Cholinergic urticaria: novel aspects of pathogenesis, diagnosis and management
- Authors: Borzova E.Y.1,2, Popova C.Y.1, Kurowski M.3, Rukhadze M.T.4,5, Darlenski R.6, Zaborova V.A.1, Kurshev V.V.1
-
Affiliations:
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
- Veltischev Research and Clinical Institute for Pediatrics
- Medical University of Lodz
- Center of Allergy and Immunology
- Teaching University Geomedi
- Trakia University
- Issue: Vol 24, No 3 (2021)
- Pages: 211-226
- Section: DERMATOLOGY
- URL: https://rjsvd.com/1560-9588/article/view/72329
- DOI: https://doi.org/10.17816/dv72329
- ID: 72329
Cite item
Abstract
Cholinergic urticaria (CholU) is a chronic inducible urticaria, characterised by itchy pinpoint wheals up to 3 mm in diameter, surrounded by a prominent flare, that occur following an exposure to characteristic triggers such as active or passive heating, physical exercise, emotions, hot or spicy foods.
Key pathophysiologic mechanisms include immediate hypersensitivity to autologous sweat antigens, functional sweating disorders, impaired acethylcholine metabolism, abnormal skin vascular permeability and disturbed skin innervation.
Clinical manifestations of CholU may vary from typical itchy pinpoint urticarial lesions, angioedema to anaphylaxis. Atypical CholU forms include cholinergic pruritus, cholinergic dermographism, cold cholinergic urticaria and persistent cholinergic erythema.
The diagnosis of cholinergic urticaria relies on patient’s history, clinical manifestations and challenge tests.
Treatment options include nonsedating H1 antihistamines in standard or increased doses. The evidence is accumulating for the use of biological treatment with omalizumab in cholinergic urticaria. The prospect of personalized treatment of cholinergic urticaria include autologous sweat desensitization.
The main research efforts in ColdU are directed at optimizing diagnostic approaches and developing innovative therapeutic options.
Full Text

About the authors
Elena Yu. Borzova
I.M. Sechenov First Moscow State Medical University (Sechenov University); Veltischev Research and Clinical Institute for Pediatrics
Author for correspondence.
Email: eborzova@gmail.com
ORCID iD: 0000-0003-1587-9137
SPIN-code: 4779-7664
MD, Dr. Sci. (Med.), Professor
Russian Federation, 4/1 Bolshaya Pirogovskaya street, 119991, Moscow; MoscowChristina Yu. Popova
I.M. Sechenov First Moscow State Medical University (Sechenov University)
Email: popova.derm@gmail.com
ORCID iD: 0000-0002-7855-6207
Postgraduate Student
Russian Federation, 4/1 Bolshaya Pirogovskaya street, 119991, MoscowMarcin Kurowski
Medical University of Lodz
Email: marcin.kurowski@umed.lodz.pl
ORCID iD: 0000-0002-0653-7533
MD, Professor, Clinics of Immunology and Allergy
Poland, LodzMaia T. Rukhadze
Center of Allergy and Immunology; Teaching University Geomedi
Email: maiarukhadze@gmail.com
ORCID iD: 0000-0002-1413-8161
MD, Dr. Sci. (Med.), Professor
Georgia, Tbilisi; TbilisiRazvigor Darlenski
Trakia University
Email: darlenski@abv.bg
ORCID iD: 0000-0002-4220-8040
MD, Dr. Sci. (Med.)
