Clinical & Experimental Allergy, 45, 731743

doi: 10.1111/cea.12465

2014 The Authors. Clinical & Experimental Allergy

Published by John Wiley & Sons Ltd

REVIEW

Management of urticaria: not too complicated, not too simple

M. Ferrer1, J. Bartra2,3, A. Gimenez-Arnau4, I. Jauregui5, M. Labrador-Horrillo6, J. Ortiz de Frutos7, J. F. Silvestre8, J. Sastre9,
M. Velasco10 and A. Valero3,11
1

Department of Allergy and Clinical Immunology, Clnica Universidad de Navarra, Pamplona, Spain, 2Allergy Unit, Pneumology Department, Hospital

Clinic, University of Barcelona, Barcelona, Spain, 3Institut dInvestigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain, 4Dermatology
Department, Hospital del Mar, Parc de Salut Mar, Universitat Autonoma Barcelona, Barcelona, Spain, 5Allergy Department, Hospital Universitario Basurto,
Bilbao, Spain, 6Allergy Section, Medicine Department, Hospital Vall dHebron, Universitat Autonoma de Barcelona, Barcelona, Spain, 7Dermatology
Department, Hospital Universitario 12 de Octubre, Madrid, Spain, 8Dermatology Department, Hospital General Universitario de Alicante, Alicante, Spain,
9

Allergy Department, Fundacion Jime nez Diaz, Madrid, Spain,

10

Dermatology Department, Hospital Arnau de Vilanova, Valencia, Spain and

11

Allergy Unit,

Pneumology and Respiratory Department, Hospital Clnic (ICT), University of Barcelona, Barcelona, Spain

Clinical
&
Experimental
Allergy
Correspondence:
Marta Ferrer, Department of Allergy,
Clnica Universidad de Navarra, Pio
XII, 36 31008-Pamplona, Spain.
E-mail: [email protected]
Cite this as: M. Ferrer, J. Bartra, A.
Gimenez-Arnau, I. Jauregui, M.
Labrador-Horrillo, J. Ortiz de Frutos, J.
F. Silvestre, J. Sastre, M. Velasco, A.
Valero, Clinical & Experimental
Allergy, 2015 (45) 731743.

Summary
In spite of being an old disease and apparently easy to diagnose, chronic spontaneous
urticaria (CSU) is still perceived as an uncontrollable and difficult to manage disease. The
perception of the patient is that his/her condition is not well understood and that is
suffering from a disorder with hidden causes that doctors are not able to tackle. Sometimes patients go through a number of clinicians until they found some CSU expert who
is familiar with the disease. It is surprising that myths and believes with no scientific
support still persist. Guidelines are not widely implemented, and recent tools to assess
severity are infrequently used. European and American recent guidelines do not agree in
several key points related to diagnosis and treatment, which further contributes to confusion. With the aim to clarify some aspects of the CSU picture, a group of allergists and
dermatologists from the Spanish Dermatology and Allergy societies developed a Frequent
Asked Questions leaflet that could facilitate physicians work in daily practice and contribute to a better knowledge of common clinical scenarios related to patients with CSU.

This is an open access article under the

terms of the Creative Commons
Attribution-NonCommercial-NoDerivs
License, which permits use and
distribution in any medium, provided
the original work is properly cited, the
use is non-commercial and no
modifications or adaptations are made.

Introduction
Chronic urticaria, defined as urticaria that persists for
longer than 6 weeks, is a frustrating condition for both
patients and caregivers due to the persistence of lesions
in spite of using available treatment options. Chronic
spontaneous urticaria (CSU) can be categorized according to the EAACI classification into two main types:
chronic spontaneous urticaria (CSU) and physical or
inducible urticaria (Table 1) [1]. CSU is defined by the
spontaneous appearance of wheals with or without

angioedema that persist for 6 weeks [1]. CSU is occasionally associated with other types of chronic urticaria,
such as inducible (physical or cholinergic) urticaria [2].
The present article is focused on CSU and covers several
aspects regarding its diagnosis and management.
Despite the impact on quality of life [3, 4] and the
morbidity associated with CSU [3], relatively little is
known about the pathophysiology of this condition.
Moreover, with the exception of physical urticaria, in
the majority of cases, a cause cannot be established. An
autoimmune origin is found in a subpopulation of CSU

732 M. Ferrer et al.

Table 1. Classification of urticaria [1]

Methods

Chronic spontaneous urticaria

Physical
urticaria

or

inducible

Spontaneous appearance of wheals,

angioedema or both lasting 6 weeks

Physical urticaria
o Symptomatic
dermatographism
o Cold urticaria
o Delayed pressure
urticaria
o Solar urticaria
o Heat urticaria
o Vibratory
angioedema
Cholinergic urticaria
Contact urticaria
Aquagenic urticaria

