CIA Update – Review Article

Int Arch Allergy Immunol 2020;181:321–333 Received: March 11, 2020

Accepted: March 11, 2020
DOI: 10.1159/000507218 Published online: March 30, 2020

Urticaria: Collegium Internationale

Allergologicum (CIA) Update 2020
Marcus Maurer a Kilian Eyerich b Stefanie Eyerich c Marta Ferrer d Jan Gutermuth e
         

Karin Hartmann f Thilo Jakob g Alexander Kapp h Pavel Kolkhir a, i Désirée Larenas-Linnemann j

         

Hae-Sim Park k Gunnar Pejler l Mario Sánchez-Borges m Knut Schäkel n Dagmar Simon o

         

Hans-Uwe Simon p, q Karsten Weller a Torsten Zuberbier a Martin Metz a

       

a Dermatological
Allergology, Allergie-Centrum-Charité, Department of Dermatology and Allergy, Charité –
Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin
Institute of Health, Berlin, Germany; b Division of Dermatology and Venerology, Department of Medicine Solna and
 

Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden; c Center for Allergy and Environment,  

Technical University and Helmholtz Center Munich, Munich, Germany; d Department of Allergy and Clinical  

Immunology, Clínica Universidad de Navarra, Instituto de Investigación Sanitaria de Navarra Pamplona, Spain, RETIC
de Asma, Reacciones Adversas y Alérgicas, Madrid, Spain; e Department of Dermatology, Universitair Ziekenhuis
 

Brussel, Vrije Universiteit Brussel, Brussels, Belgium; f Division of Allergy, Department of Dermatology, University of
 

Basel, Basel, Switzerland; g Department of Dermatology and Allergy, University Medical Center Giessen, Justus-Liebig
 

University Giessen, Giessen, Germany; h Department of Dermatology and Allergy, Hannover Medical School, Hannover,
 

Germany; i Division of Immune-Mediated Skin Diseases, I.M. Sechenov First Moscow State Medical University, Moscow,
 

Russia; j Center of Excellence in Asthma and Allergy, Médica Sur, Clinical Foundation and Hospital, Mexico City,
 

Mexico; k Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Suwon, South Korea;
 

l Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden; m Allergy and Clinical
   

Immunology Department, Centro Médico Docente La Trinidad, Caracas, Venezuela; n Department of Dermatology,  

Heidelberg University, Heidelberg, Germany; o Department of Dermatology, Inselspital, Bern University Hospital,
 

University of Bern, Bern, Switzerland; p Institute of Pharmacology, University of Bern, Bern, Switzerland; q Department of
   

Clinical Immunology and Allergology, I.M. Sechenov First Moscow State Medical University, Moscow, Russia

Keywords CU. This update is needed, as several recently reported find-

Wheals · Angioedema · Prevalence · Patient-reported ings have led to significant advances in these areas. Some of
outcomes · Treatment these key discoveries were first presented at past meetings
of the Collegium Internationale Allergologicum (CIA). New
evidence shows that the prevalence of CSU is geographical-
Abstract ly heterogeneous, high in all age groups, and increasing.
This update on chronic urticaria (CU) focuses on the preva- Several recent reports have helped to better characterize
lence and pathogenesis of chronic spontaneous urticaria two endotypes of CSU: type I autoimmune (or autoallergic)
(CSU), the expanding spectrum of patient-reported out- CSU, driven by IgE to autoallergens, and type IIb autoim-
come measures (PROMs) for assessing CU disease activity,
impact, and control, as well as future treatment options for Edited by: H.-U. Simon, Bern.

© 2020 The Author(s) Prof. Marcus Maurer

Published by S. Karger AG, Basel Dermatological Allergology, Allergie-Centrum-Charité
Department of Dermatology and Allergy, Charité – Universitätsmedizin Berlin
[email protected] This article is licensed under the Creative Commons Attribution-
NonCommercial-NoDerivatives 4.0 International License (CC BY- Charitéplatz 1, DE–10117 Berlin (Germany)
www.karger.com/iaa marcus.maurer @ charite.de
NC-ND) (http://www.karger.com/Services/OpenAccessLicense).
Usage and distribution for commercial purposes as well as any dis-
tribution of modified material requires written permission.
mune CSU, which is due to mast cell (MC)-targeted autoan- When all available studies that assessed point preva-
tibodies. The aim of treatment in CU is complete disease con- lence at different time points in the same region were
trol with absence of signs and symptoms as well as normal- compared, they all showed increasing point prevalence
ization of quality of life (QoL). This is best monitored by the over time [3]. This was especially so in the studies from
use of an expanding set of PROMs, to which the Angioedema Asia (Taiwan and Korea) [5, 9]. Geographical regions
Control Test, the Cholinergic Urticaria Quality of Life Ques- with a high point prevalence were Latin America and Asia
tionnaire, and the Cholinergic Urticaria Activity Score have with estimates of 1.5 and 1.4%, respectively [1]. In con-
recently been added. Current treatment approaches for CU trast, North America showed by far the lowest point prev-
under development include drugs that inhibit the effects of alence. The reasons for this are currently unclear. Global
signals that drive MC activation and accumulation, drugs studies are needed.
that inhibit intracellular pathways of MC activation and de- Additional unmet needs in our understanding of the
granulation, and drugs that silence MCs by binding to in- prevalence of CU and its increase include the frequencies
hibitory receptors. The understanding, knowledge, and of chronic inducible urticarias (CIndUs) as well as the
management of CU are rapidly increasing. The aim of this reasons for the differences in prevalence seen in women
review is to provide physicians who treat CU patients with an versus men, but not girls versus boys, and those of pa-
update on where we stand and where we will go. Many ques- tients from different parts of the world. Future epidemio-
tions and unmet needs remain to be addressed, such as the logical studies should also clarify the rate of CU patients
development of routine diagnostic tests for type I and type with wheals, angioedema, and both in children and adults
IIb autoimmune CSU, the global dissemination and consis- as well as the duration of the different subforms of CU.
tent use of PROMs to assess disease activity, impact, and con- As of now, virtually all studies on the duration of CU have
trol, and the development of more effective and well-toler- assessed this in patients who still had the disease rather
ated long-term treatments for all forms of CU. than in patients who had undergone spontaneous remis-
© 2020 The Author(s) sion.
Published by S. Karger AG, Basel

Type I and Type IIb Autoimmunity: Emerging

The Prevalence of Chronic Urticaria Is High in Endotypes of Chronic Spontaneous Urticaria
all Age Groups, Increasing, and Geographically
Heterogeneous Chronic spontaneous urticaria (CSU), the most com-
mon form of CU, presents with transient wheals (hives),
A recently published systematic review [1] with meta- angioedema, or both, without any definite triggers and
analyses on the prevalence of chronic urticaria (CU) re- reoccurrence of signs and symptoms for >6 weeks. CSU
vealed three major insights: (1) CU is just as common in is a mast cell (MC)-driven disease. The degranulation of
children as it is in adults; (2) the prevalence of CU is in- skin MCs is held to be the initial event in the development
creasing; (3) there are substantial differences in the prev- of skin changes, such as sensory nerve stimulation, vaso-
alence of CU across geographical regions. dilation and extravasation, as well as the recruitment of
Based on the limited published data available, the basophils, eosinophils, and T cells, which collectively lead
overall point prevalence of CU across all age groups is es- to whealing, itch, and angioedema. Over the past year,
timated at 0.7% [2, 3]. This confirms that CU is a common two groups of MC-degranulating signals have been iden-
disease. Interestingly, new data also show that the preva- tified and characterized: IgE autoantibodies to autoaller-
lence of CU in children is as high as or higher than in gens and autoantibodies that target activating MC recep-
adults, estimated on average at 1% [1]. In three studies tors (Fig. 1). These two types of autoimmune hypersensi-
that included both children and adults, the prevalence did tivity, i.e., type I autoimmunity (also called autoallergy)
not differ significantly between both age groups [4–6]. In and type IIb autoimmunity, have been postulated to be
a more recent study, the prevalence in children in Europe the relevant cause in most patients with CSU [10].
was 1.1% [7]. In a study from Korea, the prevalence in In type I autoimmune CSU, autoantigens crosslink IgE
children was even higher [8]. The point prevalence of CU autoantibodies on MCs and basophils to cause the release
in women is higher than in men (1.3 vs. 0.8%). Looking of vasoactive mediators (Fig. 1). A role of type I autoim-
at sex differences in children, a subgroup analysis yielded munity in urticaria was postulated as early as 20 years ago,
a point prevalence of 1.0% for girls and 1.1% for boys. following the demonstration of IgE autoantibodies

