Clinical Review & Education

JAMA | Review

Chronic Spontaneous Urticaria

A Review
Pavel Kolkhir, MD; Hanna Bonnekoh, MD; Martin Metz, MD; Marcus Maurer, MD

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IMPORTANCE Chronic spontaneous urticaria affects approximately 1% of the general CME at jamacmelookup.com
population worldwide, including approximately 3 million people in the US, impairs patients’
quality of life, and is associated with multiple comorbidities.

OBSERVATIONS Chronic spontaneous urticaria affects patients of any age but is most common in
females aged 30 to 50 years. Diagnosis is based on clinical presentation, ie, spontaneously
recurring wheals, angioedema, or both. Chronic spontaneous urticaria persists for more than 1
year in most patients (1 or repeated episodes) and may present with comorbidities including
chronic inducible urticaria (>10%), autoimmune thyroiditis (approximately 20%), metabolic
syndrome (6%-20%), and anxiety (10%-31%) and depression (7%-29%). Known autoimmune
endotypes (subtypes of urticaria defined by distinct pathogenesis) of chronic spontaneous
urticaria are mediated by mast cell–activating IgE and/or IgG autoantibodies (>50%).
Approximately 40% of patients with chronic spontaneous urticaria have a Dermatology Life
Quality Index of more than 10, corresponding to a very large or extremely large negative effect
on quality of life. Second-generation H1 antihistamines are first-line treatment; partial or
complete response, defined as a reduction in urticaria symptoms of greater than 50%, is Author Affiliations: Urticaria Center
of Reference and Excellence
observed in approximately 40% of patients. The 2022 international urticaria guideline
(UCARE), Institute of Allergology,
recommends the monoclonal anti-IgE antibody omalizumab as second-line treatment for Charité–Universitätsmedizin Berlin,
antihistamine-refractory chronic spontaneous urticaria. However, at least 30% of patients have Corporate Member of Freie
an insufficient response to omalizumab, especially those with IgG-mediated autoimmune Universität Berlin and
Humboldt-Universität zu Berlin,
urticaria. Cyclosporine, used off-label, can improve symptoms in approximately 54% to 73% of Berlin, Germany (Kolkhir, Bonnekoh,
patients, especially those with autoimmune chronic spontaneous urticaria and nonresponse to Metz, Maurer); Fraunhofer Institute
omalizumab, but has adverse effects such as kidney dysfunction and hypertension. for Translational Medicine and
Pharmacology ITMP, Immunology
CONCLUSIONS AND RELEVANCE Chronic spontaneous urticaria is an inflammatory skin disease and Allergology, Berlin, Germany
associated with medical and psychiatric comorbidities and impaired quality of life. (Kolkhir, Bonnekoh, Metz, Maurer).
Second-generation H1 antihistamines are first-line treatment, omalizumab is second-line Corresponding Author: Pavel
Kolkhir, MD, Institute of Allergology,
treatment, and cyclosporine is third-line treatment for chronic spontaneous urticaria.
Charité–Universitätsmedizin Berlin,
Hindenburgdamm 30, 12203 Berlin,
JAMA. 2024;332(17):1464-1477. doi:10.1001/jama.2024.15568 Germany (pavel.kolkhir@charite.de).
Published online September 26, 2024. Section Editor: Kristin Walter, MD,
Deputy Editor.

U
rticaria is a common skin disease characterized by tran- and symptoms last for at least 3 years in approximately 66% of
sient wheals, angioedema, or both.1 Wheals are itchy, su- patients.2 Most patients with chronic spontaneous urticaria (57%)
perficial skin swellings, and angioedema is pronounced develop only wheals; 37% have wheals and angioedema, and 6%
swelling of the lower dermis and subcutis or mucous membranes. have only angioedema.1,3 In some patients with chronic spontane-
Urticaria can be acute (ⱕ6 weeks) or chronic (lasting >6 weeks and ous urticaria, disease activity can be exacerbated by stress, nonste-
usually several years). Chronic urticaria is classified as inducible if roidal anti-inflammatory drugs (NSAIDs), and infections.
symptoms are elicited reproducibly by specific external triggers such This Review summarizes current evidence on the epidemiol-
as cold, skin pressure, friction, heat, water, vibration, sweating, ex- ogy, pathophysiology, diagnosis, and treatment of chronic sponta-
ercise, sunlight, ultraviolet light, and skin contact with wheal- neous urticaria. Major epidemiologic and burden-of-disease facts for
inducing agents, such as plant and animal products and metals. chronic spontaneous urticaria are summarized in Box 1.
Chronic urticaria is classified as spontaneous (previously known as
“idiopathic”) if symptoms appear without a known specific trigger,
and can occur as a single episode or repeated episodes. Chronic in-
Methods
ducible urticaria and chronic spontaneous urticaria can be present
in the same patient. A literature search of English-language articles published between
Chronic spontaneous urticaria affects approximately 1% of the January 1, 2014, and May 1, 2024, was conducted using PubMed with
global population, most commonly females aged 30 to 50 years,1 the terms (spontaneous OR idiopathic) AND urticaria. We selected

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 Chronic Spontaneous Urticaria: A Review Review Clinical Review & Education