patients as assessed by the ability of the patients sera

to activate normal donor basophils and to induce histamine release [5]. However, this subpopulation is clinically indistinguishable from the nonautoimmune group.
There are several guidelines and reviews [1, 69] on
the management of urticaria. However, these guidelines
do not completely agree on key points, such as which
test to order or the adequate treatment approach for the
different clinical scenarios. This disagreement is even
more obvious in the latest published guidelines [1, 10].
Omalizumab has emerged as a treatment that is able
to control CSU symptoms in a significant percentage of
non-responder patients to antihistamines at high doses or
in combination with other drugs [1, 1012]. Omalizumab
also opens a new avenue of research because this drug
works both in autoimmune and in nonautoimmune
urticaria [13]. Its mechanism of action is not completely
understood. Omalizumab is able to capture IgE, downregulating IgE receptors and preventing IgE binding to
its high- and low-affinity receptors, and seems to
desensitize mast cells [14]. This drug was approved for
the treatment of CSU in March 2014 by the European
Medicines Agency (EMA) [15] and the U.S. Food and
Drug Administration (FDA) [16].
There are many unsolved issues in CSU, from the
underlying lack of large epidemiology studies [17]. In
the present review, practical guidance based on common questions related to the clinical management of
patients with CSU is provided. We selected key questions from previously published guidelines and updated
them using the most recently available evidence
obtained from a careful critique of the literature. We
also tried to cover a number of topics that are given
less attention in current CSU guidelines, such as prognosis, severity assessment and urticaria duration.

We constituted a national working group of allergists

and dermatologist that have a specialized clinic dedicated to CSU. We met during 20122013 every
2 months to discuss the outcomes of each stage of the
review and set the next step to take. We first generated
a list of issues that emerge when approaching a patient
suffering from CSU. From this list, we generated a list
of specific questions that address each point. We then
distributed the questions, that were distributed previously in the meetings, among the participants and
worked remotely on each answer. Frequently asked
questions with direct clinical relevance were chosen by
the authors. Answers to these questions and summaries
of key points were agreed upon by consensus. The
questions were numbered and grouped into sections
related to diagnosis, clinical evaluation and follow-up,
as well as treatment and management in special cases.
A review of the literature on chronic urticaria (from
January 1st, 2009, up to December 1st, 2013) was performed by an independent documentalist using the
MEDLINE database through a PubMed search. The
search strategy included retrieval of documents with
the following words included in the Title field: urticaria, idiopathic, chronic, diagnosis, prognosis,
assessment, duration, severity, quality of life,
treatment, management and omalizumab. The search
was performed using these terms separately or combined to explore all possibilities. Additionally, publications included in the field Related citations in PubMed
appearing together with the Abstract of retrieved citations were reviewed. Other filters included review for
the category of article type and full text available and
free full text available for the category of text availability. In all cases, the title and abstract of the articles
were carefully read, and suitable articles were selected
based on the study content. The references of retrieved
documents were also checked for articles of interest. A
final list of articles with the corresponding abstracts
and the full text were distributed to the authors. This
information and documents from their own files were
used as a scientific background for the review.
Results
Diagnosis of CSU, physical examination and
complementary testing in chronic urticaria (work-up
studies)
What are the clinical features of CSU? What are the
characteristics of the macroscopic and microscopic cutaneous lesions?. Chronic spontaneous urticaria skin
lesions are transient and pruritic and appear daily or
almost daily for at least 6 weeks. This condition is

2014 The Authors. Clinical & Experimental Allergy Published by John Wiley & Sons Ltd, 45 : 731743

FAQ on how to manage chronic urticaria

accompanied by angioedema in 4050% of patients

[18, 19]. The hives last <24 h, with no skin lesion upon
disappearance. However, interstitial oedema with a perivascular infiltrate containing lymphocytes, monocytes
and eosinophils is observed in all cases [20]. Neutrophils and basophils may also be observed, and CD4+ T
cells [21, 22] are also present. In cases of angioedema,
the same histological findings are found, but the interstitial oedema is more intense.
Key point: Chronic urticaria lesions consist of
evanescent wheals or hives surrounded by erythema.
What exacerbating factors are known?. The large majority of patients have no evidence of any exacerbating
factor. The only recognized trigger for CSU is nonsteroidal anti-inflammatory drugs (NSAIDs) [23, 24]. In
patients presenting with CSU associated with a degree
of physical urticaria (Table 1) [1], symptoms may be
exacerbated when in contact with the corresponding
stimulus, such as pressure in the case of delayed pressure urticarial, or scratches in the case of dermatographic urticaria.
Key point: NSAIDs are the main factor that exacerbates CSU.
What is the natural clinical course?. The natural course
is unpredictable. CSU undergoes spontaneous remission,
with relapses in most cases. Few epidemiological studies
have explored the duration of symptoms. Gaig et al. [2]
found that in 70% of cases, chronic urticaria lasted one
year, whereas in 11% of patients, it lasted for more
than 5 years. In a prospective study of 139 patients followed over 5 years, the duration of urticaria correlated
with its severity of urticaria, the presence of angioedema and positive autoimmune markers (positive autologous serum skin test [ASST] and antithyroid
antibodies) [19]. That study found that 70% of patients
had hives that lasted more than one year and 14% had
symptoms 5 years after the end of the study period,
durations very similar to those reported in other studies
[2, 25].
Key point: The evolution of CSU is unpredictable,
with spontaneous remissions and relapses. No prospective and retrospective neither studies have examined
the influence of treatments on the natural course of
CSU.
Is it necessary to perform extensive diagnostic studies by
complementary testing in all patients with CSU?. The
indiscriminate search for underlying causes that may
include an extensive battery of tests is discouraged [1,
69] due to low cost-effectiveness. A careful and
detailed medical history and physical examination are
essential. Patient-oriented questions are helpful to
establish the type of chronic urticaria and to define

