FEATURE ARTICLE
2.5
Recurrent and Persistent Urticaria:
Is It Chronic Idiopathic Urticaria?
Narrative Review on Diagnosis and Management
Stanley Goldstein, Jeffrey M. Weinberg
ABSTRACT: Chronic idiopathic urticaria (CIU), defined as
wheals and/or angioedema lasting for Q6 weeks with-
out an identifiable cause, is a burdensome condition.
This review provides recommendations regarding the
efficient recognition and differential diagnosis of CIU from
other chronic urticaria forms and discusses the importance
of evaluating CIU’s impact on patients’ quality of life and
assessing unmet treatment needs.
The goal of treatment is achieving complete resolu-
tion of symptoms through a systematic approach and
close patient cooperation, thereby improving quality
of life. The U.S. Practice Parameter describes a step-care
approach to CIU management, with second-
generation H1-antihistamines at approved doses as the
first-line treatment. For patients with inadequately con-
trolled symptoms, dose advancement or add-on thera-
pies, followed by use of potent antihistamines, may be
considered. Of the alternative agents available for the
treatment of patients with refractory CIU, omalizumab, an
anti-immunoglobulin E monoclonal antibody, is the only
treatment approved by the Food and Drug Administra-
tion for use in adults and adolescents (Q12 years old) with
Stanley Goldstein, MD, Allergy and Asthma Care of Long Island,
Rockville Centre, New York, NY.
Jeffrey M. Weinberg, MD, Mount Sinai Beth Israel and Mount
Sinai St. Luke’s, Mount Sinai School of Medicine, New York, NY.
Disclosures/potential financial conflicts of interest: Stanley Goldstein
has served on advisory boards for Meda and Novartis; has received
funding for clinical research from Astra Zeneca, Genentech, Merck,
Mylan, Novartis, Perrigo, and Teva; and has served on speakers
bureau for Genentech, GSK, Meda, Merck, Mylan, and Teva. Jeffrey M.
Weinberg has received honoraria and research grants from Novartis.
Development of this manuscript was supported by Novartis Phar-
maceuticals Corporation, East Hanover, NJ.
Correspondence concerning this article should be addressed to
Stanley Goldstein, MD, Allergy and Asthma Care of Long Island, 242
Merrick Road, Suite 401, Rockville Centre, New York, NY 11570.
E-mail: drsgoldstein@gmail.com
DOI: 10.1097/JDN.0000000000000241
250
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Contact
Hours
CIU who remain symptomatic despite H1-antihistamine
therapy. Ultimately, treatment decisions should weigh
the potential clinical benefit versus harm for each
agent and consider the patient’s preference. By
discussing available treatment options and providing
evidence-based recommendations, this review aims to
support aspects of decision making when managing
this complex condition.
Key words: Chronic Idiopathic Urticaria, Chronic Urticaria,
Decision Making, H1-Antihistamine, Omalizumab, Practice
Parameter
U rticaria, defined as wheals (hives) and/or
angioedema, is classified on the basis of its
duration, frequency, and causes: acute (less
than 6 weeks) or chronic (recurrent episodes,
occurring on most days of the week, for
a period of 6 weeks or longer; Bernstein et al., 2014;
Greaves, 2000). Chronic urticaria was estimated to affect
0.8% of the population over a 12-month period (Zuberbier,
Balke, Worm, Edenharter, & Maurer, 2010).
Acute urticaria is typically short lived, with patients
experiencing symptoms on a continual basis for a period
of days or weeks or after repeat exposure to an allergen or
physical factor (Bernstein et al., 2014). Persistent urticaria
lasting 6 weeks or more can be considered chronic and
may include recurrent urticaria, depending on the frequency
and timing of episodes (Bernstein et al., 2014). On physical
examination, there are no visual differences between acute
and chronic urticaria (Zuberbier et al., 2009). Compared
with chronic urticaria, acute urticaria and angioedema
are more frequently associated with an identifiable cause
(Bernstein et al., 2014). The underlying causes of chronic
urticaria are diverse, and in many cases, the trigger is un-
identifiable (Bernstein et al., 2014). Chronic urticaria with-
out an identifiable cause is referred to as chronic idiopathic
urticaria (CIU), to distinguish it from inducible forms, which
are triggered by exposure to a physical factor (e.g., heat
Journal of the Dermatology Nurses’ Association
or pressure). CIU accounts for most cases (66%Y93%) of
chronic urticaria, with inducible forms making up the re-
mainder (Maurer et al., 2011). Two or more forms of
urticaria, for example, CIU and an inducible form, may
coexist in the same patient (Zuberbier et al., 2014).
