinical failure’ on infliximab. A comparable decrease in BP was observed in these patients (SBP −6.8 mm Hg, DBP −1.7 mm Hg for patients classified as ‘continuous clinical remission’ and SBP −4.9 mm Hg, DBP −1.0 mm Hg for those classified as ‘continuous clinical failure’). In accordance with the protocol, patients who had a continuous good response on infliximab and those who failed on the highest dose discontinued infliximab. At the end of the 2-year observation period when the average BP appeared to return to the original value, only 18% of patients were still receiving infliximab.
In total, 70 patients in groups 1–3 switched to treatment with methotrexate and infliximab because of DAS >2.4 on prior treatment steps. In these ‘delayed infliximab patients’, SBP decreased on average 2.2 and 4.7 mm Hg after 6 and 12 months, and DBP decreased 1.3 and 3.9 mm Hg after 6 and 12 months. These changes are not statistically different from the changes observed in patients initially treated with methotrexate and infliximab.
This study shows that, in patients with RA, lower disease activity is associated with lower BP. This may represent part of the mechanism by which antirheumatic treatment can reduce the increased cardiovascular morbidity and mortality in RA. It is thought that systemic inflammation in RA leads to vasoconstriction and hypertension through upregulation of the angiotensin II type 1 receptor and of endothelin and downregulation of NO2.14 Effective suppression of inflammation may inhibit this process and, as a consequence, may lower BP.
Intriguingly, we found an additional reduction in SBP (up to almost 5 mm Hg) and to a lesser extent (up to almost 3 mm Hg) in DBP in patients treated with infliximab. Given that patients with RA are at increased risk of developing cardiovascular disease, such decreases in BP could be beneficial.1 14 18 In the LMM, initial treatment with infliximab was associated with a reduction in SBP compared with the other strategies and also after correction for the improvement in disease activity. Decreases in SBP and DBP were observed in patients who received infliximab as initial therapy and in those who received infliximab after failing on previous treatments, although the latter had a less pronounced reduction in disease activity. Lower BP was seen in patients who failed on infliximab as well as in those who responded with continuous remission. These results suggest that treatment with infliximab has a drug-specific effect on BP which is independent of the level of inflammation measured by the DAS. After 2 years the benefit of infliximab on SBP seems to disappear, probably due to discontinuation of infliximab in most patients in accordance with the protocol.
To our knowledge, the effect of TNFα inhibitors on BP has not yet been described. There are, however, observations that anti-TNFα treatment is able to reverse endothelial dysfunction,13 decrease arterial stiffness19 and decrease plasminogen activator inhibitor-1 antigen in patients with RA.20
The BeSt study was not designed to analyse BP changes associated with antirheumatic treatment. The single BP measurements, done without a standardised measurement protocol, may have led to inconsistent BP measurements. Although the possibility of bias cannot be totally excluded, we think it is unlikely since the data collection occurred before the hypothesis was formulated, the nurses who measured BP were blind to treatment allocation and we found that adding the variable study centre to the analyses did not change the results. The use of cardiovascular concomitant medication and of NSAIDs and COXIBs could have interfered with the observed differences between the groups, although we tried to correct for this in the analyses. Ideally, our BP data should be combined with observations on the occurrence of cardiovascular adverse events. However, the BeSt study was not designed or powered to detect possible differences in such events and few have occurred within the first 2 years of the trial.
Being aware of these limitations, the decrease in BP in patients treated with methotrexate and infliximab remains an interesting and probably clinically relevant observation that needs further investigation.
The authors thank all the patients as well as the following rheumatologists (other than the authors) who participated in the Foundation for Applied Rheumatology Research (all locations are in The Netherlands): W M de Beus, MD (Medical Center Haaglanden, The Hague); C Bijkerk, MD (Reinier de Graaf Gasthuis, Delft); M H W de Bois, MD and G Collée, MD (Medical Center Haaglanden, The Hague); J A P M Ewals, MD (Haga Hospital, The Hague); A H Gerards, MD (Vlietland Hospital, Schiedam); B A M Grillet (ZorgSaam Hospital, Terneuzen); J H L M van Groenendael, MD (Franciscus Hospital, Roosendaal); K H Han, MD (Medical Center Rijnmond-Zuid, Rotterdam); J M W Hazes, MD (Erasmus Medical Center, Rotterdam); M H de Jager, MD (Albert Schweitzer Hospital, Dordrecht); J M de Jonge-Bok, MD (Groene Hart Hospital, Gouda); H van der Leeden, MD (retired); W F Lems, MD (Slotervaart Hospital, Amsterdam); M F van Lieshout-Zuidema, MD (Spaarne Hospital, Hoofddorp); A Linssen, MD (retired); P A H M van der Lubbe (Vlietland Hospital, Schiedam); C Mallée, MD (Kennemer Gasthuis, Haarlem); H C van Paassen, MD (Sint Franciscus Gasthuis, Rotterdam); A J Peeters, MD (Reinier de Graaf Gasthuis, Delft); H K Markusse, MD (deceased); H K Ronday (Haga Hospital, the Hague); D van Schaardenburg, MD (VU Medical Center, Amsterdam and Jan van Breemen Institute, Amsterdam); P E H Seys, MD (Lievensberg Hospital, Bergen op Zoom); R M van Soesbergen, MD (retired); P B J de Sonnaville, MD (Oosterschelde Hospital, Goes); K S S Steen, MD (Kennemer Gasthuis, Haarlem); J Ph Terwiel, MD (Spaarne Hospital, Hoofddorp); A E Voskuyl, MD (VU Medical Center, Amsterdam); M L Westedt, MD (Bronovo Hospital, The Hague); S ten Wolde, MD (Kennemer Gasthuis, Haarlem); J M G W Wouters, MD (Sint Franciscus Gasthuis, Rotterdam); D van Zeben, MD (Sint Franciscus Gasthuis, Rotterdam). We would also like to thank all other rheumatologists and trainee rheumatologists who enrolled patients in this study and all research nurses for their contributions.
Funding This study was funded by a grant of the Dutch College of Health Insurances (College Voor Zorgverzekeringen) with additional funding provided by Schering-Plough, B.V. and Centocor, Inc. The authors, not the sponsors, were responsible for the study design, the collection, analyses and interpretation of all data, the writing of this article and the decision to publish.
Ethics approval This study was conducted with the approval from all participating centres of the trial. All patients gave written informed consent before screening and entering the trial.
Provenance and peer review Not commissioned; externally peer reviewed.
Competing interests TWJH, BACD and CFA received speaker fees of less than $10000 per year from different pharmaceutical companies.