733

Table 2. Recommended data to obtain from the patients medical

history
Duration of symptoms
Family history of urticaria
Duration of wheals, if residual skin lesions
Intensity and characteristics of pruritus
Associated subjective symptoms (e.g. pain, burning sensation)
Diurnal variation of signs and symptoms
Appearance of urticaria in relation to weekends, holidays and trips
(abroad)
Size, shape and distribution of hives
Frequency and localization of associated angioedema
Concomitant systemic symptoms (e.g. joint pain, headache, nausea,
vomiting, fever)
Family history of urticaria or atopy
Seasonal variation of symptoms
Appearance of signs and symptoms in association with physical
stimuli (e.g. cold, heat, friction)
Psychiatric or psychosomatic disorders
Use of drugs (e.g. Nonsteroidal anti-inflammatories, hormonal
treatments, topical agents, alternative remedies) and its
relationship with urticaria
Relationship with the menstrual cycle
Use of substances/tobacco, and particularly the use of flavoured
cigarettes or cannabis
Occupation and hobbies
Quality of life related to urticaria and emotional impact
Previous treatments and responses
Previous diagnostic studies and results

Table 3. Minimal work-up studies on chronic spontaneous urticaria*

Clinical history (see Table 2)
Physical examination
Urticaria activity score (UAS) and angioedema activity score (AAS)
at the time of physical examination
Assessment of quality of life (CU-Q2oL)
Performance of appropriate tests to rule out physical urticaria
Blood count, thyroid antibody and thyroid function tests and
assessment of the sedimentation rate and serum C-reactive protein
Skin prick test to rule out allergy when patients history suggests
that an allergic disease may be involved.
Skin biopsy, if indicated
*As an optional work-up study ASST (Autologous serum skin test)
and an assessment of the in vitro ability of sera to stimulate normal
basophils (CD63 or histamine release test) could be performed.

baseline laboratory studies and/or other complementary

tests tailored to the individual patient (Table 2). In most
cases, there is no need to order an extensive work-up
unless data from the clinical history suggest an underlying disease. Table 3 lists the essential tests that should
be performed.
Key point: Unless suggested by the clinical history,
there is no need to perform extensive tests when examining a CSU patient.

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734 M. Ferrer et al.

Table 4. Differential diagnosis of chronic urticaria
Diseases or syndromes with typical
urticarial lesions
Diseases with fixed urticarial lesions with
atypical features

Autoinflammatory
diseases
Schnitzler syndrome
Cutaneous lupus
erythematosus
Fixed drug eruptions
Bullous pemphigoid
Reticular erythematous
mucinosis
Erythema multiform

What is the differential diagnosis to be established for a

patient with CSU?. Apart from urticaria vasculitis for
which diagnosis is made through biopsy, It can be difficult to differentiate hives from other dermatoses [26]
(Table 4). However, the natural course differs in these
pathologies. Erythema multiform clears on its own
within a maximum of 3 weeks; it is included in the differential diagnosis because of its severity and should
always be ruled out at the onset of symptoms, when it
can resemble chronic urticaria. Autoinflammatory syndromes [27] have symptoms that may be confused with
chronic urticaria, but they are rare, and although skin
rashes are always associated with systemic symptoms,
itching is not as striking a feature as it is in the case of
chronic urticaria. Certain systemic diseases are associated with urticaria-like lesions, such as systemic lupus
erythematosus, Schnitzler syndrome (IgM monoclonal
gammopathy, urticaria, fever, lymphadenopathy and
weight loss), mastocytosis and hypereosinophilic syndromes.
Key point: Chronic urticaria differs from other dermatosis on its duration, the evanescence of lesions and
intense itching.
Is skin biopsy a mandatory diagnostic tool for the diagnosis of CSU?. Skin biopsy is not mandatory to diagnose chronic spontaneous urticaria, but it is strongly
advisable when hives last more than 24 h, to exclude
urticarial vasculitis. Certain patients with urticarial vasculitis may exhibit symptoms similar to those of
patients with chronic urticaria, with wheals lasting
<24 h and with no residual skin lesions [28]. In cases
with an unusual presentation of chronic urticaria that
is, mild itching, painful skin lesions or unresponsiveness to antihistamines or when the diagnosis is not
clear, we recommend performing a skin biopsy to rule
out urticarial vasculitis.
Key point: Skin biopsy is only recommended when
skin lesions last longer than 24 h.
Is it necessary to assess patients for infections or
active infestations in the diagnosis of CSU?. Despite

