Methotrexate use, not interleukin 33, is associated with lower carotid intima-media thickness in patients with rheumatoid arthritis

Pinto, Maria Raquel Costa; Kakehasi, Adriana Maria; Souza, Adriano José; Tavares Jr, Wilson Campos; Rocha, Monaliza Angela; Trant, Cyntia Gabriele Michel Cardoso; Andrade, Marcus Vinicius

doi:10.1186/s42358-019-0060-1

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Sumário

Research • Adv. rheumatol. 59 • 2019 • https://doi.org/10.1186/s42358-019-0060-1 copy

Methotrexate use, not interleukin 33, is associated with lower carotid intima-media thickness in patients with rheumatoid arthritis

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Background:

Rheumatoid arthritis is a risk factor for early mortality due to cardiovascular disease. Interleukin-33 appears to protect against the development of atherosclerosis. The purpose of this study was to investigate the relationship between serum levels of interleukin-33 and its soluble receptor with the presence of subclinical carotid atherosclerosis in rheumatoid arthritis patients.

Methods:

Rheumatoid arthritis patients without atherosclerotic disease were subjected to clinical and laboratory assessments, including carotid ultrasound. Interleukin-33 and its soluble receptor serum levels were measured by ELISA.

Results:

102 patients were included. The prevalence of carotid plaques was 23.5% and the median intima-media thickness was 0.7 mm. The median interleukin-33 and its soluble receptor concentration was 69.1 and 469.8 pg/ml. No association was found between serum interleukin-33 or its soluble receptor and intima-media thickness or plaque occurrence. Each 0.1 mm increase of intima-media thickness raised the odds of plaque occurrence by 5.3-fold, and each additional year of rheumatoid arthritis duration increased the odds of plaque occurrence by 6%. Each additional year in patients age and each one-point increase in the Framingham Risk Score were associated with a 0.004 mm and 0.012 mm increase in intima-media thickness. Methotrexate use was associated with a 0.07 mm reduction in intima-media thickness.

Conclusions:

Interleukin-33 and its soluble receptor were not associated with subclinical atherosclerosis. Traditional risk factors for atherosclerosis and rheumatoid arthritis duration were associated with intima-media thickness and plaque occurrence; methotrexate use was associated with a lower intima-media thickness.

Keywords:
Rheumatoid arthritis; Cardiovascular diseases; Interleukins; Methotrexate

Variable		Value
Age (years - mean ± SD)		55.5 ± 10
Age at onset of symptoms (years - mean ± SD)		37.9 ±11.9
Disease length (years - mean ± SD)		17.6 ± 9.5
Female gender (n (%))		94 (92.5)
Postmenopausal (n (% female participants))		71 (75.5)
Non-white ethnicity (n (%))		74 (72.5)
Seropositive RA (n (%))^a a number of patients with positive rheumatoid factor and/or anti-CCP in any titer at any time during the clinical course of disease		84 (82.4)
Extra-articular involvement^b b number of patients with extra-articular involvement at any time during the clinical course of disease (n (%))		23 (22.5)
DAS28 (mean ± SD)		4 ± 1.4
CDAI(mean ± SD)		13.4 ± 11.7
HAQ-DI (median (IQR))		0.8 (0.3-1.4)
Sharp/van der Heijde score ^c c total Sharp/Van der Heijde modified score (0-448) (median (IQR))		38 (10-75.5)
SAP/DAP (mmHg - mean ± SD)		123 ±13/ 77.5 ± 8.6
Waist circumference (cm - mean ± SD)		94.5 ± 10.8
BMI (mean ±SD)		27.5 ±4.7
Medications in use (n patients (%))
	Oral hypoglycemic agents and/or insulin	14 (13.7)
	Hypolipidemic agents	28 (27.5)
	Antihypertensives	54 (52.9)
	DMARDs	91 (89.2)
	Methotrexate	66 (64.7)
	Leflunomide	42 (41.2)
	Anti-TNFα	15 (14.7)
	Nonsteroidal anti-inflammatory drugs	22 (21.6)
	Prednisone	62 (60.8)
Prednisone daily dose (mg - median (IQR))		2.5 (0-5)
Prednisone cumulative dose (g - mean ± SD)		21.8 ±15.7
Laboratory tests
	HDL (mg/dL - mean ± SD)	58.4 ±16.1
	LDL (mg/dL - mean ± SD)	110.6 ± 28
	TC/HDL (median (IQR))^d d total cholesterol-to-HDL ratio	3.5 (2.8-4.1)
	Triglycerides (mg/dL - median (IQR))	112 (81-165.5)
	Fasting glucose (mg/dL - median (IQR))	89 (79-97)
	CRP (mg/L - median (IQR))	8.3 (4.9-16.9)
	ESR (mm/h - median (IQR))	22 (15-32)
Traditional risk factors for CAD (n (%))
	Current smoker	12 (11.8)
	Diabetes mellitus	17 (16.7)
	Family history of early CVD	18 (17.6)
	Metabolic syndrome	53 (52)
	Systemic arterial hypertension	60 (58.8)
	Dyslipidemia	65 (63.7)
	Central obesity	88.2 (90)
Global Risk Score (Framingham) (Ref. 67) (median (IQR))		7.1 (4.1-11.6)
High cardiovascular risk (Ref. 65) (n (%))		64 (62.7)
LDL within therapeutic goal (BSC) (Ref. 65) (n (%))		22 (21.6)

