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Inducible urticarias, aquagenic pruritus, and cholinergic pruritus
Evidence Levels: A Double-blind study B Clinical trial ≥ 20 subjects C Clinical trial < 20 subjects D Series ≥ 5 subjects E Anecdotal case reports
Inducible Urticarias
About 25% of patients with chronic urticaria have a definable and reproducible inducing trigger that distinguishes them from those with spontaneous urticaria and urticarial vasculitis. Inducible urticarias are defined by the predominant inducing stimulus ( Table 114.1 ). More than one inducing stimulus elicits urticaria in some patients, and inducible urticarias can overlap with spontaneous urticaria. Physical urticarias caused by a physical stimulus (symptomatic dermographism, delayed pressure, heat and cold contact and solar urticarias, and vibratory angioedema) are now included within the inducible urticarias.
Table 114.1
Classification of inducible urticarias by the eliciting stimulus (in approximate reducing frequency of occurrence)
| Symptomatic dermographism | Stroking or rubbing the skin |
| Cholinergic urticaria (pale, papular wheals with red flares) | Rise in core temperature and other causes of sweating (exercise, hot baths, spicy food, and stress) |
| Cold urticaria | Rewarming of skin after cooling (localized or systemic) |
| Delayed pressure urticaria | Sustained perpendicular pressure |
| Solar urticaria | Ultraviolet or visible solar radiation |
| Heat urticaria | Local heat contact |
| Aquagenic urticaria | Water contact at any temperature |
| Vibratory angioedema | Vibration |
Management Strategy
Pharmacologic
The presentation of inducible urticarias may vary in morphology and severity. Milder forms may require little more than avoidance of triggers and a preemptive dose of H 1 antihistamine around 1 hour before anticipated exposure , whereas a very severe attack involving anaphylaxis could potentially require emergency treatment with intramuscular epinephrine (adrenaline) . Acute presentations of severe inducible urticaria may require short courses of oral corticosteroids (e.g., prednisolone 0.5 mg/kg body weight daily for 5 days) in addition to regular non-sedating H 1 antihistamines. Drug management should be guided by the degree of disability or impairment in quality of life.
Non-pharmacologic
The triggering stimulus should be avoided where possible. Cold tolerance induction in cold urticaria and exercise tolerance induction in cholinergic urticaria has been described but is difficult to achieve and sustain. There is no evidence that exclusion diets are effective.
With the exceptions of testing for cryoglobulins in cold urticaria and specific IgE in food- and exercise-induced anaphylaxis, laboratory investigations are unnecessary and should not be undertaken except to monitor treatment or screen for eligibility (e.g., glucose-6-phosphatase dehydrogenase in patients being considered for dapsone or sulfasalazine).
The EAACI/GA 2 LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria
Zuberbier T, Aberer W, Asero R, et al. Allergy 2018; 73(7): 1393–414.
The latest and most quoted European guideline on urticaria.
Chronic inducible urticaria: a systematic review of treatment options
Dressler C, Werner RN, Eisert L, et al. J Allergy Clin Immunol 2018; 141(5): 1726–34.
Thirty studies on chronic inducible urticarias were identified and reviewed to inform the 2017 EAACI guideline revision.
The definition, diagnostic testing, and management of chronic inducible urticarias – the EAACI/GA(2)LEN/EDF/UNEV consensus recommendations 2016 update and revision
Magerl M, Altrichter S, Borzova E, et al. Allergy 2016; 71(6): 780–802.
A comprehensive summary of provocation testing protocols.
Cold urticaria syndromes: historical background, diagnostic classification, clinical and laboratory characteristics, pathogenesis and management
Wanderer AA. J Allergy Clin Immunol 1990; 85: 965–81.
A classic review of cold urticaria and its investigation still relevant today.
Treatments of cold urticaria: a systematic review
Kulthanan K, Hunnangkul S, Tuchinda P, et al. J Allergy Clin Immunol 2019; 143(4): 1311–31.
A recent systematic review of treatment confirming the benefit of non-sedating antihistamines, up-dosing them to fourfold, and the place of omalizumab.
Heat urticaria: a revision of published cases with an update on classification and management
Pezzolo E, Peroni A, Gisondi P, et al. Br J Dermatol 2016; 175: 473–8.
A comprehensive review of this rare subtype of inducible urticaria.
First-Line Therapy
Non-sedating antihistamines ( Table 114.2 ) should be prescribed in preference to classical antihistamines, which are often sedating and can impair psychomotor performance. Up-dosing of second-generation H 1 antihistamines is now widely practiced, although sedation at higher-than-licensed doses is a potential risk.