(endotypes), IgE- and IgG-mediated autoimmunity that can occur

Box 1. Major Epidemiologic and Burden-of-Disease Facts for in isolation or together (>50%), contribute to the activation and de-
Chronic Spontaneous Urticaria granulation of skin mast cells (Figure 1). In contrast to IgE hypersen-
• Progression from acute urticaria (ⱕ6 weeks of duration) to sitivity to external allergens (eg, pollen) observed in allergic dis-
chronic spontaneous urticaria in most studies is 8% or lower.1 eases, patients with IgE-mediated autoimmune chronic spontaneous
• Prevalence is about 1% (about 80 million patients worldwide).4 urticaria (also known as autoallergic urticaria) produce IgE antibod-
• Incidence is 0.10 to 2.43 per 1000 person-years.1 ies to autoantigens (self-antigens) such as thyroid peroxidase or IL-24.
• Remission rates are 17% at 1 year and 45% at 5 years Patients with IgG-mediated autoimmunity (also known as type IIb)
(cumulative average estimate).2
have IgG autoantibodies, for example, against IgE or the high-
• Sex predominance is 70% female.1,5
• Typical age at onset is 30 to 50 years; less than 15% at 19 years affinity IgE receptor FcεRI on mast cells.8 Less than 35% of pa-
or younger vs more than 85% at 20 years or older.1,6,7,a tients with chronic spontaneous urticaria have no autoantibodies.9,14
• Diagnostic criteria are spontaneously occurring itchy wheals, The cross-linking of the IgE receptor FcεRI expressed on skin
angioedema, or both occurring for more than 6 weeks. mast cells by IgE and IgG autoantibodies activates cytoplasmic sig-
• Most common conditions in differential diagnosis include naling proteins (eg, Bruton tyrosine kinase). This activation results
chronic inducible urticaria, urticarial vasculitis, autoinflammatory
in the release of vasoactive substances including histamine, the ma-
syndromes such as Schnitzler syndrome,b and hereditary
jor contributor to urticaria symptoms, and cytokines, leading to ac-
angioedema.
• Causes/underlying pathogenesis (endotype) include tivation of sensory nerves, vasodilation, and increased vascular per-
autoimmune endotype with IgE autoantibodies, meability and migration of immune cells such as eosinophils,
IgG autoantibodies, or both (>50%); nonautoimmune endotype T lymphocytes, and basophils into the skin.1,15 Mast cells and other
(<35%)8,9; and, very rarely, infections, cancer, peptic ulcer immune cells, epithelial cells, and sensory nerves interact through
disease, hypothyroidism, hyperthyroidism, rheumatic diseases, release of cytokines (mostly Th2 cytokines) such as thymic stromal
or type 1 hypersensitivity.1
lymphopoietin, IL-4, IL-13, IL-31, eosinophil proteins, and neuropep-
• Triggers are stress, nonsteroidal anti-inflammatory drugs, and
viral infection of respiratory tract.10
tides, and further activation of mast cells through Mas-related
• Symptom frequency is daily or almost daily or an intermittent- G protein–coupled receptor X2 (MRGPRX2).1 These processes re-
recurrent course.10 sult in the development of urticaria symptoms.
• Humanistic burden includes severe impairment of quality of Susceptibility to chronic spontaneous urticaria may be deter-
life11,12,c and high burden on health care systems and society. mined by genetic factors16 and gut microbiome alterations, includ-
• Economic burden is $907 to $2984 in purchasing power parity ing lower levels of short-chain fatty acid–producing bacteria.17
dollars annually per affected individual, mostly due to
therapies.13
a
Studies included patients with chronic urticaria, of whom more than 90%
likely had spontaneous urticaria. Clinical Presentation
b
Schnitzler syndrome is an autoinflammatory disease characterized by Patients with chronic spontaneous urticaria develop individual
chronic urticarial rash (usually nonpruritic), monoclonal gammopathy and
wheals, ranging from a few millimeters in diameter to several cen-
recurrent fever, bone pain, and arthralgia or arthritis.
timeters in diameter (“giant” urticaria), that typically appear and dis-
c
Comparable with or worse than that in patients with moderate to severe
appear within a single day, usually within a few hours, whereas an-
psoriasis, atopic dermatitis, or type 1 diabetes.
gioedema typically lasts for 1 to 3 days (Figure 2A-C). Wheals are
blanching and can have irregular borders, change shape, and ap-
recent, relevant, high-quality publications, prioritizing meta- pear anywhere on the body but most commonly occur on the arms,
analyses, systematic reviews, and randomized clinical trials when legs, and trunk.18 Angioedema commonly involves the face, espe-
available. Additional articles were identified from reference lists of cially the lips and eyelids, but can also affect other body parts. In mod-
selected articles. Authors also reviewed the current version of the erate to severe disease, wheals and/or angioedema occur daily or
international urticaria guideline10 and information available in nearly daily. The clinical manifestations of urticaria are consistent
ClinicalTrials.gov. We prioritized articles published in the past 5 years. across age, sex, race, and ethnicity groups, with wheals and angio-
Of 2170 articles identified, we included 94, consisting of 27 meta- edema appearing in similar anatomical distributions. Among pa-
analyses and/or systematic reviews; 3 randomized clinical trials; 48 tients with chronic spontaneous urticaria, angioedema affects chil-
epidemiologic, observational, and/or longitudinal studies; 13 narra- dren less frequently than adults (5%-15% vs 30%-50%), and female
tive reviews; 2 clinical practice guidelines, recommendations, and predominance may be less common in children with urticaria com-
consensus documents; and 1 basic research study. For trials that re- pared with adults.19 Detection of erythema associated with wheals
ported standardized mean differences (SMDs) between therapies, can be more difficult in individuals with darker skin tones (Figure 2).
an absolute difference of ±0.2 approximates a small effect, ±0.4 In patients with chronic spontaneous urticaria, both wheals and an-
a moderate effect, and ±0.8 a large effect. gioedema resolve spontaneously without sequelae.1,10

Pathophysiology Quality of Life

Skin mast cells are the major drivers of pathogenesis of chronic For patients with chronic spontaneous urticaria, severe pruritus
spontaneous urticaria. In most patients, 2 underlying mechanisms and the unpredictable disease course marked by sudden wheals

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 Clinical Review & Education Review Chronic Spontaneous Urticaria: A Review

Figure 1. Pathophysiology of Chronic Spontaneous Urticaria

Drug targets in the pathophysiology of chronic spontaneous urticaria

Recommended therapy
Novel therapy

Itchiness
Erythema

Histamine
EPIDERMIS receptor
Activated sensory
Wheal formation nerve endings
Tezepelumab Cetirizine, loratadine
Anti–thymic stromal Second-generation
lymphopoietin (TSLP) H1 antihistamine
TSLP
Inhibits activation of mast First-line treatment
cells and other immune cells Reduces histamine
receptor activity
Neuropeptides

Autoallergens
IgE autoantibodies
IgG anti-FcεRI/IgE
Cyclosporine
TSLP Immunosuppressant
Omalizumab
receptor Third-line treatment
Anti–IgE IgE binds
FcεRI Inhibits release of mediators from
Second-line treatment T cells and other immune cells
Prevents mast cell Histamine
and basophil activation
IL-4
Mast cell IL-5
Antibody-FcεRI IL-13
cross-linking Mast cell IL-17
cytokines T cell
BTK
DERMIS IL-5
MRGPRX2 IL-31
IL-4Rα
Remibrutinib, rilzabrutinib Eosinophil
Bruton tyrosine kinase (BTK) inhibitor
EP262, EVO756
Inhibits activation of mast cells
Anti–MRGPRX2
and basophils and autoantibody
Inhibits mast cell activation Dupilumab
production by B cells
Anti–IL-4Rα

Barzolvolimab, briquilimab Inhibits activation of mast

KIT cells and other immune cells
Anti–KIT tyrosine kinase receptor Omalizumab
Causes mast cell depletion by
preventing cell survival signaling Stem cell factor Histamine BTK
produced by
eosinophils Basophil
Remibrutinib
Rilzabrutinib

Endothelial cell
Tezepelumab TSLP Edema and B cell
infiltration of receptor BTK
Cetirizine immune cells
into skin Autoantibodies
Loratadine B cell
BLOOD
VESSEL IL-4Rα
IL-23

Dupilumab

This figure provides an overview of the main pathogenetic events in chronic thyroid peroxidase and IL-24 and IgG autoantibodies against FcεRI/IgE
spontaneous urticaria and shows current therapies and novel drugs expected to (produced by B cells), with subsequent activation of cytoplasmic signaling
soon be available for routine clinical practice. The pathophysiology of chronic proteins such as Bruton tyrosine kinase. MRGPRX2 indicates Mas-related
spontaneous urticaria involves activation of skin mast cells on cross-linking of G protein–coupled receptor X2.
the IgE receptor FcεRI by IgE autoantibodies against autoallergens such as

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 Chronic Spontaneous Urticaria: A Review Review Clinical Review & Education

Figure 2. Clinical Presentation of Chronic Spontaneous Urticaria and Main Differential Diagnoses

A B C

D E F

G H I

Chronic spontaneous urticaria: wheals on less pigmented skin (A), wheals on [nettle] leaves) (G). Differential diagnoses of chronic spontaneous urticaria:
more pigmented skin (B), and angioedema (C). Chronic inducible urticaria: urticarial vasculitis (bruising, a hallmark of urticarial vasculitis, is seen) (H)
symptomatic dermographism (elicited by a scratch test) (D), cholinergic and Schnitzler syndrome (I). Images in panels B, C, and D courtesy of Jonny
urticaria (elicited by exercise) (E), cold urticaria (after provocation test with Peter, MD, Kanokvalai Kulthanan, MD, and Melba Muñoz, MD, respectively.
ice cube) (F), and contact urticaria (wheals after contact with Urtica dioica

