Sex-differential downregulation of methotrexate on plasma viscosity and whole blood viscosity in psoriasis

Abstract

BACKGROUND:

Psoriasis is associated with an increased risk for cardiovascular disease (CVD). Methotrexate (MTX) is often used as a first-line system therapy and there is a need to determine its effect on whole blood viscosity (WBV) and plasma viscosity (PV) in psoriasis.

METHODS

A prospective, single-center, interventional study with a total of 111 psoriatic patients who received MTX therapy from October 22, 2018, to December 28, 2019, and 111 age- and sex-matched healthy controls. Changes in WBV, PV, blood counts, liver and renal function were evaluated.

RESULTS

Psoriatic patients had significantly higher levels of WBV and relative viscosity (RV) at low shear rate (LSR), erythrocyte aggregation index (EAI), and PV than sex and age-matched healthy controls. PV was positively correlated with erythrocyte sedimentation rate (ESR), ESR was positively correlated with high sensitive C-reactive protein (hCRP). But only hCRP was positively associated with psoriasis area severity index (PASI) score. MTX significantly decreased the levels of PV, ESR, hCRP, and blood pressure (BP) in male patients, and the level of WBV in female patients.

CONCLUSION:

Sex-specific downregulation of MTX on WBV, PV, hCRP, and BP, indicating that the effect of MTX on the risk of cardiovascular disease was related with sex.

Keywords

Methotrexate psoriasis whole blood viscosity plasma viscosity erythrocyte aggregation index

1 Introduction

Psoriasis is an immune-mediated chronic, systemic, and inflammatory disease affecting approximately 2–4% of the population [1]. Psoriasis has been linked to an increased prevalence of cardiovascular risk factors, including atherosclerosis, hypertension, diabetes mellitus, dyslipidemia, obesity, and metabolic syndrome [2]. Methotrexate (MTX) has been uses as an economical and effective first-line treatment for moderate to severe psoriasis for more than 50 years. MTX use is associated with a reduced risk of cardiovascular disease (CVD) events in patients with chronic inflammation [3, 4].

Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Treatment with cankinumab, a monoclonal antibody that inhibits inflammation by neutrolizing interleukin-1β, resulted in a lower rate of cardiovascular events than placebo in a previous randomized trial [5]. However, among patients with stable atherosclerosis, low-dose methotrexate did not reduce levels of IL-1β, IL-6, or C-reactive protein (CRP) and did not result in fewer cardiovascular events than placebo [6]. It has been previously reported that downstream biomarkers of inflammation such as high-sensitivity CRP (hs-CRP) and IL-6 are associated with an increased risk of cardiovascular events, independent of the cholesterol level [7].

There are some more big epidemiological studies which show that the blood fluidity or plasma viscosity or hematocrit are risk factors for cardiovascular events [8 –11]. That hematocrit and plasma are the main determinants of blood viscosity [12]. There is increasing evidence that blood viscosity and its major determinants (hematocrit and plasma viscosity) are associated with increased risks of CVD and premature mortality [13]. However, it has never been reported the effect of MTX on blood viscosity. In this prospective MTX cohort, we observe the difference of whole blood viscosity (WBV) and plasma viscosity (PV) between psoriasis and sex and age-matched healthy controls, and the effect of MTX on WBV and PV. In addition, we also investigate the influencing factor of WBV and PV, and their association with other inflammatory markers erythrocyte sedimentation rate (ESR) and high sensitive C-reactive protein (hCRP) in a multiple regression analysis.

2 Methods

2.1 Study population and study design

This single-center, prospective, single-arm, interventional study was performed at the Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China, from October 22, 2018, to December 28, 2019. A total of 111 psoriatic patients who received MTX therapy without any systemic or topical treatment and 111 age- and sex-matched healthy controls were recruited. The Medical Ethics Committee of Huashan Hospital, Fudan University, reviewed and approved the protocol, and all patients provided written informed consent (MTX201501).