The differential diagnosis of the many forms of chronic
urticaria and subsequent clinical management remain a
challenge for many dermatologists. Terminology used to
define types of urticaria has been clarified. Recent advances
have been made in the understanding of its underly-
ing pathophysiology and in available treatment options.
As such, it would seem timely to revisit the differential
diagnosis and clinical management of chronic urticaria,
specifically CIU.
The objective of this review is to provide real-world and
evidence-based recommendations relating to key decision-
making aspects in the identification, diagnosis, and man-
agement of CIU (widely known as chronic spontaneous
urticaria outside of the United States; Zuberbier et al.,
2014).
CIU OVERVIEW
Clinical Characteristics
Wheals are lesions characterized by a central swelling and
surrounding erythema (Figure 1), accompanied by pruritus
(Bernstein et al., 2014). The wheals vary in size from a
few millimeters to several centimeters and may become
confluent (Greaves, 2000). Generally, wheals are tran-
sient, with individual lesions typically lasting less than
24Y48 hours, although new wheals may be developing
simultaneously, leading to persistent symptoms (Bernstein
et al., 2014). Angioedema is typically characterized by non-
pruritic, nonpitting, skin-colored swellings (edema) of
the hypodermis and subcutaneous tissue and beneath the
FIGURE 1. Different manifestations of urticaria and angioedema
in CIU. (A) Large wheal extending from the left shoulder to
the left upper chest. (B) Flat wheals of various sizes on the left
forearm. (C) Raised wheals at the base of the left side of the
neck. (D) Angioedema of the eyelids. (E) Angioedema of the
left hand.
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mucous membranes, which do not have a well-defined
margin (Figure 1; Bernstein et al., 2014; Zuberbier et al.,
2014). The swellings may be painful (although not
usually), primarily affecting the face, lips, mouth, throat,
and extremities, and can take up to 72 hours to resolve
(Schaefer, 2011; Zuberbier et al., 2014). Estimates of the
proportion of patients experiencing only hives range from
29% to 65%, whereas 33%Y67% experience both hives
and angioedema, although not necessarily at the same
time (Maurer et al., 2011). It is uncommon (estimates
range between 1% and 13% of patients) to experience
angioedema in isolation (Maurer et al., 2011).
Pathophysiologic Mechanisms and Origins
CIU is considered to be a mast cell-mediated disease,
whereby activation of mast cells in the dermis leads to
degranulation and release of inflammatory mediators, for
example, histamine and cytokines (Altman & Chang,
2013; Jain, 2014; Vonakis & Saini, 2008). Release of
these factors results in vasodilation and increased vascular
permeability, causing wheals and/or angioedema (Altman
& Chang, 2013; Jain, 2014; Vonakis & Saini, 2008).
Although not definitive as they are also found in some
healthy subjects, autoantibodies against the immuno-
globulin E (IgE) receptor ! subunit (FC(RI!; Tong,
Balakrishnan, Kochan, Kinét, & Kaplan, 1997) or IgE
(Grattan, Francis, Hide, & Greaves, 1991) have been de-
tected in the serum of a proportion of patients with chronic
urticaria, which includes patients with CIU.
Burden of Disease
Limited information is available regarding the burden of
CIU and its impact on quality of life; however, it is rea-
sonable to assume that findings in chronic urticaria ex-
tend to CIU. The burden of chronic hives is reportedly
similar or even greater than that of psoriasis (Gabriel et al.,
2015). The impact of chronic urticaria on patient quality
of life is substantial. Clinical data highlight the burden of
chronic urticaria with detrimental effects observed on as-
pects of health-related quality of life (Grob & Gaudy-
Marqueste, 2006; O’Donnell, 2014; Turner, Vietri, Tian,
Isherwood, & Balp, 2014), work productivity (Turner
et al., 2014), and ability to perform daily tasks (Grob,
Revuz, Ortonne, Auquier, & Lorette, 2005; Turner
et al., 2014) and an impact of CIU on mental health
(Uguz, Engin, & Yilmaz, 2008). An impact on health-
care resources is apparent, with increased utilization
observed in those treated for chronic urticaria compared
with matched controls (Turner et al., 2014).
