Cholinergic urticaria

Cholinergic urticaria is a type of hives (urticaria) that is triggered by an increase in body temperature, such as during exercise, sweating, or exposure to heat. It is also sometimes called exercise-induced urticaria or heat hives. The condition is caused by an overreaction of the immune system to the release of histamine and other chemicals in response to the increase in body temperature. This results in the characteristic red, itchy, and sometimes raised bumps or welts on the skin that are associated with hives.

Cholinergic urticaria
CU on the volar aspect of the forearm
SpecialtyDermatology Edit this on Wikidata
SymptomsTiny very itchy wheals and small bumps on a reddish background.[1]

Cholinergic urticaria can be painful and uncomfortable and may interfere with daily activities.

Symptoms

Cholinergic urticaria typically presents with a number of small, short-lasting hives but may also involve cutaneous inflammation (wheals) and pain which develops usually in response to exercise, bathing, staying in a heated environment, or emotional stress.[2][3] Although the symptoms subside rapidly, commonly within 1 hour, cholinergic urticaria may significantly impair quality of life, especially in relation to sporting activities.[4]

Causes

Subtypes

Sweat hypersensitivity

This subtype of CU refers to those who are hypersensitive to their own sweat.

Diagnosis

Diagnosis is made by injecting autologous (the person's own) sweat into the skin.[5]

Features

The hives are observed to coincide with perspiration points of sweating.[6]

Pathophysiology

Tanaka et al. found that the sweat hyper-sensitivities of CU and atopic dermatitis seem to be virtually the same, and therefore, the sweat-induced histamine release from basophils may also be mediated by a specific IgE for sweat in atopic dermatitis as well as CU.[6]

Treatment
  • Proposed first-line treatment: Rapid desensitization protocol using autologous sweat.[5]
  • Non-pharmacological treatment: Forced perspiration by excessive body warming (hot bath or exercise) used daily may reduce the symptoms through exhaustion of inflammatory mediators.[7] This non-pharmacological treatment is contraindicated in those with CU as a result of hypohidrosis (see below).
  • Antihistamines are a commonly prescribed first-line treatment for conventional urticaria, but its effectiveness in the treatment of CU is rather limited in most cases.[8] Some research suggests that first-generation antihistamines with anticholinergic properties such as diphenhydramine are most successful at treating CU.
  • Treatment(s) with mixed success: omalizumab (anti-IgE therapy),[9][10] danazol (synthetic androgen),[11] propranolol (beta blocker),[12][13] zileuton (antileukotriene).

Acquired anhidrosis and/or hypohidrosis

This subtype of CU refers to those who have abnormally reduced sweating.

Diagnosis

Sweat is readily visualized by a topical indicator such as iodinated starch or sodium alizarin sulphonate. Both undergo a dramatic colour change when moistened by sweat. A thermoregulatory sweat test evaluates the body's response to a thermal stimulus by inducing sweating through the use of a hot box ⁄ room, thermal blanket or exercise. Failure of the topical indicator to undergo a colour change during thermoregulatory sweat testing can indicate anhidrosis and/or hypohidrosis (see Minor test).[14]

A skin biopsy may reveal cellular infiltrates in sweat glands or ducts.[6]

Features

Severe heat intolerance (e.g., nausea, dizziness, and headache), and tingling, pricking, pinchy or burning pain over the entire body on exposure to hot environments or prolonged exercise which improve after cooling the body. Occurs in the absence of any causative skin, metabolic, or neurological disorders.[15]

Diagram visualizing the overflow of acetylcholine to adjacent mast cells.

Pathophysiology

[16] The wheals, hypohidrosis, and pain seems to result from the low expression levels of acetylcholinesterase (AchE) and cholinergic receptor, muscarinic 3 (CHRM3) in the eccrine gland epithelial cells.

Elevated expression levels of CCL2/MCP-1, CCL5/RANTES and CCL17/TARC which result in chemoattracted CD4+ and CD8+ T cell populations to the surrounding area may be responsible for exerting a downmodulatory effect on the AchE and CHRM3 expressions.

Corticosteroid inhibits the expressions of CCL2/MCP-1, CCL5/RANTES and CCL17/TARC. This further support the notion that CCL2/MCP-1, CCL5/RANTES and CCL17/TARC play a crucial role.