2.2 Treatment

The initial oral MTX dosage was 10–15 mg once weekly. The dosage was increased by 2.5 mg every 4 weeks to a maximum of 15 mg weekly depending on the patient’s clinical response and adverse effects and the results of routine hematological and blood chemistry tests. If liver enzymes were elevated more than 2-fold and less than 3-fold, the MTX dose was reduced by 2.5 mg weekly and administered once 2 to 4 weeks later. If the increases in liver enzyme levels were more than 3-fold, MTX treatment was stopped.

2.3 Effectiveness and assessments

Two certified dermatologists graded the severity and extent of psoriasis using the psoriasis area severity index (PASI) and body surface area (BSA) scores. WBV at low shear rate (LSR) of 1^–s and 5^–s and HSR of 30^–s and 200^–s, relative viscosity (RV) at LSR and HSR, erythrocyte aggregation index (EAI), and plasma viscosity (PV) was tested by SA9000 from Beijing Succeeder Technology, Inc., Beijing, China, Biochemical parameters were measured using conventional laboratory techniques. Complete blood cell counts, the erythrocyte sedimentation rate (ESR), high-sensitivity C-reactive protein (hCRP), height, weight, systolic and diastolic blood pressure were measured at baseline and week 12 of MTX treatment.

2.4 Statistical analysis

Data are expressed as the means±standard deviations (SDs). Statistical analyses were performed using the Mann-Whitney test, unpaired t test, unpaired t test with Welch correction, paired t test, univariate analysis, stepwise multiple analysis with adjustment for confounding factors, χ² test, or Fisher exact test, as appropriate. Stepwise multiple regression analysis was performed after adjustment for sex, age, age at disease onset, disease duration, height, weight, body mass index (BMI), systolic and diastolic blood pressure, smoking, alcohol consumption, ESR, PASI at baseline, waistline and hipline. Data analyses were performed using GraphPad Prism version 5 (GraphPad Software Inc) and SPSS ver. 23.0 software (SPSS Inc., Chicago, IL, USA). P < 0.05 or P < 0.025 was considered to be statistically significant.

3 Results

3.1 The difference in basic characteristics and biochemical parameters between male and female psoriatic patients

Basic characteristics and biochemical parameters of male and female psoriatic patients are summarized in Table 1. In total, 111 patients (73 men and 38 women) who received oral MTX completed the 12-week study. Men had significantly higher mean values in height (p < 0.0001), weight (p = 0.0001), waistline (p = 0.008), cumulative dose of MTX (p < 0.0001), hematocrit (HCT, p < 0.0001), hemoglobin (HGB, p < 0.0001), mean corpuscular hemoglobin concentration (MCHC, p < 0.05), red blood cell (RBC, p < 0.0001), and higher percentages of smoking (p < 0.0001) and alcohol consumption (p = 0.0004), lower mean values in ESR (p = 0.008), and platelets count (p = 0.0051) than women.