being included in several guidelines, no large randomized double-blind, placebo-controlled studies have
demonstrated a causative role for infections in CSU.
With the exception of certain geographical regions in
which specific parasites are endemic [1, 69], there is
no need to perform a search or treatment for underlying infections.
Key point: The evidence for the role of infection in
CSU is very weak. There is no need for a systematic
assessment of infection in CSU.
Is food allergy associated with CSU?. Chronic urticaria
is not a manifestation of IgE-mediated food allergy.
However, in isolated cases, certain true food allergies
can mimic chronic urticaria. This has been recorded in
allergies to foods containing omega-5 gliadin, lipid
transfer protein (LPT) or galactose-alpha-1,3-galactose.
On the other hand, it should be noted that in some
cases food allergy might occur independently from
CSU.
Key point: CSU is not related to IgE-mediated food
allergy.
Are food preservatives and additives related to CSU?. Food additives (such as preservatives and colour additives) and ingredients naturally present in food (such as
histamine and aromatic components) have been
described as causative or aggravating factors by several
uncontrolled studies [1, 7, 29, 30]. However, a recent
study yielded only two positive results from a singleblind challenge with 11 food additives of each of 100
patients with chronic urticaria. Moreover, when a double-blind test and a placebo challenge test were performed on these two positive patients, neither reacted
to the culprit additive [31]. Avoidance of food preservatives and additives is not therefore recommended.
Key point: There is no need to recommend a restrictive diet to patients suffering from CSU.
Is an assessment of autoimmunity useful from a diagnostic perspective in patients with CSU?. Autoimmunity
has long been discussed as a cause of CSU. Although
not widely used, assessing serum autoreactivity is useful, this is currently the only office procedure that can
help reveal whether an autoimmune mechanism is
responsible. The common cluster of autoimmune diseases in patients suffering from chronic spontaneous
urticaria, the presence of antithyroid antibodies, and the
serum ability to activate normal basophils, supports the
etiopathogenic role of autoimmunity. Screening can be
performed with the autologous serum skin test (ASST).
The correct approach to the ASST is described in an
EAACI/GA2LEN position paper [32]. The ASST is a nonspecific screening test that evaluates the presence of
serum histamine-releasing factors of any type not just

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FAQ on how to manage chronic urticaria

autoantibodies. According to the experience of many

urticaria experts, healthy controls and patients without
CSU do not yield a positive ASST [3341]. Nevertheless,
the specificity of this test is still a matter of discussion.
The role of coagulation factors in the development of
the wheal has been examined using the autologous
plasma skin test (APST), but there is still no consensus
about that tests use as a diagnostic tool [40, 41]. The
only way to screen for functional autoantibodies
against either IgE or FcRI (the high-affinity IgE receptor) is to demonstrate the ability of sera to activate normal basophils, showing either histamine release [4244]
or serum-induced basophil CD63 and/or CD203c
expression [45, 46] by flow cytometry. Identifying
serum-induced basophil CD63 and/or CD203c expression is the recommended approach [9].
Key point: Autoimmunity could be assessed either
through the ASST or by demonstrating in vitro the ability to activate normal basophils for diagnosis and prognosis. Patients with a positive ASST result show more
severe and longer-lasting disease.
Are there biomarkers of activity in CSU?. The severity
of CSU should be evaluated based on the intensity of
its clinical symptoms. Several biomarkers, such as interleukin (IL)-6, C-reactive protein and D-dimers, metalloproteinase-9 and complement C3 and C4, have shown
distinctive patterns in CSU patients, but these molecules
have still not been validated as useful biomarkers.
Key point: Although several substances may show
specific levels in CSU patients, they have not yet been
validated as CSU biomarkers.
Does isolated angioedema have clinical, therapeutic and/
or prognostic implications?. Isolated angioedema with
no hives that responds to antihistamines should be
explored and phenotyped. Most guidelines [1, 68]
include isolated angioedema as a subtype of CSU. However, this condition does not share the typical features
of chronic urticaria, such as being more frequent in
women or having an autoimmune profile. In certain
cases, typical CSU starts with isolated angioedema that
evolves into cutaneous wheals. On the other hand, histaminergic angioedema is clearly different from bradykinin-mediated angioedema [47], which does not
respond to antihistamines or corticosteroids, has a different physiopathology [4850] and requires a different
treatment approach [51, 52]. The differential diagnosis
for isolated angioedema is shown in Table 5 [53].
Key point: Isolated angioedema does not share the
typical features of CSU.
How should the diagnosis of CSU in children be approached?. Chronic spontaneous urticaria is less frequent in
children, but in general, it shares the underlying causes

735

Table 5. Differential diagnosis of isolated angioedema

Type

Normal C1-INH

Acquired

Idiopathic
histaminergic
angioedema
Bradykinininduced
angioedema
Angioedema
due to ACE
inhibitors
Hereditary
Angioedema of
unknown origin
Hereditary
Angioedema
with FXII
mutations
Delayed pressure
angioedema
Angioedema due
to NSAID
intolerance

Hereditary

Other

Decreased
C1-INH

Abnormal
C1-INH

Acquired
angioedema
with C1-INH
deficiency

Type I hereditary
angioedema

Type II
hereditary
angioedema

Modified from Cicardi et al. [53].

