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Research Article| Volume 103, ISSUE 1, P10-15, July 2021

Acetylcholine-induced whealing in cholinergic urticaria – What does it tell us?

  • Author Footnotes
    1 Equal distribution.
    Sabine Altrichter
    Footnotes
    1 Equal distribution.
    Affiliations
    Dermatological Allergology, Allergie-Centrum-Charité, Dpt. of Dermatology and Allergy, Charité – Universitätsmedizin Berlin, Germany

    Department of Dermatology and Venerology, Kepler University Hospital, Linz, Austria
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  • Author Footnotes
    1 Equal distribution.
    Yiyu Wang
    Footnotes
    1 Equal distribution.
    Affiliations
    Dermatological Allergology, Allergie-Centrum-Charité, Dpt. of Dermatology and Allergy, Charité – Universitätsmedizin Berlin, Germany

    Department of Dermatology, The General Hospital of Air Force, Haidian District, Beijing, China
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  • Pia Schumacher
    Affiliations
    Dermatological Allergology, Allergie-Centrum-Charité, Dpt. of Dermatology and Allergy, Charité – Universitätsmedizin Berlin, Germany
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  • Ola Alraboni
    Affiliations
    Dermatological Allergology, Allergie-Centrum-Charité, Dpt. of Dermatology and Allergy, Charité – Universitätsmedizin Berlin, Germany
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  • Martin K. Church
    Affiliations
    Dermatological Allergology, Allergie-Centrum-Charité, Dpt. of Dermatology and Allergy, Charité – Universitätsmedizin Berlin, Germany
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  • Marcus Maurer
    Correspondence
    Corresponding author at: Dermatological Allergology, Allergie-Centrum-Charité, Dpt. of ermatology and Allergy, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany.
    Affiliations
    Dermatological Allergology, Allergie-Centrum-Charité, Dpt. of Dermatology and Allergy, Charité – Universitätsmedizin Berlin, Germany
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  • Author Footnotes
    1 Equal distribution.

      Highlights

      • ACh injections elicit a wheal and flare in more than 1/3 of cholinergic urticaria (CholU) patients.
      • ACh induced wheals and flares were larger and more persistent in patients than in healthy controls.
      • Positive ACh reactions correlated with larger histamine flares and sweating.
      • Positive ACh reactions were linked clinically to longer lasting symptoms in CholU patients.

      Abstract

      Background

      Cholinergic urticaria (CholU) is characterized by the occurrence of itchy wheals induced by sweating. Intradermal injections of acetylcholine (ACh) have been proposed to help with diagnosing CholU and subgrouping of patients, but controlled studies are largely missing.

      Objective

      To compare the rates of positive ACh test results in well characterized CholU patients and controls and to identify clinical features of CholU linked to ACh reactivity.

      Methods

      Acetylcholine was injected intradermally into 38 CholU patients and 73 matched healthy controls. Wheal and flare skin responses were assessed after 15 and 30 min and correlated with clinical features of CholU.

      Results

      At 15 min after intradermal injections of ACh, wheal and flare responses were significantly more frequent in CholU patients than healthy controls, wheals: 34 % vs.15% (P = 0.028); flares: 50 % vs.18 % (P <0.001). Also, wheals were 37 % and flares 172 % larger and of longer duration in CholU patients than in healthy controls (both P < 0.01). CholU patients with ACh-induced wheals (ACh+) had larger flare but not wheal responses in response to histamine than those without (ACh; P = 0.011). Also, ACh-induced wheal responses were significantly correlated with sweating (r = 0.54, P = 0.046) in CholU patients. Finally, wheal responses lasted longer in ACh+ than in ACh patients (P = 0.03).

      Conclusion

      Intradermal ACh testing does not allow for the identification of CholU patients due to its low sensitivity. ACh-induced wheals, in patients with CholU, is linked to sweating and longer lasting symptoms. Intradermal ACh testing is an interesting tool for mechanistic studies in CholU.

      Abbreviations:

      CholU (cholinergic urticaria), CSU (chronic spontaneous urticaria), ACh (acetylcholine)