Variable	Value
IMT - CCA (mm - median (IQR))	0.7 (0.6-0.8)
Increased IMT (n (%))	19 (18.6)
Atherosclerotic plaque (n (%))	24 (23.5)
IL-33 (pg/mL - median (IQR))^a a levels below the limit of detection were considered as zero	32.1 (0-78.7)
IL-33 (pg/mL - median (IQR))^b b only considering the 68 participants with levels above the limit of detection	69.1 (31.6-114.5)
sST2 (pg/mL - median (IQR))^c c only considering the 101 participants with levels above the limit of detection	469.8 (336.3-651)
IL-33/sST2 (median (IQR))^d d IL-33-to-sST2 ratio	0.1 (0-0.3)

Variable		Plaques absent (n = 78)	Plaques present (n = 24)	p-value
Age (years - mean ± SD)		54.2 ± 9.8	59.9 ± 9.7	0.014^a a t-test;
Disease length (years - mean ± SD)		16.3 ± 9.7	21.9 ± 8	0.011^a a t-test;
Postmenopausal (n (%)):	No	21 (91.3)	2 (8.7)	0.043^b b chi-square;
	Yes	50 (70.4)	21 (29.6)
LDL within goal (Ref. 65) (n (%))	No	56 (70)	24 (30)	0.003^b b chi-square;
	Yes	22 (100)	0 (0)
Global CVR score (median (IQR))		6.3 (2.9-11.6)	8.7 (6.2-11.8)	0.048^c c Mann-Whitney test
IMT (mm - median (IQR))		0.6 (0.6-0.8)	0.8 (0.7-0.9)	0.001^c c Mann-Whitney test
IL-33 (n (%))^d d IL-33 positive: serum IL-33 ≥ 23.4 pg/mL; and IL-33 negative: serum IL-33 < 23.4 pg/mL :	positive	52 (76.5)	16 (23.5)	1^b b chi-square;
	negative	26 (76.5)	8 (23.5)
IL-33 (pg/mL - median (IQR))^e e levels below the limit of detection were considered as zero		33.1 (0-78.7)	12.1 (0-85.8)	0.856^c c Mann-Whitney test
IL-33 (pg/mL - median (IQR))^f f only considering the 68 participants with levels above the limit of detection		69.1 (33.1-124.3)	70.6 (12.1-90.1)	0.745^c c Mann-Whitney test
sST2 (pg/mL - median (IQR))^g g data from the 101 participants with detectable levels		461.7 (316.6-651)	485.9 (372.9-649)	0.675^c c Mann-Whitney test
IL-33/sST2 (median (IQR))^h h IL-33-to-sST2 ratio		0.1 (0-0.3)	0.1 (0-0.3)	0.965^c c Mann-Whitney test

Variable	Coeffident^a a Spearman's correlation coefficient	p-value
Age (years)	0.613	< 0.001
Disease length (years)	0.224	0.024
Age at onset of symptoms (years)	0.334	0.001
Time since onset of symptoms to 1st rheumatology visit (years)	0.204	0.040
Fasting glucose (mg/dL)	0.263	0.008
SAP (mmHg)	0.282	0.004
Global Cardiovascular Risk Score	0.591	< 0.001
Current prednisone daily dose	–0.205	0.039
IL-33 (pg/mL)^b b levels below the limit of detection were considered as zero	–0.77	0.439
IL-33 (pg/mL)^c c only considering the 68 participants with levels above the limit of detection	–0.035	0.775
sST2 (pg/mL)^d d data from the 101 participants with detectable levels	0.002	0.981
IL-33/sST2**	– 0.071	0.566

Variable		IMT (mm - median (IQR))	P-value
Postmenopausal	No	0.60 (0.55-0.65)	0.001^a a Mann-Whitney test;
	Yes	0.71 (0.6-0.8)
Extra-articular involvement	No	0.65 (0.58-0.76)	0.014^a a Mann-Whitney test;
	Yes	0.72 (0.63-0.88)
SAH	Absent	0.60 (0.55-0.71)	0.001^a a Mann-Whitney test;
	Present	0.72 (0.63-0.81)
Using antihypertensives	No	0.62 (0.56-0.71)	0.001^a a Mann-Whitney test;
	Yes	0.73 (0.63-0.81)
Diabetes mellitus	Absent	0.65 (0.58-0.76)	0.003^a a Mann-Whitney test;
	Present	0.84 (0.63-0.95)
Using hypoglycemic agents/insulin	No	0.65 (0.58-0.76)	0.001^a a Mann-Whitney test;
	Yes	0.84 (0.7-1.02)
LDL within goal	No	0.7 (0.6-0.8)	0.012^a a Mann-Whitney test;
	Yes	0.6 (0.6-0.7)
Metabolic syndrome	Absent	0.64 (0.58-0.74)	0.037^a a Mann-Whitney test;
	Present	0.71 (0.6-0.84)
Using methotrexate	No	0.75 (0.62-0.87)	0.005^a a Mann-Whitney test;
	Yes	0.63 (0.58-0.73)
CVR classification^c c according to the Global Risk Score (Framingham)	High	0.73 (0.61-0.84)	<0.001^b b Kruskal-Wallis test
	Intermediate	0.71 (0.64-0.77)
	Low	0.6 (0.54-0.64)
IL-33 positive^d d IL-33 positive: serum IL-33 ≥ 23.4 pg/mL	No	0.69 (0.59-0.85)	0.449^a a Mann-Whitney test;
	Yes	0.66 (0.59-0.78)

Sociedade Brasileira de Reumatologia Av. Brigadeiro Luís Antônio, 2466, Jardim Paulista, 01402-000 - São Paulo, SP, Tel.: +551132897165 - São Paulo - SP - Brazil
E-mail: rbreumatol@terra.com.br

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[1] * Correspondence: dramariaraquel@gmail.com