Table 1
Basic characteristics of male and female psoriatic patients

Characteristic Male (n = 73) Female (n = 38) p-value

Age, mean (SD), y 46.38 (15.49) 47.50 (15.71) 0.72

Age at disease onset, mean (SD), y 33.58 (14.80) 31.83 (19.34) 0.60

Disease duration, mean (SD), y 12.80 (9.79) 15.67 (11.27) 0.17

Height, mean (SD), m 1.72 (.07) 1.59 (.06) < 0.0001

Weight, mean (SD), kg 74.05 (11.44) 64.24 (11.71) 0.0001

BMI 25.09 (3.01) 25.26 (3.82) 0.81

PASI score at baseline, mean (SD) 14.78 (7.88) 12.82 (5.40) 0.17

BSA score at baseline, mean (SD) 24.81(2.78) 24.57 (2.81) 0.95

Waistline, mean (SD), cm 90.64±9.35 84.81±11.63 0.008

Hipline, mean (SD), cm 98.18±7.89 96.92±9.41 0.48

Hypertension, n (%) 22 (30.14) 9 (23.68) 0.51

Diabetes, n (%) 11 (15.07) 10 (26.32) 0.20

Smoking, n (%) 33 (45.21) 1 (2.63) < 0.0001

Alcohol, n (%) 34 (46.57) 5 (13.16) 0.0004

Cumulative dose of MTX, mean (SD), mg 147.9 (13.78) 135.8 (16.67) < 0.0001

Arthritis, n (%) 33 (45.21) 15 (39.47) 0.69

ESR, mean (SD), mm/60 min 10.46 (10.96) 14.86 (11.25) 0.008

hCRP, mean (SD), mg/L 3.11 (3.14) 2.95 (3.11) 0.80

HCT, % 46.29 (3.39) 41.41 (2.88) < 0.0001

HGB level, g/dL 156.4 (12.58) 138.3 (10.40) < 0.0001

MCHC, g/L 338.0 (10.23) 333.9 (8.02) 0.0354

RBC count,×10⁶/μl 5.12 (0.47) 4.61 (0.39) < 0.0001

Platelet count,×10³/μl 229.9 (53.18) 264.2 (71.22) 0.0051

Characteristic	Male (n = 73)	Female (n = 38)	p-value
Age, mean (SD), y	46.38 (15.49)	47.50 (15.71)	0.72
Age at disease onset, mean (SD), y	33.58 (14.80)	31.83 (19.34)	0.60
Disease duration, mean (SD), y	12.80 (9.79)	15.67 (11.27)	0.17
Height, mean (SD), m	1.72 (.07)	1.59 (.06)	< 0.0001
Weight, mean (SD), kg	74.05 (11.44)	64.24 (11.71)	0.0001
BMI	25.09 (3.01)	25.26 (3.82)	0.81
PASI score at baseline, mean (SD)	14.78 (7.88)	12.82 (5.40)	0.17
BSA score at baseline, mean (SD)	24.81(2.78)	24.57 (2.81)	0.95
Waistline, mean (SD), cm	90.64±9.35	84.81±11.63	0.008
Hipline, mean (SD), cm	98.18±7.89	96.92±9.41	0.48
Hypertension, n (%)	22 (30.14)	9 (23.68)	0.51
Diabetes, n (%)	11 (15.07)	10 (26.32)	0.20
Smoking, n (%)	33 (45.21)	1 (2.63)	< 0.0001
Alcohol, n (%)	34 (46.57)	5 (13.16)	0.0004
Cumulative dose of MTX, mean (SD), mg	147.9 (13.78)	135.8 (16.67)	< 0.0001
Arthritis, n (%)	33 (45.21)	15 (39.47)	0.69
ESR, mean (SD), mm/60 min	10.46 (10.96)	14.86 (11.25)	0.008
hCRP, mean (SD), mg/L	3.11 (3.14)	2.95 (3.11)	0.80
HCT, %	46.29 (3.39)	41.41 (2.88)	< 0.0001
HGB level, g/dL	156.4 (12.58)	138.3 (10.40)	< 0.0001
MCHC, g/L	338.0 (10.23)	333.9 (8.02)	0.0354
RBC count,×10⁶/μl	5.12 (0.47)	4.61 (0.39)	< 0.0001
Platelet count,×10³/μl	229.9 (53.18)	264.2 (71.22)	0.0051

Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); BSA, body surface area; ESR, erythrocyte sedimentation rate; hCRP, high-sensitive C-reactive protein; HCT, hematocrit; HGB, hemoglobin; MCHC, mean corpuscular hemoglobin concentration; PASI, Psoriasis Area Severity Index; RBC, red blood cell. Mann-Whitney test, unpaired t test, unpaired t test with Welch correction, or Fisher exact test were used, as appropriate. P < 0.05 was considered to be statistically significant.

3.2 Increased whole blood viscosity and relative viscosity at low shear rate, erythrocyte aggregation index, and plasma viscosity in psoriasis

Table 2 showed psoriatic patients had significantly higher WBV at 1 S^–1(p < 0.0001) and 5S^–1(p < 0.01), RV at LSR (p < 0.01), EAI (p < 0.0001), and PV (p < 0.01), compared to sex- and age- matched healthy controls. Moreover, men had significantly higher WBV at 1 S^–1(p < 0.001), 5S^–1(p < 0.0001), 30S^–1 (p < 0.0001), 200S^–1(p < 0.0001), RV at LSR (p < 0.001), and RV at HSR (p < 0.0001) than women. Furthermore, female patients with psoriasis had significantly higher EAI than male patients (p < 0.05).