and physiopathology of CSU in adults. Therefore, the

diagnostic approach in children and adults is the same
[26, 54, 55]. However, it should be noted that infants
are more prone to develop acute urticaria secondary to
an infection.
Key point: The diagnostic approach to CSU in children should be the same as that in adults.
Clinical evaluation and follow-up
How can the activity of CSU be measured?. The EAACI/
GA2LEN/EDF/WAO consensus [1] recommends the use
of a single language in the form of well-established and
simple scales, such as the urticaria activity score (UAS)
[56] and the related scale, UAS7[57] (Table 6). The
number of wheals and the intensity of pruritus are
scored individually for the past 24 h using a 3-point
Likert scale from 0 (no disease activity) to 3 (intense
activity). The sum of the scores represents disease
severity on a scale from 0 (minimum) to 6 (maximum).
The UAS7 is calculated as the sum of the intensity of
pruritus and the number of wheals over 1 week (minimum score 0, maximum score 42). UAS and UAS7 are
also recommended in other guidelines [1, 8]. These tools
have been used in controlled clinical trials and have
recently been validated for use in the follow-up and
monitoring of disease activity in patients with CSU [58,
59] Additionally, the British Academy of Dermatology
guidelines [9] recommend the use of a diary card to

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736 M. Ferrer et al.

Table 6. Urticaria activity score
How many wheals have appeared during the last 24 h?
None
Mild (<20 wheals/24 h)
Moderate (2050 wheals/24 h)
Intense (>50 wheals/24 h)
How severe was the itching during the last 24 h?
None
Mild (present but not annoying or troublesome)
Moderate (troublesome but does not interfere with normal
daily activity or sleep)
Intense (severe itch that is sufficiently troublesome to
interfere with normal daily activity or sleep)

Scoring
0
1
2
3
0
1
2
3

record the frequency, duration and severity of urticarial

episodes. Another tool is the visual analogue scale
(VAS) (100-mm line) is a commonly used tool for selfreporting pruritus intensity and for assessing the level
of sedation by antihistamine treatment [6062].
Key point: The UAS and UAS7 should be used to
assess the severity of CSU and the treatment response.
Are there any indicators of severity or poor prognosis in
CSU?. A systematic review of 34 studies that evaluated
parameters relating to the severity measured through
different scoring symptoms and duration of chronic
urticaria suggested that disease severity may predict the
duration of the disease [63]. Other CSU features related
to severity and duration are angioedema, association
with physical urticarias, old age and positive antithyroid antibodies [6467]. Similarly, a positive ASST has
been shown to be associated with more severe symptoms [68, 69]. In the most recent retrospective study,
which included 223 patients with CSU, the only prognostic factor was age, with no correlation found
between severity or duration and angioedema [25].
Regarding biomarkers, the plasma levels of prothrombin
fragments 1 + 2, D-dimers and C-reactive protein may
function as markers of CSU severity [63], but threshold
values with predictive capacity have not yet been
defined.
Key point: The duration of the disease is longer in
patients with more severe disease, angioedema, a positive ASST result, physical urticaria and old age.
Are health-related quality-of-life questionnaires useful
in the assessment of CSU?. Health-related quality of life
is increasingly recognized as an essential parameter for
assessing the condition of chronic urticaria patients
[59] and as an outcome measure in clinical trials. The
need to measure the impact of chronic urticaria on the
patients quality of life is consistently encouraged in
the different clinical guidelines, but specific recommendations for use are not included. To date, the only
questionnaire specifically developed to measure health-

related quality of life in chronic urticaria patients is the

Chronic Urticaria Quality of Life Questionnaire (CUQ2oL) [70, 71]. Other nonspecific quality-of-life instruments used in studies of chronic urticaria include the
Dermatology Life Quality Index (DLQI, which has been
shown to be a valid, reliable and clinically useful outcome measure for assessing quality of life in chronic
urticaria [72], the Nottingham Health Profile (NHP) [73],
the World Health Organization Quality of Life Assessment-Brief (WHOQOL-BREF) [74] and Skindex-29 [75,
76]. When compared to healthy controls, patients with
chronic urticaria had significantly higher scores in the
Beck Depression Inventory (BDI) and the Beck Anxiety
Inventory (BAI) [73]. Additionally, the interference of
CSU with sleep may account for a reduction of up to
30% in work/school productivity, as assessed using the
Work Productivity and Activity Impairment instrument
[77].
Key point: The CU-Q2oL is the only available instrument specifically developed to assess the quality of life
of chronic spontaneous urticaria patients.
Can response/nonresponse to the drugs used in the
treatment of chronic spontaneous urticaria be predicted?. Autoimmunity and CSU associated with physical urticarias are more resistant to treatments [68].
Patients with predominant neutrophil tissue infiltration
are believed to be less responsive to antihistamines. A
recent study suggests that elevated D-dimer levels are
able to predict the response to antihistamines treatment
[78, 79].
Key point: No predictors of treatment response are
available for CSU.
Treatment of CSU
Antihistamines. What range of doses is more appropriate
for antihistamines?: Nonsedating H1-antihistamines at
licensed doses are the recommended first-line treatment
in mild-to-moderate chronic urticaria [1]. In patients
with severe, recalcitrant urticaria in whom the standard
dose is not effective, there is evidence that increasing the
dose up to fourfold might control symptoms, without
compromising the patients safety [80, 81]. There have
been no well-designed, randomized double-blind clinical
trials comparing the efficacy of therapeutic and
upgraded doses. Some studies have been performed in
spontaneous chronic urticaria and in certain forms of
inducible chronic urticaria [82] using desloratadine (up to
20 mg), levocetirizine (up to 20 mg), cetirizine (up to
30 mg), fexofenadine (up to 240 mg), rupatadine (up to
20 mg) and bilastine (up to 80 mg) [83], but they have
had mixed results. Limited data are available for updosing,
but considering the good safety profile of most secondgeneration antihistamines, it might be worth evaluating

