Treating adult patients of severe psoriasis with methotrexate leads to reduction in biomarkers of atherosclerosis: A prospective study

Abstract

Background

Psoriasis is a common skin disorder; affecting 0.4–2% of general population and is associated with increased risk of cardiovascular diseases. We conducted this prospective study to determine change in biomarkers of atherosclerosis in plaque psoriasis in patients treated with methotrexate.

Methods

The study was carried out at a tertiary care centre over a period of 1 year after institutional ethical clearance. The study included 50 patients. Adults with severe psoriasis not receiving any systemic treatment for last 3 months were included in the study. Clinical parameters including psoriasis area and severity index (PASI), dermatology quality of life index (DLQI) and estimation of IL-6, hsCRP, and HDL levels and LDL: HDL ratio were done at baseline and at 12 weeks.

Results

A total of 50 patients were included and 42 completed the study. The mean age and mean duration of disease was 44.4 (±13.2) years and 10.8 (±9.9) years, respectively. Pre- and post-treatment mean PASI was 16.3 (±8.3) and 7.43 (±4.9), respectively (p = 0.001). The level of VEGF, IL-6, and hsCRP was 127 (±158) pg/ml, 5.3 (±2.5) pg/ml, and 4.2 (±4.1) mg/L, respectively. The levels of VEGF, IL-6, and hsCRP after 12 weeks of treatment were found to be 59.3 (±61) pg/ml (p=0.006), 3.6 (±2.1) pg/ml (p < 0.001), and 2.6 (±3.1) mg/L (p = 0.012), respectively.

Conclusion

Methotrexate use in patients with chronic plaque psoriasis reduces the level of biomarkers of atherosclerosis at 12 weeks. Early treatment with methotrexate may help in reduction of cardiovascular risk in psoriasis patients.

Introduction

Psoriasis is a T cell-mediated disorder of uncertain aetiology affecting skin, nails, and joints primarily. The prevalence in different countries varies from 0.7% in China to 4.6% in United States; it affects 0.44–2.2% of Indians.¹ It occurs in genetically predisposed individuals due to environmental triggers such as drugs, infections, or stress.² Psoriasis is now considered a multisystem inflammatory disorder associated with comorbidities such as metabolic syndrome (MetS), coronary artery disease (CAD), obesity, diabetes mellitus, hypertension, non-alcoholic fatty liver disease (NAFLD), inflammatory bowel disease (IBD), and depression. Other comorbidities that are being explored are nephropathy, chronic obstructive pulmonary disease, obstructive sleep apnoea, erectile dysfunction, and dementia. The “psoriatic march” is a relatively new concept suggesting that the chronic inflammation in psoriasis drives the cardiovascular morbidity.³ It is associated with increased risk and severity of atherosclerosis and is not entirely explained by high prevalence of traditional cardiovascular risk factors such as obesity, hypertension, smoking, and depression. The impact of severe psoriasis on cardiovascular mortality is similar to diabetes⁴ and is now considered an independent risk factor for cardiovascular disease. The exact mechanism of atherosclerosis in psoriasis is not known; however, it may be due to state of chronic inflammation. The cytokines involved in psoriasis pathogenesis are IL12 and IL23 secreted by myeloid dendritic cells, tumour necrosis factor α (TNFα), and interferon gamma (IFNγ) secreted by Th1 cells and IL17 and IL22 secreted by Th17 cells.⁵ In atherosclerosis, Th1 cytokines promote growth of atherosclerotic plaque, while Th17 cytokines promote angiogenesis and result in intraplaque haemorrhage.⁶ Atherosclerosis is a chronic vascular inflammation; various biomarkers have been studied to predict the cardiovascular risk. hsCRP is one of the most promising indicators for vascular inflammation, others being IL6, VEGF, and LDL: HDL ratio. Subclinical atherosclerosis can be diagnosed using carotid intima media thickness (CIMT), which is a rapid, non-invasive diagnostic test. Various risk assessment scores such as pooled cohort equation (PCE) and Framingham risk score (FRS) can also be used to assess the 10-year cardiovascular risk for primary prevention. We conducted this study to find the effect of systemic treatment with methotrexate on these biomarkers. This may help us to assess the effect of systemic treatment on cardiovascular risk in psoriasis patients.

