review
Allergo J Int
https://doi.org/10.1007/s40629-023-00272-7
Chronic spontaneous urticaria—status quo and future
Susanne Melchers · Jan P. Nicolay
Received: 19 June 2023 / Accepted: 20 July 2023
© The Author(s) 2023
Abstract Chronic spontaneous urticaria (CsU) is
a chronic inflammatory dermatosis whose etiology is
not yet fully understood. In affected patients, it is of-
ten associated with a high limitation of health-related
quality of life, which necessitates effective therapeu-
tic management. Different immune cell populations
such as mast cells, eosinophilic and basophilic gran-
ulocytes, and T cells are involved in the pathogenesis
of CsU, whereby mast cells playing a key role. In ad-
dition, type I autoallergic reactions with auto IgE an-
tibodies or type IIb autoimmune reactions with auto
IgG antibodies have been identified in a proportion of
patients. The current international guideline initially
recommends the use of second-generation H1 antihis-
tamines, first in standard, then in off-label quadruple
dosing. Subsequently, the anti-IgE antibody omal-
izumab should be added. However, this therapy algo-
rithm does not lead to freedom from manifestations
in all patients. Therefore, various targeted therapies
are currently being evaluated for their efficacy in CsU,
such as off-label use of the anti-interleukin receptor
Dr. S. Melchers · Prof. Dr. J. P. Nicolay ()
Department of Dermatology, Venereology and Allergology,
University Medical Center Mannheim/University of
Heidelberg, Mannheim, Germany
jan.nicolay@umm.de
Dr. S. Melchers · Prof. Dr. J. P. Nicolay
Clinical Cooperation Unit Dermato-oncology, German
Cancer Research Center (DKFZ), Heidelberg, Germany
Dr. S. Melchers · Prof. Dr. J. P. Nicolay
Section for Clinical and Experimental Dermatology, Medical
Faculty Mannheim, University of Heidelberg, Mannheim,
Germany
Prof. Dr. J. P. Nicolay
Clinic for Dermatology, Venerology and Allergology,
House 27, University Mannheim Medical Center,
Theodor-Kutzer-Ufer 1–3, 68167 Mannheim, Germany
K Chronic spontaneous urticaria—status quo and future
alpha (IL4Rα) antibody dupilumab, the anti-IL-17A
antibody secukinumab, or interleukin-5 blockade us-
ing mepolizumab, reslizumab, or benralizumab. In
addition, new promising compounds such as the Bru-
ton tyrosine kinase (BTK) inhibitors remibrutinib and
fenebrutinib, the anti-cKIT antibody barzolvolimab,
the anti-SIGLEC8 antibody lirentelimab, the anti-
TSLP antibody tezepelumab, the anti-C5aR1 antibody
advoralimab, or the topical application of Syk kinase
inhibitors are being tested, which were developed ac-
cording to new insights into the pathogenesis of CsU.
The BTK inhibitor fenebrutinib is currently not being
pursued due to a less favorable side effect profile com-
pared to remibrutinib, as well as the anti-IgE antibody
ligelizumab, which was inferior to omalizumab ther-
apy in a phase 3 study. Overall, there is a high need
for new therapeutic strategies to better treat CsU both
symptomatically and curatively. This requires a more
comprehensive understanding of pathogenesis of the
disease in order to develop new targeted therapies.
Keywords Autoallergic or autoimmune
pathogenesis · Immunoglobulin E · Antihistamines ·
Omalizumab · Fenebrutinib
Abbreviations
APAAACI Asia Pacific Association of Allergy,
Asthma, and Clinical Immunology
BTK Bruton tyrosine kinase
CindU Inducible forms of urticaria
CRP C reactive protein
CsU Chronic spontaneous urticaria
DNA Deoxyribonucleic acid
EAACI European Academy of Allergology
and Clinical Immunology
EDF European Dermatology Forum
EPO Eosinophil peroxidase
 review

