Cytokine Profiles of Chronic Urticaria Patients and the Effects of Omalizumab Treatment

Ozge Can Bostan; Ebru Damadoglu; Basak Ezgi Sarac; Busra Kilic; Ümit Murat Sahiner; Cagatay Karaaslan; Gul Karakaya; Ali Fuat Kalyoncu

doi:10.5826/dpc.1304a272

Cytokine Profiles of Chronic Urticaria Patients and the Effects of Omalizumab Treatment

Authors

Ozge Can Bostan Hacettepe University Faculty of Medicine, Department of Chest Diseases, Division of Allergy and Immunology, Ankara, Turkey
Ebru Damadoglu Hacettepe University Faculty of Medicine, Department of Chest Diseases, Division of Allergy and Immunology, Ankara, Turkey
Basak Ezgi Sarac Hacettepe University Faculty of Science, Department of Biology, Molecular Biology Section, Ankara, Turkey
Busra Kilic Hacettepe University Faculty of Science, Department of Biology, Molecular Biology Section, Ankara, Turkey
Ümit Murat Sahiner Hacettepe University Faculty of Medicine, Department of Pediatric Allergy and Asthma, Ankara, Turkey
Cagatay Karaaslan Hacettepe University Faculty of Science, Department of Biology, Molecular Biology Section, Ankara, Turkey
Gul Karakaya Hacettepe University Faculty of Medicine, Department of Chest Diseases, Division of Allergy and Immunology, Ankara, Turkey
Ali Fuat Kalyoncu Hacettepe University Faculty of Medicine, Department of Chest Diseases, Division of Allergy and Immunology, Ankara, Turkey

Keywords:

Chronic spontaneous urticaria, biomarker, cytokine, TNF-α, IL-17

Abstract

Introduction: Cytokines are key mediators in immunological and inflammatory conditions, including chronic spontaneous urticaria (CSU).

Objectives: To investigate Th1, Th2, and Th17 cytokine profiles in CSU and to evaluate the possible effect of omalizumab treatment.

Methods: Patients who were followed up for CSU, as well as healthy volunteers, were included in the study. To assess urticaria activity, the 7-day-Urticaria Activity Score (UAS-7), the Urticaria Control Test (UCT), and the Chronic Urticaria Quality of Life Questionnaire (CU-QoL) were filled. Serum levels of IL-6, IL-17, IL-31, eotaxin, RANTES, TNF-α, and TSLP were analyzed by ELISA and compared in CSU and control groups. The patients were analyzed in two groups as the omalizumab group and the non-omalizumab group based on their treatment status.

Results: Total IgE, ESR, CRP, RANTES, and TNF-a were significantly different in the overall comparison of the three groups: CSU-receiving omalizumab, CSU-not receiving omalizumab, and control groups (P <0.01, 0.015, <0.01, <0.01 and <0.01 respectively). Total IgE, CRP, RANTES, and TNF-α values were similar in those who received and did not receive omalizumab, yet these biomarkers were significantly higher in both groups than in the control group (P < 0.05). Statistical significance in ESR was observed only between the CSU-receiving omalizumab group and the control group (P = 0.01). Within the CSU patients, there was a slight but significant correlation between UCT and TNF-α (P = 0.008, r = 0.32) and IL-17 (P = 0.06, r = 0.33) levels.

Conclusions: The investigated cytokine profile in CSU patients may differ from healthy controls, particularly with the higher levels of RANTES and TNF-α, and omalizumab treatment does not seem to affect that profile in CSU patients.

References

Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. Allergy. 2018;73(7):1393-1414. DOI: 10.1111/all.13397. PMID: 29336054.

Weller K, Zuberbier T, Maurer M. Clinically relevant outcome measures for assessing disease activity, disease control and quality of life impairment in patients with chronic spontaneous urticaria and recurrent angioedema. Curr Opin Allergy Clin Immunol. 2015;15(3):220-226. DOI: 10.1097/ACI.0000000000000163. PMID: 25899695.

Zhang Y, Zhang H, Du S, Yan S, Zeng J. Advanced Biomarkers: Therapeutic and Diagnostic Targets in Urticaria. Int Arch Allergy Immunol. 2021;182(10):917-931. DOI: 10.1159/000515753. PMID: 33915552.

Deza G, Ricketti PA, Giménez-Arnau AM, Casale TB. Emerging Biomarkers and Therapeutic Pipelines for Chronic Spontaneous Urticaria. J Allergy Clin Immunol Pract. 2018;6(4):1108-1117. DOI: 10.1016/j.jaip.2018.02.024. PMID: 30033912.