Material and methods

The study was a prospective study conducted in the department of dermatology at a tertiary care centre during the study period January 2021–July 2022. Institutional ethical committee approval and informed consent from all patients was obtained. All guidelines as per the Declaration of Helsinki and good clinical practice guidelines were followed.

Sample size calculation

As per the study conducted by Strober et al. on effect of etanercept on C reactive protein levels in psoriasis and psoriatic arthritis, the difference was 1 mg/L. Assuming standard deviation of 1.5, the sample size was around 35 patients. We included 50 patients to account for lost to follow-up.

Sample recruitment

Adults (>18 years) who are clinically diagnosed as plaque psoriasis who are candidate for systemic therapy (PASI >10) and not receiving any systemic treatment for last 3 months were included. Exclusion criteria for the study were (a) patient on treatment for coronary artery disease; (b) contraindications to methotrexate as systemic therapy; (c) concomitant chronic infections—HIV, hepatitis B, C infection, or tuberculosis; (d) pregnant, lactating mother; (e) patient with diabetes, hypertension, history of smoking; (f) patient meeting criteria for psoriatic arthritis; and (g) inability to follow-up for 12 weeks.

Methodology

All the relevant clinical data collected to enable us to determine 10-year cardiovascular risk. Psoriasis severity was calculated by psoriasis area and severity index (PASI) and dermatology quality of life index (DLQI) score. Sample was drawn for estimation of IL-6, VEGF, hsCRP, lipid profile, and sugar fasting and post-prandial levels. CIMT and LDL:HDL ratio done at baseline. CIMT was measured 1 cm above the level of carotid bifurcation, a total of five readings were taken, and average CIMT was reported. Treatment with methotrexate initiated as per standard protocol, and clinical parameters including PASI; DLQI; estimation of IL-6, hsCRP, VEGF, lipid profile, and fasting; and postprandial sugar were repeated at 12 weeks. IL-6 and VEGF were measured using ELISA, and hsCRP was measured in Siemens^R auto-analyser.

Statistical analysis

All the data were entered in an Excel sheet. Statistical analysis was performed using statistical package for social sciences (SPSS version 20, Chicago). Categorical data are presented as number with percentage and continuous data as mean with standard deviation. Quantitative data were compared using paired t-test and categorical data using chi-square test. All statistical tests were two sided and were performed at a significance level of α- 0.05.

Results

A total of 92 patients were assessed for inclusion in the study. Forty-two patients did not meet the study criteria and were excluded (hypertension, 8; diabetes, 6; diabetes and hypertension, 6; smoking, 6; psoriatic arthritis, 6; chronic infections, 2; contraindications to methotrexate, 2; inability to follow-up, 6). A total of 50 patients were included in the study. Eight patients (16%) were lost to follow-up/did not complete treatment due to various reasons, and the follow-up data were available for 42 patients. The study consists of 50 patients (30 males and 20 females). The average age of the patient was 44.4 (±13.2) years, and the duration of the disease was 10.8 (±13.2) years. The mean baseline PASI and DLQI were 17.7 (±7.1) and 12.10 (±5.7), respectively. Seven patients (14%) had family history of psoriasis, 42 (84%) had scalp involvement, 31 (62%) had nail involvement, and 15 (30%) had history of alcohol intake. Ten-year coronary artery disease risk was calculated at baseline using PCE and FRS. Using PCE, low risk (<5%) was seen in 15, borderline risk (5–7.4%) in 9, intermediate risk (7.5–19.9%) in 8, and high risk (>20%) in 2. The risk could not be assessed in 16 individuals as PCE assesses the risk in age group of 40–79 years. FRS assess the risk between age group 30–79 years, and the risk was assessed to be low (<10%) in 23, intermediate (10–20%) in 12, and high (>20%) in 2. The risk could not be assessed in 13 patients. The CIMT at baseline was assessed to be 0.56 (±0.15) mm and 0.64 (±0.57) mm on the right and left side, respectively (Table 1).

Table 1.

Baseline characteristic (n = 50).

	Mean (±SD)
Age (years)	44.4 (±13.2)
Gender (M:F)	30 Males: 20 Females
Duration (years)	10.8 (±13.2)
PASI	17.7 (±7.1)
DLQI	12.10 (±5.7)
Alcohol intake	15 (30%)
Nail involvement	31 (62%)
Scalp involvement	42 (84%)
Family history	7 (14%)
CIMT right (mm)	0.56 (±0.15)
CIMT left (mm)	0.64 (±0.57)

∗PASI, psoriasis area and severity index; DLQI, dermatology life quality index; CIMT, carotid intima-media thickness.