Bulgaria, Stara ZagoraViktoriya A. Zaborova
I.M. Sechenov First Moscow State Medical University (Sechenov University)
Email: vaz111v@gmail.com
ORCID iD: 0000-0001-5044-1152
MD, Dr. Sci. (Med.), Professor
Russian Federation, 4/1 Bolshaya Pirogovskaya street, 119991, MoscowVladislav V. Kurshev
I.M. Sechenov First Moscow State Medical University (Sechenov University)
Email: kurshev.vlad@gmail.com
SPIN-code: 2766-3925
MD, Cand. Sci. (Med.), Assistant
Russian Federation, 4/1 Bolshaya Pirogovskaya street, 119991, MoscowReferences
- Araviyskaya ER, Sokolovsky EV, Gallyamova YuA. Russian Society of Dermatologists and Cosmetologists. Federal clinical guidelines for the management of patients with urticaria. Federal clinical guidelines. Dermatovenerology 2015: Skin diseases. Sexually transmitted infections. 5th ed. revised and updated. Moscow: Delovoy Express; 2016. 768 p. (In Russ).
- Danilycheva IV, Ilyina NI, Luss LV, et al. Federal clinical guidelines. Urticaria. Russian Allergological Journal. 2018;(5):47–62. (In Russ).
- Magerl M, Altrichter S, Borzova E, et al. The definition, diagnostic testing, and management of chronic inducible urticarias ― The EAACI/GA(2)LEN/EDF/UNEV consensus recommendations 2016 update and revision. Allergy. 2016;71(6):780–802. doi: 10.1111/all.12884
- Fukunaga A, Washio K, Hatakeyama M, et al. Cholinergic urticaria: epidemiology, physiopathology, new categorization, and management. Clin Auton Res. 2018;28(1):103–113. doi: 10.1007/s10286-017-0418-6
- Ruft J, Asady A, Staubach P, et al. Development and validation of the Cholinergic Urticaria Quality-of-Life Questionnaire (CholU-QoL). Clin Exp Allergy. 2018;48(4):433–444. doi: 10.1111/cea.13102
- Maurer M. Urticaria and angioedema. Chem Immunol Allergy. 2014;100:101–104. doi: 10.1159/000358614
- Duke WW. Urticaria caused specifically by the action of physical agents. J Am Med Assoc. 1924;5:3–9. doi: 10.1001/jama.1924.02660010007002
- Zuberbier T, Althaus C, Chantraine-Hess S, Czarnetzki BM. Prevalence of cholinergic urticaria in young adults. J Am Acad Dermatol. 1994;31(6):978–981. doi: 10.1016/s0190-9622(94)70267-5
- Godse K, Farooqui S, Nadkarni N, Patil S. Prevalence of cholinergic urticaria in Indian adults. Indian Dermatol Online J. 2013;4:62–63. doi: 10.4103/2229-5178.105493
- Moore-Robinson M, Warin RP. Some clinical aspects of cholinergic urticaria. Br J Dermatol. 1968;80(12):794–799. doi: 10.1111/j.1365-2133.1968.tb11948.x
- Rujitharanawong Ch, Tuchinda P, Chularojanamontri L, et al. Cholinergic urticaria: clinical presentation and natural history in a tropical country. BioMed Research International. 2020;1:6. doi: 10.1155/2020/7301652
- Mikhailov P, Berova N, Andreev VC. Physical urticaria and sport. Cutis. 1977;20(3):381–390.
- Kaplan AP, Gray L, Shaff RE, et al. In vivo studies of mediator release in cold urticaria and cholinergic urticaria. J Allergy Clin Immunol. 1975;55:394–402. doi: 10.1016/0091-6749(75)90078-0
- Dice JP. Physical urticaria. Immunol Allergy Clin North Am 2004;24:225–246. doi: 10.1016/j.iac.2004.01.005
- Sawada Y, Nakamura M, Hino R, Tokura Y. Cholinergic urticaria: studies on the muscarinic cholinergic receptor M3 in anhidrotic and hypohidrotic skin. J Investig Dermatol. 2010;130(11):2683–2686. doi: 10.1038/jid.2010.188
- Adachi J, Aoki T, Yamatodani A. Demonstration of sweat allergy in cholinergic urticaria. J Dermatol Sci. 1994;7(2):142–149. doi: 10.1016/0923-1811(94)90088-4
- Kurzen H, Schallreuter KU. Novel aspects in cutaneous biology of acetylcholine synthesis and acetylcholine receptors. Exp Dermatol. 2004;13(Suppl 4):27–30. doi: 10.1111/j.1600-0625.2004.00258.x
- Bito T, Sawada Y, Tokura Y. Pathogenesis of cholinergic urticaria in relation to sweating. Allergol Int. 2012;61(4):539–544. doi: 10.2332/allergolint.12-RAI-0485
- Commens CA, Greaves MW. Tests to establish the diagnosis in cholinergic urticaria. Br J Dermatol. 1978;98:47–51. doi: 10.1111/j.1365-2133.1978.tb07332.x
- Magnus IA, Thompson RH. Cholinesterase levels in the skin in cholinogenic urticaria and pruritus. Br J Dermatol. 1956;68:283–289. doi: 10.1111/j.1365-2133.1956.tb12819.x
- Takahashi K, Soda R, Kishimoto T, et al. The reactivity of dispersed human lung mast cells and peripheral blood basophils to acetylcholine. Arerugi. 1992;41:686–692.