Kolkhir P, Pogorelov D, Olisova O. CRP, D-dimer, fibrinogen and ESR as predictive markers of response to standard doses of levocetirizine in patients with chronic spontaneous urticaria. Eur Ann Allergy Clin Immunol. 2017;49(4):189-192. DOI: 10.23822/eurannaci.1764-1489.05. PMID: 28752724.

Toubi E, Vadasz Z. The Emerging Role of IL-17 in the Immune-Pathogenesis of Chronic Spontaneous Urticaria. Immunotargets Ther. 2020;9:217-223. DOI: 10.2147/ITT.S266410. PMID: 33134229. PMCID: PMC7592154.

Elias J, Boss E, Kaplan AP. Studies of the cellular infiltrate of chronic idiopathic urticaria: prominence of T-lymphocytes, monocytes, and mast cells. J Allergy Clin Immunol. 1986;78(5 Pt 1):914-918. DOI: 10.1016/0091-6749(86)90240-x. PMID: 3491100.

Atwa MA, Emara AS, Youssef N, Bayoumy NM. Serum concentration of IL-17, IL-23 and TNF-α among patients with chronic spontaneous urticaria: association with disease activity and autologous serum skin test. J Eur Acad Dermatol Venereol. 2014;28(4):469-474. DOI: 10.1111/jdv.12124. PMID: 23451767.

Takahagi S, Mihara S, Iwamoto K, et al. Coagulation/fibrinolysis and inflammation markers are associated with disease activity in patients with chronic urticaria. Allergy. 2010;65(5):649-656. DOI: 10.1111/j.1398-9995.2009.02222.x. PMID: 19845571.

Altrichter S, Hawro T, Hänel K, et al. Successful omalizumab treatment in chronic spontaneous urticaria is associated with lowering of serum IL-31 levels. J Eur Acad Dermatol Venereol. 2016;30(3):454-455. DOI: 10.1111/jdv.12831. PMID: 25371135.11. Romano C, Sellitto A, De Fanis U, et al. Omalizumab for difficult-to-treat dermatological conditions: clinical and immunological features from a retrospective real-life experience. Clin Drug Investig. 2015;35(3):159-168. DOI: 10.1007/s40261-015-0267-9. PMID: 25578818.

Yalcin AD, Celik B, Gumuslu S. D-dimer levels decreased in severe allergic asthma and chronic urticaria patients with the omalizumab treatment. Expert Opin Biol Ther. 2014;14(3):283-286. DOI: 10.1517/14712598.2014.875525. PMID: 24359555.

Puxeddu I, Panza F, Pratesi F, et al. CCL5/RANTES, sVCAM-1, and sICAM-1 in chronic spontaneous urticaria. Int Arch Allergy Immunol. 2013;162(4):330-334. DOI: 10.1159/000354922. PMID: 24157824.

Hossny E, Aboul-Magd M, Bakr S. Increased plasma eotaxin in atopic dermatitis and acute urticaria in infants and children. Allergy. 2001;56(10):996-1002. DOI: 10.1034/j.1398-9995.2001.00169.x. PMID: 11576081.

Kolkhir P, André F, Church MK, Maurer M, Metz M. Potential blood biomarkers in chronic spontaneous urticaria. Clin Exp Allergy. 2017;47(1):19-36. DOI: 10.1111/cea.12870. PMID: 27926978.

Ying S, Kikuchi Y, Meng Q, Kay AB, Kaplan AP. TH1/TH2 cytokines and inflammatory cells in skin biopsy specimens from patients with chronic idiopathic urticaria: comparison with the allergen-induced late-phase cutaneous reaction. J Allergy Clin Immunol. 2002;109(4):694-700. DOI: 10.1067/mai.2002.123236. PMID: 11941321.

Tedeschi A, Asero R, Marzano AV, et al. Plasma levels and skin-eosinophil-expression of vascular endothelial growth factor in patients with chronic urticaria. Allergy. 2009;64(11):1616-1622. DOI: 10.1111/j.1398-9995.2009.02069.x. PMID: 19485983.

Degirmenci PB, Kırmaz C, Vatansever S, et al. Analysis of the association of chronic spontaneous urticaria with interlekin-4, -10, transforming growth factor-β1, interferon-γ, interleukin-17A and -23 by autologous serum skin test. Postepy Dermatol Alergol. 2017;34(1):70-76. DOI: 10.5114/pdia.2016.57679. PMID: 28261034. PMCID: PMC5329100.