and angioedema are associated with impaired quality of life. Vari- P < .001),20 without mental health disorders (DLQI mean, 10.7 vs 8.8;
ous tools are available to assess quality-of-life impairment in pa- P = .01),21 and without autoimmune endotype (DLQI mean, 10.0 vs
tients with chronic spontaneous urticaria, including the Dermatol- 6.0; P = .046).9
ogy Life Quality Index (DLQI) and the Chronic Urticaria–Quality of
Life Questionnaire (CU-Q2oL). The DLQI is a 10-item quality-of-life
index for patients with dermatological conditions (score range, 0-30;
Assessment and Diagnosis
minimum clinically important difference, 3-5), with higher scores in-
dicating more disability on such items as symptoms, activities of daily The international urticaria guideline recommends the “7C” con-
living, leisure activities, and interpersonal relationships. The CU-Q2oL cept for diagnostic workup of chronic spontaneous urticaria, which
is a 23-item quality-of-life measure that is specific to patients with includes confirmation of diagnosis and exclusion of differential di-
chronic urticaria (range, 0-100), with higher scores indicating more agnoses, cause identification, cofactor (trigger) assessments, check-
disability on such items as pruritus, swelling, effect on life activi- ing for comorbidities, evaluating consequences, assessing poten-
ties, and sleep problems. A very large or extremely large negative tial biomarkers or predictors of treatment response (components),
effect on a person’s life (DLQI >10) is observed in approximately 40% and monitoring the course of chronic spontaneous urticaria.10
of patients with chronic spontaneous uriticaria, with the CU-Q2oL The diagnosis of chronic spontaneous urticaria is made clini-
showing the largest negative effect based on pruritus, sleep, and gen- cally based on history and skin examination for spontaneously ap-
eral appearance.13 Several features are associated with greater im- pearing wheals, angioedema, or both (Figure 2A-C and Figure 3).
pairment in quality of life among patients with chronic spontane- Given the transient nature of wheals and angioedema, clinicians
ous urticaria, including concomitant angioedema, mental health should review patient photographs and documentation of signs and
disorders such as depression and anxiety, and autoimmune endo- symptoms, if available.1,10 Initial laboratory measurement of com-
type, compared with patients with chronic spontaneous urticaria plete blood cell count, erythrocyte sedimentation rate, and/or
with wheals but without angioedema (DLQI mean, 9.9 vs 7.3; C-reactive protein and additional testing based on patient history

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 Clinical Review & Education Review Chronic Spontaneous Urticaria: A Review

Figure 3. Overall Approach to Management of Chronic Spontaneous Urticaria

Initial diagnosis of chronic spontaneous urticaria

Patient history and skin examination for spontaneous
wheals (typically itchy), angioedema, or both

Most common conditions in differential diagnosis

Urticarial vasculitis Autoinflammatory diseasea Hereditary angioedema and angiotensin-converting

• Average wheal duration >24 h with bruising • Recurrent unexplained fever, joint enzyme inhibitor–associated angioedema
and hyperpigmentation after resolution and/or bone pain, and malaise • Isolated angioedema >2-5 d with no response
• Elevation of erythrocyte sedimentation rate (ESR), • Elevation of ESR, CRP, or both to antihistamines and corticosteroids
C-reactive protein (CRP), or both

Chronic spontaneous urticaria confirmed

Screen for and treat comorbidities Assess disease activity, control, Identify and treat underlying cause
as some can affect disease course and quality-of-life impairment if suggested by clinical history, physical examination,
and/or contribute to quality-of-life using patient-reported outcome and/or basic laboratory tests including complete
impairment measures blood cell count, ESR, and/or CRP

• Inducible urticaria (provocation test)b • Urticaria Control Test (UCT)c • Autoimmune urticaria endotyped

Reassessment
• Autoimmune thyroiditis, • Other patient-reported measures • Overt hypo- or hyperthyroidism
hypothyroidism, and/or and tools used in specialist care • Infection
hyperthyroidism include UAS, AAS, AECT, CU-Q2oL, • Cancer
• Anxiety and depression and AE-QoL • Peptic ulcer disease
• Metabolic syndrome • Autoimmune disease

Treatment of chronic spontaneous urticaria Indications for referral to specialist

Trigger avoidance if relevant (eg, stress, NSAIDs)e • If conditions in the differential diagnosis are suspected
• If an underlying cause of urticaria is suspected
First-line treatment: • Wheals and angioedema appear associated with
Second-generation H1 antihistamines a drug reaction, food allergy, or anaphylaxis
• Increase dose up to 4 times approved dose if symptoms persist • Need for additional tests in patients with
• Refer to specialist (dermatologist or allergist) if symptoms are uncontrolled based on UCT score <12 comorbid inducible urticaria
• Disease control is not achieved with a higher than
Second-line treatment: standard-dosed second-generation H1 antihistamine
Omalizumab (added to first-line treatment)
• Begin with approved dose of 300 mg every 4 wk for patients aged 12 y and older with continued symptoms
• Increase dosage to up to 600 mg every 2 wk if no response to approved dose

Third-line treatment:
Cyclosporine (added to first-line treatment)
• Use up to 5 mg/kg/d if there is no response to second-line treatment
• May be add-on treatment to omalizumab in selected patients
• Close monitoring for adverse effects (eg, increased blood creatinine, increased blood pressure) is needed

Acute severe urticaria exacerbation:

Systemic corticosteroids
• Systemic corticosteroids should be used only short term (<10 d) for acute severe urticaria exacerbation

c
AAS indicates Angioedema Activity Score; AECT, Angioedema Control Test; Clinicians may use tools such as the Urticaria Control Test (UCT), a 4-item
AE-QoL, Angioedema Quality of Life Questionnaire; CU-Q2oL, Chronic Urticaria questionnaire administered to patients that provides objective information
Quality of Life Questionnaire; and UAS, Urticaria Activity Score. about urticaria control (UCT = 16 corresponds to complete disease
a
Autoinflammatory diseases such as Schnitzler syndrome are a group of rare control/response to treatment; UCT = 12-15 is well-controlled disease/partial
disorders caused by dysfunction of the innate immune system and are response to treatment; and UCT <12 is poor disease control/nonresponse
associated with unprovoked episodes of fever and inflammation. to treatment).
d
b
Among patients for whom there is a clinical suspicion of inducible urticarias such Subtype of urticaria defined by distinct pathogenesis
e
as symptomatic dermographism, delayed pressure urticaria, cholinergic urticaria, Certain nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin,
or cold urticaria, provocation tests include skin scratching with a closed ballpoint diclofenac, and ibuprofen, can induce urticaria exacerbation.
pen tip, suspension of a weight over the shoulder, physical exercise, and melting an
ice cube in a thin plastic bag on a patient’s volar forearm, respectively.

can be performed to rule out differential diagnoses such as urti- Differential Diagnosis
carial vasculitis and hereditary angioedema, underlying conditions Diseases presenting with wheals and/or angioedema (Figure 2)1,10
associated with chronic spontaneous urticaria, triggers, and comor- include chronic inducible urticaria, in which wheals are often
bidities (Box 2 and Box 3).10 of shorter duration (ⱕ1 hour). The diagnosis of chronic inducible

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 Chronic Spontaneous Urticaria: A Review Review Clinical Review & Education

Box 2. Questions Commonly Asked Box 3. Comorbidities and Screening Recommendations