Table 2
The difference in whole blood viscosity, erythrocyte aggregation index, and plasma viscosity between psoriatic patients and sex- and age-matched healthy controls

Male Female

HC (n = 73) PS (n = 73,0W) p-value (HC vs PS) HC (n = 38) PS (n = 38) p-value (HC vs PS) p-value (HC:M vs F) p-value (PS:M vs F)

WBV at 1 s^–1 (mPas) 19.37(1.44) 20.91(2.14) < 0.0001 17.11(1.51) 19.27(2.14) < 0.0001 < 0.0001 0.0002

WBV at 5 s^–1 (mPas) 9.13(0.66) 9.50(0.98) 0.008 8.00(0.63) 8.67(0.90) 0.0003 < 0.0001 < 0.0001

WBV at 30s^–1(mPas) 5.57(0.45) 5.64(0.61) 0.456 4.85(0.36) 5.08(0.52) 0.03 < 0.0001 < 0.0001

WBV at 200 s^–1(mPas) 4.34(0.39) 4.32(0.49) 0.86 3.75(0.29) 3.85(0.40) 0.24 < 0.0001 < 0.0001

RV at LSR 14.45(1.17) 15.17(1.73) 0.004 12.76(1.11) 13.92(1.64) 0.0006 < 0.0001 0.0004

RV at HSR 3.24(0.30) 3.14(0.39) 0.09 2.80(0.21) 2.78(0.29) 0.72 < 0.0001 < 0.0001

EAI 4.48(0.34) 4.85(0.36) < 0.0001 4.57(0.27) 5.02(0.30) < 0.0001 0.2 0.02

PV (mPas) 1.34(0.05) 1.38(0.11) 0.003 1.34(0.06) 1.39(0.08) 0.005 0.98 0.86

	Male	Female
WBV at 1 s^–1 (mPas)	19.37(1.44)	20.91(2.14)	< 0.0001	17.11(1.51)	19.27(2.14)	< 0.0001	< 0.0001	0.0002
WBV at 5 s^–1 (mPas)	9.13(0.66)	9.50(0.98)	0.008	8.00(0.63)	8.67(0.90)	0.0003	< 0.0001	< 0.0001
WBV at 30s^–1(mPas)	5.57(0.45)	5.64(0.61)	0.456	4.85(0.36)	5.08(0.52)	0.03	< 0.0001	< 0.0001
WBV at 200 s^–1(mPas)	4.34(0.39)	4.32(0.49)	0.86	3.75(0.29)	3.85(0.40)	0.24	< 0.0001	< 0.0001
RV at LSR	14.45(1.17)	15.17(1.73)	0.004	12.76(1.11)	13.92(1.64)	0.0006	< 0.0001	0.0004
RV at HSR	3.24(0.30)	3.14(0.39)	0.09	2.80(0.21)	2.78(0.29)	0.72	< 0.0001	< 0.0001
EAI	4.48(0.34)	4.85(0.36)	< 0.0001	4.57(0.27)	5.02(0.30)	< 0.0001	0.2	0.02
PV (mPas)	1.34(0.05)	1.38(0.11)	0.003	1.34(0.06)	1.39(0.08)	0.005	0.98	0.86

Abbreviation: EAI, erythrocyte aggregation index; HC, healthy control; HSR, high shear rate; LSR, low shear rate; PS: psoriasis; PV, plasma viscosity. RV, relative viscosity; WBV; whole blood viscosity. Mann-Whitney test, unpaired t test, unpaired t test with Welch correction, or paired t test were used, as appropriate. P < 0.025 was considered to be statistically significant.

3.3 Sex-differential downregulation of MTX on plasma viscosity and whole blood viscosity

Table 3 summarized the effect of MTX on WBV, RV, EAI, and PV. MTX significantly downregulated the level of PV in male patients with psoriasis (p < 0.001), and the levels of WBV at 1 S^–1(p < 0.001), 5S^–1(p < 0.001), 30S^–1 (p < 0.01), 200S^–1(p < 0.05), RV at LSR (p < 0.01), and EAI (p < 0.05) in female patients with psoriasis.