- Sawada Y, Nakamura M, Bito T, et al. Decreased expression of acetylcholine esterase in cholinergic urticaria with hypohidrosis or anhidrosis. J Investig Dermatol. 2014;134:276–279. doi: 10.1038/jid.2013.244
- Shelley WB, Shelley ED, Ho AK. Cholinergic urticaria: acetylcholine-receptor-dependent immediate-type hypersensitivity reaction to copper. Lancet. 1983;1(8329):843–846. doi: 10.1016/s0140-6736(83)91386-7
- Horikawa T, Fukunaga A, Nishigori C. New concepts of hive formation in cholinergic urticaria. Curr Allergy Asthma Reports 2009;9:273–279. doi: 10.1007/s11882-009-0038-x
- Soter NA, Wasserman SI, Austen F, Regis McFadden E. Release of mast-cell mediators and alterations in lung function in patients with cholinergic urticaria. NEJM. 1980;302(11):604–608. doi: 10.1056/NEJM198003133021104
- Murphy GM, Greaves MW, Zollman PE, Winkelmann RK. Cholinergic urticaria, passive transfer experiments from human to monkey. Dermatologica. 1988;177(6):338–340. doi: 10.1159/000248603
- Illig L, Heinicke A. Zur Pathogenese der cholinergischen Urticaria. IV. Zur Frage einer echten Antigen-Antikörperreaktion [On the pathogenesis of cholinergic urticaria. IV. On the problem of a true antigen-antibody reaction]. Arch Klin Exp Dermatol. 1967;229(4):360–371.
- Sabroe RA, Grattan CE, Francis DM, et al. The autologous serum skin test: a screening test for autoantibodies in chronic idiopathic urticaria. Br J Dermatol. 1999;140:446–452. doi: 10.1046/j.1365-2133.1999.02707.x
- Takahagi S, Tanaka T, Ishii K, et al. Sweat antigen induces histamine release from basophils of patients with cholinergic urticaria associated with atopic diathesis. Br J Dermatol. 2009;160:426–428. doi: 10.1111/j.1365-2133.2008.08862.x
- Hiragun T, Ishii K, Hiragun M, et al. Fungal protein MGL_1304 in sweat is an allergen for atopic dermatitis patients. J Allergy Clin Immunol. 2013;132(608-615):e604. doi: 10.1016/j.jaci.2013.03.047
- Kobayashi H, Aiba S, Yamagishi T, et al. Cholinergic urticaria, a new pathogenic concept: hypohidrosis due to interference with the delivery of sweat to the skin surface. Dermatology. 2002;3:173–178. doi: 10.1159/000057877
- Abajian M, Schoepke N, Altrichter S, et al. Physical urticarias and cholinergic urticarias. Immunol Allergy Clin North Am 2014;34(1):73–88. doi: 10.1016/j.iac.2013.09.010
- Dai X, Okazaki H, Hanakawa Y, et al. Eccrine sweat contains IL-1a, IL-1b and IL-31 and activates epidermal keratinocytes as a danger signal. PLoS One. 2013;8(7):e67666. doi: 10.1371/journal.pone.0067666
- Nakamizo S, Egawa G, Miyachi Y, Kabashima K. Cholinergic urticaria: pathogenesis-based categorization and its treatment options. J Eur Acad Dermatol Venereol. 2011;26:114–116. doi: 10.1111/j.1468-3083.2011.04017.x
- James MP, Eady RA, Kobza-Black A, et al. Physical urticaria: a microscopical and pharmacological study of mast cell involvement, abstracted. J Invest Dermatol. 1980;74:451.