322 Int Arch Allergy Immunol 2020;181:321–333 Maurer et al.

DOI: 10.1159/000507218
against the thyroid microsomal antigen in the serum of a
CSU patient [11]. Since then, many studies have further Autoimmunity type I
Allergen
characterized the prevalence and pathogenic relevance of
type I autoimmunity in CSU [12]: Thyroperoxidase Autoallergen
(TPO) has been demonstrated to be a common and rel-
IgE
evant autoallergen in CSU. In one study, more than half
of the 478 analyzed CSU patients were found to have el-
evated levels of IgE autoantibodies against TPO (IgE-an-
ti-TPO). In Xolair in Chronic Urticaria Induced by serum
IgE Targeting Endoallergens, the first multicentric ran-
domized controlled CSU trial with the therapeutic anti-
IgE omalizumab, patients with IgE-anti-TPO showed a
rate of complete response (i.e., no more wheals) of 70%, IgG anti-IgE
FcεRI
higher than that of any subsequent trial in which patients
IgG anti-FcεRI
were not required to have IgE-anti-TPO. Basophils load-
ed with the IgE of CSU patients before exposure to TPO Autoimmunity type IIb
ex vivo show activation and mediator release [13, 14]. Re-
cently, Sánchez et al. [13] reported that 6 and 9 of 50 CSU
Fig. 1. Endotypes of CSU. In CSU, MCs are thought to be activat-
patients showed a positive response to skin prick testing ed in most patients by IgE autoantibodies to autoallergens (type I
and intradermal injection of TPO, respectively. Also, autoimmunity or autoallergy) or IgG autoantibodies targeting ac-
whealing in response to TPO skin prick testing was adop- tivating MC receptors (type IIb autoimmunity). CSU, chronic
tively transferred from CSU patients to healthy subjects spontaneous urticaria; MC, mast cell.
[13].
CSU patients also have IgE autoantibodies directed to
a large assortment of autoantigens beyond TPO, of which
many are expressed in the skin. These include thyroglob- er, Grattan et al. [20] confirmed the presence of these au-
ulin, tissue factor, and IL-24 [15, 16]. In one study, IgE- toantibodies in CSU patients with a positive reaction in
anti-IL-24 was recognized by the IgE of 70% of CSU pa- the autologous serum skin test (ASST), i.e., a wheal and
tients. Similar to TPO, exposure of basophils loaded with flare response to intradermal injection of their own se-
the IgE of CSU patients to subsequent incubation with rum. Another 2 years later, IgG autoantibodies to FcεRI,
IL-24 leads to the degranulation of MCs [16]. The IgE- the high-affinity receptor for IgE on MCs and basophils,
anti-IL-24 levels of patients with CSU correlate with their were described in CSU patients [21]. Very recently, CSU
disease activity and are reduced by autologous serum patients were found to also have IgM and IgA autoanti-
therapy in patients who respond to this treatment [17]. bodies to FcεRI [22]. More CSU patients had IgM auto-
CSU patients were also found to have elevated levels of antibodies to FcεRI (60%) than IgG against FcεRI (24%),
IgE autoantibodies against DNA, but not of IgG against and elevated levels of IgM against FcεRI, but not of IgG
DNA, and in some patients, incubation of their basophils against FcεRI, were linked to low blood basophil and eo-
with DNA resulted in degranulation and mediator release sinophil counts, markers of high CSU disease activity
[18]. [22]. The concept that type IIb autoimmune mechanisms
Furthermore, it has been shown in some but not all can drive CSU is further supported by the results of baso-
studies that IgE autoantibodies are responsible for the in- phil tests. The serum of a subpopulation of CSU patients
creased total IgE levels in CSU patients. In the studies activates heterologous basophils, and this basophil-acti-
demonstrating increased IgE autoantibodies in CSU pa- vating serum activity is linked to the presence of autoan-
tients, most of the IgE was found to be directed against tibodies against FcεRI and positive ASST responses [23,
autoantibodies in contrast to individuals who did not 24].
have CSU. Several independent, albeit indirect, lines of evidence
A type IIb hypersensitivity mechanism in which auto- suggest that type I autoimmune and type IIb autoimmune
antibodies, usually IgG or IgM, bind to antigen on a target CSU patients differ in their disease features, laboratory
cell (Fig. 1) was first described in CSU in 1988 [19], dem- markers, and response to treatment (Table 1). Based on
onstrating IgG autoantibodies against IgE. Two years lat- the comparison of CSU patients who do or do not express

Urticaria: CIA Update 2020 Int Arch Allergy Immunol 2020;181:321–333 323
DOI: 10.1159/000507218
Table 1. Features of type I and type IIb autoimmune CSU

Features Type I versus type IIb autoimmunity

Autoantibodies auto-IgE (e.g., against TPO, TG, TF, IL-24, dsDNA) in type I [12, 13, 15, 111],
auto-IgG (against IgE, FcεRI) in type IIb [112–114]
Diagnosis total auto-IgE and specific IgE to autoallergens1 in type I [115], triple positivity:
BHRA/BAT+ASST+WB/ELISA+ in type IIb [24, 25]
Disease activity/severity tends to be higher in type IIb [12, 14, 25, 111]2
Disease duration tends to be longer in type IIb as shown in some [116, 117] but not all [25] studies
Rates of concomitant autoimmune diseases tend to be higher in type IIb [25, 118–121]
Rates of concomitant allergic diseases might be higher in type I [119]
Total IgE levels low in type IIb and normal or high in type I [14, 25]
Basopenia rates might be higher in type IIb [24, 111]2
Eosinopenia rates tend to be higher in type IIb [122]
C-reactive protein levels may be higher in type IIb [25, 123]
ANA positivity rates may be higher in type IIb [124]
Responder rates to sgAHs may be lower in type IIb [122–125]
Responder rates to omalizumab high in type I [28] and low in type IIb [62, 122, 126]
Speed of response to omalizumab slow in type IIb [127]
Immunosuppressive therapy can be effective in type IIb [128–134]3

TPO, thyroperoxidase; TG, thyroglobulin; TF, tissue factor; IL, interleukin; dsDNA, double-stranded DNA; BHRA, basophil
histamine release assay; BAT, basophil activation test; ASST, autologous serum skin test; WB, Western blot; ELISA, enzyme-linked
immunosorbent assay; CRP, C-reactive protein; ANA, antinuclear antibodies; sgAHs, second-generation antihistamines. 1 Measured by
ELISA or radioimmunoassay. 2 In one study, IgE-anti-IL-24 levels showed a correlation with disease activity and a negative correlation
with blood basophil counts. 3  Cyclosporine, plasmapheresis, rituximab, intravenous immunoglobulins, methotrexate, mycophenolate
mofetil. Most studies are case reports.

markers of type IIb autoimmunity (autoantibodies, baso- suggested to be different in type IIb versus type I CSU pa-
phil tests, and/or ASST), type IIb autoimmune CSU pa- tients include C-reactive protein and antinuclear anti-
tients have been suggested to have higher disease activity bodies (Table 1).
and longer disease duration as well as higher rates of co- The efficacy of anti-IgE treatment with omalizumab or
morbid autoimmunity. Basopenia and eosinopenia may ligelizumab supports both type I and type IIb autoim-
also be more common in these patients. mune pathomechanisms in CSU. Omalizumab reduces
In the recent PURIST study, the first to characterize the levels of IgE, the driver of type I autoimmune CSU,
CSU patients who are positive for all three defining mark- and of its high-affinity receptor FcεRI, the target of type
ers of type IIb autoimmune CSU, i.e., IgG-anti-FcεRI/ IIb autoantibodies. More importantly, type I and type IIb
IgE-positive, basophil test-positive, and ASST-positive, autoimmune CSU patients treated with anti-IgE differ in
8% of 184 patients were triple-positive, i.e., had bona fide their rates of response and in their speed of onset of im-
type IIb CSU [25]. These patients showed higher IgG- provement [26–30]. Most CSU patients treated with
anti-TPO levels and higher rates of elevated IgG-anti- omalizumab become symptom-free within the first
TPO as well as lower IgE levels and higher rates of low IgE month of their first injection. This is in line with type I
as compared to triple-negative patients. In fact, the IgG- autoimmunity, where anti-IgE rapidly binds free IgE, in-
anti-TPO/IgE ratio was found to be the best predictor of cluding IgE against autoantigens, and IgE/anti-IgE com-
type IIb autoimmune CSU. Other markers that have been plexes bind autoallergens, thereby reducing MC degranu-

324 Int Arch Allergy Immunol 2020;181:321–333 Maurer et al.

DOI: 10.1159/000507218
Table 2. PROMs in CSU and areas of use

UAS CU-Q2oL UCT AAS AE-QoL AECT

Applicable in patients with:

Wheals and no angioedema + + + – – –
Wheals and angioedema + + + + + +
No wheals and angioedema – – + + + +
Number of items 2 23 4 5 17 4
Retrospective assessment – + + – + +
(recall period) 2 weeks 4 weeks 4 weeks 4 weeks
3 months
Prospective assessment + – – + – –
(frequency) 1× or 2×/day 1×/day
MCID 11 3–153 3 8 6 not yet
established
Cost-free for:
Patient management + + + + + +
Academic research + + + + + +
Industry studies + – – – – –
Language/country versions + Italian, German, Greek, >20 language >70 language >25 language German,
available1, 2 Hebrew, Korean, Persian, versions versions versions American
Polish, Portuguese, available2 available2 available2 English
Spanish, Thai, Turkish

AAS, Angioedema Activity Score; AECT, Angioedema Control Test; AE-QoL, Angioedema Quality of Life Questionnaire; CSU, chronic spontaneous
urticaria; CU-Q2oL, Chronic Urticaria Quality of Life Questionnaire; MCID, minimal clinically important difference; PROMs, patient-reported outcome
measures; UAS, Urticaria Activity Score; UCT, Urticaria Control Test. 1 The UAS is available in several languages. The original source is the EAACI/GA2LEN/
EDF/WAO urticaria guideline. Due to its easy structure, the UAS is usually translated but not formally linguistically validated. 2 For more details with regard
to available language versions of the AAS, AE-QoL, UCT, and AECT go to www.moxie-gmbh.de. Additional language/country versions may be or are in
preparation; for more information, please contact Moxie at [email protected]). 3  The MCID of the CU-Q2oL has been assessed in two independent
studies performed in different patient collectives in Europe and Asia. While one study found an MCID of 3 points [46], the MCID identified in the other
study was higher with 15 points [134].