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FAQ on how to manage chronic urticaria

the efficacy of antihistamines at higher-than-licensed

doses before switching to other therapies [80, 81]. Regarding the best way to apply this treatment, the guidelines
advise to employ high doses of antihistamines as a second
treatment step. However, as in the case of cold urticaria, a
useful approach may include starting with four times
higher dose, with subsequent dose reduction in the presence of a clinical response.
Key point: Given the safety of most antihistamines,
doses can be increased up to four times the standard
dose on an individual basis.
Can switching from one antihistamine to another
attain an individualized response?: According to the
British [9] American [10] and EAACI 2014 [1] guidelines, all patients should be offered a choice between
two or more nonsedating H1-antihistamines, because
individual differences in response and tolerance to different antihistamines have been reported.
Is it useful to combine different antihistamines (i.e.
sedating and nonsedating)?: In patients with severe,
recalcitrant urticaria for whom the standard dose is not
effective, combinations of antihistamines are frequently
used as another way of updosing. This might involve,
for example, two different second-generation antihistamines, or a second-generation antihistamine in the
morning and a first-generation antihistamine in the
evening. However, first-generation antihistamines are
no longer recommended in chronic urticaria [84], and
the clinical benefit of combining antihistamines is
probably limited when H1-receptors are already occupied by another H1-antihistamine.
Key point: There are no studies that demonstrate that
treatment with the combined use of sedating and nonsedating antihistamines is more effective than updosing
the same antihistamine.
Is it useful to combine H1- and H2-antihistamines?:
Several relatively small studies have shown that combined use of H1-antihistamines and H2-antihistamines
(cimetidine, ranitidine) may be more effective than
using H1-antihistamines alone [85, 86]. This effect is
related to an increase in the plasma levels of H1-antihistamine [87], most likely due to a pharmacologic
interaction with the isoenzyme cytochrome P-450 in
the liver. This phenomenon does not occur when cimetidine is associated with cetirizine [88]. Accordingly, a
review of recent studies does not allow confident decision-making about the use of H2-receptor antagonists
in urticaria [89].
Regarding the use of anti H2 antihistamines, most
guidelines deleted this point but the American guidelines [10].
Should treatment for CSU be provided on-demand or
in a sustained manner?: The beneficial effects of nonsedating H1-antihistamines given on demand appear to be
low [90].

737

Key point: Nonsedating H1-antihistamines should be

given in a sustained manner.
Does antihistamines induced somnolence affect its use
of in CSU?: It is well known that H1-antihistamines
cause sedation, somnolence and fatigue, leading to
impairment of cognitive function, memory and psychomotor performance. A position paper of the Global
Allergy and Asthma European Network (GA2LEN) [84]
highlights the risk posed by the fact that first-generation H1-antihistamines, all of which are sedating,
are generally regarded as safe simply because of their
long-standing use. Given the unwanted side-effects and
potential dangers of first-generation H1-antihistamines,
newer, nonsedating second-generation H1-antihistamines with superior risk/benefit ratios (which are
widely available at competitive prices) are strongly recommended.
Key point: Nonsedating antihistamines are recommended for CSU treatment.
Nonantihistamine medications. Should corticosteroids be
used in the treatment of CSU?: Controlled clinical trials
have not provided any evidence supporting long-term
treatment with systemic steroids in CSU, and the prolonged use of steroids is not recommended due to
their side-effects. Short courses of systemic steroids
could be used in patients with severe exacerbation
episodes [91], particularly when accompanied by
angioedema or in patients with a minimal or partial
response to antihistamine treatment [6, 8]. The dosages
and weaning regimens of steroids for urticaria are variable, ranging from progressive reduction over 10 days
to complex therapeutic regimens with alternate-day
dose reduction.
Key point: Corticosteroids are not recommended as
long-term CSU therapy. However, a short course of steroids might be useful to control exacerbation.
In which patients with CSU may oral calcineurin
inhibitors be used as an therapeutic option in CSU?:
Four randomized controlled trials have reported favourable effects from the use of cyclosporine in patients
with chronic urticaria/angioedema who are unresponsive to high doses of second-generation antihistamines
[8]. Treatment for 24 months has been used, with better results [92]. One study [93] noted improvement after
discontinuation of cyclosporine, one-third of patients
had complete remission, one-third had their disease
controlled with antihistamines, and one-third returned
to the severity level previous to cyclosporine therapy.
However, cyclosporine has serious side-effects that may
outweigh its benefits especially the high risk of developing renal injury. Minimal data are available on the
use of tacrolimus in chronic urticaria [94]. However,
the place of cyclosporine has varied as the approval of
omalizumab as an indication for CSU.