Irinyi B, Aleksza M, Antal-Szalmás P, Sipka S, Hunyadi J, Szegedi A. Cytokine production of CD4+ and CD8+ peripheral T lymphocytes in patients with chronic idiopathic urticaria. Acta Derm Venereol. 2002;82(4):249-253. DOI: 10.1080/000155502320323199. PMID: 12361127.

Weller K, Groffik A, Church MK, et al. Development and validation of the Urticaria Control Test: a patient-reported outcome instrument for assessing urticaria control. J Allergy Clin Immunol. 2014;133(5):1365-1372, 1372.e1-6. DOI: 10.1016/j.jaci.2013.12.1076. PMID: 24522090.

Kocatürk E, Kızıltaç U, Can P, et al. Validation of the Turkish version of the Urticaria Control Test: Correlation with other tools and comparison between spontaneous and inducible chronic urticaria. World Allergy Organ J. 2019;12(1):100009. DOI: 10.1016/j.waojou.2018.11.007. PMID: 30937134. PMCID: PMC6439411.

Baiardini I, Pasquali M, Braido F, et al. A new tool to evaluate the impact of chronic urticaria on quality of life: chronic urticaria quality of life questionnaire (CU-QoL). Allergy. 2005;60(8):1073-1078. DOI: 10.1111/j.1398-9995.2005.00833.x. PMID: 15969690.

Kocatürk E, Weller K, Martus P, et al. Turkish version of the chronic urticaria quality of life questionnaire: cultural adaptation, assessment of reliability and validity. Acta Derm Venereol. 2012;92(4):419-425. DOI: 10.2340/00015555-1199. PMID: 21918791.

Atwa MA, Emara AS, Youssef N, Bayoumy NM. Serum concentration of IL-17, IL-23 and TNF-α among patients with chronic spontaneous urticaria: association with disease activity and autologous serum skin test. J Eur Acad Dermatol Venereol. 2014;28(4):469-474. DOI: 10.1111/jdv.12124. PMID: 23451767.

Walsh LJ, Trinchieri G, Waldorf HA, Whitaker D, Murphy GF. Human dermal mast cells contain and release tumor necrosis factor alpha, which induces endothelial leukocyte adhesion molecule 1. Proc Natl Acad Sci U S A. 1991;88(10):4220-4224. DOI: 10.1073/pnas.88.10.4220. PMID: 1709737. PMCID: PMC51630.

Noga O, Hanf G, Brachmann I, et al. Effect of omalizumab treatment on peripheral eosinophil and T-lymphocyte function in patients with allergic asthma. J Allergy Clin Immunol. 2006;117(6):1493-1499. DOI: 10.1016/j.jaci.2006.02.028. PMID: 16751018.

Sand FL, Thomsen SF. TNF-Alpha Inhibitors for Chronic Urticaria: Experience in 20 Patients. J Allergy (Cairo). 2013;2013:130905. DOI: 10.1155/2013/130905. PMID: 24167521. PMCID: PMC3791586.

Kasperska-Zajac A, Grzanka A, Damasiewicz-Bodzek A. IL-6 Transsignaling in Patients with Chronic Spontaneous Urticaria. PLoS One. 201;10(12):e0145751. DOI: 10.1371/journal.pone.0145751. PMID: 26699882. PMCID: PMC4689405.

Ucmak D, Akkurt M, Toprak G, Yesilova Y, Turan E, Yıldız I. Determination of dermatology life quality index, and serum C-reactive protein and plasma interleukin-6 levels in patients with chronic urticaria. Postepy Dermatol Alergol. 2013;30(3):146-151. DOI: 10.5114/pdia.2013.35615. PMID: 24278066. PMCID: PMC3834718.

Kasperska-Zajac A, Sztylc J, Machura E, Jop G. Plasma IL-6 concentration correlates with clinical disease activity and serum C-reactive protein concentration in chronic urticaria patients. Clin Exp Allergy. 2011;41(10):1386-1391. DOI: 10.1111/j.1365-2222.2011.03789.x. PMID: 21645137.

Rasool R, Ashiq I, Shera IA, Yousuf Q, Shah ZA. Study of serum interleukin (IL) 18 and IL-6 levels in relation with the clinical disease severity in chronic idiopathic urticaria patients of Kashmir (North India). Asia Pac Allergy. 2014;4(4):206-211. DOI: 10.5415/apallergy.2014.4.4.206. PMID: 25379480. PMCID: PMC4215435.

Metz M, Krull C, Maurer M. Histamine, TNF, C5a, IL-6, -9, -18, -31, -33, TSLP, neopterin, and VEGF are not elevated in chronic spontaneous urticaria. J Dermatol Sci. 2013;70(3):222-225. DOI: 10.1016/j.jdermsci.2013.03.003. PMID: 23602531.