- Haas N, Schadendorf D, Henz BM. Differential endothelial adhesion molecule expression in early and late whealing reactions. Int Arch Allergy Immunol. 1998;115(3):210–214. doi: 10.1159/000023902
- Winkelmann RK. The histology and immunopathology of dermographism. J Cutan Pathol. 1985;12(6):486–492. doi: 10.1111/j.1600-0560.1985.tb00447.x
- Federal clinical guidelines for the treatment of urticaria. Russian Association of Allergologists and Immunologists; 2019. (In Russ).
- 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;73:1393–1414. doi: 10.1111/all.13397
- Maurer M, Fluhr JW, Kha DA. How to approach chronic inducible urticaria. J Allergy Clin Immunol Pract. 2018;6(4):1119–1130. doi: 10.1016/j.jaip.2018.03.007
- Komarow HD, Arceo S, Young M, et al. Metcalfe dissociation between history and challenge in patients with physical urticaria. J Allergy Clin Immunol Pract. 2014;2(6):786–790. doi: 10.1016/j.jaip.2014.07.008
- Vadas P, Sinilaite А, Chaim M. Cholinergic urticaria with anaphylaxis: an underrecognized clinical entity. J Allergy Clin Immunol Pract. 2016;4(2):284–291. doi: 10.1016/j.jaip.2015.09.021
- Montgomery MD. Cholinergic urticaria and exercise-induced anaphylaxis. Curr Sports Med Rep. 2015;14(1):61–63. doi: 10.1249/jsr.0000000000000111
- Ilyina NI, Zabolotskikh IB, Astafyeva NG, et al. Anaphylactic shock. Clinical recommendations of the Russian Association of Allergologists and Clinical Immunologists and the All-Russian Public organization “Federation of Anesthesiologists and Resuscitators”. Bulletin of Intensive care named after A.I. Saltanov. 2020;(3):15–26. (In Russ). doi: 10.21320/1818-474X-2020-3-15-26
- Petalas K, Kontou-Fili K, Gratziou C. Bronchial hyperresponsiveness in patients with cholinergic urticaria. Ann Allergy Asthma Immunol. 2009;102(5):416–421. doi: 10.1016/S1081-1206(10)60514-5
- Mayou SC, Kobza Black A, Eady RA, Greaves MW. Cholinergic dermographism. Br J Dermatol. 1986;115(3):371–377. doi: 10.1111/j.1365-2133.1986.tb05754.x
- Oda Y, Fukunaga A, Tsujimoto M, et al. Combined cholinergic urticaria and cold-induced cholinergic urticaria with acquired idiopathic generalized anhidrosis. Allergol Int. 2015;64:214–215. doi: 10.1016/j.alit.2014.12.004
- Maltseva N, Borzova E, Fomina D, et al. COLD-CE steering committee. Cold urticarial ― What we know and what we do not know. Allergy. 2021;76(4):1077–1094. doi: 10.1111/all.14674
- Murphy GM, Black AK, Greaves MW. Persisting cholinergic erythema: a variant of cholinergic urticaria. Br J Dermatol. 1983;109(3):343–348. doi: 10.1111/j.1365-2133.1983.tb03551.x
- Shoenfeld Y, Harari Z, Sheonfeld Y, Keren G. Cholinergic urticaria. A seasonal disease. Arch Intern Med. 1981;141:1029–1030. doi: 10.1001/archinte.141.8.1029
- Rho NK. Cholinergic urticaria and hypohidrosis: a clinical reappraisal. Dermatology. 2006;213:357–358. doi: 10.1159/000096205
- Altrichter S, Koch K, Church MK, Maurer M. Atopic predisposition in cholinergic urticaria patients and its implications. J Eur Acad Dermatol Venereol. 2016;30:2060–2065. doi: 10.1111/jdv.13765
- Washio K, Fukunaga A, Onodera M, et al. Clinical characteristics in cholinergic urticaria with palpebral angioedema: report of 15 cases. J Dermatol Sci. 2017;85:135–137. doi: 10.1016/j.jdermsci.2016.11.001
- Anaphylactic shock. In: Allergology. Federal clinical recommendations. Ed. by R.M. Khaitov, N.I. Ilyina. Moscow: Farmarus Print Media; 2014. Р. 35–47. (In Russ).