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738 M. Ferrer et al.

Key point: Cyclosporine may be considered as an offlabel therapeutic option for controlling CSU in patients
who are refractory to antihistamines and omalizumab.
What is the role of oral antileukotrienes in the treatment of CSU?: The efficacy of antileukotrienes has been
reported in small randomized double-blind studies [95
97] with inconsistent results. Monotherapy with antileukotrienes is not advisable [98].
Key point: The evidence supporting leukotriene
inhibitors as a therapeutic option in CSU is weak, and
their use in CSU is not recommended.
Which patients with CSU should be treated with omalizumab?: The efficacy and safety of omalizumab have
been demonstrated in two randomized, placebo-controlled phase III studies in patients with CSU who
remained symptomatic despite H1-antihistamine therapy
at the approved dose [11, 99]. A third study [12] primarily evaluated the safety of omalizumab in patients
with CSU who remained symptomatic despite treatment
with H1-antihistamines at up to four times the approved
dose, and with H2-antihistamine and/or leukotriene
inhibitors treatment. Omalizumab is the only drug indicated in Europe and the United States as an add-on
therapy for the treatment of CSU in adult and adolescent (12 years and older) patients with an inadequate
response to H1-antihistamine treatment [1, 6, 8].
Key point: Consideration should be given to the thesis that patients suffering from CSU with no response to
treatment at high doses of H1-antihistamines should be
treated with omalizumab [100].
What is dosage of omalizumab is recommended for
refractory CSU?: Omalizumab dosage in CSU has been
evaluated in three phase III clinical trials that assessed
clinical endpoints such as pruritus control, the number
of wheals, the UAS and UAS7 and episodes of angioedema. The recommended dose of omalizumab is
300 mg administered subcutaneously every 4 weeks, as
this amount ensures maximum efficacy without serious
safety concerns. Although other doses achieved statistical significance for the primary endpoints and most of
the secondary endpoints, it was concluded that 300 mg
provided the best benefitrisk profile for most adult
patients, regardless of other variables, such as body
mass index and IgE levels. Other retrospective, noncontrolled, observational studies also reported significant
symptom control with different doses and scheme
protocols [101, 102]. However, large randomized doubleblind, placebo-controlled clinical trials should be
performed before these protocols could be recommended.
Key point: Omalizumab is recommended for use in
refractory CSU at 300 mg administered subcutaneously
every 4 weeks.
What side-effects are associated with omalizumab
treatment in CSU?: In randomized trials, side-effects
reported in more that 3% of patients receiving consisted

in headache, diarrhoea, joint pain, dysmenorrhoea and

upper respiratory tract infections, without differences
between the groups receiving active treatment and placebo [103].
Key point: Omalizumab given at 300 mg has a
favourable safety profile.
When can treatment with omalizumab be discontinued
or modified?: In a phase III study, Kaplan et al.[104]
reported that after discontinuation of omalizumab, most
patients recurred in a 10-week period. Interestingly, an
acute rebound of hives was not observed, and reappearance of symptoms was slow. It has also been reported
that retreatment is effective [105]. In another study in
which omalizumab was reintroduced in 20 (47.5%)
patients because of recurrence of symptoms, control
was achieved in 18 patients (90%), indicating a good
retreatment rate with omalizumab [101].
Key point: Once discontinued, retreatment with omalizumab has a good response rate. No rebound effect
upon withdrawal of omalizumab has been observed.
After 6 months of therapy, most patients return to their
baseline level [11, 12] so further studies regarding duration of treatment are needed.
Third-line therapies: The use of other therapies for CSU
is based in clinical trials with low evidence level (doxepin,
nifedipine, warfarin or hydroxychloroquine), uncontrolled and/or case series studies (methotrexate, mycophenolate, interferon, intravenous gammaglobulin,
colchicine, thyroid hormone treatment, phototherapy).
One recent double-blind, placebo study of dapsone suggests efficacy [106] but the placebo group has very low
response rate so the efficacy may be inflated. Sulfasalazine is better studied [107] than most of the other
agents listed but without clear control groups. Both tranexamic acid and cromoglycate showed no efficacy in
placebo-controlled trials. Two recent reviews cover
extensively available options and studies published in
the literature on third-line and fourth-line therapies in
CSU [108, 109].
Management in special cases
How should CSU be managed in children?. Several studies have assessed the efficacy of treatment in paediatric
patients with chronic urticaria, and recommendations
for adults have been extrapolated to children [7, 9,
110]. The treatment of choice is standard dosage of second-generation H1-antihistamines, according to the
products technical specifications. Currently, ketotifen
and cetirizine can be used in infants from the age of
6 months; levocetirizine, loratadine, desloratadine and
ebastine can be used from 2 years of age; and rupatadine can be used from 6 years of age. Recent guidelines
[1, 8] include specific recommendations to avoid firstgeneration H1-antihistamines due to the probable