lation. Some CSU patients take months to respond to sophils, alarmins, and other signals in the pathogenesis of
omalizumab, and this is in line with type IIb autoimmu- CSU. More research is needed to clarify whether mecha-
nity, where the reduction of free IgE results in the slow nisms of skin MC degranulation other than type I and
loss of membrane-bound FcεRI from skin MCs, the target type IIb autoimmune activation support the existence of
of type IIb-driving autoantibodies. distinct and separate endotypes.
Future studies need to characterize in detail the role
and relevance of type I and type IIb autoimmunity in
CSU. Standardized and validated diagnostic tests for IgE Use of Patient-Reported Outcome Measures
autoantibodies to autoallergens and for relevant MC-ac- Improves the Management of CU
tivating autoantibodies need to be developed to better de-
fine these CSU endotypes and their differences. A clearer Why We Should Measure Disease Activity, Impact,
picture of the prevalence, mechanisms, and clinical pro- and Control in Patients with CU
files of type I and type IIb autoimmune CSU will help to Patient-reported outcome measures (PROMs) are es-
develop targeted therapies and facilitate optimal treat- sential for optimizing the management of CU [36, 37].
ment of both subpopulations of CSU patients. They are also of key importance for assessing treatment
Recent reports [31–35] suggest that additional endo- effects in clinical trials. Over the past years, disease-spe-
types of CSU may exist, with evidence pointing to a role cific PROMs have been developed for CU (Table 2). They
of factors of the coagulation pathway, ligands of the MAS- are widely used in clinical practice and trials, and they as-
related G protein-coupled receptor X2 (MRGPRX2), ba- sess disease activity, impact, or control. Why is it impor-

Urticaria: CIA Update 2020 Int Arch Allergy Immunol 2020;181:321–333 325
DOI: 10.1159/000507218
tant to obtain information on these three aspects of CU? version has been reported [65]. It is not suitable for as-
Disease activity (i.e., symptom burden), disease impact sessing disease activity in patients with CIndU. The docu-
(i.e., impairment of quality of life [QoL]), and the control mentation of itch and its intensity may reflect non-CSU-
that patients have over their disease are concepts that are related itch. It does not entail angioedema, a common and
linked. High disease activity often comes with low QoL important clinical manifestation of CSU. The prospective
and low levels of disease control. However, disease activ- character of the UAS7 makes an ad hoc evaluation impos-
ity only moderately correlates with QoL impairment in sible, as the results are only available at the next appoint-
patients with CSU [38]. In other words, some patients ment after its administration.
exhibit markedly impaired QoL although their symptom CSU patients experience markedly impaired QoL.
burden is rather low. Other patients show high disease General QoL questionnaires and QoL instruments devel-
activity, but only moderately impaired QoL. The reasons oped for patients with dermatological diseases such as the
for this are largely unknown, but may include the pres- Dermatology Life Quality Index, the Children’s Derma-
ence or absence of effective coping strategies or of comor- tology Life Quality Index, the Dermatology Quality of
bid diseases, such as depression and anxiety, which are Life Scales, and the Dermatology-Specific Quality of Life
common in CU patients [39–41]. What is clear though is instrument have been used in CSU [66, 67]. While these
that the aims of effective treatment, i.e., absence of signs tools are well suited to compare QoL impairment in pa-
and symptoms, normalization of QoL, and complete con- tients with CSU with that in patients with other diseases,
trol, are best achieved when assessed by appropriate tools. they do not provide information on CSU-specific aspects
of QoL impairment nor on its changes over time, e.g., in
What Tools Should Be Used to Assess Patients with response to treatment [68]. The CU-Q2oL was developed
CSU for Disease Activity, Impact, and Control? to assess the QoL impairment specific to CSU [47, 68]
Patients with CSU present with wheals, angioedema, (Table 2). It is the guideline-recommended QoL tool for
or both, which is important in the correct selection of the CSU [61] and available in many languages [48, 49, 69–
PROMs to use. In patients with wheals (with or without 72]. The CU-Q2oL shows good sensitivity to change, and
angioedema), the Urticaria Activity Score (UAS) [42–45], its MCID has been found to be 3–15 (3 and 15 in inde-
the Chronic Urticaria Quality of Life Questionnaire (CU- pendent studies and patient collectives from Europe and
Q2oL) [46–49], and the Urticaria Control Test (UCT) Asia). It has been used in many clinical studies, including
[50–54] are the PROMs of choice to measure disease ac- pharmacological randomized controlled trials [28, 73,
tivity, impact, and control, respectively. In patients with 74]. The CU-Q2oL also has limitations. Most important-
predominant angioedema (with or without wheals), the ly, it was not specifically designed to assess the QoL im-
Angioedema Activity Score (AAS) [55, 56], the Angio- pairment due to angioedema, which occurs in many pa-
edema Quality of Life Questionnaire (AE-QoL) [57–59], tients and can impact on their disease-specific QoL, and
and the Angioedema Control Test (AECT) [59] should be therefore it is not useful in patients with CSU predomi-
used (Table 2). nantly affected by angioedema. Also, there is no version
The UAS7 records, over 7 consecutive days, the daily for the use in children, and it is not suitable for CIndU.
number of wheals and the intensity of itch. It is the guide- Disease control is a major treatment aim in CSU, and
line-recommended gold standard for measuring disease the UCT was specifically developed and validated to mea-
activity in CSU patients with wheals [60, 61] (Table 2). sure this in all forms of CU, including CIndU. The UCT
The two available versions of the UAS7 differ slightly in is a 4-question retrospective PROM with a minimum val-
that they require either a twice-daily or once-daily docu- ue of 0 points (no control) and a maximum value of 16
mentation and in their categories for daily numbers of points (complete control). A score of ≤11 points indicates
wheals. Both versions yield comparable results [43, 44]. poorly-controlled urticaria, whereas a score of ≥12 points
The once-daily UAS is preferred for routine clinical use: indicates well-controlled disease. The UCT strongly cor-
Patients only need to document their wheals and itch relates with the UAS [54, 75], has high levels of validity
once every day, it has been thoroughly validated [60], its and reliability, and accurately identifies patients with in-
minimal clinically important difference (MCID) of 11 sufficiently controlled disease. Its MCID is 3 points [52,
points is well characterized [42], and it has been used in 53]. No version for children is available as of yet.
numerous randomized controlled trials and real-life The AAS is the tool of choice for the assessment of dis-
studies [17, 62–64]. The UAS7 has several limitations. It ease activity in patients with CSU who present with recur-
has not been validated in children, although a modified rent angioedema without wheals and in patients where

326 Int Arch Allergy Immunol 2020;181:321–333 Maurer et al.

DOI: 10.1159/000507218
angioedema is a predominant factor. Like the UAS, the scores, such as the Cholinergic Urticaria Activity Score
AAS is a prospective, diary-type tool. Patients document [81], that should be validated. Disease activity scores for
every day for 4 weeks (AAS28) whether angioedema oc- CIndUs take into account the actual daily exposure of pa-
curred during the last 24 h, in which case five additional tients to relevant triggers. CIndU-specific QoL question-
questions on severity and impact are answered [56]. The naires are available for some CIndUs, for example the
AAS shows high levels of validity and test-retest reliabil- Cholinergic Urticaria Quality of Life Questionnaire for
ity and is sensitive to changes of angioedema activity over cholinergic urticaria [82], but not all. Disease control in
time, with an MCID of 8 points for the 7-day AAS (AAS7). patients with CIndU is measured with the UCT.
The AAS has also been used in recent randomized con-
trolled trials [74, 76]. PROMs in CU: Unmet Needs and Questions to
The AE-QoL is the first symptom-specific PROM to Be Addressed
assess angioedema-specific QoL impairment in patients As of now, none of the urticaria-specific PROMs de-
with CSU [58]. It consists of 17 questions with 5 answer veloped are available for use in children. The UAS7, CU-
options each scored from 0 to 4 points, which are summed Q2oL, and UCT as well as the AAS, AE-QoL, and AECT
up to a total score but fall in four different domain scores should be validated in adolescents, and corresponding
(“functioning,” “fatigue/mood,” “fears/shame,” “food”), tools for younger children must be developed. The same
which are each displayed on a 0–100 scale The AE-QoL holds for the PROMs that were recently developed for
demonstrates high sensitivity to change, and its MCID is CIndUs. Many PROMs, but also CIndU trigger threshold
6 points [59]. The AE-QoL is available in many different tests, have not yet been investigated for their MCIDs,
languages and has been used in randomized controlled which is needed for their optimal use in clinical trials and
clinical trials [74, 76]. Again, no version for children is routine specialist practice. The global dissemination of
available yet. available PROMs needs to be increased. Cross-cultural
The AECT is a novel tool that quantifies disease con- adaptations, translations, and the validation of PROMs
trol in CSU patients with angioedema as well as in pa- are needed for international studies and for comparing
tients with other forms of recurrent angioedema [77, 78]. patients from different regions of the world. For this, ap-
The AECT is a retrospective PROM. Two versions exist, propriate procedures must be followed to ensure that
one with a 4-week recall period and one with a 3-month questionnaires are adapted to local conditions and that
recall period. The AECT consists, like the UCT, of only equivalent versions are produced.
four questions. It is easy to administer, easy to complete,
and easy to score.
Emerging MC-Targeted Treatment Options for CU
What Tools Should Be Used to Assess Disease Activity
and Control in Patients with CIndU? MCs are the critical effector cells in urticaria; there-
Disease activity in CIndU is assessed by testing pa- fore, targeting MC activity is a promising treatment ap-
tients for their trigger thresholds. Patients with low dis- proach [83]. Here, the guideline recommends as third-
ease activity have high trigger thresholds and vice versa. and fourth-line treatments omalizumab and cyclosporine
In cold urticaria for example, patients with high disease for CU. Omalizumab inhibits MC activation via the IgE
activity can be made to develop wheals by exposure to receptor and cyclosporine interferes with MC signal
warmer temperatures (e.g., 20 ° C) than those required to
     transduction and activation. The next generation of
produce whealing in patients with low disease activity MC-targeted treatments for CU fall into three groups:
(e.g., 8 ° C). Protocols and test devices are available for
     (1) compounds that inhibit the effects of signals that drive
threshold testing in cold urticaria, symptomatic dermo­g­ MC activation and numbers, (2) compounds that inhibit
raphism, cholinergic urticaria, pressure urticaria, and intracellular pathways of MC activation and degranula-
solar urticaria [79]. Cold urticaria patients for example tion, and (3) compounds that silence MCs by binding to
are assessed for their individual critical temperature inhibitory receptors (Fig. 2).
thresholds, i.e., the warmest temperature that is cold
enough to produce a wheal, with the help of the Temptest Drugs Inhibiting the Effects of Signals That Drive
[80]. Trigger threshold measurements for determining MC Activation and Numbers
disease activity in patients with CIndU can be comple- Activation of skin MCs via FcεRI has been shown to
mented by the use of CIndU-specific disease activity drive the development of the signs and symptoms of CSU,