EuroGuiDerm European Centre for Guidelines De- populations are involved. In the pathogenesis of CsU,
velopment autoimmune and non-autoimmune processes are dis-
GA2LEN Global Allergy and Asthma European tinguished. Of central importance are the mast cells.
Network Mast cells are highly plastic cells that can mature in
IgA Immunoglobulin A the tissues in which they reside and form different
IgE Immunoglobulin E subtypes with divergent properties. Histamine, which
IgG Immunoglobulin G is released from the granules of mast cells, contributes
IgM Immunoglobulin M significantly to the symptoms of CsU through acti-
IL4Rα Anti-interleukin receptor alpha vation of sensory nerves, vasodilation, and increased
IL Interleukin vascular permeability [6–9].
JTFPP Joint Task Force on Practice Parame- In skin biopsies of CsU patients, infiltrates consist-
ters ing of various cells of the immune system such as mast
MBP Major basic protein cells, eosinophils, basophils, neutrophils, and CD4+
NSAIDs Nonsteroidal anti-inflammatory drugs T cells are found [10, 11].
RCT Randomized controlled trial In the skin of CsU patients, mast cells are primarily
Syk Spleen tyrosine kinase of the MTC subtype, which express tryptase and chy-
TPO Thyroperoxidase mase and are considered to be independent of T cells.
TSLP Thymic stromal lymphopoietin Mast cells are activated by IgE-mediated stimulation;
UAS Urticaria activity score IgE binds to the high-affinity IgE receptor FcεRI. Sub-
UCT Urticaria Control Test sequently, IgE cross-links and activates intracellular
signaling cascades and eventually releases various
Introduction mediators such as histamine. Furthermore, mast cells
can be activated by an IgE-independent mechanism
Urticaria is a polyetiological, acute or chronic der- mediated by the Mas-related G protein-coupled re-
matological disease, in which different forms are dis- ceptor X2 (MRGPRX2). There is evidence that higher
tinguished. The main symptom is itchy wheals that numbers of MRGPRX2+ mast cells are found in the
persist for less than 24 h. In addition, angioedema skin of CsU patients than in healthy individuals [11].
occurs in 40–50% of patients, although angioedema Since significantly increased eosinophils were de-
is thought to be underdiagnosed in patients with tected in skin biopsies of CsU patients, eosinophils
chronic spontaneous urticaria (CsU) [1]. Angioedema are thought to be involved in the pathogenesis of CsU.
alone is seen in 10% of patients. Here, it is unclear Eosinophils, together with mast cells, are thought to
whether this is a distinct entity or a separate form of prime the skin for wheal formation. In nonlesional
urticaria. and lesional skin of CsU patients, besides to increased
In most cases, urticaria is a spontaneously self-lim- numbers of eosinophils and mast cells, increased
iting condition, and the lifetime prevalence for acute numbers of CD31+-endothelial cells and blood vessels
spontaneous urticaria is 20% [2]. Spontaneous remis- have also been identified, suggesting that immune
sion occurs in most patients, but the course of the cells contribute to increased vascular permeability
disease is unpredictable for the individual patient. If [12].
symptoms persist beyond 6 weeks on several days per In addition, there are numerous interactions be-
week, the disease is referred to as CsU; the prevalence tween eosinophils and mast cells. Mast cells and
for this is 1–5%. Inducible forms of urticaria (CindU), T cells produce IL-5, which mobilizes eosinophils
such as delayed pressure urticaria, cold urticaria, or from the bone marrow and prolongs their half-life.
symptomatic dermographism, are distinguished from Furthermore, eosinophils can induce degranulation
CsU. This work focuses on the treatment of CsU [3], in mast cells via the release of eosinophil peroxidase
whereas the therapy of the inducible forms is very sim- (EPO) or major basic protein (MBP) via MRGPRX2. In
ilar to the CsU treatment. addition, eosinophils produce tissue factor and thus
Patients with CsU have a variable disease course can activate the coagulation cascade, which in turn
that may be associated with comorbidities and have can act as a mediator for mast cell activation [11, 13,
significantly lowered health-related quality of life [4]. 14].
It is important to emphasize that currently there is Basophils also appear to be important in the patho-
no curative therapy for CsU, consequently only symp- genesis of CsU. They also express FcεRI, to which IgE
tomatic treatment can be given until spontaneous re- binds and activates the basophils. In addition, ba-
mission occurs [5]. Therefore, there is a high need for sopenia has often been found in the peripheral blood
effective and well-tolerated therapeutic options. of CsU patients, which is why it is suspected that ba-
sophils migrate from the peripheral blood to the skin
Pathogenesis [11, 15].
Regarding an autoimmune/autoallergic pathogen-
The pathogenesis of CsU has not been conclusively esis, both type I autoallergic reactions and type IIb
clarified, but it is certain that different immune cell autoimmune reactions according to Coombs and Gell