About Chronic Spontaneous Urticaria
Chronic Inducible Urticaria
Which Laboratory Tests Should Be Done for Patients Provocation testing (the appearance of pruritic wheals within 5-10
With Chronic Spontaneous Urticaria? minutes after applying specific stimulus) can help confirm the
Basic tests include a complete blood cell count with differential diagnosis. Some simple tools, such as skin scratching with closed
and C-reactive protein and/or erythrocyte sedimentation rate, ballpoint pen tip, suspension of weight over shoulder, physical
which help to exclude other diagnoses and may identify exercise, and melting ice cube in thin plastic bag on a patient’s
comorbidities and underlying causes such as autoimmunity, volar forearm, can be performed in primary care to diagnose most
infection, and cancer. common forms of inducible urticaria, namely symptomatic
dermographism (Figure 2D), delayed pressure urticaria,
Which Treatments Should Be Implemented
cholinergic urticaria (Figure 2E), and cold urticaria (Figure 2F),
in Primary Care Settings?
respectively.
Primary care clinicians should initiate treatment with a standard
dose of a second-generation H1 antihistamine and increase the Autoimmune Diseases
dose up to 4 times the standard dose if complete disease control is Patients should be asked about signs and symptoms of
not achieved, as assessed with the Urticaria Control Test. autoimmune diseases such as autoimmune thyroid disorders (and
their consequences, such as hypothyroidism and
When Should Patients Be Referred to a Dermatologist or Allergist?
hyperthyroidism), vitiligo, and rheumatoid arthritis. In patients
Patients should be referred to a dermatologist or allergist if they
with chronic spontaneous urticaria and high titers of antithyroid
have any of the following symptoms: individual wheals of 24 hours
antibodies, annual reassessment of thyroid function can be
or longer in duration resolving with postinflammatory
considered.
hyperpigmentation; long-lasting antihistamine-refractory
angioedema (>2-5 days) without wheals; or extracutaneous Other Comorbidities
symptoms such as fever, arthralgia, or abdominal pain. Other Patients with chronic spontaneous urticaria should be screened for
reasons for referral include need for additional special tests, such anxiety and depression with specific questionnaires, such as the
as allergy and/or provocation tests or lack of disease control Hospital Anxiety and Depression Scale (HADS)23 or the Patient
(Urticaria Control Test score <12) with higher than standard-dosed Health Questionnaire (PHQ-9), and should have measurement of
second-generation H1 antihistamine therapy.10,22 metabolic syndrome components along with routine body mass
index and blood pressure measurement. Laboratory testing for
autoimmune diseases other than thyroiditis and other
comorbidities should be performed only if suspected due to
urticaria is based on history (eg, contact with nettle plants [Urtica patient history, physical examination, and/or results of basic
dioica] causing contact urticaria or cooling of the skin causing cold laboratory tests.24-26
urticaria) and provocation testing to identify triggers and assess trig-
ger thresholds (Box 3 and Figure 2D-G). Chronic spontaneous urti-
caria is not associated with anaphylaxis, although anaphylaxis can
present with wheals, angioedema, or both.10 Neutrophilic urticaria titis B and hepatitis C infection,33 cancer,34 and hypothyroidism,24
with systemic inflammation, Schnitzler syndrome (an autoinflam- with no clear evidence supporting screening for these conditions in
matory disease characterized by chronic urticarial rash [usually non- all patients.35 Similarly, there is limited evidence that treating these
pruritic], monoclonal gammopathy, and bone pain [Figure 2I]), and conditions leads to improvement in urticaria. The international ur-
urticarial vasculitis (Figure 2H) are rare conditions associated with ticaria guideline advises against intensive and costly testing to iden-
antihistamine-resistant wheals (in urticarial vasculitis, wheals are tify causes of urticaria.10 A search for underlying causes should be
usually of >24 hours’ duration and resolving with bruising and/or performed only if presence of a condition, such a parasitic infec-
postinflammatory hyperpigmentation) and are often associated tion, hypothyroidism, cancer, or peptic ulcer disease, is suggested
with systemic symptoms such as recurrent fever and arthralgia or by a patient’s clinical history, physical examination, and/or basic ur-
arthritis.27 Hereditary angioedema should be suspected in pa- ticaria workup. In these cases, treatment of the underlying cause may
tients with antihistamine- and corticosteroid-refractory isolated improve urticaria symptoms.10
angioedema and a possible family history of angioedema. For pa- Factors that suggest autoimmune chronic spontaneous urti-
tients with angiotensin-converting enzyme inhibitor–induced caria include female sex, symptoms for more than 5 days per week,
angioedema, symptom remission usually occurs within a few days angioedema, nocturnal symptoms of itch and wheals, low eosino-
(rarely, within weeks or months) after drug withdrawal.10,28 Laryn- phil counts (<0.05 × 109/L), low basophil counts (<0.01 × 109/L), and
geal swelling associated with a fatal outcome, which can occur with insufficient response to antihistamines and omalizumab. Addi-
angiotensin-converting enzyme inhibitor–induced and hereditary an- tional tests can be helpful to identify autoimmune chronic sponta-
gioedema, has not been reported in patients with chronic sponta- neous urticaria, such as low total IgE levels (<30-43 IU/mL), high IgG
neous urticaria.29 anti–thyroid peroxidase levels (ⱖ34 kU/L),36 positive in vitro test
findings based on the degree of basophil degranulation in re-
Underlying Causes sponse to patients’ serum (basophil histamine release assay and/or
Patients with chronic spontaneous urticaria have been evaluated for basophil activation test), and/or detection of autoantibodies by
different underlying causes, including chronic bacterial infections immunoassay.9,10
such as Helicobacter pylori,30 sinusitis and dental infections, con- Allergy, ie, IgE-mediated hypersensitivity to external aller-
nective tissue diseases,31 peptic ulcer disease,30 parasites,32 hepa- gens such as food, drugs, and pollen, is a rare cause of chronic

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 Clinical Review & Education Review Chronic Spontaneous Urticaria: A Review

Table 1. Comorbidities of Patients With Chronic Spontaneous Urticaria

Chronic inducible Cancer, infection,
Parameters Mental health disorders Metabolic syndrome Autoimmune diseases urticaria allergy
Patients with chronic 8.5%-31.6%23,38,41,42,a 5.9%-19.7%38,43 10.5%-28%25,38,44 >10%1 Cancer: about 1%;
spontaneous urticaria who infection: varies
have comorbidity depending on infection
type; allergic diseases:
7%-22%34,45
Appearance in relation to In many cases, after Unknown In about 80% of patients Often at the same Unknown
chronic spontaneous diagnosis of chronic with autoimmune time (67.4%)46
urticaria spontaneous urticaria41 diseases, autoimmune
disease is diagnosed after
urticaria44
Most common forms Anxiety (9.6%-30.6%), Central obesity (13.9%), Autoimmune thyroiditis Symptomatic Solid cancers,
mood disorders including dyslipidemia (11.3%), (Hashimoto thyroiditis) in dermographism Helicobacter pylori,
25
depression (6.6%-29.4%), hyperglycemia (5.9%), about 20% of patients (24.8%), cold allergic rhinitis45,48
sleep-wake disorders arterial hypertension urticaria (13.4%),
including insomnia (19.7%)38 delayed pressure
(36.7%)23,38,42 urticaria (7.3%)1,47
Pathogenetic or causal Due to urticaria symptoms Low-grade chronic In rare cases can also Possible Causal association is
relation to chronic and impairment in quality inflammation induce urticaria, eg, due pathogenetic possible but rare34,37
spontaneous urticaria of life (consequence of to systemic lupus association
urticaria) erythematosus
Association with chronic Any endotype Any endotype Autoimmune endotype25 Any endotype except Any endotype
spontaneous urticaria IgG-mediated
endotypeb autoimmune
endotype46
Association with chronic Further decrease in quality Probably longer urticaria Possibly longer urticaria Longer duration of Urticaria can improve
spontaneous urticaria of life49 duration duration, more active urticaria, further after successful
characteristics, response urticaria, worse response decrease in quality treatment of
to treatment, and quality to treatment of life46,50 underlying cause32
of life
a
Pooled prevalence in patients with chronic urticaria.42 autoantibodies, whereas nonautoimmune endotype does not show the
b
A subtype of urticaria defined by a distinct pathobiological mechanism: presence of these autoantibodies.
autoimmune endotype is mediated by IgG and/or IgE mast cell–activating