Urticaria: CIA Update 2020 Int Arch Allergy Immunol 2020;181:321–333 327
DOI: 10.1159/000507218
 pared to their nonlesional skin and the skin of control
FcεRI subjects [34]. Therefore, IL-33, IL-25, and thymic stromal
MRGPRX2
lymphopoietin should be explored as targets of novel
C5aR IL-4R treatment strategies for CSU.
KIT
CRTH2 Skin MCs express Kit, the receptor for stem cell fac-
IL-5R
tor, which is the major driver of MC differentiation, acti-
vation, migration, proliferation, and survival [95]. MC
ST2 TSLPR
numbers are increased in the skin of CSU patients, which
Btk
may be due to the effects of stem cell factor, which is also
Syk a potent activator of MCs [96, 97]. Reducing the number
of MCs may help patients with CSU. Neutralization of
stem cell factor with anti-stem cell factor may reduce MC
numbers and inhibit MC activation.
MCs express receptors for the Th2 cytokines IL-4 and
IL-5. Both cytokines have been shown to promote MC
CD300a survival and to prime them for their FcεRI-mediated pro-
CD200R Siglec-8
duction and secretion of proinflammatory cytokines [98,
99]. IL-4 levels are elevated in the serum of patients with
CSU, and IL-4-expressing cells are increased in the skin
Fig. 2. MC-targeted treatments for CU under development. Ex-
amples of activating (upper half) or inhibiting (lower half) recep-
of CSU patients [100, 101]. Recently dupilumab, which
tors and signaling molecules (within the cell) that are currently inhibits IL-4 and IL-13 effects through blockade of their
under development for the treatment of CU. Btk, Bruton’s tyrosine shared IL-4α receptor subunit, was shown to benefit pa-
kinase; CU, chronic urticaria; MC, mast cell; Syk, spleen tyrosine tients with refractory CSU unresponsive to omalizumab
kinase. [102]. The effects of dupilumab in CU are currently being
assessed in two phase II randomized clinical trials, one in
CSU and one in cholinergic urticaria.
IL-5, in addition to its effects on MCs, may contribute
and treatment with omalizumab, an anti-IgE antibody, is to the pathogenesis of CSU by recruiting eosinophils and
effective in CSU [84–91]. Omalizumab has been shown basophils to lesional skin sites, where they are often found
to dissociate pre-bound IgE from MCs and basophils, re- in high numbers. Benralizumab, an anti-IL-5 receptor an-
sulting in a decrease in degranulation [92]. Ligelizumab tibody, as well as the anti-IL-5 antibodies mepolizumab
is another humanized monoclonal anti-IgE antibody and reslizumab have been successfully used to treat pa-
with a 50-fold higher affinity to IgE than omalizumab. It tients with CSU and CIndU [103, 104]. Benralizumab and
was recently tested in a phase II multicenter randomized mepolizumab are currently in CSU trials.
controlled trial against placebo and omalizumab. In this Several additional receptors, such as the complement
trial, ligelizumab demonstrated superiority to both pla- C5a receptor (C5aR, CD88) and MRGPRX2, are ex-
cebo and omalizumab and was characterized by a rapid pressed by MCs and have been proposed to be the targets
onset of action and dose-dependent efficacy [63]. Inter- of signals that drive the development of the signs and
estingly, ligelizumab also showed a longer time to relapse symptoms of CU. C5aR is expressed by skin MCs, but not
after the last injection, i.e., 10 versus 4 weeks with omali- lung or other MCs, and the degranulation of MCs via the
zumab. Phase III studies are ongoing in adults and ado- MC-activating autoantibodies of type IIb autoimmune
lescents with CSU. This clinical efficacy of ligelizumab CSU patients is, at least in part, mediated by activation of
may involve effects of this molecule on IgE production by C5aR [105, 106]. MRGPRX2, like C5aR, is preferentially
B cells [93]. expressed by skin MCs, where its expression is upregu-
The alarmins and innate type 2 immunity-inducing lated in patients with severe CSU [32]. Substance P, major
cytokines IL-33, IL-25, and thymic stromal lymphopoi- basic protein, and eosinophil peroxidase induce hista-
etin all have effects on MCs and have been implicated in mine release from human skin MCs through activation of
the pathogenesis of CSU [34, 94]. For example, the wheals MRGPRX2 independent of the NK1 receptor [32]. Fur-
of CSU patients show markedly more cells that express thermore, the levels of substance P, a neuropeptide and
IL-33, IL-25, and thymic stromal lymphopoietin as com- agonist of both MRGPRX2 and the NK1 receptor, are in-

328 Int Arch Allergy Immunol 2020;181:321–333 Maurer et al.

DOI: 10.1159/000507218
creased in the serum of CSU patients and correlate with of further studies, across all age groups. Despite many
disease activity [107, 108]. Thus, targeting MRGPRX2 important recent insights on the pathogenesis of CU, the
and/or its agonists (e.g., substance P) is a promising endotypes and pathomechanisms of CSU are still insuf-
mechanism for decreasing MC activation in patients with ficiently characterized and the causes of CIndU remain
CSU. unknown. Autoallergy and type IIb autoimmunity ap-
pear to be distinct endotypes of CSU, but better tests are
Drugs That Inhibit Intracellular Pathways of MC needed to identify patients with one or the other or nei-
Activation and Degranulation ther. This is needed to optimize the treatment of patient
Bruton’s tyrosine kinase and spleen tyrosine kinase are subgroups with the drugs available today and to develop
key players in the transduction of signals downstream of treatments that can prevent all of the subforms of CU, al-
the high-affinity IgE receptor FcεRI. Inhibitors of Bru- ter their course, and cure patients. Antihistamines and
ton’s tyrosine kinase or spleen tyrosine kinase inhibit the omalizumab are the only currently licensed treatments,
degranulation of human MCs [109, 110]. Treatment with and additional and better treatments for CU are needed,
a Bruton’s tyrosine kinase inhibitor inhibits IgE- and especially for CIndU. The development of novel treat-
MC-mediated responses in mice and humans [110]. Two ments for CIndUs and CSU also needs instruments that
Bruton’s tyrosine kinase inhibitors, Fenebrutinib and allow to assess their efficacy. Significant progress has been
Remibrutinib, are currently under development for the made with this over the past years, but more efforts are
oral treatment of patients with CSU, and the spleen tyro- needed to extend the existing tools to children, to develop
sine kinase inhibitor GSK2646264 is in clinical trials for and validate tools for all forms of CU, and to make urti-
cold urticaria and CSU. caria and angioedema PROMs available and their use
routine practice on a global scale. The future of urticaria
Drugs That Silence MCs by Binding to Inhibitory drug development has never been more promising, with
Receptors several strategies being pursued.
The vast majority of receptors expressed by MCs are
activating receptors, i.e., their engagement by ligands re-
sults in degranulation, migration, differentiation, or pro- Acknowledgements
liferation. A small set of MC receptors are inhibitory re-
ceptors that, upon engagement by ligands, silence MCs We acknowledge the support of the GA2LEN network of Urti-
caria Centers of Reference and Excellence (UCAREs; www.ga2len-
and inhibit their activation including degranulation. Si- ucare.com) and of the GA2LEN/HAEi network of Angioedema
glec-8 and CD200Ra are two of these inhibitory MC re- Centers of Reference and Excellence (ACAREs; www.acare-net-
ceptors, and antibodies targeting them are currently un- work.com). P. Kolkhir was supported by the Russian Academic
der development for CU. For example antolimab, a Excellence Project 5-100 and a GA2LEN stipend. We thank Aldona
von Gunten for help with the figures and Beate Schinzel for edito-
monoclonal antibody that targets Siglec-8, was shown to
rial assistance.
inhibit MC activation and to deplete eosinophils. Anto-
limab was tested in a phase IIa, open-label pilot study in
patients with omalizumab-naïve and omalizumab-re-
Disclosure Statement
fractory CSU as well as patients with symptomatic der-
mographism or cholinergic urticaria. The engagement of M. Maurer has received honoraria (advisory board, speaker)
CD200Ra by agonist antibodies also inhibits MC activa- and/or institutional grant/research support from Allakos, Amgen,
tion and degranulation [111]. The CD200Ra-targeted an- Astra-Zeneca, Bayer, Dr. Pfleger, FAES, Genentech, GSK, Innate
tibody LY3454738 is currently under development for Pharma, Kyowa Kirin, Lilly, Merckle Recordati, Moxie, Novartis,
CSU. Regeneron, Roche, Sanofi, MSD, UCB, and Uriach. M. Ferrer has
received honoraria (advisory board, speaker) from Genentech,
Menarini, Uriach, FAES, and MSD and has received a research
grant and advisory and speaker fees from Novartis. K. Schäkel has
Summary, Conclusion, and Outlook received honoraria (advisory board, speaker) from ALK-Abelló,
Almirall, Celgene, Eli Lilly, Galderma, Janssen, Leo Pharma, and
CU is a heterogeneous, persistent, severely debilitating Novartis and grants/research support from Novartis. J. Gutermuth
has received honoraria (advisory board, speaker) from Abbvie,
and often poorly controlled disease. Recent findings sug- Almirall, Celgene, Eli-Lilly, Janssen, MSD, Leo Pharma, Pierre-
gest that the prevalence of CU and its subforms may be Fabre, Pfizer, Regeneron-Sanofi, and Thermo Fisher Scientific. K.
more heterogeneous than previously thought and in need Hartmann has received honoraria (advisory board, speaker) from

