JEADV

DOI: 10.1111/jdv.12385

SHORT REPORT

‘Short-term treatment with methotrexate does not affect microvascular endothelial function in patients with psoriasis’ M. Gyldenløve,1,* P. Jensen,1 M.B. Løvendorf,1 C. Zachariae,1 P.R. Hansen,2 L. Skov1 Departments of 1Dermato-Allergology and 2Cardiology, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark *Correspondence: M. Gyldenløve. E-mail: [email protected]

Abstract Background Psoriasis is associated with increased risk of cardiovascular disease (CVD), possibly due to chronic lowgrade systemic inflammation. Systemic anti-inflammatory treatment might reduce the risk of CVD. Objective Our aim was to investigate if short-term treatment with methotrexate influences microvascular endothelial function (MEF), an early surrogate marker of atherosclerosis, in patients with psoriasis. Methods We prospectively studied a hospital cohort of patients with psoriasis. Measurements of MEF were performed with the Endo-PAT2000© device at baseline and after 8–10 weeks of treatment with methotrexate. At the same time points, we recorded anamnestic information, measured body mass index (BMI), waist and hip circumferences and blood pressure, and drew blood samples (lipid profile, HbA1 and hs-CRP). Psoriasis severity was evaluated by psoriasis area and severity index (PASI) and the dermatology life quality index (DLQI). Results A total of 32 patients with psoriasis were included. Median age was 46 (range 18–82) years, and 50% were men. Twenty-seven patients completed the study. After 8–10 weeks, median PASI had decreased significantly by 6.2 (from 9.8 to 3.6), and DLQI had decreased by 7 (from 9 to 2). No significant changes were observed in MEF, expressed by reactive hyperaemia index and augmentation index. Also, we saw no significant changes in BMI, waist–hip ratio, blood pressure and blood samples. Conclusion Short-term treatment with methotrexate did not affect MEF in patients with psoriasis. Further studies are warranted. Received: 8 July 2013; Accepted: 7 January 2014

Conflicts of interest M. Gyldenløve, P. Jensen, M.B. Løvendorf and P.R. Hansen declares no conflict of interest. C. Zachariae has in the last 2 years participated in local and international advisory boards for Jannsen-Cilag, Abbvie, Pfizer and Eli Lilly. L. Skov has received consultancy and/or speaker honoraria from Abbott, Pfizer, MSD, Leo Pharma, and Jannsen-Cilag.

Funding sources This work was supported by grants from LEO Pharma Denmark, Gentofte Hospital, University of Copenhagen, and Aase og Ejner Danielsens Fond.

Introduction Psoriasis is associated with increased risk of cardiovascular disease (CVD), possibly due to higher prevalences of traditional cardiovascular risk factors and shared immunoinflammatory mechanisms.1 As for psoriasis, systemic low-grade inflammation is a central feature of atherogenesis and thereby provides a pathophysiological link between the two diseases. Risk of CVD can be assessed by measuring endothelial dysfunction, which is a pathological state of the endothelium characterized by reduction in endothelial nitric oxide

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bioactivity.2 Endothelial dysfunction is often used as a surrogate marker for atherosclerosis, and some studies have shown impaired endothelial function in patients with moderate to severe psoriasis or psoriatic arthritis.3 Peripheral arterial tonometry (PAT) is a relatively new technique, enabling the non-specialist to measure microvascular function in a noninvasive way. Numerous studies have proven PAT to be a valid measure of endothelial function.4 Accordingly, it has been proposed that endothelial function measured by PAT is correlated with the burden of cardiovascular risk factors and

© 2014 European Academy of Dermatology and Venereology

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is comparable to endothelial function derived from more central arterial pressure measurements.5,6 Epidemiological data suggest that systemic anti-inflammatory therapy might be beneficial in reducing CVD risk among patients with psoriasis.7,8 Methotrexate is a disease-modifying antirheumatic agent, which is widely used in the treatment of psoriasis. In this prospective study, we aimed to investigate if short-term treatment with methotrexate affects the microvascular endothelial function (MEF) in a cohort of patients with psoriasis.

augmentation index (AI) is a measure of arterial stiffness where values provided by the Endo-PAT2000© are normalized to a heart rate of 75 beats per min and given in % of values in an age- and gender-matched control population. Statistical analysis

Materials and methods

Statistical analyses were performed using IBM SPSS Statistics 19.0 (IBM SPSS, Chicago, IL, USA). Data are presented in medians and range or percentages. The Wilcoxon signed rank test was used to compare non-parametric paired continuous variables between groups, and P-values below 0.05 were considered statistically significant.

