TNF-alpha and IL-17 cytokine levels in Brazilian patients with ankylosing spondylitis after anti-TNF therapy

Lara-Armi, Fernanda Formaggi; Visentainer, Jeane Eliete Laguila; Braga, Matheus; Zacarias, Joana Maira Valentini; Rocha-Loures, Marco Antônio; Neves, Janisleya Silva Ferreira; Moliterno, Ricardo Alberto; Sell, Ana Maria

doi:10.1590/s2175-97902023e22746

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Brazilian Journal of Pharmaceutical Sciences

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Article • Braz. J. Pharm. Sci. 59 • 2023 • https://doi.org/10.1590/s2175-97902023e22746 copy

TNF-alpha and IL-17 cytokine levels in Brazilian patients with ankylosing spondylitis after anti-TNF therapy

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

The aim of this study was to evaluate tumor necrosis factor alpha (TNF-α), interleukin (IL)- 17A/F levels in the serum of ankylosing spondylitis (AS) patients after anti-TNF therapy, in order to understand how these cytokines are involved in this therapeutic response. Forty-four AS patients were included in the study: thirty using anti-TNF therapy were classified according to their therapy response as responders (15) and non-responders (15) and 14 without anti-TNF therapy were classified as AS control. Fifteen healthy individuals formed the control group. Serum levels of TNF-α were determined using Luminex technology and for IL-17A and IL-17F using ELISA. The non-responder patients presented higher serum levels of TNF-α than the responders and AS control; the same results were found when HLA-B*27 positive or negative patients were separately analyzed. IL-17A and IL17F serum levels were similar for all groups. According to the clinical disease activity, AS patients with BASDAI ≥4 had higher serum levels of TNF-α than AS patients with BASDAI <4. Positive correlation was found between TNF-α levels and BASDAI. In AS patients, TNF-α serum levels were associated with anti-TNF therapy and disease activity independently of HLA-B*27, and IL-17A and IL-17F were not related to anti-TNF treatment.

Key-words:
Genetic association studies. Polymorphism; genetic. Spondylitis; ankylosing. Cytokines.

Variable	Patients N=44	Responders N=15	Non-responders N=15	AS control N=14	Healthy individuals N=15
Age mean + SD (year)	44.34 ± 14.42	44.93 ± 15.33	43.73 ± 14.13	44.35 ± 14.8	39.26 ± 11.59
Sex n (%)
Male	25 (56.81)	8 (53.30)	7 (46.67)	10 (71.43)	9 (60.00)
Female	19 (43.19)	7 (46.67)	8 (53.30)	4 (28.57)	6 (40.00)
BASDAI mean ± SD	3.64 ± 1.80	2.26 ± 1.31*	5.6 ± 1.19*	3.02 ± 0.49
HLA-B27 n (%)
Presence	27 (61.36)	11 (73.33)	8 (53.33)
Absence	17 (38.63)	4 (26.66)	7 (46.67)
Anti-TNF n (%)	N=30	N=15	N=15
Adalimumab	16 (53.33)	10 (66.66)	6 (40.00)
Certolizumab	1 (3.33)	1 (6.67)	0
Etanercept	8 (26.66	1 (6.67)	7 (46.67)
Golimumab	2 (6.66)	2 (13.33)	0
Infliximab	3 (10.00)	1 (6.67)	2 (13.33)
NSAID n (%)	26 (59.09)	8 (53.3)	6 (40.00)	13 (92.85)
DMARD n (%)	14 (31.81)	8 (53.3)	6 (40.00)
Sulfasalazine	14 (31.81)	8 (53.3)	6 (40.00)
Methotrexate	1 (2.27)	0	1 (6.66)
Age of disease onset (year)	34.88 ± 15.19	38.13 ± 16.59	30.73 ± 12.46	35.85 ± 16.30
Disease duration (months)	48 (2-348)	48 (9-40)	84 (12-348)	20 (2-324)

Cytokines	Groups	Responders		Non-responders		AS controls		Healthy individuals		P value
TNF-α	AS patients	N= 15	0.33 (0.33-2.89)	N= 15	5.05 (0.33-31.14)	N= 14	1.39 (1.39-11.30)	N= 15	1.39 (0.33-7.24)	<0.0001^a
										0.008^bd
										0.02^c
										0.01^e
	HLA-B27+*	N= 11	0.33 (0.33-2.14)	N= 7	5.00 (1.39-25.94)	N= 8	1.39 (1.39-2.89)			0.005^a
	HLA-B27+*	N= 11	0.33 (0.33-2.14)	N= 7	5.00 (1.39-25.94)	N= 8	1.39 (1.39-2.89)			0.04^b
	HLA-B27-*	N= 4	0.33 (0.33-2.89)	N= 8	5.05 (1.39-31.14)	N= 6	1.39 (1.00-11.30)			0.02^a
IL-17A	AS patients	N= 15	12.31 (0.18-54.29)	N= 15	1.15 (0.18-191.55)	N= 14	18.09 (0.18-247.38)	N= 15	9.13 (0.18-111.37)	ns
	HLA-B27+*	N= 11	4.91 (0.18-48.23)	N= 7	14.75 (0.29-191.55)	N= 8	16.38 (0.18-247.38)			ns
	HLA-B27-*	N= 4	30.43 (0.18-54.29)	N= 8	0.75 (0.18-51.55)	N= 6	21.43 (5.57-170.98)			0.02^d
IL-17F	AS patients	N= 15	0.59 (0.59-74.1)	N= 15	0.59 (0.59-1749.9)	N= 14	1.27 (0.59-1833.8)	N= 15	0.59 (0.59-328)	ns
	HLA-B27+*	N= 11	0.59 (0.59-74.1)	N= 7	11.73 (0.59-1749.86)	N= 8	206.05 (0.59-1833.77)			ns
	HLA-B27-*	N= 4	0.59 (0.59-9.23)	N= 8	0.59 (0.59-100.14)	N= 6	1.27 (0.59-1771.95)			ns