Urticaria: CIA Update 2020 Int Arch Allergy Immunol 2020;181:321–333 329
DOI: 10.1159/000507218
ALK-Abelló, Allergopharma, Blueprint, Deciphera, Menarini, Novartis, Pfizer, Sanofi, Sanoflore, Stallergenes, Takeda, Teva, and
Novartis, and Takeda and institutional grant/research support UCB. M. Metz has received honoraria (advisory board, speaker)
from Euroimmun and Thermo Fisher Scientific. T. Jakob has re- from Amgen, Aralez, argenx, Bayer, Beiersdorf, Celgene, Menlo,
ceived honoraria (advisory board, speaker) from ALK-Abelló, Al- Moxie, Novartis, Roche, Sanofi, Shire, Siennabio, and Uriach. K.
lergopharma, Bencard/Allergy Therapeutics, Celgene, Novartis, Eyerich, S. Eyerich, A. Kapp, H.-S. Park, G. Pejler, D. Simon, and
and Thermo Fisher Scientific and grants/research support from H.-U. Simon have no conflicts of interest related to this paper.
ALK-Abelló, Bencard/Allergy Therapeutics, and Novartis. P.
Kolkhir has received speaker fees from Novartis and Roche. D.
Larenas-Linnemann has received honoraria (advisory board,
speaker) and/or grants for guideline development support from Funding Sources
Allakos, Alerquim, Astra-Zeneca, Boehringer Ingelheim, DBV,
Diemsa, Glenmark, GSK, Menarini, Mylan, Novartis, Sanofi, and The authors have no funding to declare.
UCB. M. Sánchez-Borges has received honoraria from Allakos for
advisory boards and speaker fees from Novartis. K. Weller has re-
ceived honoraria (advisory board, speaker) from Dr. R. Pfleger, Author Contributions
Essex Pharma (now MSD), Novartis, UCB, Uriach, and Moxie. T.
Zuberbier has received honoraria (advisory board, speaker) from M. Maurer and M. Metz prepared the outline and the first draft
AstraZeneca, AbbVie, ALK-Abelló, Almirall, Astellas, Bayer of the manuscript. All authors reviewed and revised the manu-
Health Care, Bencard, Berlin Chemie, FAES, HAL, Henkel, script and helped to develop the final version.
Kryolan, Leti, Lofarma, L’Oreal, Meda, Menarini, Merck, MSD,

References
  1 Fricke J, Ávila G, Keller T, Weller K, Lau S,   9 Chu CY, Cho YT, Jiang JH, Lin EI, Tang CH. 17 Yu L, Buttgereit T, Stahl Skov P, Schmetzer O,
Maurer M, et al. Prevalence of chronic urti- Epidemiology and comorbidities of patients Scheffel J, Kocatürk E, et al. Immunological
caria in children and adults across the globe: with chronic urticaria in Taiwan‫‏‬: A nation- effects and potential mechanisms of action of
systematic review with meta-analysis. Aller- wide population-based study. J Dermatol Sci. autologous serum therapy in chronic sponta-
gy. 2020 Feb;75(2):423–32. 2017 Nov;88(2):192–8. neous urticaria. J Eur Acad Dermatol Vene-
  2 Gaig P, Olona M, Muñoz Lejarazu D, Cabal- 10 Kolkhir P, Church MK, Weller K, Metz M, reol. 2019 Sep;33(9):1747–54.
lero MT, Domínguez FJ, Echechipia S, et al. Schmetzer O, Maurer M. Autoimmune 18 Hatada Y, Kashiwakura J, Hayama K, Fujisa-
Epidemiology of urticaria in Spain. J Investig chronic spontaneous urticaria: what we know wa D, Sasaki-Sakamoto T, Terui T, et al. Sig-
Allergol Clin Immunol. 2004;14(3):214–20. and what we do not know. J Allergy Clin Im- nificantly high levels of anti-dsDNA immu-
  3 Lapi F, Cassano N, Pegoraro V, Cataldo N, munol. 2017 Jun;139(6):1772–81.e1. noglobulin E in sera and the ability of dsDNA
Heiman F, Cricelli I, et al. Epidemiology of 11 Bar-Sela S, Reshef T, Mekori YA. IgE antithy- to induce the degranulation of basophils from
chronic spontaneous urticaria: results from a roid microsomal antibodies in a patient with chronic urticaria patients. Int Arch Allergy
nationwide, population-based study in Italy. chronic urticaria. J Allergy Clin Immunol. Immunol. 2013;161(Suppl 2):154–8.
Br J Dermatol. 2016 May;174(5):996–1004. 1999 Jun;103(6):1216–7. 19 Gruber BL, Baeza ML, Marchese MJ, Agnello
  4 Broder MS, Raimundo K, Antonova E, Chang 12 Altrichter S, Peter HJ, Pisarevskaja D, Metz V, Kaplan AP. Prevalence and functional role
E. Resource use and costs in an insured popu- M, Martus P, Maurer M. IgE mediated autoal- of anti-IgE autoantibodies in urticarial syn-
lation of patients with chronic idiopathic/ lergy against thyroid peroxidase – a novel dromes. J Invest Dermatol. 1988 Feb; 90(2):
spontaneous urticaria. Am J Clin Dermatol. pathomechanism of chronic spontaneous ur- 213–7.
2015 Aug;16(4):313–21. ticaria? PLoS One. 2011 Apr;6(4):e14794. 20 Grattan CE, Boon AP, Eady RA, Winkelmann
  5 Lee N, Lee JD, Lee HY, Kang DR, Ye YM. Ep- 13 Sánchez J, Sánchez A, Cardona R. Causal Re- RK. The pathology of the autologous serum
idemiology of Chronic Urticaria in Korea Us- lationship Between Anti-TPO IgE and skin test response in chronic urticaria resem-
ing the Korean Health Insurance Database, Chronic Urticaria by In Vitro and In Vivo bles IgE-mediated late-phase reactions. Int
2010–2014. Allergy Asthma Immunol Res. Tests. Allergy Asthma Immunol Res. 2019 Arch Allergy Appl Immunol. 1990; 93(2–3):
2017 Sep;9(5):438–45. Jan;11(1):29–42. 198–204.
  6 Zuberbier T, Balke M, Worm M, Edenharter 14 Shin YS, Suh DH, Yang EM, Ye YM, Park HS. 21 Hide M, Francis DM, Grattan CE, Hakimi J,
G, Maurer M. Epidemiology of urticaria: a Serum Specific IgE to Thyroid Peroxidase Ac- Kochan JP, Greaves MW. Autoantibodies
representative cross-sectional population tivates Basophils in Aspirin Intolerant Urti- against the high-affinity IgE receptor as a
survey. Clin Exp Dermatol. 2010 Dec; 35(8): caria. J Korean Med Sci. 2015 Jun;30(6):705– cause of histamine release in chronic urticar-
869–73. 9. ia. N Engl J Med. 1993 Jun;328(22):1599–604.
  7 Balp MM, Weller K, Carboni V, Chirilov A, 15 Cugno M, Asero R, Ferrucci S, Lorini M, Car- 22 Altrichter S, Zampeli V, Ellrich A, Zhang K,
Papavassilis C, Severin T, et al. Prevalence and bonelli V, Tedeschi A, et al. Elevated IgE to Church MK, Maurer M. IgM and IgA in ad-
clinical characteristics of chronic spontane- tissue factor and thyroglobulin are abated by dition to IgG autoantibodies against FcεRIα
ous urticaria in pediatric patients. Pediatr Al- omalizumab in chronic spontaneous urticar- are frequent and associated with disease
lergy Immunol. 2018 Sep;29(6):630–6. ia. Allergy. 2018 Dec;73(12):2408–11. markers of chronic spontaneous urticaria. Al-
  8 Lee SJ, Ha EK, Jee HM, Lee KS, Lee SW, Kim 16 Schmetzer O, Lakin E, Topal FA, Preusse P, lergy. 2020; under revision.
MA, et al. Prevalence and Risk Factors of Ur- Freier D, Church MK, et al. IL-24 is a common 23 Kikuchi Y, Kaplan AP. Mechanisms of auto-
ticaria With a Focus on Chronic Urticaria in and specific autoantigen of IgE in patients immune activation of basophils in chronic ur-
Children. Allergy Asthma Immunol Res. 2017 with chronic spontaneous urticaria. J Allergy ticaria. J Allergy Clin Immunol. 2001 Jun;
May;9(3):212–9. Clin Immunol. 2018 Sep;142(3):876–82. 107(6):1056–62.