Table 3
The effect of methotrexate on whole blood viscosity, erythrocyte aggregation index, and plasma viscosity

Male Female

PS (n = 73,0W) PS (n = 73,12W) p-value (0W vs 12W) PS (n = 38, 0W) PS (n = 38,12W) p-value (0W vs 12W)

WBV at 1 s^–1 (mPas) 20.91(2.14) 20.41(2.06) 0.06 19.27(2.14) 18.08(1.78) 0.0003

WBV at 5 s^–1(mPas) 9.50(0.98) 9.32(0.89) 0.12 8.67(0.90) 8.25(0.68) 0.0007

WBV at 30s^–1 (mPas) 5.64(0.61) 5.53(0.54) 0.13 5.08(0.52) 4.89(0.36) 0.008

WBV at 200 s^–1 (mPas) 4.32(0.49) 4.23(0.44) 0.08 3.85(0.40) 3.74(0.27) 0.04

RV at LSR 15.17(1.73) 15.28(1.61) 0.61 13.92(1.64) 13.15(1.33) 0.002

RV at HSR 3.14(0.39) 3.16(0.33) 0.58 2.78(0.29) 2.72(0.22) 0.18

EAI 4.85(0.36) 4.84(0.35) 0.81 5.02(0.30) 4.84(0.31) 0.01

PV (mPas) 1.38(0.11) 1.34(0.06) 0.0003 1.39(0.08) 1.38(0.06) 0.48

	Male	Female
WBV at 1 s^–1 (mPas)	20.91(2.14)	20.41(2.06)	0.06	19.27(2.14)	18.08(1.78)	0.0003
WBV at 5 s^–1(mPas)	9.50(0.98)	9.32(0.89)	0.12	8.67(0.90)	8.25(0.68)	0.0007
WBV at 30s^–1 (mPas)	5.64(0.61)	5.53(0.54)	0.13	5.08(0.52)	4.89(0.36)	0.008
WBV at 200 s^–1 (mPas)	4.32(0.49)	4.23(0.44)	0.08	3.85(0.40)	3.74(0.27)	0.04
RV at LSR	15.17(1.73)	15.28(1.61)	0.61	13.92(1.64)	13.15(1.33)	0.002
RV at HSR	3.14(0.39)	3.16(0.33)	0.58	2.78(0.29)	2.72(0.22)	0.18
EAI	4.85(0.36)	4.84(0.35)	0.81	5.02(0.30)	4.84(0.31)	0.01
PV (mPas)	1.38(0.11)	1.34(0.06)	0.0003	1.39(0.08)	1.38(0.06)	0.48

As shown in Table 5, MTX significantly decreased the levels of ESR (p < 0.05), hCRP (p < 0.05), systolic blood pressure (p < 0.01), and diastolic blood pressure (p < 0.01) in male patients with psoriasis, not in female patients.

Table 5

Multivariate analysis of whole blood viscosity, plasma viscosity, and inflammatory markers