spontaneous urticaria. In a prospective study, specific IgE antibod- symptomatic dermographism, cold urticaria, cholinergic urticaria,
ies to allergens were detected in 46.7% of 128 patients with and delayed pressure urticaria. In cholinergic urticaria, wheals and
chronic spontaneous urticaria, but only 2 patients (1.5%) had clini- angioedema are triggered by sweating, such as due to physical ac-
cally relevant allergy (1 to artemisia pollen and 1 to food), without tivity and/or passive warming (eg, sauna or hot bath). Delayed pres-
complete remission of their chronic urticaria after withdrawal of sure urticaria is characterized by recurrent erythematous and of-
these allergens.37 ten painful swelling that develops 4 to 6 hours after the skin is
exposed to sustained pressure (Table 1, Box 3, and Figure 2D-G).1,47
Triggers In an international cross-sectional study of 551 patients with cold ur-
Clinicians should ask patients with chronic spontaneous urticaria ticaria, cold-induced anaphylaxis was rare among individuals with
about potential triggers that exacerbate disease activity. A multi- cold urticaria and concomitant chronic spontaneous urticaria (4%)
center observational study of 3698 patients with chronic sponta- and higher among those with cold urticaria alone (39%).51
neous urticaria, the Chronic Urticaria Registry (CURE) reported sev- Approximately 10% to 28% of patients with chronic spontane-
eral triggers of urticaria exacerbation, including stress (13.9%), ous urticaria have at least 1 autoimmune disease, most commonly
NSAIDs (6.7%), infection (5.5%; mostly viral infections of the respi- Hashimoto thyroiditis (about 20%), which is associated with sub-
ratory tract), and, rarely, foods such as milk, fish, nuts, spices, fruits, clinical or overt hypothyroidism.25,26,38,52 In a meta-analysis of 19
chocolate, and alcohol.38 To identify the effect of stress on the case-control studies including 14 351 patients with chronic urti-
disease, questionnaires such as the Social Readjustment Rating caria, patients with urticaria had a 5-fold higher risk (pooled odds
Scale39 can be used and/or patients may be referred to a psycholo- ratio, 5.18; 95% CI, 3.27-8.22) of developing anti–thyroid peroxi-
gist. Avoidance of NSAIDs can identify NSAIDs as a trigger. In a cross- dase antibodies than controls.26 Female patients aged 40 years or
sectional, international, questionnaire-based, multicenter study of older with chronic spontaneous urticaria and a family history of au-
79 patients with chronic urticaria, 37% of patients with chronic ur- toimmune disease such as autoimmune thyroiditis have the high-
ticaria experienced disease exacerbation after COVID-19 infection.40 est risk of developing 1 or more autoimmune diseases.25,44 In a ret-
Avoidance of triggers such as NSAIDs and stress, if possible, can rospective study of 12 778 patients with chronic spontaneous
help reduce disease exacerbations (Figure 3).10 urticaria, approximately 17% had autoimmune diseases, including
autoimmune thyroid diseases, rheumatoid arthritis, Sjögren syn-
Comorbidities drome, celiac disease, type 1 diabetes, and systemic lupus erythem-
Recommended evaluation for comorbidities in patients with chronic atosus; most (80%) developed autoimmune disease within 10 years
spontaneous urticaria is presented in Box 3. of an urticaria diagnosis.44
More than 10% of patients with chronic spontaneous urticaria In a study of a national database in Taiwan of 154 048 to 177 879
have 1 or more type of chronic inducible urticaria, most commonly cases of chronic spontaneous urticaria per year from 2009 to 2012,

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 Chronic Spontaneous Urticaria: A Review Review Clinical Review & Education

patients had an increasing prevalence of psychiatric disorders such placebo in total symptom score changes from baseline (SMDs from
as depression and anxiety during the first 3 years of their urticaria −0.67 to −1.26, suggesting moderate to large effect).53 In a meta-
(years 1, 2, and 3: 7.5%, 9.6%, and 10.9%, respectively).41 A cross- analysis of 7 cohorts with 5664 patients with chronic spontaneous
sectional community-based study of 11 261 patients with chronic ur- urticaria, receiving a standard-dose second-generation H1 antihista-
ticaria and 67 216 age- and sex-matched controls without urticaria mine was associated with a partial or complete response, defined as
reported increased risk of metabolic syndrome in patients with ur- a greater than 50% reduction in urticaria symptoms, in 38.6% of pa-
ticaria relative to controls (15.5% vs 14.2%; odds ratio, 1.12; 95% CI, tients (95% CI, 34.7%-42.7%).69 In a registry-based study of 2078
1.1-1.2) after adjustment for corticosteroid use, supporting evalua- patients with chronic spontaneous urticaria, complete disease con-
tion for risk factors of metabolic syndrome such as obesity and high trol, defined as a UCT score of 16, with standard and increased doses
blood pressure.43 A systematic review and meta-analysis of 38 stud- of second-generation antihistamines was observed in 8.7% and 4.6%
ies and more than 5 million participants reported a pooled point of patients taking standard-dose and high-dose second-generation
prevalence of atopic disorders (atopic dermatitis, asthma, and al- antihistamines, respectively.67 In a meta-analysis of 13 randomized
lergic rhinoconjunctivitis) in patients with chronic spontaneous ur- clinical trials with 3079 patients with chronic spontaneous urticaria,
ticaria comparable with the general population (7%-22%).45 How- patients who received high-dose second-generation H1 antihista-
ever, increased risk of atopic diseases was reported by studies that mines, compared with those who received standard-dose second-
compared patients with chronic urticaria with controls from the generation H1 antihistamines, had more somnolence (9% vs 5%;
same population, although the results were heterogeneous in all P = .02) (Table 2).54 Referral to a specialist (allergist or dermatolo-
analyses.45 gist) should be considered if the UCT score is less than 12 despite use
A cross-sectional analysis of a national health insurance data- of high-dose second-generation antihistamines for 2 to 4 weeks
base in Korea with 1 399 078 to 1 431 448 participants per year from (Box 2).10
2010 to 2013 reported an increased risk of solid cancer in patients
with chronic spontaneous urticaria compared with age- and sex- Omalizumab
matched controls without urticaria (4.9% vs 2.6%; odds ratio, 1.37; Omalizumab is recommended by the international urticaria guide-
95% CI, 1.27-1.48).48 line as add-on therapy for patients with chronic spontaneous urti-
caria who are aged 12 years or older and whose symptoms persist
despite use of high-dose antihistamines.10,57 In patients with no or
insufficient response to the FDA-approved dose of 300 mg every 4
Treatment
weeks, omalizumab can be increased to up to 600 mg and/or the
The goal of treatment is to achieve complete disease control with interval can be shortened to every 2 weeks (off-label).10,70 In a sys-
the absence of signs and symptoms of chronic spontaneous tematic review and network meta-analysis that included 23 ran-
urticaria.10,67 The international urticaria guideline provides a step- domized clinical trials and 2480 participants with chronic sponta-
wise algorithm of systemic therapy for chronic spontaneous urti- neous urticaria, omalizumab, 300 mg, was more efficacious than
caria including use of second-generation H1 antihistamines; omali- placebo in decreasing urticaria symptoms (SMD, −0.77; 95% CI, −0.91
zumab, an anti-IgE monoclonal antibody; and cyclosporine.10 to −0.63)56 and improving health-related quality of life (SMD, −0.53;
These medications should be taken daily (antihistamines, cyclo- 95% CI, −0.67 to −0.39).71 In a meta-analysis of 7 randomized trials
sporine) (Table 2) or monthly (omalizumab) rather than on with 1312 patients, more patients who received omalizumab, 300 mg,
demand, sometimes for many years.10 Clinicians may use tools had a complete response (Urticaria Activity Score = 0) compared
such as the 4-question Urticaria Control Test (UCT), which is with those who received placebo (36.0% vs 5.6%, respectively;
administered to patients and provides objective information about P < .001).72 In a meta-analysis of 45 observational studies with 1158
urticaria control. A UCT score of 16 corresponds to complete dis- patients, mean complete and partial response rates were 72.2% and
ease control/response to treatment, 12 to 15 is well-controlled 17.8%, respectively.58 Omalizumab is considered safe with long-
disease/partial response to treatment, and less than 12 is poor dis- term use,57,58 with approximately 4.0% of patients having adverse
ease control/nonresponse to treatment. events such as headache, fatigue, and injection site reactions.58
Omalizumab can also be used for patients with spontaneous and
Second-Generation H1 Antihistamines concomitant inducible urticaria59,60 and/or IgE-mediated comor-
Second-generation H1 antihistamines such as cetirizine, deslorata- bidities (eg, asthma).73 Chronic spontaneous urticaria that pre-
dine,fexofenadine,levocetirizine,loratadine,rupatadine,bilastine,and sents with isolated angioedema or with inducible urticaria is rarely
ebastine are first-line treatment for chronic spontaneous urticaria in autoimmune and is more responsive to omalizumab than chronic
US Food and Drug Administration (FDA)–approved doses. The anti- spontaneous urticaria with wheals (with or without angioedema) or
histamine dose may be increased up to 4 times the maximum ap- without inducible urticaria, respectively.46,74
proved dose in off-label use if the approved dose is insufficient to con- For patients with complete response to treatment, antihista-
trol symptoms.10 Compared with first-generation H1 antihistamines, mines and omalizumab should be tapered after 3 months and dis-
second-generation H1 antihistamines are more potent, have longer du- continued after 6 to 12 months to determine if remission has
ration of action, and cross the blood-brain barrier to a lesser extent, occurred.75 In the event of relapse, antihistamines with or without
so they are less likely to induce sedation or impair cognitive function omalizumab should be restarted.
and psychomotor performance.10,68 In a network meta-analysis of 22 Approximately one-third to one-fourth of patients with anti-
randomized clinical trials with 3943 patients with chronic spontane- histamine-refractory chronic spontaneous urticaria have a partial or
ous urticaria, second-generation H1 antihistamines were superior to no response to omalizumab (Table 2).58

