Cholinergic Urticaria: Classification and Clinical Approach

Abstract and Introduction

Abstract

Cholinergic urticaria (CholU) is a subtype of chronic inducible urticaria with a chief complaint of itching and/or stinging, painful papular wheals that develop simultaneously with sweating. This review specifically focuses on several subtypes of CholU and specifically investigates the relationship between CholU and anhidrosis. We review recent publications and update the evidence around CholU, including the epidemiology, clinical features, diagnostic approaches, physiopathology, subtype classification, and therapeutic approaches. Multiple mechanisms contribute in a complex manner to the development of CholU, including histamine, sweat allergy, cholinergic-related substances, poral occlusion, and hypohidrosis/anhidrosis. A new schematic of the currently known pathological conditions has been created. Specific methods for diagnosing CholU, a provocation test, and evaluation methods for disease severity/activity and disease burden of CholU are summarized. The characteristics of the diseases that should be differentiated from CholU and examination methods are also summarized. The primary finding of this review is that CholU should be categorized based on the etiology and clinical characteristics of each subtype to properly manage and treat the disease. This categorization leads to improvement of therapeutic resistance status of this disease. In particular, a sweating abnormality should be given more attention when examining patients with CholU. Because CholU is not a homogeneous disease, its subtype classification is important for selection of the most suitable therapeutic method. Further elucidation of the pathophysiology of each subtype is expected.

Introduction

Cholinergic urticaria (CholU), first described by Duke^[1] in 1924, manifests as pinpoint, highly pruritic, or often painful wheals with surrounding erythema. These wheals occur after sweating induced by an increase in the body temperature, which occurs in response to hot bathing, physical exercise, and emotional stress.^[2,3] Cholinergic urticaria is a common form of chronic inducible urticaria, which is a subgroup of chronic urticaria [a group of diseases characterized by the recurrence of itchy wheals and/or angioedema (AE) for longer than 6 weeks], and affects up to 20% of young adults.^[4–6] Cholinergic urticaria is defined as inducible urticaria in the Japanese Dermatological Association guidelines for the diagnosis and treatment of urticaria.^[7] The symptoms usually subside rapidly, usually within 1 hour. However, most patients with CholU complain of stinging or tingling pain and/or itching at the onset of symptoms, and these sensations impact to disturb their quality of life.^[8–12] Severe symptoms such as AE, respiratory symptoms, and/or anaphylaxis often accompany CholU and disturb patients' activities of daily living, including study and work.^{[2,8,13–17]} Cholinergic urticaria is sometimes associated with cold urticaria.^[18] The etiology of each subtype of CholU is being gradually elucidated, but the overall pathophysiology is not yet well understood. The pathophysiology involves acetylcholine (ACh), poral occlusion, cholinergic/Ach receptor M3 (CHRM3), sweat allergy, serum factors, and dyshidrosis, and each subtype of CholU has different causes.^[19–22] We have proposed four subtypes of CholU based on the pathogenesis and clinical characteristics of this condition: (i) conventional sweat allergy-type CholU, (ii) follicular-type CholU with a positive autologous serum skin test (ASST) result, (iii) CholU with palpebral AE (CholU-PA), and (iv) CholU with acquired anhidrosis and/or hypohidrosis (CholU-Anhd).^{[10,17,19,21,23–25]} Conventional sweat allergy-type CholU and CholU with palpebral AE are characterized by type I allergy to the patient's own sweat; thus, both can be considered sweat allergy-type CholU. Cholinergic urticaria with acquired anhidrosis and/or hypohidrosis is characterized by a reduced amount of sweat without a clear cause and can be classified as acquired idiopathic generalized anhidrosis (AIGA) accompanied by CholU.^[26] Because the etiology and therapeutic approach differ greatly for each subtype, it is very important to not only consider CholU as a single disease but also conduct medical examinations with awareness of the subtypes. In the present review, we focus on the classification of CholU, especially with respect to the relationship between CholU and sweating function, and present an overview of the current knowledge of the pathogenesis and therapeutic methods of CholU.

Table 1. Subtype categorization and pathophysiological features of CholU
Subtype	Histamine	Sweat allergy	Cholinergic-related substances	Autologous serum skin test	Sex predominance	Atopic predisposition	Hypohidrosis	Pathology	Severity (author's opinion)
Conventional sweat allergy-type CholU	Deeply involved	Positive	Acetylcholine test: positive	Negative	None	ND	None	Sweat allergy, sweat leaking	Moderate
Follicular-type CholU	Involved	Negative	Acetylcholine test: negative	Positive	None	ND	ND	Serum factor	Mild
CholU-PA	Deeply involved	Positive	ND	Negative	Female	Strong	None	Sweat allergy, pre-existence of eczema	Severe
CholU-Anhd	Less involved	Negative	Acetylcholine test: negative	ND	Male	Weak	Always	Excess acetylcholine following decrease of CHRM3 expression on sweat gland, CHRM3 expression on mast cells, poral occlusion, carcinoembryonic antigen	Severe

CholU cholinergic urticaria, CholU-Anhd cholinergic urticaria with acquired anhidrosis and/or hypohidrosis, CholU-PA cholinergic urticaria with palpebral angioedema, CHRM3 cholinergic/acetylcholine receptor M3, ND not determined

Table 2. Differential diagnosis of cholinergic urticaria
	Characteristics	Provocation test
Exercise-induced anaphylaxis	Flushing, increased warmth, malaise, diffuse itching, urticaria, angioedema, gastrointestinal symptoms (nausea, vomiting, abdominal cramps, and diarrhea), hypotension, syncope, laryngeal edema, anaphylaxis, and rarely asthma. Wheals are typically large, could also be small or even absent, and appear as a diffuse erythematous change	Standard treadmill exercises for approximately 30 minutes after specific food or drug intake
Heat urticaria	Itchy erythema and well-demarcated wheals appearing soon after heat exposure, restricted to the heated area	Skin testing with metal/glass cylinders filled with hot water, hot water baths, or TempTest® measurements
Aquagenic urticaria	Small pruritic wheals surrounded by flare after contact with any source of water, regardless of its temperature or pH	A compress or towel soaked with 35–37 °C water or physiological saline is placed on the patient's trunk. The compress or towel can be taken off within 20 minutes if the patient reports pruritus and first wheals are seen at the skin test site
Adrenergic urticaria	Small red or pink pruritic wheals surrounded by a white halo of vasoconstriction, triggered by stress, trauma, or emotional upset	Intradermal injection of adrenaline or noradrenaline (1 μg/mL), which produces the characteristic rash