		Univariate analysis			Stepwise regression analysis
	Predictors	p-value	B	95% CI for B	p-value	B	95% CI for B
WBV (1 s^–1)	HGB	0.000	0.109	(0.087–0.131)	0.000	0.115	(0.092–0.137)
	BMI	0.040	0.138	(0.006–0.269)	0.001	0.321	(0.151–0.491)
	Waistline	0.037	0.044	(0.003–0.086)	0.018	–0.066	(–0.120– –0.012)
WBV (5 s^–1)	Height	0.000	4.256	(2.163–6.350)	0.028	–2.389	(–4.512– –0.267)
	Weight	0.000	0.031	(0.016–0.046)	0.001	0.022	(0.009–0.036)
	HCT	0.000	0.198	(0.166–0.231)	0.000	0.193	(0.155–0.231)
WBV(30 s^–1)	Weight	0.000	0.02	(0.011–0.030)	0.006	0.009	(0.003–0.015)
	HCT	0.000	0.131	(0.112–0.149)	0.000	0.115	(0.096–0.135)
WBV (200 s^–1)	Weight	0.000	0.016	(0.008–0.023)	0.012	0.006	(0.001–0.011)
	HCT	0.000	0.106	(0.092–0.121)	0.000	0.095	(0.080–0.110)
RV at LSR	HGB	0.000	0.077	(0.059–0.096)	0.000	0.073	(0.052–0.093)
	RDW-SD	0.000	–0.204	(–0.313–0.095)	0.015	–0.123	(–0.221– –0.025)
RV at HSR	HCT	0.000	0.074	(0.061–0.087)	0.000	0.073	(0.059–0.086)
EAI	HCT	0.003	–0.025	(–0.042– –0.009)	0.001	–0.029	(–0.046– –0.012)
	RDW-CV	0.044	–0.105	(–0.207– –0.003)	0.006	–0.145	(–0.247– –0.043)
PV	ESR	0.000	0.004	(0.002–0.005)	0.000	0.004	(0.002–0.006)
ESR	Age at disease onset	0.004	0.178	(0.057–0.298)	0.018	0.12	(0.021–0.220)
	HGB	0.001	–0.23	(–0.362– –0.098)	0.000	–0.211	(–0.325– –0.096)
	hCRP	0.000	1.288	(0.677–1.899)	0.002	0.885	(0.335–1.435)
	PV	0.000	46.267	(26.151–66.382)	0.000	36.943	(19.509–54.377)
hCRP	PASI score at baseline	0.001	0.146	(0.065–0.227)	0.023	0.091	(0.013–0.169)
	Monocyte (%)	0.005	0.503	(0.156–0.850)	0.009	0.423	(0.108–0.739)
	WBC	0.001	0.506	(0.209–0.804)	0.014	0.359	(0.073–0.645)
	ESR	0.000	0.11	(0.058–0.162)	0.004	0.074	(0.024–0.124)

Abbreviation: BMI, body mass index; ESR, erythrocyte sedimentation rate; hCRP, high-sensitive C-reactive protein; HCT, hematocrit; HGB, hemoglobin; HSR, high shear rate; LSR, low shear rate; PASI, Psoriasis Area Severity Index; PV, plasma viscosity; RDW-CV, Red cell distribution width-variable coefficient; RDW-SD, red cell distribution width-standard deviation; WBC, white blood cell; WBV, whole blood viscosity. Stepwise regression analysis was performed after adjustment for sex, age, age at disease onset, disease duration, arthritis, PASI, height, weight, BMI, waistline, hipline, waistline-hipline ratio, systolic pressure, diastolic pressure, diabetes, smoking, alcohol, and blood routine parameters. P < 0.05 was considered to be statistically significant.

3.4 Multivariate analysis of plasma viscosity and whole blood viscosity and inflammatory markers

As shown in Table 4, stepwise regression analysis demonstrated that WBV at 1S^–1 was positively correlated with HGB (p = 0.000), BMI (p = 0.001), and negatively related with waistline (p < 0.05). WBV at 5S^–1 was positively correlated with HCT (p = 0.000), weight (p = 0.001), and negatively associated with height (p < 0.05). WBV at 30S^–1 and 200S^–1 were positively correlated with HCT (p = 0.000), and weight (p < 0.05). RV at LSR was positively related with HGB (p = 0.000), and negatively associated with RDW-SD (p < 0.05). RV at HSR was positively correlated with HCT (p = 0.000). EAI was positively associated with HCT (p = 0.001), and negatively related with RDW-CV (p = 0.006). PV was positively associated with ESR (p = 0.000). ESR was positively correlated with age at disease onset (p < 0.05), hCRP (p = 0.002), PV (p = 0.000), and negatively associated with HGB (p = 0.000). hCRP was positively correlated with PASI score at baseline (p < 0.05), ESR (p = 0.004), WBC count (p < 0.05), and the percentage of monocytes (p = 0.009).