- Itakura A, Tani Y, Kaneko N, Hide M. Impact of chronic urticaria on quality of life and work in Japan: Results of a real-world study. J Dermatol. 2018;45(8):963–970. doi: 10.1111/1346-8138.14502
- Poon E, Seed PT, Greaves MW, Kobza-Black A. The extent and nature of disability in different urticarial conditions. Br J Dermatol. 1999;140(4):667–671. doi: 10.1046/j.1365-2133.1999.02767.x
- Borzova EY. Diagnosis of chronic induced urticarial. Russian Allergological Journal. 2019;16(2):5–13. (In Russ).
- Kiistala R, Kiistala U. Local cholinergic urticaria at methacholine test site. Acta Derm Venereol. 1997;77(1):84–85.
- Volcheck GW, Li JT. Exercise-induced urticaria and anaphylaxis. Mayo Clin Proc. 1997;72(2):140–147. doi: 10.4065/72.2.140
- Payls JD, Cross D. Food-dependent exercise-induced anaphylaxis to corn. J Allergy Clin Immunol. 1998;101:853–854. doi: 10.1016/s0091-6749(98)70317-3
- Bonini M, Palange P. Anaphylaxis and sport. Curr Opin Allergy Clin Immunol. 2014;14(4):323–327. doi: 10.1097/ACI.0000000000000074
- Bennett JR. Anaphylaxis attributed to exercise: considerations for sports medicine specialists. Phys Sportsmed. 2015;43(1):1–12. doi: 10.1080/00913847.2015.1000233
- Maulitz RM, Pratt DS, Schocket AL. Exercise-induced anaphylactic reaction to shellfish. J Allergy Clin Immunol. 1979;63(6):433–434. doi: 10.1016/0091-6749(79)90218-5
- Foong R, Giovannini M, Toit G. Food-dependent exercise-induced anaphylaxis. Curr Opin Allergy Clin Immunol. 2019;19(3):224–228. doi: 10.1097/ACI.0000000000000531
- Kounis NG, Kounis GN, Soufras GD. Exercise-induced urticaria, cholinergic urticaria, and Kounis syndrome. J Pharmacol Pharmacother. 2016;7(1):48–50. doi: 10.4103/0976-500X.179355
- Castells MC, Horan RF, Sheffer AL. Exercise-induced anaphylaxis. Curr Allergy Asthma Rep. 2003;3(1):15–21. doi: 10.1007/s11882-003-0005-x
- Luong KV, Nguyen LT. Aquagenic urticaria: report of a case and review of the literature. Ann Allergy Asthma Immunol. 1998;80:483–485. doi: 10.1016/S1081-1206(10)63071-2
- Kawakami Y, Gokita M, Fukunaga A, Nishigori C. Refractory case of adrenergic urticaria successfully treated with clotiazepam. J Dermatol. 2015;42:635–637. doi: 10.1111/1346-8138.12855
- Muraro A, Roberts G, Worm M, et al. EAACI Food Allergy and Anaphylaxis Guidelines Group. Anaphylaxis: guidelines from the European Academy of Allergy and Clinical Immunology. Allergy. 2014;69(8):1026–1045. doi: 10.1111/all.12437
- Kobza Black A, Aboobaker J, Gibson JR, et al. Acrivastine versus hydroxyzine in the treatment of cholinergic urticaria. A placebo-controlled study. Acta Dermatovenereol. 1988;68:541–544.