Comparative data

The weight and waist circumference at baseline were 69.10 (±11.4) kg and 91.7 (±8) cm respectively and at 12 weeks were 70.6 (±11.7) kg and 93.5 (±12.6) cm respectively. The systolic and diastolic blood pressure at baseline was 128.8 (±15.8) and 84.9 (±11.3) mm Hg and at 12 weeks was 126.5 (±15.3) and 81.3 (±14.8) mm Hg respectively. The blood sugar fasting and post prandial at baseline was 93.3 (±11.7) and 110.2 (±18.9) mg/dL respectively and at 12 weeks was 94.4 (±18.4) and 115.6 (±25.2) mg/dl respectively. The total cholesterol, triglyceride, LDL and HDL at baseline was 182.2 (±34.5), 135.9 (±78.1), 110.3 (±31.2) and 43.6 (±10.2) mg/dl respectively and at 12 weeks was 184.4 (±30.6), 140.7 (±71.6), 113 (±33.3) and 44.9 (±8.9) mg/dl respectively. The LDL: HDL ratio at baseline and at 12 weeks was 2.68 (±1) and 2.67 (±0.98) respectively. None of these parameters had any statistical difference at baseline and at 12 weeks follow up (Table 2).

Table 2.

Comparison of clinical and biochemical characteristics (n = 42).

Sr No	Parameters			P-value
		Baseline	12 weeks
1	Weight (kg)	69.10 (±11.4)	70.6 (±11.7)	0.37
2	Waist circumference (cm)	91.7 (±8)	93.5 (±12.6)	0.17
3	Systolic blood pressure (mm Hg)	128.8 (±15.8)	126.5 (±15.3)	0.06
4	Diastolic blood pressure (mm Hg)	84.9 (±11.3)	81.3 (±14.8)	0.09
5	PASI	16.6 (±8.1)	7.4 (±4.9)	<0.001
6	DLQI	12.1 (±5.7)	4.9 (±3.4)	<0.001
7	Blood sugar fasting (mg/dL)	93.3 (±11.7)	94.4 (±18.4)	0.79
8	Blood sugar post prandial (mg/dL)	110.2 (±18.9)	115.6 (±25.2)	0.11
9	Total cholesterol (mg/dl)	182.2 (±34.5)	184.4 (±30.6)	0.50
10	Triglyceride (mg/dl)	135.9 (±78.1)	140.7 (±71.6)	0.51
11	LDL (mg/dl)	110.3 (±31.2)	113 (±33.3)	0.95
12	HDL (mg/dl)	43.6 (±10.2)	44.9 (±8.9)	0.18
13	LDL: HDL ratio	2.68 (±1)	2.67 (±0.98)	0.53
14	VEGF (pg/ml)	117 (±147.2)	59 (±61)	0.006
15	IL6 (pg/ml)	5.1 (±2.3)	3.6 (±2.1)	<0.001
16	hsCRP (mg/L)	4.3 (±4.2)	2.6 (±3)	0.012

PASI, psoriasis area and severity index; DLQI, dermatology quality of life index; LDL, low-density lipoprotein; HDL, high-density lipoprotein; VEGF, vascular endothelial growth factor; IL6, interleukin 6; hsCRP, High-sensitivity C reactive protein.

The mean PASI at baseline and 12 weeks was 16.6 (±8.1) and 7.4 (±4.9) respectively (p < 0.001), the mean DLQI at baseline and at 12 weeks was 12.1 (±5.7) and 4.9 (±3.4) respectively (p < 0.001). VEGF level at baseline and at 12 weeks was found to be 117 (±147.2) and 59 (±61) pg/ml respectively (p, 0.006). The IL6 at baseline and at 12 weeks was 5.1 (±2.3) and 3.6 (±2.1) pg/ml (p < 0.001). The hsCRP at baseline and at 12 weeks was 4.3 (±4.2) and 2.6 (±3) mg/L respectively (p, 0.012).