It is recommended that patient-reported outcomes be
used in routine practice (Baiardini et al., 2011). Disease-
specific symptoms can be measured using the urticaria
activity score (Baiardini et al., 2011), and disease control
can be measured using the Urticaria Control Test (Weller
et al., 2014). Quality of life can be evaluated using the
Dermatological Life Quality Index (Lennox & Leahy,
251
2004) or Chronic UrticariaYQuality of Life Questionnaire
(Baiardini et al., 2011). Engaging patients regarding their
everyday life and feelings, as well as assessing their health
behavior in general, is key to further gauge the real-life
burden of their condition and to identify ways of optimiz-
ing management of their symptoms (Maurer, Ortonne, &
Zuberbier, 2009a, 2009b; Box 1).
BOX 1. Recommended patient questions
to be asked by the healthcare provider to
help understand the impact of CIU and unmet
treatment needs (Maurer et al., 2009b;
Weller et al., 2014)
1. To what extent do you suffer from the physical
symptoms of urticaria?
2. To what extent is your quality of life affected by
urticaria?
3. Does urticaria have a negative impact on your
work, school, or leisure activities?
4. To what extent do you feel that urticaria has
affected your appearance?
5. At what time of day is urticaria most bothersome?
6. How often does urticaria affect your sleep quality?
7. What do you do when urticaria prevents you
from sleeping?
8. On which treatments are you most reliant?
9. Do you take medication to prevent an outbreak?
10. How often is the treatment for your urticaria not
sufficient to control your symptoms?
11. Overall, how well controlled is your urticaria?
12. Which aspect of your urticaria would you
particularly like me to help you manage?
Diagnosis
Patient history and physical examination
Given that a patient will typically present to the derma-
tologist with chronic urticaria, a thorough patient history
and physical examination is necessary to differentiate CIU
from other subtypes (Box 2). If, during the evaluation, a
possible precipitating cause is questioned or patient his-
tory and physical examination do not lead to a conclusive
diagnosis, referral to a specialist (e.g., dermatologist, aller-
gist, or an urticaria-focused clinic) for limited laboratory
evaluations or skin or provocation tests can be considered
(Box 2; Bernstein et al., 2014).
Diagnostic Laboratory Tests
Routine tests for chronic urticaria without atypical features
have been agreed by expert consensus (Practice Parameters
Task Force, a 13-member group that oversaw the develop-
ment of the U.S. Practice Parameter; Box 2), specifically,
complete blood count with differential, erythrocyte sedi-
mentation rate and/or C-reactive protein and measurement
of liver enzymes and thyroid-stimulating hormone levels
252
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BOX 2. Recommendations for the differential
diagnosis of CIU (Bernstein et al., 2014)
Step 1:
& Assess patient history and perform a physical
examination:
) Extent and nature of the urticaria lesions: onset;
frequency, duration, severity, and localization
of wheals and itching; diurnal/weekly/seasonal
variation; presence/absence of angioedema;
associated symptoms, for example, pain or
burning sensation; pigmentation after
wheals resolve
) Include examination of the head, eyes, ears,
nose, mouth, throat, neck, lymph nodes, lungs,
heart, abdomen, and musculoskeletal system
) Family history of urticaria, relevant medical
history, and current conditions; allergies,
intolerances, systemic illnesses, infections, or
other potential origins; correlation with food,
physical factors, exertion, or the menstrual
cycle, where relevant; use of medication and
supplements; of previous therapies for urticaria
and previous diagnosis; stress levels; lifestyle
factors, professional and personal activities, travel
history, and impact on quality of life
Step 2:
& Refer to specialist for further investigation if, based
on patient history and physical examination, the
physician is unable to establish a diagnosis or the
diagnosis is inconclusive (i.e., vasculitis is suspected).