Table 4
The differential effect of MTX on ESR, hCRP, and blood pressure

Characteristic Male (0W) Male (12W) p-value Female (0W) Female (12W) p-value

ESR 9.63 (9.88) 7.63 (6.88) 0.0385 14.86 (11.25) 14.41 (12.65) 0.3977

hCRP 3.11 (3.15) 2.23 (2.96) 0.0114 2.95 (3.11) 2.52 (2.80) 0.2145

Systolic blood pressure 133.2 (14.79) 127.8 (16.86) 0.0014 128.2 (21.75) 123.7 (21.34) 0.1578

Diastolic blood pressure 87.02 (9.76) 83.26 (10.22) 0.005 81.70 (12.23) 79.52 (9.61) 0.1558

Characteristic	Male (0W)	Male (12W)	p-value	Female (0W)	Female (12W)	p-value
ESR	9.63 (9.88)	7.63 (6.88)	0.0385	14.86 (11.25)	14.41 (12.65)	0.3977
hCRP	3.11 (3.15)	2.23 (2.96)	0.0114	2.95 (3.11)	2.52 (2.80)	0.2145
Systolic blood pressure	133.2 (14.79)	127.8 (16.86)	0.0014	128.2 (21.75)	123.7 (21.34)	0.1578
Diastolic blood pressure	87.02 (9.76)	83.26 (10.22)	0.005	81.70 (12.23)	79.52 (9.61)	0.1558

Abbreviation: BMI, body mass index; ESR, erythrocyte sedimentation rate; hCRP, high sensitive C-reactive protein. Paired t test were used. P < 0.05 was considered to be statistically significant.

4 Discussion

Our study demonstrated that psoriatic patients had significantly higher levels of WBV at LSR, RV at LSR, EAI, and PV compared to sex- and age- matched healthy controls. Moreover, the levels of WBV and RV were significantly higher in men than in women, which is in accordance with previous report that WBV was significantly lower in women than in men at all shear rates [14]. However, the association between sex and WBV was lost after adjustment for blood routine parameters. Therefore, sex difference in WBV is attributed to partly higher weight, HCT and HGB in men, which were positively associated with WBV and RV. Our results are in accordance with previous report that the WBV of psoriatic patients was higher than that of healthy controls [15, 16]. EAI and ESR were negatively associated with HCT and HGB, respectively. Was the hematocrit standardized before the measurement of erythrocyte aggregation? EAI clearly depends from the hematocrit [17, 18]. Therefore, female patients with psoriasis had significantly higher levels of EAI and ESR than male patients. There is a strong correlation between elevated EAI and inflammation [19, 20]. Moreover, increased WBV at LSR was associated with acute myocardial infarction [21]. Significantly increased low shear rate viscosity, blood elastic modulus, and EAI have also been reported in adults following cardiac surgery [22]. This indicates psoriasis itself is an independent risk factor for increased WBV and RV at LSR, PV, and EAI, which are a result of systemic inflammation.

The effect of MTX on the decrease in the risk of cardiovascular disease was controversial. One meta-analysis showed that use of MTX predicted a reduction of 20% in the risk of cardiovascular events [23]. However, another study found that there was no effect of MTX on the levels of HDL, LDL, TG, TC, IL-1β, IL-6 and CRP. Low-dose MTX did not result in fewer cardiovascular events among patients with stable atherosclerosis than placebo. But this study did not stratify the patients by sex [6]. Our study found MTX significantly decreased the levels of PV, ESR, hCRP, systolic blood pressure, and diastolic blood pressure in male patients with psoriasis, and the levels of WBV and RV at LSR in female patients. This is the first time to report the effect of MTX on WBV, PV, ESR, hCRP, and blood pressure was related with sex. The mechanism remains to be further elucidated.

PV is a specific measure of plasma protein changes, is independent of red cell changes and smoking, and shows little variation with demographic factors. However, ESR is influenced not only by plasma protein changes, but also by HCT, red cell deformability and aggregation, to a greater degree by demographic factors. Multiple regression analysis demonstrated that ESR was important determinants of PV, which was positively correlated with PV, hCRP, age at disease onset, but negatively associated with HGB. hCRP was positively related with disease severity PASI score, ESR, WBC count, and the percentage of monocytes. The sensitivity and specificity of PV are better than that of ESR or CRP in rheumatoid arthritis (RA) [24]. Our data demonstrated that increased PV in psoriasis was not correlated with disease severity. Only hCRP level was positively associated with PASI score, which is concordant with the weak correlation between CRP and PASI score was observed in Japanese patients with psoriasis vulgaris [25]. Increasing evidence demonstrated that CRP may be considered as a useful marker of psoriasis severity that could be used to monitor psoriasis and its treatment. Elevated levels of CRP may be an independent risk factor for cardiovascular diseases (CVD) in patients with psoriasis [26]. Therefore, hCRP has been shown to be superior to ESR and PV in the monitoring of disease severity in psoriasis.