Cytokines	Groups	BASDAI <4	BASDAI ≥4	P value
TNF-α	AS patients	1.39 (0.33-2.89)	5.05 (1.39-31.14)	<0.0001
	AS HLA-B27* positive	1.39 (0.33-2.89)	5.00 (1.39-25.94)	0.008
	AS HLA-B27* negative	1.39 (0.33-11.30)	5.05 (1.39-31.14)	0.01
IL-17A	AS patients	14.06 (0.18-54.29)	1.15 (0.18-51.55)	ns
	AS HLA-B27* positive	10.63 (0.18-247.38)	14.75 (0.29-191.55)	ns
	AS HLA-B27* negative	21.90 (0.18-170.98)	0.75 (0.18-51.55)	0.02
IL-17F	AS patients	0.59 (0.59-1833.77)	0.59 (0.59-1749.86)	ns
	AS HLA-B27* positive	0.59 (0.59-1833.77)	11.73(0.59-1749.86)	ns
	AS HLA-B27* negative	0.59 (0.59-1771.95)	0.59 (0.59-45.14)	ns

	AS patients		AS patients HLA-B27+*		AS patients HLA-B27-*
	N=44		N=27		N=17
Variable	rs	P	rs	P	rs	P
Age x BASDAI	-0.0644	ns	-0.1711	ns	0.0959	ns
Age x TNF-α	-0.0153	ns	-0.1734	ns	0.2424	ns
Age x IL-17A	-0.3670	0.0142	-0.5009	0.0077	-0.2127	ns
Age x IL-17F	-0.3871	0.0102	-0.5503	0.0029	-0.2448	ns
BASDAI x TNF-α	0.5706	<0.0001	0.4163	0.0307	0.6382	0.0058
BASDAI x IL-17A	-0.0734	ns	0.0327	ns	-0.3428	ns
BASDAI x IL-17F	0.0130	ns	-0.0079	ns	-0.0304	ns
TNF-α x IL-17A	0.1112	ns	0.1464	ns	0.0405	ns
TNF-α x IL-17F	0.2533	ns	0.2161	ns	0.3760	ns
IL-17A x IL-17F	0.7385	<0.0001	0.7357	<0.0001	0.7497	0.0005

		Groups
Genotype		N	Responders	N	Non-responders	N	AS control	N	Healthy individuals
TNF-308 (rs18000629)	G/G	9	0.33 (0.33-2.88)	7	4.32 (0.33-31.14)	7	1.39 (1.00-2.89)	8	1.39 (0.33-7.24)
TNF-308 (rs18000629)	G/A + A/A	6	0.86 (0.33-2.14)	8	6.10 (1.39-15.34)	7	1.39 (1.39-11.29)	7	2.00 (0.33-6.90)
IL17A (rs2275913)	G/G	9	2.96 (0.18-21.92)	2	25.86 (0.18-51.55)	9	22.12(0.18-188.35)	8	16.14(0.52-57.32)
IL17A (rs2275913)	G/A + A/A	6	36.59 (0.18-54.29)	13	1.15 (0.18-191.55)	5	14.06 (1.60-247.38)	7	8.44 (0.54-111.37)
IL17F (rs763780)	T/T	9	0.59 (0.59-74.10)	8	1.05(0.59-45.14)	12	1.27 (0.59-1771.95)	14	0.59 (0.59-328.00)
IL17F (rs763780)	T/C + C/C	6	0.59 (0.59-36.85)	7	0.59 (0.59-1749.86)	2	917.18 (0.59-1833.97)	1	71.05

Universidade de São Paulo, Faculdade de Ciências Farmacêuticas Av. Prof. Lineu Prestes, n. 580, 05508-000 S. Paulo/SP Brasil, Tel.: (55 11) 3091-3824 - São Paulo - SP - Brazil
E-mail: bjps@usp.br

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[1] *Correspondence: F. F. Lara-Armi. Programa de Pós-Graduação em Biociências e Fisiopatologia. Universidade Estadual de Maringá, Bloco T20, Laboratório de Imunogenética. Av. Colombo, 5790, Maringá, PR, Brasil. CEP 87020900. Phone: (55) 44 3011-5392. Fax (55) 44 3011-4833, (55) 44 99914-1351. E-mail: fernandauem@hotmail.com.