Chronic spontaneous urticaria—status quo and future K

 review

have been identified in patients with CsU [16]. In
type I autoallergy, IgE antibodies against autoanti-
gens/autoallergens such as thyroperoxidase (TPO), in-
terleukin-24, or double-stranded DNA could be de-
tected. The IgE autoantibodies bind to the FcεRI,
crosslinking occurs, and finally mast cell degranulate
[11, 14].
Type IIb autoimmunity involves IgG autoantibod-
ies to FcεRI or to IgE [17, 18]. The IgG autoantibod-
ies against FcεRI or IgE bound to FcεRI can directly
lead to mast cell degranulation or activate comple-
ment factor C5. In addition, IgG anti-FcεRII antibod-
ies can activate eosinophils, which can also initiate
mast cell degranulation [11, 14]. IgM or IgA anti-FcεRI
antibodies have been identified in addition to IgE and
IgG autoantibodies; furthermore, IgE and IgG autoan-
tibodies may coexist in an affected individual [14, 19].
Depending on the Coombs and Gell type present,
patients show different characteristics. Patients with
type IIb reaction show higher disease activity and
higher scores in UAS7 score, later onset of disease,
preferential occurrence in females, and increased
prevalence for autoimmune comorbidities [17].
Overall, however, it should be emphasized that ap-
proximately 50% of patients have neither IgE nor IgG
autoantibodies, which is why non-autoimmune pro-
cesses are also involved in the pathogenesis, such as
the coagulation cascade. The serum of CsU patients
shows increased levels of prothrombin fragments F1
and F2, activated factor VII, and D-dimers. In par-
ticular, D-dimers were shown to be elevated only in
active disease and returned to normal in remission.
In addition, eosinophils can release tissue factor,
which leads to activation of the extrinsic coagulation
cascade. Within the extrinsic coagulation cascade,
thrombin and activated factor X increase vascular
permeability. Furthermore, binding to the protease-
activating receptors PAR-1 and PAR-2 and the forma-
tion of C5a result in mast cell degranulation [14].
Furthermore, neuropeptides such as substance P,
infections such as Helicobacter pylori gastritis, or
nonsteroidal anti-inflammatory drugs (NSAIDs) play
a role in the pathogenesis of CsU [14]. In summary,
the pathogenesis of CsU is polyetiologic and not yet
fully understood.
Guideline-based diagnosis and therapy of
chronic spontaneous urticaria
Diagnosis and therapy of CsU should be performed
according to the guidelines. The international guide-
line was last updated in 2022 by the European
Academy of Allergology and Clinical Immunology
(EAACI), the Global Allergy and Asthma European
Network (GA2 LEN), the European Dermatology Fo-
rum (EDF), and the Asia Pacific Association of Al-
lergy, Asthma, and Clinical Immunology (APAAACI),
methodologically supported by the European Centre
for Guidelines Development (EuroGuiDerm) [20]. The
current German AWMF guideline (AWMF Register No.
013-028, 2022) is strongly based on the international
guideline. It entered into force on 01 February 2022
and is valid until 31 January 2025 [21, 22]. The goal
of therapy for CsU is complete control of the disease.

Fig. 1 Recommended
treatment algorithm of Second Generation H1 Antihistamines
chronic spontaneous ur-
ticaria of the international Start with the standard dose
guideline. s.c. subcuta-
neous (Figure was created If needed: Increase up to the quadruple dose as off-label use
with BioRender. Modified
after Zuberbier et al. [20]) If inadequate control on high
dose after 2 -4 weeks

Omalizumab
Dose: 300 mg s.c. every 4 weeks
If needed: Increase up to 600 mg s.c. every 2 weeks as off-label use
+ Second Generation H1 Antihistamines