      Keywords

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      References

        • Magerl M.
        • Altrichter S.
        • Borzova E.
        • Gimenez-Arnau A.
        • Grattan C.E.
        • Lawlor F.
        • 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: 780-802
        • Kim J.E.
        • Eun Y.S.
        • Park Y.M.
        • Park H.J.
        • Yu DS Kang H.
        • et al.
        Clinical characteristics of cholinergic urticaria in Korea.
        Ann. Dermatol. Venereol. 2014; 26: 189-194
        • Krupa Shankar D.S.
        • Ramnane M.
        • Rajouria E.A.
        Etiological approach to chronic urticaria.
        Indian J. Dermatol. 2010; 55: 33-38
        • Zuberbier T.
        • Althaus C.
        • Chantraine-Hess S.
        • Czarnetzki B.M.
        Prevalence of cholinergic urticaria in young adults.
        J. Am. Acad. Dermatol. 1994; 31: 978-981
        • Asady A.
        • Ruft J.
        • Ellrich A.
        • Hawro T.
        • Maurer M.
        • Altrichter S.
        Cholinergic urticaria patients of different age groups have distinct features.
        Clin. Exp. Allergy. 2017; 47: 1609-1614
        • Poon E.
        • Seed P.T.
        • Greaves M.W.
        • Kobza-Black A.
        The extent and nature of disability in different urticarial conditions.
        Br. J. Dermatol. 1999; 140: 667-671
        • Altrichter S.
        • Koch K.
        • Church M.K.
        • Maurer M.
        Atopic predisposition in cholinergic urticaria patients and its implications.
        J. Eur. Acad. Dermatol. Venereol. 2016; 30: 2060-2065
        • Horikawa T.
        • Fukunaga A.
        • Nishigori C.
        New concepts of hive formation in cholinergic urticaria.
        Curr. Allergy Asthma Rep. 2009; 9: 273-279
        • Bito T.
        • Sawada Y.
        • Tokura Y.
        Pathogenesis of cholinergic urticaria in relation to sweating.
        Allergol. Int. 2012; 61: 539-544
        • Hiragun M.
        • Hiragun T.
        • Ishii K.
        • Suzuki H.
        • Tanaka A.
        • Yanase Y.
        • et al.
        Elevated serum IgE against MGL_1304 in patients with atopic dermatitis and cholinergic urticaria.
        Allergol. Int. 2014; 63: 83-93
        • Kobayashi H.
        • Aiba S.
        • Yamagishi T.
        • Tanita M.
        • Hara M.
        • Saito H.
        • et al.
        Cholinergic urticaria, a new pathogenic concept: hypohidrosis due to interference with the delivery of sweat to the skin surface.
        Dermatology. 2002; 204: 173-178
        • Murphy G.M.
        • Smith S.E.
        • Smith S.E.A.
        • Greaves M.W.
        Autonomic function in cholinergic urticaria and atopic eczema.
        Br. J. Dermatol. 1984; 110: 581-586
        • Sawada Y.
        • Nakamura M.
        • Bito T.
        • Fukamachi S.
        • Kabashima R.
        • Sugita K.
        • et al.
        Cholinergic urticaria: studies on the muscarinic cholinergic receptor M3 in anhidrotic and hypohidrotic skin.
        J. Invest. Dermatol. 2010; 130: 2683-2686
        • Schmutzler W.
        • Delmich K.
        • Eichelberg D.
        • Gluck S.
        • Greven T.
        • Jurgensen H.
        • et al.
        The human adenoidal mast cell. Susceptibility to different secretagogues and secretion inhibitors.
        Int. Arch. Allergy Appl. Immunol. 1985; 77: 177-178
        • Tokura Y.
        Direct and indirect action modes of acetylcholine in cholinergic urticaria.
        Allergol. Int. 2020;
        • Abajian M.
        • Schoepke N.
        • Altrichter S.
        • Zuberbier T.
        • Maurer M.
        Physical urticarias and cholinergic urticaria.
        Immunol. Allergy Clin. North Am. 2014; 34: 73-88
        • Altrichter S.
        • Salow J.
        • Ardelean E.
        • Church M.K.
        • Werner A.
        • Maurer M.
        Development of a standardized pulse-controlled ergometry test for diagnosing and investigating cholinergic urticaria.
        J. Dermatol. Sci. 2014; 75: 88-93
        • Illig L.
        On the pathogenesis of cholinergic urticaria. I. Clinical observations and histological studies.
        Arch. Klin. Exp. Dermatol. 1967; 229: 231-247
        • Commens C.A.
        • Greaves M.W.
        Tests to establish the diagnosis in cholinergic urticaria.
        Br. J. Dermatol. 1978; 98: 47-51
        • Hirschmann J.V.
        • Lawlor F.
        • English J.S.
        • Louback J.B.
        • Winkelmann R.K.
        • Greaves M.W.