& Laboratory evaluation should be selective:
) Routine diagnostic tests, if CIU is suspected
include complete blood count with differential,
erythrocyte sedimentation rate or C-reactive
protein, liver enzymes, thyroid-stimulating hormone
) Extended diagnostic tests may be warranted,
if considered appropriate based on patient
history and physical examination (Table 1)
(Bernstein et al., 2014). Of note, the clinical utility of
routinely performing these tests has not been clearly estab-
lished (Bernstein et al., 2014). Chronic urticaria has been
reported with several systemic conditions, including thyroid
disease. A pooled meta-analysis of studies investigating
the association between thyroid autoimmunity and urti-
caria found that the prevalence of thyroid autoantibodies
(e.g., thyroglobulin and thyroid peroxidase) was signifi-
cantly higher in patients with urticaria compared with
nonurticaria controls (Pan, Gu, & Shan, 2015). However,
supporting evidence that treatment of the underlying thy-
roid condition affects the course of urticaria is limited
(Altman & Chang, 2013). The U.S. Practice Parameter
recommends that screening for thyroid disease is of
Journal of the Dermatology Nurses’ Association
little value in patients with CIU without symptoms relat-
ing to thyroid dysfunction (Bernstein et al., 2014).
Suspicion of autoimmunity could be confirmed by mea-
suring autoimmune biomarkers such as antinuclear anti-
bodies, antithyroid antibodies, antithyroid peroxidase
antibody, and functional autoantibody to Fc(RI! (Viegas,
Ferreira, & Kaplan, 2014; Viswanathan, Biagtan, &
Mathur, 2012). Diagnostic tests to detect autoimmunity
to IgE or FC(RI, including the Chronic Urticaria (CU)
Index (Viracor-IBT Laboratories, 2015), are rarely used
A
in routine clinical practice. The specificity and clinical
utility of these tests are questioned, and accordingly, the
U.S. Practice Parameter indicates that current evidence
does not support their routine use in the differential
diagnosis of chronic urticaria (Bernstein et al., 2014).
The U.S. Practice Parameter also states that a biopsy
can be considered in patients with CIU, although it is not
required in most cases (Bernstein et al., 2014). Biopsy
should be performed in cases of suspected urticarial vas-
culitis (characterized by palpable, nonblanching lesions,
associated with pain or a burning sensation, which often
last for several days, followed by residual hyperpigmen-
tation; Bernstein et al., 2014).
Classification of Chronic Urticaria Subtypes
As outlined above, assessing the patient’s history, physical
examination, and referral to a specialist for evaluation and
other diagnostic testing, where appropriate, may guide the
differential diagnosis of CIU from other types of chronic
urticaria and skin conditions. The distinguishing charac-
teristics of CIU, other types of chronic urticaria, and skin
conditions that may be confused with CIU are summarized
in Table 1. Of note, if angioedema is present without
wheals, other potential causes (e.g., hereditary angioedema
or acquired angioedema caused by C1-inhibitor deficiency)
should be considered. Hereditary angioedema is charac-
terized by edema (typically painless and nonpruritic) of the
subcutaneous tissue and/or submucosa affecting the face,
tongue, larynx, trunk, extremities, bowels, or genitals,
which develops over 24 hours and subsides during the
following 48Y72 hours (Tse & Zuraw, 2013). Appropriate
diagnostic testing, for example, complement levels in-
cluding C4, C1-inhibitor levels and function, C1q, and
C1-inhibitor antibodies, may aid the differential diag-
nosis of angioedema syndromes (Tse & Zuraw, 2013).
MANAGEMENT OF CIU
The U.S. Practice Parameter proposes a step-care approach
for the treatment of chronic urticaria, including CIU
(Figure 2; Bernstein et al., 2014). This step-care approach
and the recommendations outlined in the U.S. Practice
Parameter are summarized below. In addition to pharma-
cological approaches, patients with CIU may also benefit
from avoiding factors that could exacerbate associated
physical urticaria, for example, heat or tight clothing
(Bernstein et al., 2014).