Treatment
  • First-line treatment: H1RAs are first-line therapy for patients with CholU, but many patients show only a mild to moderate response to standard H1RA doses. The addition of an H2RA was reported to be effective in patients with refractory CholU that was unresponsive to up-dosing of an H1RA. Other studies have demonstrated the efficacy of scopolamine butylbromide (an anticholinergic agent); combinations of propranolol (a b2-adrenergic blocker), antihistamines, and montelukast; and treatment and injection with botulinum toxin. [17]
  • Non-pharmacological treatment: In the absence of sweat, cold-water sprays and wet towels can be used to increase the evaporative loss of heat from the skin. Shifting to a cooler or air-conditioned environments when necessary can also reduce discomfort. In the event of severe hyperthermia (body temperature >106 °F/41 °C), drastic measures such as immersion in ice-cold water are necessary to prevent irreversible brain damage.[18]

Idiopathic

Unknown or unclassified at this time. This represents those who do not fall under any of the above categories.

Prevalence

Though overall research is limited, various studies indicate that CU is relatively common across populations with prevalence rates reportedly ranging from 5% to 20% (depending on locale, race, and age).[19][20][21] The condition is more common in young adults, and prevalence appears to peak in adults aged 26–28 (up to 20%).[19] The vast majority of cases are reported to be mild, and proportionally few individuals seek medical attention regarding the condition.

History

Cholinergic urticaria was first described by Duke[22] in 1924 as "urticaria calorica". The term cholinergic is derived from the finding that hives similar to those of CU can be evoked using cholinergic agonists (e.g. methacholine).