Discussion

Cardiovascular diseases are common cause of morbidity and mortality across the world. Atherosclerosis is the underlying cause of cardiovascular diseases (coronary artery disease [CAD], cerebrovascular disease, and peripheral vascular disease). The traditional risk factors for atherosclerosis are age, male gender, Asian race, dyslipidemia, hypertension, diabetes mellitus, obesity, sedentary lifestyle, stress, and smoking.⁷ Psoriasis is associated with vascular inflammation and result in increase in cardiovascular risk.⁸ The study involving large databases have found that psoriasis per se contributes to increased risk of CAD when adjusted for higher prevalence of traditional risk factors. A population-based, prospective cohort study including 1,27,139 mild and 3837 severe psoriasis found higher relative risk (RR) of myocardial infarction (MI) in patients with psoriasis. The risk was higher in younger patients with severe psoriasis.⁹ These findings were confirmed by analysis of healthcare database in United States.¹⁰ In another study, the authors concluded that after adjusting for age, gender, hypertension, dyslipidemia, and tobacco use, psoriasis confers additional 6.2% absolute risk of major adverse cardiac events.¹¹ In our study, we excluded patients with traditional risk factors to better understand the effect of psoriasis on various parameters. El-mongy et al. used carotid intima media thickness as a marker of subclinical atherosclerosis in their study and found increased carotid intima media thickness in patients with chronic psoriasis in absence of traditional cardiovascular risk factors.¹² In our study, we found baseline CIMT values in severe psoriasis patients to be within normal limits, this may be because the mean age in our study was 44.4 (±13.2) years, and mean PASI was 17.7 (±7.1) and mean age and PASI in the quoted study was 51.1 ± 14.1 years and 29.1 ± 16, respectively. This combination of higher mean age and more severe disease may be responsible for higher CIMT value as compared to our study. Obese individuals have nearly twice the risk of psoriasis as compared to normal weight individuals (RR, 1.87; 95% CI 1.38, 2.52). The risk of psoriasis was increased with all measures of adiposity; a single standard deviation increases in BMI (3.81 kg/m²), waist circumference (11.14 cm), and waist-hip ratio (0.08) increase the risk of psoriasis with almost same magnitude.¹³ Body mass index (BMI) is commonly used measure of body composition, but evidence increasingly suggests that measures of abdominal obesity such as waist circumference and waist-hip ratio are better indicators of metabolic abnormalities and cardiovascular disease risk. Hence, we used waist circumference as a baseline measure in our study. In Indian population, waist circumference of less than 90 cm in male and 80 cm in female is considered to be optimal. In our study, we found mean waist circumference in females and males to be 90.7 (±3.4) cm and 92.46 (±4.95) cm, respectively. There are various risk-assessment scores available for primary prevention of CAD. These tools estimate 10-year risk of development of CAD and can be used for targeted therapies to lower the risk and follow-up. The commonest risk score assessment tools used are FRS and PCE.^48,49 The other risk scores being used are systemic coronary risk evaluation (SCORE) by European society of cardiology, World Health Organisation/International society of hypertension (WHO/ISH) risk assessment charts and Joint British Societies (JBS) risk calculator.¹⁴ We used FRS and PCE in our study. These risk assessment tools may also underestimate risk in patients with chronic inflammation like psoriasis, rheumatoid arthritis, and human immunodeficiency virus infection.¹⁵ National psoriasis foundation guidelines advocate that patients should be made aware of the increased cardiovascular risk and suggest that patient with >10% body surface area can apply a multiplication factor of 1.5- to 10-year cardiovascular risk score.¹⁶ In our study, risk assessed using PCE was assessed as low risk in 15 (44.1%), borderline risk in 9 (26.4%), intermediate risk in 8 (23.5%), and high risk in 2 (5.8%). Using FRS, the risk was assessed to be low in 23 (62.1%), intermediate in 12 (32.4%) and high in 2 (5.4%). A study by Fernandez- Torres et al. in their study on 395 patients with psoriasis found that 30.5% had intermediate and 11.4% had high risk using FRS. The lower 10-year risk in our study may be due to exclusion of smokers and patients suffering from diabetes and hypertension, which are major risk factor for cardiovascular risk.¹⁷