Patients

Results

A total of 32 consecutive patients were enrolled in the study. The power calculation was based on a minimum relevant difference in reactive hyperaemia index (RHI) of 0.5, 95% power, 0.05 significance level and a standard deviation of 0.71 known from previous studies. Inclusion criteria were plaque psoriasis, age above 18 years and an indication for treatment with methotrexate. Patients were excluded in case of systemic antipsoriatic treatment 1 month prior to inclusion. The ethics committee of the Capital Region of Denmark approved the study (H-4-2010-140) and informed consent was obtained from all participants.

Patient characteristics and results are presented in Table 1. Thirty-two patients were enrolled in the study. At inclusion, median age was 46 (range 18–82) years, and 50% of the patients were men. Mean duration of psoriasis was 15 (range 2–67) years. The prevalence of hypertension, diabetes and hyperlipidaemia was 15.6%, 21.9% and 12.5%, respectively, and 31.3% of the patients were current tobacco smokers. Median BMI was 26.1 (range 18.8–49.5) and median systolic and diastolic blood pressures were 127 (range 95–160) mmHg and 80 (range 50–110) mmHg. Twenty-seven of the 32 patients (84%) completed the study after a median treatment period of 64 (range 49–80) days. Five patients were excluded due to lack of compliance in relation to the examinations (n = 3) or therapy discontinuation (n = 1 had unacceptable side-effects, and n = 1 showed no clinical improvement). No patients were lost to follow-up. Methotrexate was administered orally (n = 19) or subcutaneously (n = 8) in doses of 7.5 mg (n = 2), 10 mg (n = 4) or 15 mg (n = 21) per week. At follow-up, median PASI had decreased significantly by 6.2 (from 9.8 to 3.6, P < 0.001), and median DLQI had decreased by 7 (from 9 to 2, P < 0.001). No significant changes were observed in MEF, expressed by RHI (P = 0.876) and AI (P = 0.786). Also, we saw no significant changes in BMI, waist and hip circumferences and blood pressures throughout the study period. Ten patients reached PASI75, and a subgroup analysis of their data yielded results comparable to the overall analysis.

Measurements

Information about psoriasis duration, genetic predisposition, medical history, current medications, tobacco smoking and alcohol habits was recorded. Physical measurements included resting blood pressure, bodyweight and height. Body mass index (BMI) was calculated, and waist and hip circumferences were measured with a centimetre (cm) tape to the nearest 0.5 cm. Psoriasis severity was evaluated by psoriasis area and severity index (PASI) and the dermatology life quality index (DLQI). In addition, non-fasting blood samples were drawn for analysis of glycosylated glucose (HbA1c), high-sensitivity C-reactive protein (hs-CRP), total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol and triglycerides. All blood analyses were performed at the Department of Clinical Biochemistry at our institution. Measurements of MEF were performed by PAT with the Endo-PAT2000© device (Itamar Medical, Caesarea, Israel) at baseline and after 8–10 weeks of treatment with methotrexate. Hyperaemia was induced by a 5 min left upper arm cuff occlusion, and the pulse amplitude was simultaneously recorded in both index fingers, with the right finger serving as control. The results were automatically derived from a computerized algorithm. RHI is a measure of endothelial function and is defined as the ratio of the pulse wave amplitude after cuff release to the preocclusion baseline pulse wave amplitude, normalized to the concurrent signal from the contra lateral hand.9 The

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Discussion We prospectively investigated the effect of short-term antipsoriatic therapy with methotrexate on MEF, a validated surrogate marker of early atherosclerosis,10 and found no significant improvement after 8–10 weeks of continuous treatment. Also, despite a substantial clinical reduction in the skin symptoms, we saw no significant changes in circulating levels of hs-CRP, which is a well-established risk marker for CVD.11 Only two small clinical studies have previously addressed the effect of systemic anti-inflammatory treatment on endothelial function in psoriasis patients. Boehncke et al. performed venous

© 2014 European Academy of Dermatology and Venereology

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Table 1 Patient characteristics and MEF measured by PAT Baseline n = 32

Weeks 8–10 n = 27

P-value

Demographics Age, year Men, % Duration of psoriasis, year

46 (18–82) 50.0 15 (2–67)

Current smoking, %

31.3

Hypertension, %

15.6

Hyperlipidaemia, %

12.5

Diabetes, %

21.9

Prior CVD, %

3.1

PASI

9.8 (3.6–21.8)

DLQI

3.6 (0.0–11.1)

'Short-term treatment with methotrexate does not affect microvascular endothelial function in patients with psoriasis'.

Psoriasis is associated with increased risk of cardiovascular disease (CVD), possibly due to chronic low-grade systemic inflammation. Systemic anti-in...
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