If inadequate control on high

dose after 6 months

Ciclosporin A
Dose up to 5 mg/kg bw as off-label use

+ Second generation H1 Antihistamines

Upon inadequate control a therapy with other immunomodulators

or immunosuppressants can be evaluated

K Chronic spontaneous urticaria—status quo and future

 review
For this purpose, the treatment algorithm should
be regularly reevaluated and adapted to the disease
activity ([20]; Fig. 1).
Diagnostics
While no basic diagnostic routine measures are rec-
ommended for acute spontaneous urticaria, diagnos-
tic clarification should be performed in patients with
CsU. The goals of the diagnostic process are based on
the “7 Cs”, which include “confirm”, “cause”, “cofac-
tors”, “comorbidities”, “consequences”, “components”
and “course” and are particularly highlighted in the
new guideline. This includes excluding differential di-
agnoses, looking for indicators of triggering a type I
or type IIb CsU, and identifying additional triggers or
trigger factors, such as NSAIDs [20].
In addition, comorbidities such as chronic in-
ducible urticaria, autoimmunity or psychiatric syn-
dromes should be assessed and problems with sleep,
work, or social environment should be identified.
Furthermore, potential biomarkers and predictors of
response to the chosen therapy and disease activity
and control should be monitored [20]. Specifically,
laboratory determination of differential blood count,
C-reactive protein (CRP) and erythrocyte sedimen-
tation rate, IgG anti-TPO and total IgE are recom-
mended. The determination of IgG anti-TPO and to-
tal IgE is a novelty, these parameters are determined
for clarification regarding autoallergic or autoimmune
genesis of CsU [20, 21].
Measurement of disease activity
The new guideline emphasizes more strongly the im-
portance of measuring disease activity using the UAS7
and, in particular, disease control using the Urticaria
Control Test (UCT). This should be determined regu-
larly during patient consultations and therapy adjust-
ments should be made based on these values [20]. In
addition, health-related quality of life should be de-
termined using the CU questionnaire [20, 21].
Measurement of the disease activity of CsU should
be performed by the UCT [23] or the urticaria activity
score (UAS) [24, 25]. These are validated question-
naires that can be completed by patients themselves
and ask about the most common urticarial signs and
symptoms. The UAS7 is calculated as a sum score of
seven consecutive days from the UAS. In particular,
the UAS7 is also used in studies to ensure compara-
bility [20, 21].
Disease control is determined by UCT. Thresh-
olds for UCT have been defined at which adjustment
of therapy is recommended. At UCT = 16, complete
disease control can be assumed and dose reduction
of current therapy is recommended. At UCT = 12–15,
well-controlled disease is assumed and the therapy
regimen should be continued and optimized if nec-
essary. Uncontrolled disease is assumed at UCT < 12,
Chronic spontaneous urticaria—status quo and future
and in this case therapy should be intensified, for ex-
ample, by increasing the dose of current therapy or
switching therapy [20, 22].
Therapy algorithm of the guideline
The overall treatment algorithm of the new interna-
tional guideline has been streamlined, and specific
dosing recommendations, including off-label use of
omalizumab, have been made [20, 22, 26].
A list of treatment options has also been created
that are no longer listed in the therapy algorithm,
but for which clinical experience suggests that they
may be successful if no therapeutic success occurs
under the therapy algorithm or it cannot be imple-
mented. For example, this list includes H2 antihis-
tamines, leukotriene receptor antagonists, or the low
pseudoallergen diet [20, 22, 26].
Antihistamines
First-generation antihistamines (H1-AH-1G) have
been available for the treatment of CsU since the
1950s, but should no longer be used due to their se-
dating effects and possible impairment, for example,
in road traffic, according to the GA2LEN position pa-
per [27, 28]. Second-generation antihistamines (H1-
AH-2G) have minimal or no sedative effect and no
anticholinergic effect, so they are now recommended
as first-line therapy for all forms of urticaria. Initially,
H1-AH-2G should be administered at the standard
dosage; if there is no therapeutic response under this,
the dosage should be increased up to fourfold.
It should be noted here that this is an “off label
use”, although the benefit of increasing the dose has
been shown in several studies [20, 27, 29]. Off-label
dosing has been recommended in the guideline since
2000, and so far no evidence of adverse events or side
effects due to accumulation has been shown. In gen-
eral, patient education should be provided regarding
the potential side effects of antihistamines, which in-
clude dizziness, impaired driving ability, fatigue, and
dry mucous membranes. In addition, written educa-
tion should be provided regarding “off-label use” [20,
22].
Omalizumab
In case of inadequate treatment response under H1-
AH-2G, the guideline recommends additional ther-
apy with omalizumab [20]. Omalizumab is a mon-
oclonal, humanized, anti-IgE antibody that exhibits
direct competitive inhibition with IgE at FcεRI and
FcεRII. Binding of IgE occurs, reducing the amount of
free IgE, and downregulation of the FcεRI receptor oc-
curs. In addition, the interaction between potentially
present IgE autoantibodies and FcεRI is inhibited, and
depletion of IgE autoantibodies has been described
[30–32].
K