Vascular inflammation is considered a biomarker of cardiovascular risk. A prospective observational study found aortic vascular inflammation using ¹⁸ FDG PET/CT to correlate with psoriasis severity.¹⁸ Biomarkers such as hsCRP, IL6, and VEGF are considered surrogate markers of vascular inflammation and is associated with higher cardiovascular risk. hsCRP correlates with psoriasis severity, vascular inflammation, and atherosclerosis and is a strong predictor of future coronary events in asymptomatic individuals.¹⁹ The reduction in hsCRP results in decrease incidence of cardiovascular events.²⁰ The IL6 is an important cytokine in the cytokine milieu that promotes atherosclerosis. An IL6 inhibitor, Ziltivekimab, is undergoing trial to reduce the cardiovascular risk.²¹ VEGF-A is a homodimeric glycoprotein and is a key factor in angiogenesis and vascular permeability. Cardiomyocytes are a major source of VEGF-A. High VEGF levels are associated with myocardial infarction, ongoing inflammation and have negative prognostic value.²² The evidence that psoriasis increases cardiovascular risk is not in question anymore; however, the debate is still on about the effect of systemic treatment of psoriasis on cardiovascular risk. The evidence is mounting in favour of early treatment of psoriasis using systemic treatment and cardiovascular risk reduction. The registry data suggest that treatment of skin disease reduces vascular inflammation and atherosclerosis and decrease cardiovascular risk; however, randomised placebo trials are inconclusive. The biomarkers are surrogate markers for atherosclerosis and are easier to study as compared to hard end points such as myocardial infarction, which requires large sample size and long follow-up. In our study, we found that, at the end of 12 weeks, methotrexate resulted in significant reduction in biomarkers of atherosclerosis. We also noted that there was significant reduction in PASI, but not much effect on other metabolic parameters such as blood sugar and lipid profile. Wu et al. analysed patients on TNFα inhibitors and found 50% reduction in myocardial infarction as compared to topical therapy.²³ Similar to our study, reduction in biomarkers was found in patients treated with methotrexate and TNFα inhibitors.²⁴ Secukinumab, an IL17 inhibitor, also resulted in reduction of aortic vascular inflammation as assessed using ¹⁸ FDG PET.²⁵ The effect of ustekinumab on cardiovascular risk is conflicting and needs more studies. The effect of other IL17 inhibitors such as ixekizumab and brodalumab, IL23 p19 inhibitors such as guselkumab, tildrakizumab, and risankizumab on cardiovascular risk is not yet clear, and the studies are ongoing to assess the cardiovascular benefit/risk of using these drugs in psoriasis patients.^26,27 A systematic review and meta-analysis on effect of methotrexate on cardiovascular events in psoriasis, psoriatic arthritis, and rheumatoid arthritis found that beneficial association of methotrexate use and cardiovascular risk reduction in cardiovascular events in rheumatoid arthritis patients on methotrexate (RR, 0.72; 95% CI 0.57 to 0.91; p = 0.007). The risk reduction was similar to risk reduction with TNF inhibitors (RR, 0.70; 95% CI 0.54 to 0.90; p = 0.005). The number of studies for psoriasis in this analysis was less, and the study concluded that systemic therapy in psoriasis is associated with reduction in cardiovascular events.²⁸ A study conducted by Ridker et al. used low dose methotrexate for prevention of atherosclerotic event did not find any reduction in biomarkers of inflammation such as IL6 or hsCRP or less cardiovascular events as compared to placebo.²⁹ A recent review by Verhoeven et al. concluded that methotrexate reduces cardiovascular risk in psoriasis, psoriatic arthritis, and rheumatoid arthritis patients by reducing systemic inflammation; however, it does not reduce cardiovascular risk in HIV patients and in general population.³⁰ In our study, we also found significant reduction in biomarkers of vascular inflammation in patients with chronic plaque psoriasis. In patients with severe psoriasis, use of methotrexate early may reduce cardiovascular risk.

Limitations of the study

Biomarkers of vascular inflammation are surrogate marker for cardiovascular risk. The study with hard end points such as myocardial infarction and stroke is required to conclude whether methotrexate reduces cardiovascular risk in patients with severe psoriasis.

Conclusion

Psoriasis is a common skin disease and is associated with systemic inflammation. This systemic inflammation results in increase cardiovascular risk in these patients and decrease life expectancy. Our study has shown that use of methotrexate in patients with severe psoriasis results in significant reduction in biomarkers of vascular inflammation.

Patients/ Guardians/ Participants consent

Patients informed consent was obtained.

Ethical clearance

Institute/hospital ethical clearance certificate was obtained.

Source of support

This paper is based on Armed Forces Medical Research Committee Project No. 5300/2020 granted and funded by office of the Directorate General Armed Forces Medical Services and Defence Research Development Organization, Government of India.

Disclosure of competing interest

The authors have none to declare.