Cholinergic Urticaria(Cholinergic hives): Subtypes, Diagnosis, and Treatment

Introduction

Cholinergic urticaria (CholU, Cholinergic hives) is a common form of chronic inducible urticaria characterized by small, itchy wheals triggered by an increase in body temperature due to activities like exercise, hot baths, or emotional stress. Comprehensive studies by Fukunaga et al. have significantly advanced the understanding of CholU, particularly by identifying various subtypes based on distinct pathophysiological mechanisms and clinical features.

Epidemiology and Clinical Features

CholU primarily affects young adults, with a prevalence ranging from 4% to 20% in different populations. The condition typically manifests as rapid-onset, pinpoint wheals accompanied by stinging or itching sensations. More severe cases can include symptoms like angioedema or anaphylaxis. These symptoms usually resolve within an hour but can significantly impact the quality of life due to their sudden and intense nature.

Pathophysiology

The pathophysiology of CholU involves multiple mechanisms, including histamine release, sweat allergy, cholinergic stimulation, and sweat duct occlusion. These mechanisms contribute to the development of different subtypes of CholU:

Acetylcholine released from the sympathetic nerves fail to become trapped by receptors on the eccrine sweat glands resulting in overflow and activation of mast cells.

1. Histamine Release: During CholU episodes, serum histamine levels increase, triggering urticarial reactions. Histamine H1 receptor antagonists (H1RAs) are commonly used for treatment, although their effectiveness varies among patients.
2. Sweat Allergy: Some patients with CholU exhibit an allergic reaction to their own sweat. This is demonstrated by positive reactions in autologous sweat skin tests (ASwST), indicating a type I hypersensitivity reaction to sweat components like MGL_1304 from Malassezia globosa.
3. Cholinergic Stimulation: Acetylcholine, a neurotransmitter, plays a significant role in CholU. Intradermal injections of cholinergic agents such as acetylcholine can induce symptoms in some patients, suggesting that cholinergic stimulation is crucial in the pathogenesis.
4. Sweat Duct Occlusion: In some cases, the occlusion of sweat ducts leads to the leakage of sweat into the surrounding skin, triggering local inflammation and urticarial reactions. This mechanism is particularly relevant in patients with hypohidrosis or anhidrosis.

Subtypes of Cholinergic Urticaria

Fukunaga et al. have proposed four distinct subtypes of CholU based on pathogenesis and clinical features. Each subtype presents unique characteristics and requires specific diagnostic and therapeutic approaches.

Conventional Sweat Allergy-Type CholU

This subtype is characterized by a type I hypersensitivity reaction to the patient’s own sweat. Histamine is deeply involved in this subtype, and patients often have positive autologous sweat skin tests (ASwST) but negative autologous serum skin tests (ASST). There is no specific sex predominance or strong association with atopic predisposition. The primary pathological feature includes sweat allergy and sweat leaking, leading to moderate disease severity.

Follicular-Type CholU

Follicular-type CholU involves histamine but is not associated with a sweat allergy. Instead, it is linked to serum factors that trigger mast cell activation around hair follicles. Patients with this subtype usually have positive ASST results and negative ASwST results. There is no specific sex predominance or atopic predisposition identified. The pathology is primarily related to serum factors, and this subtype is considered mild in severity.

CholU with Palpebral Angioedema (CholU-PA)

This subtype is marked by severe symptoms including angioedema around the eyelids. Histamine is deeply involved, and patients often have a positive reaction to sweat allergy tests. There is a strong association with atopic conditions, and this subtype predominantly affects females. Pathologically, this subtype involves sweat allergy and pre-existing eczema, leading to severe disease severity.

CholU with Acquired Anhidrosis/Hypohidrosis

This severe subtype involves reduced or absent sweating due to abnormalities in cholinergic signaling and sweat gland function. Histamine involvement is less pronounced, and patients typically do not exhibit sweat allergies. This subtype mainly affects males and is weakly associated with atopic predisposition. The pathology includes excess acetylcholine following decreased expression of cholinergic/acetylcholine receptor M3 (CHRM3) on sweat glands and mast cells, poral occlusion, and carcinoembryonic antigen involvement.

Diagnosis

Diagnosing CholU typically involves a combination of clinical evaluation and provocation tests. Key diagnostic methods include:

1. Provocation Tests: These involve increasing the body temperature through exercise (treadmill or stationary bicycle) or a hot bath (42°C for 15 minutes). The appearance of characteristic wheals confirms the diagnosis.
2. Intradermal Injection Tests: Cholinergic agents such as acetylcholine or methacholine can be injected intradermally to observe the reaction. Positive reactions support the diagnosis of CholU.
3. Autologous Sweat Skin Test (ASwST): This test involves injecting the patient’s sweat to check for immediate-type skin reactions, indicating a sweat allergy.
4. Autologous Serum Skin Test (ASST): Used to detect serum factors that may trigger urticarial reactions. Positive results are more common in the follicular-type CholU.

Differential Diagnosis

Differential diagnosis for CholU includes other forms of inducible urticaria and conditions that can present with similar symptoms:

1. Heat Urticaria: Unlike CholU, heat urticaria is triggered specifically by direct contact with heat rather than an increase in core body temperature.
2. Cold Urticaria: Triggered by exposure to cold temperatures, this condition can sometimes coexist with CholU.
3. Aquagenic Urticaria: Characterized by wheals triggered by contact with water at any temperature.
4. Exercise-Induced Anaphylaxis: This condition can present similarly to CholU but is often associated with food intake or other specific triggers.
5. Contact Urticaria: Triggered by direct contact with an allergen rather than changes in body temperature.
6. Dermographism: This type of physical urticaria is triggered by mechanical pressure or scratching of the skin. Unlike CholU, dermographism results in linear wheals corresponding to the area of skin trauma.
7. Solar Urticaria: Triggered by exposure to ultraviolet (UV) or visible light, solar urticaria presents with erythema and wheals in areas exposed to sunlight. It differs from CholU, which is triggered by increased body temperature.
8. Adrenergic Urticaria: This rare form of urticaria is characterized by small white or pale wheals surrounded by a red flare, triggered by stress or anxiety. The wheals are smaller and less pruritic compared to those seen in CholU.

Treatment

The treatment of cholinergic urticaria (CholU) is tailored based on whether the patient has anhidrosis/hypohidrosis. The management strategies are categorized into two main groups as shown in the provided therapeutic algorithm.

Conclusion

Cholinergic urticaria (CholU) is a multifaceted condition with varying presentations depending on the underlying pathophysiological mechanisms. By classifying CholU into distinct subtypes, clinicians can tailor diagnostic and therapeutic strategies to each patient’s specific needs, improving overall outcomes and quality of life. Comprehensive understanding of these subtypes and their unique characteristics is essential for effective management of this often challenging and distressing condition.

Continued research and clinical observation will further elucidate the complex mechanisms underlying CholU, potentially leading to more refined and targeted treatments in the future. For patients suffering from CholU, accurate diagnosis and subtype classification are the first steps toward effective symptom management and improved daily functioning.

References

1. Fukunaga, Atsushi, et al. “Cholinergic urticaria: epidemiology, physiopathology, new categorization, and management.” Clinical Autonomic Research 28 (2018): 103-113.
2. Fukunaga, Atsushi, et al. “Cholinergic urticaria: subtype classification and clinical approach.” American Journal of Clinical Dermatology 24.1 (2023): 41-54.