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The currently recommended first-line pharmacological
treatment is monotherapy with an approved dose of a
second-generation, nonsedating H1-antihistamine (Bernstein
et al., 2014; Figure 2, Step 1; Table 2). Of a number of
second-generation antihistamines available, cetirizine,
desloratadine, fexofenadine, levocetirizine, and loratadine
have been extensively evaluated in patients with CIU
(Belsito, 2010; Sánchez-Borges, Caballero-Fonseca, &
Capriles-Hulett, 2013). H1-antihistamines are effective
and generally well tolerated in most patients with CIU.
Although estimates vary between studies and may depend
on the specific H1-antihistamine evaluated, it is well estab-
lished that only a proportion of patients (e.g., 30% and
52% in clinical trials of cetirizine 10 mg) achieve complete
symptom control with recommended approved doses
(Breneman et al., 1995; Handa, Dogra, & Kumar, 2004).
Efficacy is reportedly greater when H1-antagonists are ad-
ministered daily on a continuous basis, as opposed to
‘‘as needed’’ (Grob, Auquier, Dreyfus, & Ortonne, 2009;
Weller et al., 2013).
Patients not achieving control of symptoms with recom-
mended approved doses of H1-antihistamines should be
referred to a specialist for further treatment. For these
patients, treatment with higher doses (two- to four-fold
increase in the U.S. Food and Drug Administration [FDA]-
approved dose) of second-generation H1-antihistamines
might prove effective as a second-line approach (Bernstein
et al., 2014; Sánchez -Borges et al., 2013; Staevska et al.,
2010; Figure 2, Step 2). However, approximately one
quarter to one third of patients continue to experience
symptoms despite treatment with up to four times the ap-
proved dose (Maurer et al., 2011). When comparing the
clinical profile of patients with CIU resistant to treatment
with four-times approved doses of H1-antihistamines and
patients responsive to H1-antihistamines, a greater propor-
tion of treatment-resistant patients (58.7% compared with
28.5% of responsive patients) experienced angioedema
(Magen, Mishal, Zeldin, & Schlesinger, 2011).
For those nonresponsive to higher-than-approved doses
of H1-antihistamines, use of another second-generation
H1-antihistamine, H2-antihistamine or leukotriene recep-
tor antagonist (LTRA), may be considered as an add-on
therapy, if tolerability permits (Bernstein et al., 2014;
Figure 2, Step 2). Combination treatment with H2- and
H1-antihistmamines is reportedly more effective than
H1-antihistamines alone (Bernstein et al., 2014). A recent
systematic review of data from 10 clinical trials in patients
with chronic urticaria reported limited efficacy of LTRAs
compared with placebo or H1-antihistamines, with most
trials not showing superiority of LTRAs. There was some
evidence for efficacy of LTRAs in combination with
H1-antihistamines, along with an acceptable tolerability
profile (de Silva, Damayanthi, Rajapakse, Rodrigo, &
Rajapakse, 2014). One study reported a positive response
to combined LTRA, H2-antihistamine, and H1-antihistamine
treatment in patients nonresponsive to treatment with
253
 TABLE 1. CIU, Chronic (Inducible) Urticarias, and Other Skin Conditions That May Be
Confused With CIU (Bernstein et al., 2014)
Diagnosis Distinguishing Characteristics
CIU & Spontaneous onset of wheals,
angioedema, or both, occurring for
Q6 weeks, without a known cause
& Wheals: central swelling of variable size,
surrounded by reflex erythema; associated
pruritus; transient, typically resolves within
24Y48 hours; no residual pigmentation
after wheal resolves
& Angioedema: nonpruritic, nonpitting
swelling (edema), without a well-defined
margin
Inducible urticarias
Dermatographia & Rapid onset of urticaria upon stroking or
rubbing of unblemished skin
Cold urticaria & Pruritus and swelling after exposure to a
cold stimulus
Delayed pressure & Often painful swellings typically occurring
urticaria/angioedema 4Y6 hours after sustained pressure on the
skin (e.g., from working with tools or wearing
tight clothing)
Solar urticaria & Development of urticaria quickly after
exposure of skin to sunlight (generally
within 1Y3 minutes)
Vibratory & Localized pruritus and swelling after
angioedema contact with a vibratory stimulus
Cholinergic urticaria & Small wheals (1Y3 mm in diameter) with
large surrounding flares, triggered by
a rise in core body temperature