Table 114.2
Examples of non-sedating and mildly sedating H 1 antihistamines
| Acrivastine | Non-sedating, three-times-daily dosing |
| Bilastine | Non-sedating, once-daily dosing |
| Cetirizine | May be mildly sedating, once-daily dosing |
| Levocetirizine | Active enantiomer of cetirizine |
| Fexofenadine | Non-sedating, once-daily dosing |
| Loratadine | Non-sedating, once-daily dosing |
| Desloratadine | Active metabolite of loratadine |
| Mizolastine | Non-sedating, once-daily dosing |
| Rupatadine | Non-sedating, once-daily dosing |
High-dose desloratadine decreases wheal volume and improves cold provocation thresholds compared with standard-dose treatment in patients with acquired cold urticaria: a randomized, placebo-controlled, cross-over study
Siebenhaar F, Degener F, Zuberbier T, et al. J Allergy Clin Immunol 2009; 123: 672–9.
Fourfold up-dosing a second-generation antihistamine has additional inhibitory effects on wheal formation in cold urticaria.
Rupatadine and its effects on symptom control, stimulation time, and temperature thresholds in patients with acquired cold urticaria
Metz M, Scholz E, Ferrán M, et al. Ann Allergy Asthma Immunol 2010; 104: 86–92.
A crossover, randomized, double-blind, placebo-controlled study of double-dose rupatadine, a second-generation H 1 antihistamine. Fifty-two percent of patients showed a complete response. There was also a significant improvement in critical cold stimulation time and critical temperature threshold.
Second-Line Therapies
| Symptomatic dermographism | |
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| Cold urticaria | |
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| Heat urticaria | |
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| Delayed pressure urticaria | |
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| Solar urticaria | |
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Symptomatic Dermographism
Omalizumab is effective in symptomatic dermographism – results of a randomized placebo-controlled trial
Maurer M, Schütz A, Weller K, et al. J Allergy Clin Immunol 2017; 140(3): 870–3. e5.
Narrow-band ultraviolet B phototherapy is beneficial in antihistamine-resistant symptomatic dermographism: a pilot study
Borzova E, Rutherford A, Konstantinou G, et al. J Am Acad Dermatol 2008; 59: 752–7.
A small, open study of H 1 antihistamine–unresponsive symptomatic dermographism showing subjective and objective improvement in itch and whealing after 6 weeks’ treatment, but relapse 6–12 weeks after stopping.
In dermographic urticaria H 2 receptor antagonists have a small but therapeutically irrelevant additional effect compared with H 1 antagonists alone
Sharpe GR, Shuster S. Br J Dermatol 1993; 129: 575–9.
In this double-blind, crossover study, 19 patients were randomized to treatment with cetirizine 10 mg at night plus either ranitidine 150 mg twice daily or placebo. There was an increase in whealing threshold with additional H 2 blockade, but no subjective benefit on itch.
Addition of an H 2 to an H 1 antihistamine may provide better control of some inducible urticarias despite a lack of trial evidence. They may benefit wheal and erythema but not itch.
Cholinergic Urticaria
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
Gastaminza G, Azofra J, Nunez-Cordoba JM, et al. J Allergy Clin Immunol Pract 2019; 7(5): 1599–609. e1.
About a third of cholinergic urticaria patients became negative on an exercise challenge test after 48 weeks of treatment with omalizumab, demonstrating some benefit under conditions of the study but disappointing overall. Relapse of symptoms was seen in the majority 3 months after finishing treatment.
Real-life treatment of cholinergic urticaria with omalizumab
Altrichter S, Chuamanochan M, Knoth H, et al. J Allergy Clin Immunol 2019; 143(2): 788–91. e8.
In this retrospective analysis, six (37%) of 16 cholinergic urticaria patients had a complete response and five (31%) had useful benefit from omalizumab at different doses, the majority receiving 300 mg at some point in their treatment.
Beneficial effects of danazol on symptoms and laboratory changes in cholinergic urticaria
Wong E, Eftekhari N, Greaves MW, et al. Br J Dermatol 1987; 116: 553–6.
Seventeen male patients treated with danazol 200 mg three times daily in a double-blind, crossover study had sustained improvement in the number of exercise-induced wheals over 12 weeks.
Anabolic steroids should only be considered for severe cholinergic urticaria not responding adequately to up-dosed H 1 antihistamines, because of their potential for virilization and hepatotoxicity. Danazol should be reserved for severe cases and avoided during pregnancy. Androgenic adverse effects may be dose-limiting in women.
Severe cholinergic urticaria successfully treated with scopolamine butylbromide in addition to antihistamines
Ujiie H, Shimizu T, Natsuga K, et al. Clin Exp Dermatol 2006; 31: 978–81.
Although this case report suggests that anticholinergics may be successful for cholinergic urticaria, the general experience with this class of drugs is disappointing, and unwanted effects often outweigh any benefits.
Scopolamine butylbromide is better known as hyoscine butylbromide, approved for gastrointestinal spasm and not to be confused with hyoscine hydrobromide used for motion sickness.
Cold Urticaria
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