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 1472
Table 2. Current Therapy and Treatments Under Investigation for Patients With Chronic Spontaneous Urticariaa

Treatments Mechanism of action Dosing Efficacy Safety considerations Additional considerations

First-line treatment
Second-generation H1 Bind to histamine receptors, Standard (approved) or increased More efficacious than placebo in Generally safe, but higher In a prospective, randomized,
antihistamines stabilizing their inactive state up to 4-fold (off-label)b changes of total symptom score somnolence rates at higher doses open-label trial of 109 patients with
(inverse agonists) from baseline (SMDs from −0.67 to (9% vs 5%; risk difference, 0.05)54 chronic urticaria, a 4-fold increased
−1.26; 1 meta-analysis with 22 dose of the same antihistamine was
RCTs; n = 3943)53c more effective for complete urticaria
control than combination of 4
different antihistamines (40.0% vs
10.7%).55 There is limited efficacy in
Clinical Review & Education Review

autoimmune urticaria.36
Second-line treatment
Omalizumabd Recombinant humanized IgG1 300 mg every 4 weeks (approved) Doses of 300 mg and 600 mg Safe, including long term57,58; Patients with autoimmune urticaria
anti-IgE monoclonal antibody and up to 600 mg every 2 weeks monthly are more efficacious than mean adverse event rate, 4.0%, and low levels of total IgE usually
(off-label) placebo in decreasing urticaria most commonly headache, fatigue, show insufficient response to
symptoms (SMDs, −0.77 [95% CI, and injection site reaction58; omalizumab.36 Omalizumab is
−0.91 to −0.63] and −0.59 [95% CI, anaphylaxis is extremely rare similarly effective in chronic inducible

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−1.10 to −0.08], respectively; 1 urticaria (off-label) vs spontaneous
meta-analysis with 23 RCTs; urticaria (odds ratio, −0.83; 95% CI,
n = 2480).56 −0.84 to 2.21; P > .05), suggesting
that patients with both urticaria

JAMA November 5, 2024 Volume 332, Number 17 (Reprinted)

forms can benefit.59,60
Third-line treatment
Cyclosporined Immunosuppressant (off-label) 1 to 5 mg/kg per day; 3 mg/kg per After 4 weeks of cyclosporine Adverse events were dose Effective in patients with autoimmune
day is a reasonable starting dose for treatment, the pooled estimate of dependent and occurred in 6%-57% urticaria and low levels of total IgE62
most patients (off-label)61 mean change in relative weekly of patients, including hypertension
Urticaria Activity Score from and abnormal serum creatinine
baseline was −17.89 (95% CI, (6.2%-12.8%), as well as
−21.95 to −13.83) vs −2.3 (95% CI, gastrointestinal symptoms,
−3.72 to −0.88) with placebo; headache, hirsutism, infection, and
response rates at week 4 were 42% paresthesia (5.7%-46.2%).61
vs 0% with placebo and at week 8,
62.5% vs 23.3% with placebo (1
meta-analysis and systematic
review of 2 RCTs and 16 real-world
studies; n = 909).61e
Only in acute exacerbation of chronic spontaneous urticaria
Systemic corticosteroids Immunosuppressants 20-50 mg/d (off-label)10 Compared with patients treated Compared with control group, Short-term use only (<10 days)10

© 2024 American Medical Association. All rights reserved.

with second-generation H1 systemic corticosteroids increased
antihistamines, add-on systemic adverse events (22.5% vs 9.0%;
corticosteroids improved symptoms odds ratio, 2.76; 95% CI,
by 2.2%-15.0% (absolute 1.00-7.62), most commonly
difference, 31.5%-98.0% vs gastrointestinal, headache, anxiety,
17.5%-95.8%; 1 meta-analysis of fatigue, and sedation.63
12 RCTs; n = 944).63f

(continued)

jama.com
Chronic Spontaneous Urticaria: A Review
 Table 2. Current Therapy and Treatments Under Investigation for Patients With Chronic Spontaneous Urticariaa (continued)

Treatments Mechanism of action Dosing Efficacy Safety considerations Additional considerations

jama.com
Therapies in phase 3 developmentg
Dupilumab (n = 138)64 Fully human IgG4/κ anti-4Rα Loading dose of 400-600 mg, RCT: change in weekly Itch Severity Similar proportions of patients with Not superior to omalizumab64;
monoclonal antibody followed by 200-300 mg every 2 Scale scoreh at week 24 with any treatment-emergent adverse patients with urticaria and other
weeks based on age and weight dupilumab vs placebo: difference, event with dupilumab vs placebo diseases, approved indications for
−4.2 (95% CI, −6.6 to −1.8), with (57.3% vs 56.6%) dupilumab, can have additional
rates of complete response benefit65i
(Urticaria Activity Score = 0) of
31.4% vs 13.2% (odds ratio, 2.9;
95% CI, 1.2-7.2) and ≥5-point
reduction in weekly Itch Severity
Chronic Spontaneous Urticaria: A Review

Scale score (minimum clinically

important difference) of 72.9% vs
42.6% (P = .001)
Remibrutinib (n = 311)66 Small-molecule Bruton tyrosine 10 mg, 35 mg, or 100 mg once RCT: weekly Urticaria Activity Score Mild, moderate, and severe adverse Rapid onset of action, observed as
kinase inhibitor daily; 10 mg, 25 mg, or 100 mg change from baseline at week 4: events across all doses in 38.6%, early as week; effective in patients
twice daily from −14.7 to −20.0 vs −5.4 for 16.9%, and 2.6% of patients, with and without autoimmune
placebo; complete response rates respectively, most commonly urticaria; may be beneficial in