330 Int Arch Allergy Immunol 2020;181:321–333 Maurer et al.

DOI: 10.1159/000507218
24 Konstantinou GN, Asero R, Ferrer M, Knol 37 Weller K, Zuberbier T, Maurer M. Chronic 49 Młynek A, Magerl M, Hanna M, Lhachimi S,
EF, Maurer M, Raap U, et al. EAACI taskforce urticaria: tools to aid the diagnosis and assess- Baiardini I, Canonica GW, et al. The German
position paper: evidence for autoimmune ur- ment of disease status in daily practice. J Eur version of the Chronic Urticaria Quality-of-
ticaria and proposal for defining diagnostic Acad Dermatol Venereol. 2015 Jun; 29 Suppl Life Questionnaire: factor analysis, valida-
criteria. Allergy. 2013 Jan;68(1):27–36. 3:38–44. tion, and initial clinical findings. Allergy.
25 Schoepke N, Asero R, Ellrich A, Ferrer M, 38 Koti I, Weller K, Makris M, Tiligada E, Psal- 2009 Jun;64(6):927–36.
Gimenez-Arnau A, E H Grattan C, et al. Bio- topoulou T, Papageorgiou C, et al. Disease ac- 50 Irani C, Hallit S, Weller K, Maurer M, El
markers and clinical characteristics of auto- tivity only moderately correlates with quality Haber C, Salameh P. Chronic urticaria in
immune chronic spontaneous urticaria: re- of life impairment in patients with chronic most patients is poorly controlled. Results of
sults of the PURIST study. Allergy. 2019 Dec; spontaneous urticaria. Dermatology. 2013; the development, validation, and real life ap-
74(12):2427–36. 226(4):371–9. plication of the Arabic urticaria control test.
26 Chang TW, Chen C, Lin CJ, Metz M, Church 39 Balp MM, Khalil S, Tian H, Gabriel S, Vietri J, Saudi Med J. 2017 Dec;38(12):1230–6.
MK, Maurer M. The potential pharmacologic Zuberbier T. Burden of chronic urticaria rela- 51 Kocatürk E, Kızıltaç U, Can P, Öztaş Kara R,
mechanisms of omalizumab in patients with tive to psoriasis in five European countries. J Erdem T, Kızıltaç K, et al. Validation of the
chronic spontaneous urticaria. J Allergy Clin Eur Acad Dermatol Venereol. 2018 Feb;32(2): Turkish version of the Urticaria Control Test:
Immunol. 2015 Feb;135(2):337–42. 282–90. correlation with other tools and comparison
27 Kaplan AP, Joseph K, Maykut RJ, Geba GP, 40 Konstantinou GN, Konstantinou GN. Psychi- between spontaneous and inducible chronic
Zeldin RK. Treatment of chronic autoim- atric comorbidity in chronic urticaria pa- urticaria. World Allergy Organ J. 2019 Jan;
mune urticaria with omalizumab. J Allergy tients: a systematic review and meta-analysis. 12(1):100009.
Clin Immunol. 2008 Sep;122(3):569–73. Clin Transl Allergy. 2019 Aug;9(1):42. 52 Kulthanan K, Chularojanamontri L, Tuchin-
28 Maurer M, Altrichter S, Bieber T, Bieder- 41 Staubach P, Eckhardt-Henn A, Dechene M, da P, Rujitharanawong C, Maurer M, Weller
mann T, Bräutigam M, Seyfried S, et al. Effi- Vonend A, Metz M, Magerl M, et al. Quality K. Validity, reliability and interpretability of
cacy and safety of omalizumab in patients of life in patients with chronic urticaria is dif- the Thai version of the urticaria control test
with chronic urticaria who exhibit IgE against ferentially impaired and determined by psy- (UCT). Health Qual Life Outcomes. 2016
thyroperoxidase. J Allergy Clin Immunol. chiatric comorbidity. Br J Dermatol. 2006 Apr;14(1):61.
2011 Jul;128(1):202–9.e5. Feb;154(2):294–8. 53 Ohanyan T, Schoepke N, Bolukbasi B, Metz
29 Metz M, Ohanyan T, Church MK, Maurer M. 42 Hawro T, Ohanyan T, Schoepke N, Metz M, M, Hawro T, Zuberbier T, et al. Responsive-
Omalizumab is an effective and rapidly acting Peveling-Oberhag A, Staubach P, et al. The ness and minimal important difference of the
therapy in difficult-to-treat chronic urticaria: urticaria activity score – validity, reliability, urticaria control test. J Allergy Clin Immunol.
a retrospective clinical analysis. J Dermatol and responsiveness. J Allergy Clin Immunol 2017 Dec;140(6):1710–13.e11.
Sci. 2014 Jan;73(1):57–62. Pract. 2018 Jul–Aug;6(4):1185–90.e1. 54 Weller K, Groffik A, Church MK, Hawro T,
30 Metz M, Staubach P, Bauer A, Brehler R, Ger- 43 Hawro T, Ohanyan T, Schoepke N, Metz M, Krause K, Metz M, et al. Development and val-
icke J, Ashton-Chess J, et al. Omalizumab Peveling-Oberhag A, Staubach P, et al. Com- idation of the Urticaria Control Test: a pa-
normalizes levels of high affinity immuno- parison and interpretability of the available tient-reported outcome instrument for assess-
globulin E receptor-positive skin cells in pa- urticaria activity scores. Allergy. 2018 Jan; ing urticaria control. J Allergy Clin Immunol.
tients with chronic spontaneous urticaria: 73(1):251–5. 2014 May;133(5):1365–72, 1372.e1–6.
a randomized, double-blind, placebo-con- 44 Hollis K, Proctor C, McBride D, Balp MM, 55 Kulthanan K, Chularojanamontri L, Rujitha-
trolled study. J Invest Dermatol. 2014;134:30. McLeod L, Hunter S, et al. Comparison of Ur- ranawong C, Weerasubpong P, Weller K,
31 Asero R. Severe CSU and activation of the co- ticaria Activity Score Over 7 Days (UAS7) Maurer M. Angioedema Activity Score
agulation/fibrinolysis system: clinical aspects. Values Obtained from Once-Daily and (AAS): A Valid and Reliable Tool to Use in
Eur Ann Allergy Clin Immunol. 2019 Oct; Twice-Daily Versions: results from the AS- Asian Patients. BioMed Res Int. 2019 Oct;
52(1):15–7. SURE-CSU Study. Am J Clin Dermatol. 2018 2019:9157895.
32 Fujisawa D, Kashiwakura J, Kita H, Kikukawa Apr;19(2):267–74. 56 Weller K, Groffik A, Magerl M, Tohme N, Mar-
Y, Fujitani Y, Sasaki-Sakamoto T, et al. Ex- 45 Mathias SD, Crosby RD, Zazzali JL, Maurer tus P, Krause K, et al. Development, validation,
pression of Mas-related gene X2 on mast cells M, Saini SS. Evaluating the minimally impor- and initial results of the Angioedema Activity
is upregulated in the skin of patients with se- tant difference of the urticaria activity score Score. Allergy. 2013 Sep;68(9):1185–92.
vere chronic urticaria. J Allergy Clin Immu- and other measures of disease activity in pa- 57 Kulthanan K, Chularojanamontri L, Rujitha-
nol. 2014 Sep;134(3):622–633.e9. tients with chronic idiopathic urticaria. Ann ranawong C, Weerasubpong P, Maurer M,
33 Huang AH, Chichester KL, Saini SS. Associa- Allergy Asthma Immunol. 2012 Jan; 108(1): Weller K. Angioedema quality of life ques-
tion of basophil parameters with disease se- 20–4. tionnaire (AE-QoL) – interpretability and
verity and duration in chronic spontaneous 46 Baiardini I, Fasola S, Maurer M, Weller K, Ca- sensitivity to change. Health Qual Life Out-
urticaria (CSU). J Allergy Clin Immunol nonica GW, Braido F. Minimal important dif- comes. 2019 Oct;17(1):160.
Pract. 2020 Feb;8(2):793–5.e6. ference of the Chronic Urticaria Quality of 58 Weller K, Groffik A, Magerl M, Tohme N,
34 Kay AB, Clark P, Maurer M, Ying S. Eleva- Life Questionnaire (CU-Q2oL). Allergy. 2019 Martus P, Krause K, et al. Development and
tions in T-helper-2-initiating cytokines (in- Dec;74(12):2542–4. construct validation of the angioedema qual-
terleukin-33, interleukin-25 and thymic stro- 47 Baiardini I, Pasquali M, Braido F, Fumagalli ity of life questionnaire. Allergy. 2012 Oct;
mal lymphopoietin) in lesional skin from F, Guerra L, Compalati E, et al. A new tool to 67(10):1289–98.
chronic spontaneous (“idiopathic”) urticaria. evaluate the impact of chronic urticaria on 59 Weller K, Magerl M, Peveling-Oberhag A,
Br J Dermatol. 2015;172(5):1294–302. quality of life: chronic urticaria quality of life Martus P, Staubach P, Maurer M. The Angio-
35 Yanase Y, Takahagi S, Hide M. Chronic spon- questionnaire (CU-QoL). Allergy. 2005 Aug; edema Quality of Life Questionnaire (AE-
taneous urticaria and the extrinsic coagula- 60(8):1073–8. QoL) – assessment of sensitivity to change
tion system. Allergol Int. 2018 Apr; 67(2): 48 Brzoza Z, Badura-Brzoza K, Młynek A, Mag- and minimal clinically important difference.
191–4. erl M, Baiardini I, Canonica GW, et al. Adap- Allergy. 2016 Aug;71(8):1203–9.
36 Weller K, Siebenhaar F, Hawro T, Altrichter tation and initial results of the Polish version 60 Młynek A, Zalewska-Janowska A, Martus P,
S, Schoepke N, Maurer M. Clinical Measures of the GA(2)LEN chronic urticaria quality of Staubach P, Zuberbier T, Maurer M. How to
of Chronic Urticaria. Immunol Allergy Clin life questionnaire (CU-Q(2)oL). J Dermatol assess disease activity in patients with chronic
North Am. 2017 Feb;37(1):35–49. Sci. 2011 Apr;62(1):36–41. urticaria? Allergy. 2008 Jun;63(6):777–80.