Omalizumab is approved for the treatment of se-
vere allergic bronchial asthma, in weight-adjusted
doses. Since 2014, it has been approved as add-
on therapy in CsU in addition to H1-AH-2G at the
fixed dosage of 300 mg s.c. every 4 weeks [20]. The
efficacy of omalizumab was demonstrated by the
X-CUISITE trial, and dose finding was performed in
the MYSTIQUE trial [33].
In general, there are two patient populations with
different characteristics with regard to therapy re-
sponse. There are patients in whom a significant
improvement in symptoms already occurs in the first
week of therapy, and a second patient population in
whom an improvement in findings only occurs after
6–12 weeks [34, 35].
Total IgE can be used as a biomarker for treatment
response. The ratio of the total IgE at the start of ther-
apy to the total IgE after 4 weeks of therapy can be cal-
culated. Subsequently, the so-called 2 × 4 rule applies,
which states that in the case of a ratio smaller than
–0.5, only a therapy response of 32% is to be expected
[36–38]. To assess the response to therapy, it has been
suggested that an unchanged UAS7 or > 16 points in
the UAS7 should be considered a nonresponder and
a reduction in the UAS7 of at least 30%, but not 90%,
or a UAS7 > 6 points, but which has improved, should
be considered a partial response to therapy.
With a good response to therapy, good disease
control should be achieved for 4–6 months. Subse-
quently, a discontinuation trial is recommended to
check whether CsU has resolved in the meantime.
Alternatively, an interval extension of 1 week at a time
can be considered off-label [39]. Predictors of poor
response to therapy include a positive autologous
serum test or basophil activation test, eosinopenia,
basopenia, or an elevated CRP [40, 41].
Due to the mechanism of action of omalizumab,
the drug has also been tested in the indications of iso-
lated angioedema, where case reports of treatment re-
sponse exist. In addition, the efficacy of omalizumab
has been reported in chronic inducible urticaria and
urticarial vasculitis [42, 43].
Regarding the side effect profile of omalizumab, it
should be noted that the therapy is usually well tol-
erated, but two single case reports exist on the oc-
currence of alopecia areata and methemoglobinemia.
The underlying pathophysiology cannot be fully elu-
cidated here. Regarding alopecia areata, an activa-
tion of the Th1 signaling pathway and a reduction of
mast cell activity are discussed, since mast cells may
influence the regulation of the hair cycle. Similarly,
methemoglobinemia may be clearly temporally asso-
ciated with omalizumab administration, but again the
pathophysiology remains unclear. Heterozygous cy-
tochrome B5 reductase deficiency increases the risk
of developing methemoglobinemia. It is not known
whether such a mutation was present in the affected
patient, as the patient declined investigation [44, 45].
K Chronic spontaneous urticaria—status quo and future
review
Off-label use of omalizumab
If there is an inadequate response to therapy with
omalizumab, the guideline recommends adjusting the
dosage in an “off-label use” setting [20]. In principle,
there are two different approaches, either a shorten-
ing of the interval to 3 or 2 weeks or an increase of the
dosage to 450 mg or 600 mg s.c. can be performed [46].
Dosages up to 600 mg s.c. every 2 weeks were tested,
under which no additional adverse effects occurred.
With dosage adjustment, symptomatic improvement
was achieved in 61% of patients [47].
In particular, patients with obesity (body mass in-
dex [BMI] > 30 kg/m2), age older than 57 years, low to-
tal IgE, and prior therapy with ciclosporin A seem to
benefit from dosage adjustment. In general, patients
with signs of autoimmune etiology show a poorer re-
sponse to omalizumab, such as positive antinuclear
antibodies [48]. It should be noted that administra-
tion of 150 mg omalizumab s.c. every 2 weeks is also
possible, and this is not an off-label therapy [49].
Ciclosporin A
Ciclosporin A blocks T-cell functions as a calcineurin
inhibitor and inhibits the release of histamine by
mast cells and basophils. Due to the poorer side
effect profile compared to omalizumab and the fact
that ciclosporin A has no approval status for urticaria,
therapy with ciclosporin A is recommended in the
current guideline only after omalizumab therapy has
been completed. Specifically, doses of ciclosporin A of
up to 5 mg/kg body weight are recommended [20, 22].
In particular, patients with type IIb CsU show a better
response to therapy with ciclosporin A, whereas they
often respond poorly or slowly to therapy with H1-
AH-2G or omalizumab [31]. In principle, combination
therapy of ciclosporin A and omalizumab can also be
administered. Overall response rates of 76% have
been reported [46].
If therapy with ciclosporin A is unsuccessful, ref-
erence is made to the list of other therapeutic alter-
natives in the international guideline, which includes
various immunosuppressants such as methotrexate,
mycophenolate mofetil or intravenous immunoglob-
ulins [20].
Oral glucocorticoids
Oral glucocorticoids inhibit eosinophil recruitment
and immune cell extravasation. Long-term therapy
with oral glucocorticoids cannot be recommended
due to the side effect profile. However, the current
guideline indicates that short-term therapy with oral
glucocorticoids may be considered in severe exacer-
bation, at doses of 20–50 mg prednisolone equivalent
to break up the episode [20, 22].
 review