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(Urticaria Activity Score = 0) for all infections and infestations (24%), patients with urticaria and other
doses vs placebo at week 12: skin/subcutaneous tissue disorder autoimmune diseases; probable
26.7%-41.9% vs 14.3% (16.9%) such as flare of chronic disease-modifying properties
urticaria, and in >5% patients
headache, nasopharyngitis, nausea,
upper respiratory tract infection,
diarrhea, and pyrexia
f
Abbreviations: RCT, randomized clinical trial; SMD, standardized mean difference. Based on a meta-analysis that included patients with any type of urticaria.
a g
According to the latest revision of the international urticaria guideline.10 Expected to soon be available for routine clinical practice. In February 2024, Japan was the first country to
b approve dupilumab for chronic spontaneous urticaria in patients aged 12 years or older whose disease is not
Examples of standard daily doses for an adult patient: cetirizine, 10 mg; fexofenadine, 180 mg; rupatadine, 10
mg; ebastine, 10 mg; examples of increased doses of antihistamines for an adult patient: cetirizine, 10 mg, 2-4 adequately controlled with existing therapy.
h
tablets daily, or ebastine, 20 mg, 1-2 tablets daily. Among omalizumab-naive patients with chronic spontaneous urticaria inadequately controlled with H1
c antihistamines.
Olopatadine, fexofenadine, bilastine, rupatadine, and levocetirizine.
i
d Also approved for patients with atopic dermatitis aged 6 months or older and for patients with asthma, chronic
As add-on to second-generation H1 antihistamines.
e
rhinosinusitis with nasal polyposis, prurigo nodularis, and eosinophilic esophagitis.
Response rates are from 2 RCTs included in the meta-analysis.

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(Reprinted) JAMA November 5, 2024 Volume 332, Number 17
Review Clinical Review & Education

1473
 Clinical Review & Education Review Chronic Spontaneous Urticaria: A Review

Cyclosporine equally or more effective at reducing symptoms in older vs younger

The immunosuppressant cyclosporine is recommended by the in- adults (45.5%-88.5% vs 31.8%-65.9%, respectively).86 Children may
ternational urticaria guideline as an off-label third-line therapy10 as also have higher response rates to antihistamines than adults (61%-
add-on to antihistamines for patients with severe chronic sponta- 82% vs 46%-75%, respectively).19
neous urticaria refractory to the combination of any dose of anti-
histamines and omalizumab.10,61 A meta-analysis of 909 patients Novel Therapies
with chronic spontaneous urticaria treated with cyclosporine re- Several targeted therapies are currently being developed for pa-
ported a higher mean change in Urticaria Activity Score after 4 weeks tients with antihistamine-refractory and/or omalizumab-refractory
compared with controls (−17.89 vs −2.3) (Table 2).61 Overall re- chronic spontaneous urticaria, including Bruton tyrosine kinase in-
sponse rates to low to moderate dose of cyclosporine, defined as hibitors (eg, remibrutinib, rilzabrutinib), anti-KIT (barzolvolimab,
less than 2 to 5 mg/kg per day were 54% at 4 weeks, 66% at 48 briquilimab), anti–IL-4Rα (dupilumab), anti–thymic stromal lympho-
weeks, and 73% at 12 weeks. Adverse events were dose depen- poietin (tezepelumab), and MRGPRX2 antagonists (Table 2).64,66,87
dent, occurred in 6% to 57% of patients, and included hyperten- In a randomized clinical trial of 138 patients with antihistamine-
sion, elevated serum creatinine (6.2%-12.8%), abdominal pain, nau- refractory chronic spontaneous urticaria, dupilumab was more effi-
sea and vomiting, headache, hirsutism, infection, and paresthesia.61 cacious than placebo at 24 weeks, with a 5-point or greater reduc-
In selected patients, cyclosporine may be considered as add-on tion in weekly Itch Severity Scale (minimum clinically important
treatment to omalizumab in patients with chronic spontaneous ur- difference) of 72.9% vs 42.6%, respectively (P = .001).64
ticaria who have a partial response to omalizumab.70 In countries
where omalizumab is unavailable, cyclosporine may be safer than
long-term use of systemic corticosteroids,10 with lower relapse rates
Prognosis
after discontinuation compared with prednisolone.76
According to most studies, acute urticaria progresses to chronic spon-
Systemic Corticosteroids taneous urticaria in less than 8% of cases.1 Chronic spontaneous ur-
There is strong expert-based consensus and recommendation ticaria has a mean or median disease duration of approximately 1 to 4
against long-term use of systemic corticosteroids in patients with years.1 Cumulative estimates for spontaneous remission are 17% at 1
chronic spontaneous urticaria because of increased risk of adverse year, 45% at 5 years, and 73% at 20 years.2 Chronic spontaneous ur-
effects such as hyperglycemia, hypertension, neuropsychiatric con- ticariarelapsesinuptoone-thirdofpatients,1 withrecurrenceat5years
ditions, osteoporosis and osteonecrosis, infections, and weight in 17.1% of cases.88 Presence of antithyroid antibodies6,24,89 and an-
gain.77 However, evidence-based recommendations support a short tihistamine refractoriness90-92 has been associated with a higher risk
course of corticosteroids (<10 days; doses between 20 and 50 mg/d of progression from acute to chronic spontaneous urticaria, longer
of prednisone equivalent) for adults with an acute severe exacer- urticaria duration, and urticaria recurrence.
bation of chronic spontaneous urticaria.10,63

Other Treatments
Practical Considerations
Because signs and symptoms of chronic spontaneous urticaria typi-
cally appear at multiple body sites and usually in large numbers, ap- Extensive investigations to identify a cause of urticaria such as rou-
plication of topical corticosteroids or topical antihistamines is nei- tine allergy testing or serology for infections should be avoided in
ther feasible nor recommended. Despite low quality of evidence, patients with chronic spontaneous urticaria unless suggested by pa-
treatment with methotrexate, hydroxychloroquine, dapsone, plas- tients’ history and physical examination.10,93,94 Generalists should
mapheresis, and other immunomodulatory therapies may be con- advise patients that chronic spontaneous urticaria is not a life-
sidered under the guidance of specialists (eg, dermatologists or al- threatening disease, is rarely allergic, often occurs due to autoim-
lergists) for patients with long-lasting, severe, therapy-refractory munity, and typically resolves within several years.22 Patients should
autoimmune urticaria.10,56,71,78-80 Despite limited evidence of effi- be treated until their symptoms resolve10 and should be referred to
cacy, first-generation H1 antihistamines such as diphenhydramine, a dermatologist or allergist if
tricyclic antidepressants such as doxepin, and H2 antagonists such • individual wheals persist for longer than 24 hours and resolve
as ranitidine are available worldwide, are affordable, and may be pre- with postinflammatory hyperpigmentation, to rule out urticarial
scribed for patients with chronic spontaneous urticaria if first-line vasculitis;
treatments are not available.10 Treatments with conflicting evi- • an underlying cause of urticaria such as autoimmune endotype is
dence or evidence against their use include sodium cromoglycate suspected;
(cromolyn sodium), leukotriene receptor antagonists, and tranex- • patients report long-lasting isolated angioedema (>2-5 days) but
amic acid.10,81 do not develop wheals, to rule out bradykinin-mediated angio-
edema including hereditary angioedema;
Special Populations • patients experience systemic symptoms such as fever, arthralgia,
Some antihistamines, such as cetirizine and loratadine,82,83 and and abdominal pain in addition to wheals and/or angioedema, to
omalizumab70 are considered effective and safe in pregnancy, dur- rule out urticarial vasculitis and autoinflammatory conditions such
ing breastfeeding, and in older adults (Table 2).84-86 In a system- as Schnitzler syndrome;
atic review of 85 studies with 1 112 066 patients older than 60 years • wheals and angioedema appear associated with a drug reaction,
with chronic urticaria, second-generation H1 antihistamines were food allergy, or anaphylaxis;

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 Chronic Spontaneous Urticaria: A Review Review Clinical Review & Education

• there is a need for additional special tests, such as provocation tests

in patients with comorbid inducible urticaria; and/or Conclusions
• disease control is not achieved with a higher than standard-
dosed second-generation antihistamine.10,22 Chronic spontaneous urticaria is an inflammatory skin disease that
presents with spontaneously recurring wheals, angioedema, or both,
and may be associated with medical and psychiatric comorbidities
and decreased quality of life. First-line treatment is use of a second-
Limitations
generation H1 antihistamine; omalizumab is second-line treatment
ThisReviewhaslimitations.First,somerelevantstudiesmayhavebeen and cyclosporine is an off-label third-line treatment. Systemic cor-
missed. Second, the quality of included studies was not formally evalu- ticosteroids should be used only in the short term (<10 days) to treat
ated. Third, novel therapies have been only briefly discussed. acute severe exacerbations of chronic spontaneous urticaria.