2014 The Authors. Clinical & Experimental Allergy Published by John Wiley & Sons Ltd, 45 : 731743

FAQ on how to manage chronic urticaria

impact on school performance. There are reports of successful use of cyclosporine in children [111, 112] similar to the response found in adults. There is little
evidence of the efficacy of other therapeutic alternatives, such as systemic corticosteroids, dapsone, omalizumab,
intravenous
immunoglobulins
and
plasmapheresis; these options should be evaluated on
an individual basis in cases of severe refractory chronic
urticaria [1, 7, 9, 113, 114]. None of the currently
licensed antihistamines is contraindicated in children
aged 12 or older, according to the British Association
of Dermatologists Therapy Guidelines and Audit Subcommittee [9]. As dosing and age restrictions for individual products vary in younger children, it is
recommended that the relevant datasheets be consulted
before prescribing antihistamines in children.
Key point: CSU in children should be managed in the
same way as for adults.
A suggested treatment approach is included in Figure 1. It should be noted that as omalizumab is just
approved as an add-on therapy, long-term data are
needed to assess that omalizumab is safer and better
cost-saving alternative than the remaining therapies
available.
How should CSU be managed during pregnancy and lactation?. During pregnancy, urticaria should be controlled using the minimum level of medication that is
effective [115]. The use of H1-antihistamines (preferably
second-generation) should be considered as the first
therapeutic step. However, no H1-antihistamine agent is
in category A regarding safety in pregnancy. Category
B of safety in pregnancy has been assigned to loratadine, cetirizine, levocetirizine and chlorpheniramine.
Hydroxyzine is the only antihistaminic drug that is

739

contraindicated in pregnancy, as specifically mentioned

in the products specifications.
Lactation could also pose a challenge to treat CSU.
During lactation, loratadine and cetirizine are the only
H1-antihistamines recommended for use. The minimum
possible dose of H1-antihistamines and the shortest
duration of treatment should be used, but only when
the benefits outweigh the potential risks. H1-antihistamine is excreted in breast milk. Chlorpheniramine can
cause sedation and poor feeding in babies so should be
avoided [7].
As it is the case in rheumatologic diseases [116,
117] or asthma [118], in CSU [109] systemic corticosteroids may be administered in pregnancy but only at
the lowest possible doses and for the minimum period
of time due to potential areas of concern, including
congenital malformations during the first trimester of
pregnancy, neonatal adrenal insufficiency and low
birthweight. However, the absolute risk is low. Moreover, systemic corticosteroids have the potential risk
of inducing hypertension, gestational diabetes and preterm delivery due to the premature rupture of membranes. Corticosteroids appear to be safe for nursing
infants because of low levels in breast milk. The concentrations in breast milk are generally 525% of
maternal serum levels, with rapid and bi-directional
exchange between the serum and breast milk. When
high doses are required, it is reasonable to delay
breastfeeding for up to 4 h after each dose of steroids.
Prolonged treatments and high doses of systemic corticosteroids should be avoided.
Key point: During pregnancy and lactation antihistamines, labelled as B category should be used as firstline therapy in urticaria, using the minimum level of
medication that is effective.
Concluding remarks

Fig. 1. CSU treatment algorithm (CSU management with treatment

options supported by strong evidence). Use of omalizumab as a firstline treatment once patients are shown to be refractory to antihistamines (in agreement with the most recent review) [100].

Due to the lack of knowledge of the physiopathological

CSU mechanisms, a plethora of causative theories and
alternative therapies have always emerged. CSU landscape has greatly changed. We now have much better
tools to assess severity and quality of life. More importantly at the present time, we could offer a real hope to
control symptoms to these desperate patients. For that
reason, it is very important to provide physicians with
updated knowledge. Delivering clear and simple recommendations on when and how apply these new tools
and treatments also reinforces good clinical practice
that in turn will greatly improve patients life and
healthcare performance. It is quite discouraging to
observe differences between the American and European CSU diagnosis and treatment approaches. Both
sides have points to make and each of them has
strengths and weaknesses. We tried to offer a FAQ (Fre-

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740 M. Ferrer et al.

quent Asked Questions) section for the physician who
approaches a CSU patient. Our main point would be to
take into consideration the recent existence of a very
effective treatment and not to continue offering outdated treatment options.
Conflict of interest
Dr. Ferrer is on the scientific advisory board and a
speaker for Novartis, and FAES, has served on the scientific advisory board for Genentech, receives research
grant from Novartis and has received speaker honorarium
from MSD, Novartis, FAES and GSK. Dr Bartra reports
have served as consultant to Novartis, Faes Farma, Hal
Allergy, had been paid lecture fees by Novartis, Stallergenes, UCB, Thermofisher, Menarini and Chiesi. Dr.
Gimenez-Arnau is on the scientific advisory board of
Uriach Pharma, Genentech and Novartis, has received
research grants supported by Uriach Pharma, Pharma
and Novartis and is a speaker for Uriach Pharma, Novartis, Genentech, Menarini, GSK and MSD. Dr. Jauregui
has acted as a paid consultant or medical writer for
Novartis, FAES farma and Pfizer and has also received
speaker honorarium from MSD and FAES farma. Dr.
Labrador-Hornillo has acted as a paid consultant for
Novartis and Shire having received speaking honorar-

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