Differentiation from the American guideline
The U.S. Joint Task Force on Practice Parameters
(JTFPP) guideline, produced by the American Academy
of Allergy, Asthma, and Immunology and the Ameri-
can College of Allergy, Asthma, and Immunology, and
the international guideline have multiple differences
[20, 50]. For example, the American guideline, like
the international guideline, recommends the use of
monotherapy of an H1-AH-2G first and then a dose
increase to four times that amount. However, the
addition of a second H1-AH-2G, an H2 antagonist, or
an H1-AH-1G at night is recommended as an alterna-
tive. A mixture of different antihistamines is decidedly
not recommended in the international and German
guidelines [20, 22].
Furthermore, the international and German guide-
lines recommend the addition of omalizumab as
a third therapeutic step, whereas the American guide-
line recommends therapy with the H1-AH-1G doxepin
or hydrazine. In the American guideline, omalizumab
is listed only as a fourth therapeutic step, which is
listed equally with ciclosporin A or other anti-inflam-
matory or immunosuppressive drugs or biologics.
Ciclosporin is listed in the international guideline as
the fourth therapeutic step following therapy with
omalizumab [11, 20, 50].
New therapy options
In general, randomized controlled trials should be
conducted for new therapeutic options, with a direct
comparison to omalizumab therapy as the current
gold standard [8]. An overview of new therapeutic op-
tions and their targets, as well as approved therapies
is provided in Fig. 2.
Off-label therapies
Dupilumab
Dupilumab is a humanized anti-interleukin-4 recep-
tor-alpha (IL4Rα) monoclonal antibody. Interleukin 4
(IL-4) and interleukin 13 (IL-13) contribute to a Th2
immune response and IgE class switching through
their activity at the IL4Rα subunit. Increased levels
of IL-4 and IL-13 were detected in serum from CsU
patients, and increased numbers of IL-4 mRNA-ex-
pressing cells were also shown in skin biopsies from
CsU patients [52].
Currently, dupilumab is approved for the treatment
of atopic dermatitis, prurigo nodularis, bronchial
asthma, chronic rhinosinusitis with nasal polyposis,
and eosinophilic esophagitis. Because CsU has char-
acteristics of a Th2 disease, dupilumab has been stud-
ied as an off-label therapy in CsU patients, and case
reports have described a good therapeutic response
in CsU patients [52–55]. Currently, a randomized con-
trolled trial (RCT) of dupilumab therapy in refractory
CsU patients has been completed, while another RCT
on this is still recruiting. Furthermore, clinical trials of
dupilumab therapy in CindU have been initiated, as
well as dupilumab therapy in children aged 2–12 years
in CsU and CindU [14, 56].
Mepolizumab, reslizumab, and benralizumab
Mepolizumab and reslizumab are anti-interleukin-5
(IL-5) antibodies, while benralizumab is an anti-

Fig. 2 Established and Endothelial cells

Barzolvolimab
potential future targeted IL-13
therapies for chronic spon- Dupilumab
taneous urticaria. BTK Bru-
ton tyrosine kinase, Syk spleen Mast cell IL-4
TSLP
tyrosine kinase, TSLP thymic cKIT
Tezepe- T cell
stromal lymphopoietin. lumab IL-4R
(This figure was created Histamine Omalizumab
with BioRender. Modified Ligelizumab
Syk-Inhibitor
after Maurer et al. [51] and
Syk
Kolkhir et al. [52]) Remibrutinib
BTK
Fenebrutinib