Urticaria: CIA Update 2020 Int Arch Allergy Immunol 2020;181:321–333 331
DOI: 10.1159/000507218
61 Zuberbier T, Aberer W, Asero R, Abdul Latiff 73 Metz M, Weller K, Neumeister C, Izquierdo I, 84 Altrichter S, Chuamanochan M, Knoth H,
AH, Baker D, Ballmer-Weber B, et al. The Bödeker RH, Schwantes U, et al. Rupatadine Asady A, Ohanyan T, Metz M, et al. Real-life
EAACI/GA²LEN/EDF/WAO guideline for in Established Treatment Schemes Improves treatment of cholinergic urticaria with omali-
the definition, classification, diagnosis and Chronic Spontaneous Urticaria Symptoms zumab. J Allergy Clin Immunol. 2019 Feb;
management of urticaria. Allergy. 2018 Jul; and Patients’ Quality of Life: a Prospective, 143(2):788–91.e8.
73(7):1393–414. Non-interventional Trial. Dermatol Ther 85 Maurer M, Kaplan A, Rosén K, Holden M,
62 Ertas R, Ozyurt K, Atasoy M, Hawro T, Mau- (Heidelb). 2015 Dec;5(4):217–30. Iqbal A, Trzaskoma BL, et al. The XTEND-
rer M. The clinical response to omalizumab in 74 Staubach P, Metz M, Chapman-Rothe N, Sieder CIU study: long-term use of omalizumab in
chronic spontaneous urticaria patients is C, Bräutigam M, Canvin J, et al. Effect of omal- chronic idiopathic urticaria. J Allergy Clin
linked to and predicted by IgE levels and their izumab on angioedema in H1-antihistamine- Immunol. 2018 Mar;141(3):1138–9.e7.
change. Allergy. 2018 Mar;73(3):705–12. resistant chronic spontaneous urticaria pa- 86 Maurer M, Metz M, Brehler R, Hillen U, Jakob
63 Maurer M, Giménez-Arnau AM, Sussman G, tients: results from X-ACT, a randomized con- T, Mahler V, et al. Omalizumab treatment in
Metz M, Baker DR, Bauer A, et al. Ligelizum- trolled trial. Allergy. 2016 Aug;71(8):1135–44. patients with chronic inducible urticaria: a
ab for Chronic Spontaneous Urticaria. N Engl 75 Weller K, Church MK, Metz M, Hawro T, Oh- systematic review of published evidence. J Al-
J Med. 2019 Oct;381(14):1321–32. anyan T, Staubach P, et al. The response to lergy Clin Immunol. 2018 Feb;141(2):638–49.
64 Stull D, McBride D, Tian H, Gimenez Arnau treatment in chronic spontaneous urticaria de- 87 Maurer M, Rosén K, Hsieh HJ, Saini S, Grat-
A, Maurer M, Marsland A, et al. Analysis of pends on how it is measured. J Allergy Clin Im- tan C, Gimenéz-Arnau A, et al. Omalizumab
disease activity categories in chronic sponta- munol Pract. 2019 Jul–Aug;7(6):2055–6.e4. for the treatment of chronic idiopathic or
neous/idiopathic urticaria. Br J Dermatol. 76 Aygören-Pürsün E, Magerl M, Graff J, Marti- spontaneous urticaria. N Engl J Med. 2013
2017 Oct;177(4):1093–101. nez-Saguer I, Kreuz W, Longhurst H, et al. Mar;368(10):924–35.
65 Potter P, Mitha E, Barkai L, Mezei G, Santa- Prophylaxis of hereditary angioedema at- 88 Maurer M, Schütz A, Weller K, Schoepke N,
maría E, Izquierdo I, et al. Rupatadine is effec- tacks: a randomized trial of oral plasma kal- Peveling-Oberhag A, Staubach P, et al. Omal-
tive in the treatment of chronic spontaneous likrein inhibition with avoralstat. J Allergy izumab is effective in symptomatic dermogra-
urticaria in children aged 2–11 years. Pediatr Clin Immunol. 2016 Sep;138(3):934–6.e5. phism – results of a randomized placebo-con-
Allergy Immunol. 2016 Feb;27(1):55–61. 77 Weller K, Donoso D, Magerl M, Aygören- trolled trial. J Allergy Clin Immunol. 2017
66 Baiardini I, Braido F, Bindslev-Jensen C, Pürsün E, Staubach P, Martinez-Saguer I, et Sep;140(3):870–3.e5.
Bousquet PJ, Brzoza Z, Canonica GW, et al. al. Validation of the Angioedema Control 89 Metz M, Schütz A, Weller K, Gorczyza M,
Recommendations for assessing patient-re- Test (AECT) – a patient reported outcome in- Zimmer S, Staubach P, et al. Omalizumab is
ported outcomes and health-related quality of strument for assessing angioedema control. J effective in cold urticaria – results of a ran-
life in patients with urticaria: a GA(2) LEN Allergy Clin Immunol Pract. 2020 doi: domized placebo-controlled trial. J Allergy
taskforce position paper. Allergy. 2011 Jul; 10.1016/j.jaip.2020.02.038. Clin Immunol. 2017 Sep;140(3):864–7.e5.
66(7):840–4. 78 Weller K, Donoso T, Magerl M, Aygören- 90 Staubach P, Metz M, Chapman-Rothe N, Sie-
67 Jáuregui I, Ortiz de Frutos FJ, Ferrer M, Gi- Pürsün E, Staubach P, Martinez-Saguer I, et der C, Bräutigam M, Maurer M, et al. Omali-
ménez-Arnau A, Sastre J, Bartra J, et al. As- al. Development of the Angioedema Control zumab rapidly improves angioedema-related
sessment of severity and quality of life in Test – A patient-reported outcome measure quality of life in adult patients with chronic
chronic urticaria. J Investig Allergol Clin Im- that assesses disease control in patients with spontaneous urticaria: X-ACT study data. Al-
munol. 2014;24(2):80–6. recurrent angioedema. Allergy. 2019 Dec. lergy. 2018 Mar;73(3):576–84.
68 Weller K, Church MK, Kalogeromitros D, 79 Magerl M, Altrichter S, Borzova E, Giménez- 91 Zhao ZT, Ji CM, Yu WJ, Meng L, Hawro T,
Krause K, Magerl M, Metz M, et al. Chronic Arnau A, Grattan CE, Lawlor F, et al. The def- Wei JF, et al. Omalizumab for the treatment of
spontaneous urticaria: how to assess quality inition, diagnostic testing, and management chronic spontaneous urticaria: a meta-analy-
of life in patients receiving treatment. Arch of chronic inducible urticarias – The EAACI/ sis of randomized clinical trials. J Allergy Clin
Dermatol. 2011 Oct;147(10):1221–3. GA(2) LEN/EDF/UNEV consensus recom- Immunol. 2016 Jun;137(6):1742–50.e4.
69 Dias GA, Pires GV, Valle SO, França AT, Papi mendations 2016 update and revision. Aller- 92 Serrano-Candelas E, Martinez-Aranguren R,
JA, Dortas SD Jr, et al. Cross-cultural adapta- gy. 2016 Jun;71(6):780–802. Valero A, Bartra J, Gastaminza G, Goikoetxea
tion of the Brazilian-Portuguese version of 80 Magerl M, Abajian M, Krause K, Altrichter S, MJ, et al. Comparable actions of omalizumab
the chronic urticaria quality-of-life question- Siebenhaar F, Church MK. An improved Pel- on mast cells and basophils. Clin Exp Allergy.
naire – CU-Q2oL. Allergy. 2011 Nov; 66(11): tier effect-based instrument for critical tem- 2016 Jan;46(1):92–102.
1487–93. perature threshold measurement in cold- and 93 Gasser P, Tarchevskaya SS, Guntern P, Brigger
70 Kocatürk E, Weller K, Martus P, Aktaş S, Ka- heat-induced urticaria. J Eur Acad Dermatol D, Ruppli R, Zbären N, et al. The mechanistic
vala M, Sarigul S, et al. Turkish version of the Venereol. 2015 Oct;29(10):2043–5. and functional profile of the therapeutic anti-
chronic urticaria quality of life questionnaire: 81 Gastaminza G, Azofra J, Nunez-Cordoba JM, IgE antibody ligelizumab differs from omali-
cultural adaptation, assessment of reliability Baeza ML, Echechipia S, Gaig P, et al. Efficacy zumab. Nat Commun. 2020 Jan;11(1):165.
and validity. Acta Derm Venereol. 2012 Jul; and safety of omalizumab (Xolair) for cholin- 94 Lin W, Zhou Q, Liu C, Ying M, Xu S. In-
92(4):419–25. ergic urticaria in patients unresponsive to a creased plasma IL-17, IL-31, and IL-33 levels
71 Tavakol M, Mohammadinejad P, Baiardini I, double dose of antihistamines: a randomized in chronic spontaneous urticaria. Sci Rep.
Braido F, Gharagozlou M, Aghamohammadi mixed double-blind and open-label placebo- 2017 Dec;7(1):17797.
A, et al. The Persian version of the chronic controlled clinical trial. J Allergy Clin Immu- 95 Okayama Y, Kawakami T. Development, mi-
urticaria quality of life questionnaire: factor nol Pract. 2019 May–Jun;7(5):1599–609.e1. gration, and survival of mast cells. Immunol
analysis, validation, and initial clinical find- 82 Ruft J, Asady A, Staubach P, Casale T, Suss- Res. 2006;34(2):97–115.
ings. Iran J Allergy Asthma Immunol. 2014 mann G, Zuberbier T, et al. Development and 96 Petersen LJ, Brasso K, Pryds M, Skov PS. His-
Aug;13(4):278–85. validation of the Cholinergic Urticaria Quali- tamine release in intact human skin by mono-
72 Valero A, Herdman M, Bartra J, Ferrer M, ty-of-Life Questionnaire (CholU-QoL). Clin cyte chemoattractant factor-1, RANTES,
Jáuregui I, Dávila I, et al. Adaptation and val- Exp Allergy. 2018 Apr;48(4):433–44. macrophage inflammatory protein-1 alpha,
idation of the Spanish version of the Chron- 83 Kolkhir P, Altrichter S, Munoz M, Hawro T, stem cell factor, anti-IgE, and codeine as de-
ic Urticaria Quality of Life Questionnaire Maurer M. New treatments for chronic urti- termined by an ex vivo skin microdialysis
(CU-Q2oL). J Investig Allergol Clin Immu- caria. Ann Allergy Asthma Immunol. 2020 technique. J Allergy Clin Immunol. 1996 Oct;
nol. 2008;18(6):426–32. Jan;124(1):2–12. 98(4):790–6.