Noga O, Hanf G, Kunkel G. Immunological and clinical changes in allergic asthmatics following treatment with omalizumab. Int Arch Allergy Immunol. 2003;131(1):46-52. DOI: 10.1159/000070434. PMID: 12759489.

Kay AB, Clark P, Maurer M, Ying S. Elevations in T-helper-2-initiating cytokines (interleukin-33, interleukin-25 and thymic stromal lymphopoietin) in lesional skin from chronic spontaneous ('idiopathic') urticaria. Br J Dermatol. 2015;172(5):1294-1302. DOI: 10.1111/bjd.13621. PMID: 25523947.

Kocatürk E, Maurer M, Metz M, Grattan C. Looking forward to new targeted treatments for chronic spontaneous urticaria. Clin Transl Allergy. 2017;7:1. DOI: 10.1186/s13601-016-0139-2. PMID: 28078079. PMCID: PMC5223554.

Raap U, Wichmann K, Bruder M, Ständer S, Wedi B, Kapp A, Werfel T. Correlation of IL-31 serum levels with severity of atopic dermatitis. J Allergy Clin Immunol. 2008;122(2):421-423. DOI: 10.1016/j.jaci.2008.05.047. PMID: 18678344.

Kasraie S, Niebuhr M, Werfel T. Interleukin (IL)-31 induces pro-inflammatory cytokines in human monocytes and macrophages following stimulation with staphylococcal exotoxins. Allergy. 2010;65(6):712-721. DOI: 10.1111/j.1398-9995.2009.02255.x. PMID: 19889120.

Lin W, Zhou Q, Liu C, Ying M, Xu S. Increased plasma IL-17, IL-31, and IL-33 levels in chronic spontaneous urticaria. Sci Rep. 2017;7(1):17797. DOI: 10.1038/s41598-017-18187-z. PMID: 29259273. PMCID: PMC5736548.

Raap U, Gehring M, Kleiner S, et al. Human basophils are a source of - and are differentially activated by - IL-31. Clin Exp Allergy. 2017;47(4):499-508. DOI: 10.1111/cea.12875. PMID: 28000952.

Grimstad O, Sawanobori Y, Vestergaard C, et al. Anti-interleukin-31-antibodies ameliorate scratching behaviour in NC/Nga mice: a model of atopic dermatitis. Exp Dermatol. 2009;18(1):35-43. DOI: 10.1111/j.1600-0625.2008.00766.x. PMID: 19054054.

Raap U, Weißmantel S, Gehring M, Eisenberg AM, Kapp A, Fölster-Holst R. IL-31 significantly correlates with disease activity and Th2 cytokine levels in children with atopic dermatitis. Pediatr Allergy Immunol. 2012;23(3):285-288. DOI: 10.1111/j.1399-3038.2011.01241.x. PMID: 22509760.

Neis MM, Peters B, Dreuw A, et al Enhanced expression levels of IL-31 correlate with IL-4 and IL-13 in atopic and allergic contact dermatitis. J Allergy Clin Immunol. 2006;118(4):930-937. DOI: 10.1016/j.jaci.2006.07.015. PMID: 17030248.

Raap U, Wieczorek D, Gehring M, et al. Increased levels of serum IL-31 in chronic spontaneous urticaria. Exp Dermatol. 2010;19(5):464-466. DOI: 10.1111/j.1600-0625.2010.01067.x. PMID: 20163453.

Sharma P, Sharma PK, Chitkara A, Rani S. To Evaluate the Role and Relevance of Cytokines IL-17, IL-18, IL-23 and TNF-α and Their Correlation with Disease Severity in Chronic Urticaria. Indian Dermatol Online J. 2020;11(4):594-597. DOI: 10.4103/idoj.IDOJ_396_19. PMID: 32832449. PMCID: PMC7413447.

Chen Q, Zhong H, Chen WC, et al. Different expression patterns of plasma Th1-, Th2-, Th17- and Th22-related cytokines correlate with serum autoreactivity and allergen sensitivity in chronic spontaneous urticaria. J Eur Acad Dermatol Venereol. 2018;32(3):441-448. DOI: 10.1111/jdv.14541. PMID: 28846158.

Giménez-Arnau AM, DeMontojoye L, Asero R, et al. The Pathogenesis of Chronic Spontaneous Urticaria: The Role of Infiltrating Cells. J Allergy Clin Immunol Pract. 2021;9(6):2195-2208. DOI: 10.1016/j.jaip.2021.03.033. PMID: 33823316.