ARTICLE INFORMATION Asian Pac J Allergy Immunol. 2023;41(1):12-19. doi: endotyping patients with CSU. J Allergy Clin
Accepted for Publication: July 17, 2024. 10.12932/AP-151222-1515 Immunol Glob. 2023;2(4):100159. doi:10.1016/j.
4. Fricke J, Ávila G, Keller T, et al. Prevalence of jacig.2023.100159
Published Online: September 26, 2024.
doi:10.1001/jama.2024.15568 chronic urticaria in children and adults across the 15. Giménez-Arnau AM, DeMontojoye L, Asero R,
globe: systematic review with meta-analysis. Allergy. et al. The pathogenesis of chronic spontaneous
Author Contributions: Drs Kolkhir and Bonnekoh 2020;75(2):423-432. doi:10.1111/all.14037 urticaria: the role of infiltrating cells. J Allergy Clin
are co–first authors and Drs Metz and Maurer are Immunol Pract. 2021;9(6):2195-2208. doi:10.1016/j.
co–last authors. 5. Maurer M, Staubach P, Raap U, et al.
H1-antihistamine-refractory chronic spontaneous jaip.2021.03.033
Conflict of Interest Disclosures: Dr Kolkhir urticaria: it’s worse than we thought—first results of 16. Losol P, Yoo HS, Park HS. Molecular genetic
reported receipt of personal fees from Novartis, the multicenter real-life AWARE study. Clin Exp mechanisms of chronic urticaria. Allergy Asthma
ValenzaBio, and Roche. Dr Bonnekoh reported Allergy. 2017;47(5):684-692. doi:10.1111/cea.12900 Immunol Res. 2014;6(1):13-21. doi:10.4168/aair.
receipt of personal fees from AbbVie, Intercept 2014.6.1.13
Pharma, Novartis, Sanofi, and ValenzaBio. Dr Metz 6. Eun SJ, Lee JY, Kim DY, Yoon HS. Natural course
reported receipt of honoraria for advising and/or of new-onset urticaria: results of a 10-year 17. Zhu L, Jian X, Zhou B, et al. Gut microbiota
speaking from Amgen, AstraZeneca, Argenx, follow-up, nationwide, population-based study. facilitate chronic spontaneous urticaria. Nat Commun.
Celldex, Celltrion, Escient, Jasper, Novartis, Allergol Int. 2019;68(1):52-58. doi:10.1016/j.alit. 2024;15(1):112. doi:10.1038/s41467-023-44373-x
Regeneron, Sanofi, Third Harmonic Bio, and Incyte. 2018.05.011 18. Maurer M, Ortonne JP, Zuberbier T. Chronic
Dr Maurer reported receipt of personal fees from 7. Tayefi M, Bradley M, Neijber A, Fastberg A, urticaria: an internet survey of health behaviours,
Allakos, Amgen, AstraZeneca, Lilly, Evommune, Ceynowa D, Eriksson M. Chronic urticaria: symptom patterns and treatment needs in
GSK, Leo Pharma, Mitsubishi Tanabe Pharma, a Swedish registry-based cohort study on European adult patients. Br J Dermatol. 2009;160
Noucor, Novartis, Sanofi, Teva, Third Harmonic Bio, population, comorbidities and treatment (3):633-641. doi:10.1111/j.1365-2133.2008.08920.x
and Yuhan and receipt of grants from Celldex and characteristics. Acta Derm Venereol. 2022;102: 19. Saini S, Shams M, Bernstein JA, Maurer M.
Moxie. adv00624. doi:10.2340/actadv.v101.737 Urticaria and angioedema across the ages. J Allergy
Additional Contributions: We thank Kanokvalai 8. Schoepke N, Asero R, Ellrich A, et al. Biomarkers Clin Immunol Pract. 2020;8(6):1866-1874. doi:10.
Kulthanan, MD (Urticaria Center of Reference and and clinical characteristics of autoimmune chronic 1016/j.jaip.2020.03.030
Excellence [UCARE], Department of Dermatology, spontaneous urticaria: results of the PURIST study. 20. Sussman G, Abuzakouk M, Bérard F, et al.
Faculty of Medicine, Siriraj Hospital, Mahidol Allergy. 2019;74(12):2427-2436. doi:10.1111/all.13949 Angioedema in chronic spontaneous urticaria is
University, Bangkok, Thailand), Melba Muñoz, MD 9. Xiang YK, Kolkhir P, Scheffel J, et al. Most underdiagnosed and has a substantial impact:
(Institute of Allergology, Charité– patients with autoimmune chronic spontaneous analyses from ASSURE-CSU. Allergy. 2018;73(8):
Universitätsmedizin Berlin, Berlin, Germany), and urticaria also have autoallergic urticaria, but not 1724-1734. doi:10.1111/all.13430
Jonny Peter, MD (UCARE, Division of Allergy and vice versa. J Allergy Clin Immunol Pract. 2023;11(8):
Clinical Immunology, Department of Medicine, 21. Ghazanfar MN, Sørensen JA, Zhang D,
2417-2425. doi:10.1016/j.jaip.2023.02.006 Holgersen NK, Vestergaard C, Thomsen SF.
University of Cape Town, Cape Town, South Africa),
for providing clinical photographs for this article. 10. Zuberbier T, Abdul Latiff AH, Abuzakouk M, Occurrence and risk factors of mental disorders in
et al. The international EAACI/GA2LEN/ patients with chronic urticaria. World Allergy
Additional Information: This publication is in EuroGuiDerm/APAAACI guideline for the definition, Organ J. 2023;16(11):100835. doi:10.1016/j.waojou.
memory of Professor Marcus Maurer, a brilliant classification, diagnosis, and management of 2023.100835
person, an outstanding teacher, a remarkable urticaria. Allergy. 2022;77(3):734-766. doi:10.1111/
scientist, and a warm-hearted friend. 22. Ryan D, Tanno LK, Angier E, et al. Clinical
all.15090 review: the suggested management pathway for
Submissions: We encourage authors to submit 11. Brzoza Z, Nabrdalik K, Moos L, et al. Chronic urticaria in primary care. Clin Transl Allergy. 2022;12
papers for consideration as a Review. Please spontaneous urticaria and type 1 diabetes (10):e12195. doi:10.1002/clt2.12195
contact Kristin Walter, MD, at kristin.walter@ mellitus—does quality of life impairment always
jamanetwork.org. 23. Tzur Bitan D, Berzin D, Cohen A. The
reflect health danger? J Clin Med. 2020;9(8):2505. association of chronic spontaneous urticaria (CSU)
doi:10.3390/jcm9082505 with anxiety and depression: a nationwide cohort
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