        Cholinergic urticaria. A clinical and histologic study.
        Arch. Dermatol. 1987; 123: 462-467
        • Itakura E.
        • Urabe K.
        • Yasumoto S.
        • Nakayama J.
        • Furue M.
        Cholinergic urticaria associated with acquired generalized hypohidrosis: report of a case and review of the literature.
        Br. J. Dermatol. 2000; 143: 1064-1066
        • Nakamizo S.
        • Egawa G.
        • Miyachi Y.
        • Kabashima K.
        Cholinergic urticaria: pathogenesis-based categorization and its treatment options.
        J. Eur. Acad. Dermatol. Venereol. 2012; 26: 114-116
        • Sawada Y.
        • Nakamura M.
        • Bito T.
        • Sakabe J.I.
        • Kabashima-Kubo R.
        • Hino R.
        • et al.
        Decreased expression of acetylcholine esterase in cholinergic urticaria with hypohidrosis or anhidrosis.
        J. Invest. Dermatol. 2014; 134: 276-279
        • Fukunaga A.
        • Washio K.
        • Hatakeyama M.
        • Oda Y.
        • Ogura K.
        • Horikawa T.
        • et al.
        Cholinergic urticaria: epidemiology, physiopathology, new categorization, and management.
        Clin. Auton. Res. 2018; 28: 103-113
        • Maurer M.
        • Metz M.
        • Bindslev-Jensen C.
        • Bousquet J.
        • Canonica G.W.
        • Church M.K.
        • et al.
        Definition, aims, and implementation of GA(2) LEN urticaria centers of reference and excellence.
        Allergy. 2016; 71: 1210-1218
        • Finlay A.Y.
        • Khan G.K.
        Dermatology Life Quality Index (DLQI)--a simple practical measure for routine clinical use.
        Clin. Exp. Dermatol. 1994; 19: 210-216
        • Diepgen T.L.
        • Sauerbrei W.
        • Fartasch M.
        Development and validation of diagnostic scores for atopic dermatitis incorporating criteria of data quality and practical usefulness.
        J. Clin. Epidemiol. 1996; 49: 1031-1038
        • Fukunaga A.
        • Bito T.
        • Tsuru K.
        • Oohashi A.
        • Yu X.
        • Ichihashi M.
        • et al.
        Responsiveness to autologous sweat and serum in cholinergic urticaria classifies its clinical subtypes.
        J. Allergy Clin. Immunol. 2005; 116: 397-402
        • Rosa A.C.
        • Fantozzi R.
        The role of histamine in neurogenic inflammation.
        Br. J. Pharmacol. 2013; 170: 38-45
        • Groene D.
        • Martus P.
        • Heyer G.
        Doxepin affects acetylcholine induced cutaneous reactions in atopic eczema.
        Exp. Dermatol. 2001; 10: 110-117
        • Heyer G.
        • Vogelgsang M.
        • Hornstein O.P.
        Acetylcholine is an inducer of itching in patients with atopic eczema.
        J. Dermatol. 1997; 24: 621-625
        • Rukwied R.
        • Heyer G.
        Cutaneous reactions and sensations after intracutaneous injection of vasoactive intestinal polypeptide and acetylcholine in atopic eczema patients and healthy controls.
        Arch. Dermatol. Res. 1998; 290: 198-204
        • Fantozzi R.
        • Masini E.
        • Blandina P.
        • Mannaioni P.F.
        • Bani-Sacchi T.
        Release of histamine from rat mast cells by acetylcholine.
        Nature. 1978; 273: 473-474
        • Blandina P.
        • Fantozzi R.
        • Mannaioni P.F.
        • Masini E.
        Characteristics of histamine release evoked by acetylcholine in isolated rat mast cells.
        J. Physiol. 1980; 301: 281-293
        • Cyphert J.M.
        • Kovarova M.
        • Allen I.C.
        • Hartney J.M.
        • Murphy D.L.
        • Wess J.
        • et al.
        Cooperation between mast cells and neurons is essential for antigen-mediated bronchoconstriction.
        J. Immunol. 2009; 182: 7430-7439
        • Asero R.
        • Tedeschi A.
        • Lorini M.
        • Cugno M.
        Antihistamines do not inhibit the flare induced by the intradermal injection of autologous plasma in chronic urticaria patients.
        Eur. Ann. Allergy Clin. Immunol. 2009; 41: 181-186
        • Chapman L.F.
        Mechanisms of the flare reaction in human skin.
        J. Invest. Dermatol. 1977; 69: 88-97
        • Green A.Q.
        • Krishnan S.T.
        • Rayman G.
        C-fiber function assessed by the laser doppler imager flare technique and acetylcholine iontophoresis.
        Muscle Nerve. 2009; 40: 985-991
        • Hiragun T.
        • Hiragun M.
        • Ishii K.
        • Kan T.
        • Hide M.
        Sweat allergy: Extrinsic or intrinsic?.
        J. Dermatol. Sci. 2017; 87: 3-9