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Figure Legends
Fig. 1 Diversity of clinical picture of CholU
(a) Typical appearance of CholU: pinpoint-sized, highly pruritic red wheals occur after
sweating. (b) CholU-PA: angioedema associated with cholinergic urticaria. (c) Folliculartype CholU: CholU matching hair follicles. (d) Goosebump-like punctate rash with
surrounding erythematous halo.
CholU, cholinergic urticaria; CholU-PA, cholinergic urticaria with palpebral angioedema
Fig. 2 Satellite urticarial response induced by intradermal acetylcholine injection (Ovisot®;
Daiichi Sankyo, Tokyo, Japan)
Arrowhead: small satellite wheal. Arrow: intradermal injection site of acetylcholine.
Fig. 3 Pathophysiology of each subtype of CholU
(a) Conventional sweat allergy-type CholU (i); Follicular-type CholU (ii); CholU-PA (iii).
In the sweat allergy type [(i) and (iii)], wheals are formed around sweat glands due to
leakage of sweat into the dermis and IgE-mediated reaction of surrounding mast cells. In
follicular-type CholU (ii), serum factor and acetylcholine stimulate mast cells around the
hair follicles to form wheals consistent with the hair follicles.
(b) CholU with acquired anhidrosis and/or hypohidrosis (iv).
In CholU-Anhd, CHRM3 expression (ACh receptor) is decreased in the sweat glands, and
ACh overflows to promote degranulation from the adjacent mast cells. There may be
39
infiltration of inflammatory cells such as lymphocytes and mast cells around the sweat
glands. Sweat leakage and/or polal occlusion may also be involved.
CholU, cholinergic urticaria; CholU-Anhd, cholinergic urticaria with acquired anhidrosis
and/or hypohidrosis; CholU-PA, cholinergic urticaria with palpebral angioedema
Fig. 4 Appearance of foot bath thermal sweating test
Fig. 5 Proposed therapeutic algorithm for CholU with and without hypohidrosis (opinion of
authors)
CholU, cholinergic urticaria; H1RA, histamine H1 receptor antagonist; H2RA, histamine
H2 receptor antagonist Solid lines indicate strong recommendations and dashed lines are
conditional recommendations.
40
Table 1. Subtype categorization and pathophysiological features of CholU
Subtype
Conventional
sweat allergy-type
CholU
Histamine
Sweat
allergy
Cholinergicrelated
substances
Autologous
serum skin test
Sex
predominance
Atopic
predisposition
Hypohidrosis
Pathology
Severity
(author’s
opinion)
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,
preexistence of
eczema
Severe
Always
Excess acetylcholine
following decrease of
CHRM3 expression on
sweat gland, CHRM3
expression on mast
cells, poral occlusion,
carcinoembryonic
antigen
Severe
CholU-Anhd
Less involved
Negative
Acetylcholine
test: negative
ND
Male
Weak
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
41
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 large and may
converge.
Heat urticaria
Itchy erythema and well-demarcated wheals appearing
soon after heat exposure, restricted to the heated area.
Aquagenic urticaria
Small pruritic wheals surrounded by flare after contact
with any source of water, regardless of its temperature
or pH.
Adrenergic urticaria
Small red or pink pruritic wheals surrounded by a white
halo of vasoconstriction, triggered by stress, trauma, or
emotional upset.
42
Standard treadmill exercises for approximately 30
min after specific food or drug intake.
Skin testing with metal/glass cylinders filled with
hot water, hot water baths, or TempTest®
measurements.
A compress or towel soaked with 35°C to 37°C
water or physiological saline is placed on the
patient’s trunk. The compress or towel can be
taken off within 20 min if the patient reports
pruritus and first wheals are seen at the skin test
site.
Intradermal injection of adrenaline or
noradrenaline (1 μg/mL), which produces the
characteristic rash.
Fig. 1
Fig. 2
(i) Conventional sweat allergy-type CholU
(ii) Follicular-type CholU
(iii) CholU with palpebral angioedema (CholU-PA)
(ii) Follicular-type CholU
(i) (iii) Sweat allergy-type
Contamination of skin surface
antigens (Malassezia etc.)
Hair follicle
Follicular wheal
Sweat
apparatus
Duct barrier ↓
MGL_1304
antigen etc.
(i) Conventional sweat
allergy-type CholU
Leakage
of sweat
Around sweat
gland wheal
IgE
Degranulation
(histamine etc.)
Serum factor
Acetylcholine
Mast cell
Angioedema
Fig. 3 (a)
(iii) CholU with palpebral
angioedema (CholU-PA)
(iv) CholU with acquired anhidrosis and/or hypohidrosis (CholU-Anhd)
Poral occlusion
Sweat
apparatus
(iv) CholU with acquired anhidrosis
and/or hypohidrosis (CholU-Anhd)
Leakage of sweat ?
Lymphocyte
Decreased
CHRM3 expression
CEA↑
Reduced
sweat production
Other skin organs
Hair follicle ?
Mast cell
Acetylcholine
overflow CHRM3
Fig. 3 (b)
Degranulation
(histamine etc.)
Fig. 4
CholU without anhidrosis
or hypohidrosis
CholU with anhidrosis
and/or hypohidrosis
1st line:
Second generation H1RA
Mild
Second generation H1RA
(Up-dosing)
2st line:
Up-dosing H1RA
3rd line:
Add Omalizumab
Add H2RA
Autologous sweat
desensitization
Severe
Steroid pulse therapy
Omalizumab
Anti-keratotic agents
Oral immunosuppressants
Oral pilocarpine
Medicine for pain relief
Regular sweating activity (physical exercise/bathing)
Fig. 5
...
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