See also

References
  1. James, William D.; Elston, Dirk; Treat, James R.; Rosenbach, Misha A.; Neuhaus, Isaac (2020). "7. Erythema and urticaria". Andrews' Diseases of the Skin: Clinical Dermatology (13th ed.). Elsevier. pp. 151–152. ISBN 978-0-323-54753-6.
  2. Moore-Robinson, M.; Warin, R. P. (1968). "Some clinical aspects of cholinergic urticaria". The British Journal of Dermatology. 80 (12): 794–799. doi:10.1111/j.1365-2133.1968.tb11948.x. PMID 5706797. S2CID 58415911.
  3. Hirschmann, J. V.; Lawlor, F.; English, J. S.; Louback, J. B.; Winkelmann, R. K.; Greaves, M. W. (1987). "Cholinergic urticaria. A clinical and histologic study". Archives of Dermatology. 123 (4): 462–467. doi:10.1001/archderm.1987.01660280064024. PMID 3827277.
  4. Poon, E.; Seed, P. T.; Greaves, M. W.; Kobza-Black, A. (1999). "The extent and nature of disability in different urticarial conditions". The British Journal of Dermatology. 140 (4): 667–671. doi:10.1046/j.1365-2133.1999.02767.x. PMID 10233318. S2CID 731524.
  5. Kozaru, T.; Fukunaga, A.; Taguchi, K.; Ogura, K.; Nagano, T.; Oka, M.; Horikawa, T.; Nishigori, C. (2011). "Rapid Desensitization with Autologous Sweat in Cholinergic Urticaria". Allergology International. 60 (3): 277–281. doi:10.2332/allergolint.10-OA-0269. PMID 21364312.
  6. Bito, T.; Sawada, Y.; Tokura, Y. (2012). "Pathogenesis of cholinergic urticaria in relation to sweating". Allergology International. 61 (4): 539–544. doi:10.2332/allergolint.12-RAI-0485. PMID 23093795.
  7. Kobayashi, H.; Aiba, S.; Yamagishi, T.; Tanita, M.; Hara, M.; Saito, H.; Tagami, H. (2002). "Cholinergic urticaria, a new pathogenic concept: Hypohidrosis due to interference with the delivery of sweat to the skin surface". Dermatology. 204 (3): 173–178. doi:10.1159/000057877. PMID 12037443. S2CID 43259005.
  8. Nakamizo, S.; Egawa, G.; Miyachi, Y.; Kabashima, K. (2012). "Cholinergic urticaria: Pathogenesis-based categorization and its treatment options". Journal of the European Academy of Dermatology and Venereology. 26 (1): 114–116. doi:10.1111/j.1468-3083.2011.04017.x. PMID 21371134. S2CID 35802279.
  9. Metz, M.; Bergmann, P.; Zuberbier, T.; Maurer, M. (2008). "Successful treatment of cholinergic urticaria with anti-immunoglobulin E therapy". Allergy. 63 (2): 247–249. doi:10.1111/j.1398-9995.2007.01591.x. PMID 18186820. S2CID 8657377.
  10. Sabroe, R. A. (2010). "Failure of omalizumab in cholinergic urticaria". Clinical and Experimental Dermatology. 35 (4): e127–e129. doi:10.1111/j.1365-2230.2009.03748.x. PMID 19925484. S2CID 37421783.
  11. La Shell, M. S.; England, R. W. (2006). "Severe refractory cholinergic urticaria treated with danazol". Journal of Drugs in Dermatology. 5 (7): 664–667. PMID 16865874.
  12. Pachor, M. L.; Lunardi, C.; Nicolis, F.; Cortina, P.; Accordini, C.; Marchi, G.; Corrocher, R.; De Sandre, G. (1987). "Usefulness of propranolol in the treatment of cholinergic urticaria". La Clinica Terapeutica. 120 (3): 205–210. PMID 2973859.
  13. Ammann, P.; Surber, E.; Bertel, O. (1999). "Beta blocker therapy in cholinergic urticaria". The American Journal of Medicine. 107 (2): 191. doi:10.1016/S0002-9343(99)00038-8. PMID 10460061.
  14. Chia, K. Y.; Tey, H. L. (2012). "Approach to hypohidrosis". Journal of the European Academy of Dermatology and Venereology. 27 (7): 799–804. doi:10.1111/jdv.12014. PMID 23094789. S2CID 206038609.
  15. Nakazato, Y.; Tamura, N.; Ohkuma, A.; Yoshimaru, K.; Shimazu, K. (2004). "Idiopathic pure sudomotor failure: Anhidrosis due to deficits in cholinergic transmission". Neurology. 63 (8): 1476–1480. doi:10.1212/01.wnl.0000142036.54112.57. PMID 15505168. S2CID 25029977.
  16. Sawada, Y.; Nakamura, M.; Bito, T.; Sakabe, J. I.; Kabashima-Kubo, R.; Hino, R.; Kobayashi, M.; Tokura, Y. (2013). "Decreased Expression of Acetylcholine Esterase in Cholinergic Urticaria with Hypohidrosis or Anhidrosis". Journal of Investigative Dermatology. 134 (1): 276–9. doi:10.1038/jid.2013.244. PMID 23748235.
  17. doi=10.1007/s10286-017-0418-6
  18. Thami, G. P.; Kaur, S.; Kanwar, A. J. (2003). "Acquired idiopathic generalized anhidrosis: A rare cause of heat intolerance". Clinical and Experimental Dermatology. 28 (3): 262–264. doi:10.1046/j.1365-2230.2003.01208.x. PMID 12780708. S2CID 1547067.
  19. Zuberbier, T.; Althaus, C.; Chantraine-Hess, S.; Czarnetzki, B. M. (1994). "Prevalence of cholinergic urticaria in young adults". Journal of the American Academy of Dermatology. 31 (6): 978–981. doi:10.1016/S0190-9622(94)70267-5. PMID 7962780.
  20. Silpa-Archa, N.; Kulthanan, K.; Pinkaew, S. (2011). "Physical urticaria: Prevalence, type and natural course in a tropical country". Journal of the European Academy of Dermatology and Venereology. 25 (10): 1194–1199. doi:10.1111/j.1468-3083.2010.03951.x. PMID 21175877. S2CID 23090828.
  21. Godse, K.; Farooqui, S.; Nadkarni, N.; Patil, S. (2013). "Prevalence of cholinergic urticaria in Indian adults". Indian Dermatology Online Journal. 4 (1): 62–63. doi:10.4103/2229-5178.105493. PMC 3573461. PMID 23437429.
  22. DDuke, W. W. (1924). "Urticaria Caused Specifically by the Action of Physical Agents". JAMA: The Journal of the American Medical Association. 83: 3–9. doi:10.1001/jama.1924.02660010007002.
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