FcεRI
Basophil IgE

Lirentelimab
C5aR1 IL-17 Secuki-
SIGLEC 8 numab
B cell

IL-5R
Advoralimab IL-5

IgE-auto-
IgG-auto- antibody
Eosinophil
antibody Mepolizumab
Benralizumab

Chronic spontaneous urticaria—status quo and future K


interleukin-5 receptor (IL5R) antibody. IL-5 is pro-
duced by mast cells and Th2 T cells and recruits mast
cells, eosinophils, and basophils from bone marrow.
In addition, IL-5 has an anti-apoptotic effect and
leads to upregulation of chemotactic receptors on
eosinophils, prolonging the half-life of eosinophils in
tissues [8]. Blockade of IL-5 is thought to result in
decreased disease activity.
IL-5 and IL-5R antibodies are used in eosinophilic
bronchial asthma. Mepolizumab is additionally ap-
proved for the treatment of chronic rhinosinusitis with
nasal polyps, hypereosinophilic syndrome (HES), and
eosinophilic granulomatosis with polyangiitis. A sin-
gle-center, single-label study of benralizumab therapy
in 12 antihistamine-refractory CsU patients has al-
ready been conducted, showing significant improve-
ment in UAS7, comparable to that of therapy with
omalizumab [57, 58]. Currently, additional clinical
trials with mepolizumab and benralizumab are be-
ing conducted for the treatment of CsU, the results of
which are currently pending [14, 59–61].
Secukinumab
Secukinumab is an anti-interleukin-17A (IL-17A) an-
tibody used in the treatment of psoriasis vulgaris and
psoriatic arthritis. An increase in IL-17 is seen in nu-
merous autoimmune diseases, including CsU both in
the blood and in the skin [62]. Patients with proven IL-
17 elevation who received therapy with secukinumab
showed remission of CsU [61].
New substances
Ligelizumab
Ligelizumab is a humanized anti-IgE monoclonal
antibody that binds to a different epitope than omal-
izumab. Ligelizumab has a 50-fold higher affinity for
and lower dissociation rate of IgE than omalizumab
[52]. Thus, IgE circulating in peripheral blood is
bound longer than by omalizumab. However, omal-
izumab has stronger direct competitive inhibition at
FcεRII than ligelizumab. A phase 2b study demon-
strated superiority of ligelizumab compared with
omalizumab. However, in the phase 3 study, lige-
lizumab therapy was superior to placebo therapy but
not to omalizumab therapy, and therefore the devel-
opment and approval of this antibody are currently
not being pursued further [8, 63].
Advoralimab and avacopan
Advoralimab is an anti-C5aR1 antibody and avaco-
pan is a C5aR1 inhibitor. Activation of the comple-
ment cascade results in the production of C5a, which
leads to degranulation of mast cells and basophils via
C5aR1. C5aR1 is preferentially expressed by mast cells
in the skin, whereas mast cells in the lung, uterus,
K Chronic spontaneous urticaria—status quo and future
review
or tonsil do not express C5aR1 [52]. Administration
of the antibody or inhibitor can inhibit mast cell de-
granulation [64]. Currently, no clinical trials of therapy
with advoralimab or avacopan are being conducted in
CsU patients.
Tezepelumab
Tezepelumab is a humanized antibody against thymic
stromal lymphopoietin (TSLP). TSLP is an alarmin
and type II immunity-inducing cytokine released by
epithelial cells. Increased numbers of TSLP-express-
ing cells have been detected in lesional skin from
CsU patients, and some studies have shown increased
serum TSLP levels. Tezepelumab is approved in Ger-
many and the United States for the treatment of severe
bronchial asthma and is another promising candidate
for the treatment of CsU [52, 65].
Barzolvolimab
This is an anti-cKIT antibody. cKIT is expressed by
mast cells, which is why this antibody leads to mast
cell depletion. In addition, the tryptase in the serum
decreases when administered [8, 66]. An open-label
phase 1b study was conducted in 21 patients suffering
from chronic inducible urticaria (cold urticaria and
symptomatic dermographism), in which a single ad-
ministration of barzolvolimab was administered. This
showed improvement in symptoms in all patients
and complete remission in 95%, for cold urticaria for
77+ days and for symptomatic dermographism for
57+ days with good tolerability of the drug [66]. Cur-
rently, two RCT studies are recruiting for therapy with
barzolvolimab, the one CsU patients and the CindU
patients [56].
Lirentelimab
Lirentelimab is an anti-SIGLEC8 antibody. SIGLEC8
is an inhibitory receptor of the CD33-related family
of sialic acid-binding immunoglobulin-like lectins. It
is expressed on the cell surface marker of mast cells,
eosinophils, and basophils. Activation of SIGLEC8 on
eosinophils leads to their apoptosis and thus causes
eosinophil depletion [52, 67–69]. In addition, SIGLEC8
has been shown to inhibit mast cell activation. In
a phase 2a study, positive clinical effects have already
been shown in patients with CsU [52, 70]. Currently,
another phase 2 study is recruiting antihistamine-re-
fractory CsU patients for therapy with lirentelimab
[71].
Remibrutinib, fenebrutinib
Bruton tyrosine kinase inhibitors such as remibruti-
nib or fenebrutinib also represent promising new ap-
proaches. BTK is involved in the FcεRI signaling path-