- Zuberbier T, Aberer W, Burtin B, et al. Efficacy of cetirizine in cholinergic urticaria. Acta Dermatovenereol. 1995;75:147–149. doi: 10.2340/0001555575147149
- Zuberbier T, Munzberger C, Haustein U, et al. Double-blind crossover study of high-dose cetirizine in cholinergic urticaria. Dermatology. 1996;193:324–327. doi: 10.1159/000246281
- Wosny K, Weller K, Werner A, et al. Antihistamine updosing reduces disease activity in difficult-to-treat cholinergic urticaria patients. J Allergy Clin Immunol. 2016;138(5):1483–1485.e9. doi: 10.1016/j.jaci.2016.05.026
- Dressler C, Werner RN, Eisert L, et al. Maurer M. Chronic inducible urticaria: a systematic review of treatment options. J Allergy Clin Immunol. 2018;141(5):1726–1734. doi: 10.1016/j.jaci.2018.01.031
- Ghazanfar MN, Holm JG, Thomsen SF. Omalizumab for cholinergic urticaria: 6 months prospective study and systematic review of the literature. Dermatol Ther. 2020;33(6):e14010. doi: 10.1111/dth.14010
- Gastaminza G, Azofra J, Nunez-Cordoba JM, et al. Efficacy and safety of omalizumab (xolair) for cholinergic urticaria in patients unresponsive to a double dose of antihistamines: a randomized mixed double-blind and open-label placebo-controlled clinical trial. J Allergy Clin Immunol Pract. 2019;7(5):1599–1609.e1. doi: 10.1016/j.jaip.2018.12.025
- Metz M, Ohanyan T, Church MK, Maurer M. Omalizumab is an effective and rapidly acting therapy in difficult-to-treat chronic urticaria: a retrospective clinical analysis. J Dermatol Sci. 2014;73(1):57–56. doi: 10.1016/j.jdermsci.2013.08.011
- Maurer M, Metz M, Brehler R, et al. Omalizumab treatment in patients with chronic inducible urticaria: a systematic review of published evidence. J Allergy Clin Immunol. 2018;141(2):638–649. doi: 10.1016/j.jaci.2017.06.032
- Sabroe RA. Failure of omalizumab in cholinergic urticaria. Clin Exp Dermatol. 2010;35(4):e127–129. doi: 10.1111/j.1365-2230.2009.03748.x
- Ujiie H, Shimizu T, Natsuga K, et al. Severe cholinergic urticaria successfully treated with scopolamine butylbromide in addition to antihistamines. Clin Exp Dermatol. 2006;31(4):588–589. doi: 10.1111/j.1365-2230.2006.02117.x
- Feinberg JH, Toner CB. Successful treatment of disabling cholinergic urticaria. Mil Med 2008;173(2):217–220. doi: 10.7205/milmed.173.2.217
- Sheraz A, Halpern S. Cholinergic urticaria responding to botulinum toxin injection for axillary hyperhidrosis. Br J Dermatol. 2013;168(6):1369–1370. doi: 10.1111/bjd.12200
- La Shell MS, England RW. Severe refractory cholinergic urticaria treated with danazol. J Drugs Dermatol. 2006;5(7):664–667.
- Kozaru T, Fukunaga A, Taguchi K, et al. Rapid desensitization with autologous sweat in cholinergic urticaria. Allergol Int. 2011;60(3): 277–281. doi: 10.2332/allergolint.10-OA-0269
- Tanaka T, Ishii K, Suzuki H, et al. Cholinergic urticaria successfully treated by immunotherapy with partially purified sweat antigen. Arerugi. 2007;56:54–57.
Supplementary files