Our study demonstrated that the increased risk of CVD in psoriasis might be related to the increased WBV and PV, which is in accordance with previous report that increased WBV and PV were statistically associated with incident cardiovascular events in a large random sample of the general population [27]. Mechanistically, the presence of common inflammatory pathways, secretion of adipokines, insulin resistance, angiogenesis, oxidative stress, microparticles, and hypercoagulability may explain the association between psoriasis and cardiometabolic disorders [28]. The reduce of MTX on PV in male psoriatic patients and WBV in female psoriatic patients might be one reason for MTX decreasing the risk of CVD in patients with psoriasis [29]. MTX significantly decrease the levels of systolic and diastolic blood pressure in male psoriatic patients, which might be associated with higher cumulative MTX dosage in male patients than female patients, and have stronger anti-inflammation action. RA patients on MTX treatment had significantly lower clinic and 24-hour peripheral and central blood pressure compared to those who did not take MTX [30]. This indicates MTX may confer a protective effect against stiffness mediated increases in blood pressure in patients with RA [31]. The effect of MTX on blood pressure might account for the reduced cardiovascular risk with MTX.

In conclusion, rheological parameters might also influence clot formation [32]. Increased WBV and RV at LSR in patients with psoriasis is a crucial reason for increasing the risk of CVD. MTX significantly reduced WBV in female psoriatic patients, and PV in male psoriatic patients. This indicates the effect of MTX on the risk of CVD in psoriasis might exist sex difference, which deserves further study.

Funding

This research was supported by the National Natural Science Foundation of China (Nos. 81773322, 82173420, 81673054, 81673073, 81974471), the Key Project in Basic Research Advocated by Shanghai Science and Technology Commission (13JC1402300), and Clinical Research Plan of SHDC (Nos. SHDC2020CR6022 and SHDC2020CR1014B).

IRB approval status

Reviewed and approved by Huashan Hospital, Fudan University institutional review board; approval #MTX201501.

Conflicts of interest

The authors have no conflicts of interest to declare.

Footnotes

Acknowledgments

We thank statistician Jianfeng Luo for guidance with statistics in this study.

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	Male			Female
	HC (n = 73)	PS (n = 73,0W)	p-value (HC vs PS)	HC (n = 38)	PS (n = 38)	p-value (HC vs PS)	p-value (HC:M vs F)	p-value (PS:M vs F)
WBV at 1 s^–1 (mPas)	19.37(1.44)	20.91(2.14)	< 0.0001	17.11(1.51)	19.27(2.14)	< 0.0001	< 0.0001	0.0002
WBV at 5 s^–1 (mPas)	9.13(0.66)	9.50(0.98)	0.008	8.00(0.63)	8.67(0.90)	0.0003	< 0.0001	< 0.0001
WBV at 30s^–1(mPas)	5.57(0.45)	5.64(0.61)	0.456	4.85(0.36)	5.08(0.52)	0.03	< 0.0001	< 0.0001
WBV at 200 s^–1(mPas)	4.34(0.39)	4.32(0.49)	0.86	3.75(0.29)	3.85(0.40)	0.24	< 0.0001	< 0.0001
RV at LSR	14.45(1.17)	15.17(1.73)	0.004	12.76(1.11)	13.92(1.64)	0.0006	< 0.0001	0.0004
RV at HSR	3.24(0.30)	3.14(0.39)	0.09	2.80(0.21)	2.78(0.29)	0.72	< 0.0001	< 0.0001
EAI	4.48(0.34)	4.85(0.36)	< 0.0001	4.57(0.27)	5.02(0.30)	< 0.0001	0.2	0.02
PV (mPas)	1.34(0.05)	1.38(0.11)	0.003	1.34(0.06)	1.39(0.08)	0.005	0.98	0.86