way, which ultimately leads to mast cell degranulation
 review
[72]. In addition, BTK is involved in the synthesis of
IgG and IgE by B cells. Thus, BTK inhibitors can re-
duce both mast cell degranulation and synthesis of IgE
and IgG, providing efficacy in both type I autoallergy
and type IIb autoimmunity [73].
Fenebrutinib is an oral, selective, noncovalent BTK
inhibitor, whereas remibrutinib is an oral, selective,
but covalent BTK inhibitor [52, 72]. A phase 2 study
already demonstrated the efficacy of fenebrutinib
in CsU patients with significant improvement in ur-
ticaria symptoms, and another phase 2b study showed
that remibrutinib therapy resulted in a reduction in
UAS7 score [72]. Few adverse events were seen, but
reversible transaminase elevation was a side effect of
fenebrutinib.
Currently, two phase 3 RCTs of remibrutinib ther-
apy for CsU are underway, the results of which have
not yet been published. In addition, a follow-up study
on the efficacy, safety, and tolerability of remibrutinib
patients who have already received remibrutinib in
clinical trials is recruiting [56, 61].
Topical spleen tyrosine kinase (Syk) inhibitors
Syk is a component of the intracellular FcεRI recep-
tor signaling cascade and is involved in the release of
histamine, leukotrienes, and cytokines by mast cells
and basophils. Topical Syk inhibitors enter the der-
mis to inhibit IgE-mediated release of histamine [52].
An early phase I study of therapy with topical Syk in-
hibitors has already been performed in CsU and other
CindU patients. Here, a reduction of the critical tem-
perature threshold was shown in patients with cold
urticaria, whereas no conclusive conclusions could be
drawn for CsU patients due to the small number of
patients [11, 52, 74].
Special patient groups
Children and pregnant women represent special pa-
tient groups. For a detailed discussion of urticaria
therapy in children, please refer to the paper on this
topic in the current issue. Therapy with omalizumab
is approved from the age of 12 years, but is also used
in the indication of bronchial asthma in children of
younger age [75, 76].
Therapy with omalizumab for the indication of al-
lergic asthma was investigated in pregnant women in
the EXPECT study, in which no increased incidence of
congenital abnormalities, miscarriages, or stillbirths
was observed [77, 78].
Conclusion and outlook
CsU is a chronic inflammatory dermatosis, whose
etiology is not yet fully understood and which is
associated with a high restriction of health-related
quality of life in affected patients. Currently, there
is no curative therapeutic approach, therefore only
Chronic spontaneous urticaria—status quo and future
symptomatic therapy can be administered or a spon-
taneous remission can be waited for.
In dermatology, the improved understanding of
chronic inflammatory diseases such as psoriasis vul-
garis and atopic dermatitis has led to major advances
in therapy by means of targeted, anti-inflammatory
therapies. Since an autoimmune/autoallergic genesis
could be identified in at least some of the patients
with CsU, such a therapeutic approach could also be
promising here. The anti-IgE antibody omalizumab
already represents such a selective therapy, which,
however, does not lead to therapeutic success and
freedom from manifestations in all patients. Con-
sequently, there is a high need for new therapeutic
strategies to treat CsU both symptomatically and cu-
ratively. In this context, several promising treatment
approaches are currently being tested in clinical trials.
Other phenotypes of CsU are currently not fully
characterized and the role of other immune cells such
as T cells, eosinophils and basophils is not yet conclu-
sively understood. For better treatment, a more com-
prehensive understanding of the pathogenesis is first
required in order to develop new targeted therapies.
Funding Open Access funding enabled and organized by
Projekt DEAL.
Conflict of interest S. Melchers received honoraria from Ky-
owa Kirin. J.P. Nicolay received funding for travel and congress
attendance from TEVA and Novartis and consulting fees from
TEVA, Almirall, Biogen, Novartis, Kyowa Kirin, Innate Pharma,
Takeda and Actelion, UCB Pharma and Recordati.
Open Access This article is licensed under a Creative Com-
mons Attribution 4.0 International License, which permits
use, sharing, adaptation, distribution and reproduction in
any medium or format, as long as you give appropriate credit
to the original author(s) and the source, provide a link to
the Creative Commons licence, and indicate if changes were
made. The images or other third party material in this article
are included in the article’s Creative Commons licence, unless
indicated otherwise in a credit line to the material. If material
is not included in the article’s Creative Commons licence and
your intended use is not permitted by statutory regulation or
exceeds the permitted use, you will need to obtain permis-
sion directly from the copyright holder. To view a copy of this
licence, visit http://creativecommons.org/licenses/by/4.0/.
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