332 Int Arch Allergy Immunol 2020;181:321–333 Maurer et al.

DOI: 10.1159/000507218
  97 Terhorst D, Koti I, Krause K, Metz M, Mau- 110 Schmetzer O, Lakin E, Topal FA, Preusse P, 123 Magen E, Waitman DA, Dickstein Y, Davi-
rer M. In chronic spontaneous urticaria, Freier D, Church MK, et al. IL-24 is a com- dovich V, Kahan NR. Clinical-laboratory
high numbers of dermal endothelial cells, mon and specific autoantigen of IgE in pa- characteristics of ANA-positive chronic id-
but not mast cells, are linked to recurrent tients with chronic spontaneous urticaria. J iopathic urticaria. Allergy Asthma Proc.
angio-oedema. Clin Exp Dermatol. 2018 Allergy Clin Immunol. 2018;142(3):876–82. 2015 Mar–Apr;36(2):138–44.
Mar;43(2):131–6. 111 Fiebiger E, Maurer D, Holub H, Reininger B, 124 de Montjoye L, Darrigade AS, Giménez-Ar-
  98 Ochi H, De Jesus NH, Hsieh FH, Austen KF, Hartmann G, Woisetschlager M, et al. Se- nau A, Herman A, Dumoutier L, Baeck M.
Boyce JA. IL-4 and -5 prime human mast rum IgG autoantibodies directed against the Correlations between disease activity, auto-
cells for different profiles of IgE-dependent alpha chain of Fc epsilon RI: a selective immunity and biological parameters in pa-
cytokine production. Proc Natl Acad Sci marker and pathogenetic factor for a distinct tients with chronic spontaneous urticaria.
USA. 2000 Sep;97(19):10509–13. subset of chronic urticaria patients? J Clin Eur Ann Allergy Clin Immunol. doi:
  99 Yanagida M, Fukamachi H, Ohgami K, Ku- Invest. 1995;96(6):2606–12. 10.23822/EurAnnACI.1764-1489.132
waki T, Ishii H, Uzumaki H, et al. Effects of 112 Sabroe RA, Fiebiger E, Francis DM, Maurer [Epub ahead of print].
T-helper 2-type cytokines, interleukin-3 D, Seed PT, Grattan CE, et al. Classification 125 Marzano AV, Genovese G, Casazza G, Fier-
(IL-3), IL-4, IL-5, and IL-6 on the survival of of anti-FcepsilonRI and anti-IgE autoanti- ro MT, Dapavo P, Crimi N, et al. Predictors
cultured human mast cells. Blood. 1995 Nov; bodies in chronic idiopathic urticaria and of response to omalizumab and relapse in
86(10):3705–14. correlation with disease severity. J Allergy chronic spontaneous urticaria: a study of
100 Caproni M, Cardinali C, Giomi B, Antiga E, Clin Immunol. 2002 Sep;110(3):492–9. 470 patients. J Eur Acad Dermatol Venereol.
D’Agata A, Walter S, et al. Serological detec- 113 Sun L, Erxun K, Li J, Yang J, Han C. Correla- 2019 May;33(5):918–24.
tion of eotaxin, IL-4, IL-13, IFN-gamma, MIP- tions between Anti-Mast Cell Autoantibod- 126 Gericke J, Metz M, Ohanyan T, Weller K,
1alpha, TARC and IP-10 in chronic autoim- ies and Chronic Idiopathic Urticaria. Ann Altrichter S, Skov PS, et al. Serum autoreac-
mune urticaria and chronic idiopathic urticar- Dermatol. 2014 Apr;26(2):145–9. tivity predicts time to response to omali-
ia. J Dermatol Sci. 2004 Oct;36(1):57–9. 114 Lakin E, Church MK, Maurer M, Schmetzer zumab therapy in chronic spontaneous urti-
101 Ying S, Kikuchi Y, Meng Q, Kay AB, Kaplan O. On the Lipophilic Nature of Autoreactive caria. J Allergy Clin Immunol. 2017 Mar;
AP. TH1/TH2 cytokines and inflammatory IgE in Chronic Spontaneous Urticaria. 139(3):1059–61.e1.
cells in skin biopsy specimens from patients Theranostics. 2019 Jan;9(3):829–36. 127 Chakravarty SD, Yee AF, Paget SA. Ritux-
with chronic idiopathic urticaria: compari- 115 Kulthanan K, Jiamton S, Thumpimukvatana imab successfully treats refractory chronic
son with the allergen-induced late-phase cu- N, Pinkaew S. Chronic idiopathic urticaria: autoimmune urticaria caused by IgE recep-
taneous reaction. J Allergy Clin Immunol. prevalence and clinical course. J Dermatol. tor autoantibodies. J Allergy Clin Immunol.
2002 Apr;109(4):694–700. 2007 May;34(5):294–301. 2011 Dec;128(6):1354–5.
102 Lee JK, Simpson RS. Dupilumab as a novel 116 Staubach P, Onnen K, Vonend A, Metz M, 128 Grattan CE, Francis DM, Slater NG, Barlow
therapy for difficult to treat chronic sponta- Siebenhaar F, Tschentscher I, et al. Autolo- RJ, Greaves MW. Plasmapheresis for severe,
neous urticaria. J Allergy Clin Immunol gous whole blood injections to patients with unremitting, chronic urticaria. Lancet. 1992
Pract. 2019 May–Jun;7(5):1659–61.e1. chronic urticaria and a positive autologous May;339(8801):1078–80.
103 Bergmann KC, Altrichter S, Maurer M. Ben- serum skin test: a placebo-controlled trial. 129 Grattan CE, O’Donnell BF, Francis DM, Ni-
efit of benralizumab treatment in a patient Dermatology. 2006;212(2):150–9. imi N, Barlow RJ, Seed PT, et al. Random-
with chronic symptomatic dermographism. 117 Kikuchi Y, Fann T, Kaplan AP. Antithyroid ized double-blind study of cyclosporin in
J Eur Acad Dermatol Venereol. 2019 Nov; antibodies in chronic urticaria and angio- chronic “idiopathic” urticaria. Br J Derma-
33(11):e413–5. edema. J Allergy Clin Immunol. 2003 Jul; tol. 2000 Aug;143(2):365–72.
104 Magerl M, Terhorst D, Metz M, Altrichter 112(1):218. 130 Marsland AM, Soundararajan S, Joseph K,
S, Zuberbier T, Maurer M, et al. Benefit of 118 Sánchez J, Sánchez A, Cardona R. Clinical Kaplan AP. Effects of calcineurin inhibitors
mepolizumab treatment in a patient with Characterization of Patients with Chronic on an in vitro assay for chronic urticaria.
chronic spontaneous urticaria. J Dtsch Der- Spontaneous Urticaria according to Anti- Clin Exp Allergy. 2005 May;35(5):554–9.
matol Ges. 2018 Apr;16(4):477–8. TPO IgE Levels. J Immunol Res. 2019 Dec; 131 O’Donnell BF, Barr RM, Black AK, Francis
105 Ferrer M, Nakazawa K, Kaplan AP. Comple- 2019:4202145. DM, Kermani F, Niimi N, et al. Intravenous
ment dependence of histamine release in 119 Confino-Cohen R, Chodick G, Shalev V, immunoglobulin in autoimmune chronic
chronic urticaria. J Allergy Clin Immunol. Leshno M, Kimhi O, Goldberg A. Chronic urticaria. Br J Dermatol. 1998 Jan; 138(1):
1999 Jul;104(1):169–72. urticaria and autoimmunity: associations 101–6.
106 Kikuchi Y, Kaplan AP. A role for C5a in aug- found in a large population study. J Allergy 132 Perez A, Woods A, Grattan CE. Methotrex-
menting IgG-dependent histamine release Clin Immunol. 2012 May;129(5):1307–13. ate: a useful steroid-sparing agent in recalci-
from basophils in chronic urticaria. J Allergy 120 Matsui Y, Heiner DC, Beall GN. IgE and IgE trant chronic urticaria. Br J Dermatol. 2010
Clin Immunol. 2002 Jan;109(1):114–8. autoantibodies in patients with autoim- Jan;162(1):191–4.
107 Vena GA, Cassano N, Di Leo E, Calogiuri mune thyroid disorders and their relatives. 133 Zimmerman AB, Berger EM, Elmariah SB,
GF, Nettis E. Focus on the role of substance Proc Soc Exp Biol Med. 1978 May; 158(1): Soter NA. The use of mycophenolate mofetil
P in chronic urticaria. Clin Mol Allergy. 73–6. for the treatment of autoimmune and chron-
2018 Nov;16(1):24. 121 Kolkhir P, Church MK, Altrichter S, Skov ic idiopathic urticaria: experience in 19 pa-
108 Metz M, Krull C, Hawro T, Saluja R, Groffik PS, Hawro T, Frischbutter S, et al. Eosinope- tients. J Am Acad Dermatol. 2012 May;
A, Stanger C, et al. Substance P is upregu- nia, in chronic spontaneous urticaria, is as- 66(5):767–70.
lated in the serum of patients with chronic sociated with high disease activity, autoim- 134 Kulthanan K, Chularojanamontri L, Tuchin-
spontaneous urticaria. J Invest Dermatol. munity, and poor response to treatment. J da P, Rujitharanawong C, Baiardini I, Braido
2014 Nov;134(11):2833–6. Allergy Clin Immunol Pract. 2020 Jan; 8(1): F. Minimal clinical important difference
109 Ramirez Molina C, Falkencrone S, Skov PS, 318–25.e5. (MCID) of the Thai Chronic Urticaria Qual-
Hooper-Greenhill E, Barker M, Dickson 122 Kolkhir P, Altrichter S, Hawro T, Maurer M. ity of Life Questionnaire (CU-Q2oL). Asian
MC. GSK2646264, a spleen tyrosine kinase C-reactive protein is linked to disease activ- Pac J Allergy Immunol. 2016 Jun;34(2):137–
inhibitor, attenuates the release of histamine ity, impact, and response to treatment in pa- 45.
in ex vivo human skin. Br J Pharmacol. 2019 tients with chronic spontaneous urticaria.
Apr;176(8):1135–42. Allergy. 2018 Apr;73(4):940–8.

Urticaria: CIA Update 2020 Int Arch Allergy Immunol 2020;181:321–333 333
DOI: 10.1159/000507218