(e.g., exercise or hot baths)
Aquagenic urticaria & Rare condition
& Development of wheals (1Y3 mm in size) on
areas of skin that have come into contact
with water, independent of temperature
Urticarial vasculitis & Palpable, nonblanching, purpuric lesions,
typically lasting for several days, although
in some cases, lesions may be evanescent,
lasting less than 24 hours
& Residual hyperpigmentation
& Often associated with pain or a burning
sensation
Exercise-induced & Anaphylaxis triggered by physical exertion,
urticaria and sometimes related to ingestion of a certain
anaphylaxis food or medication
& Urticaria may arise as a manifestation of
anaphylaxis
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Diagnostic Test
& Patient history and physical examination
& Complete blood count with differential,
ESR or CRP, liver enzymes, TSH
& Depending on patient history, consider
(but not limited to) testing thyroid
autoantibodies, lesional skin biopsy, and/or
skin tests (including physical tests) to rule
out other causes of chronic urticaria
& If angioedema presents in isolation,
rule out hereditary or drug-induced (e.g.,
ACE inhibitors) angioedema
& In all cases, assess patient history and
perform a physical examination
& Stroking skin with a firm object
(dermographism)
& Application of a cold stimulus (e.g., ice
cube on forearm); wheal and flare
reaction observed on rewarming
& Application of pressure (e.g., weight
suspended over patients shoulder), with
monitoring for development of delayed
angioedema
& Phototesting with light (various wavelengths)
& Test with a vibratory source, e.g., a vortex
& Provocative challenges that raise core body
temperature, (e.g., hot water immersion or
methacholine intradermal challenge)
& Water compress (35-C) applied to the skin
of the upper body for 30 minutes
& Lesional biopsy
& Exercise challenge in a controlled
environment
& Important to distinguish from cholinergic
urticaria, where systemic reactions may
also arise (described above)
(continues)
Journal of the Dermatology Nurses’ Association
 TABLE 1. CIU, Chronic (Inducible) Urticarias, and Other Skin Conditions That May Be
Confused With CIU (Bernstein et al., 2014), Continued
Diagnosis Distinguishing Characteristics Diagnostic Test
Cryopyrin-associated & Characterized by abnormality in C1AS1 & Skin biopsy
periodic syndromes gene (cryopyrin protein)
(cryopyrinopathies) & Symptoms include urticaria-like rash

Referral to a specialist should be considered where diagnostic or procedural assistance is required. ACE = angiotensin-converting enzyme;
CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; IgE = immunoglobulin E; TSH = thyroid-stimulating hormone.

H1-antihistamines and H2-antihistamines or LTRAs and
H1-antihistamines (Wan & Chang, 2014). Given that
LTRAs (e.g., montelukast) are generally well tolerated,
they can be considered in patients with CIU experiencing
symptoms despite antihistamine therapy (Bernstein et al.,
2014; Figure 2, Step 2). Use of a first-generation anti-
histamine may also be prescribed; efficacy is similar to
second-generation agents, although it is recommended that
they be taken before bedtime, because of the potential for
sedating effects (Bernstein et al., 2014; Figure 2, Step 2).
In patients still continuing to experience symptoms de-
spite treatment with higher-than-approved doses of second-
generation H1-antihistamines and one or more of the above
add-on therapies, treatment with a potent antihistamine,
for example, hydroxyzine (H1-antihistamine) or doxepin
(antidepressant with H1- and H2-antihistamine activity),
may be considered, if tolerated (Bernstein et al., 2014;
Figure 2, Step 3). Side effects with hydroxyzine are typi-
cally mild and transient and include dry mouth and drowsi-
ness (Pfizer, 2004), whereas doxepin has been associated

FIGURE 2. Step-care approach for the management of CIU including strength of recommendations based on levels of
evidence (Bernstein et al., 2014). Initiate treatment at an appropriate step, based on patient’s disease severity and previous
treatment history. Patient tolerance and efficacy of medications should be assessed at each step. Treatment can be
‘‘stepped down,’’ once consistent symptomatic control is achieved. With the exception of antihistamines (standard doses)
and omalizumab (patients who remain symptomatic despite H1-antihistamine treatment), all other therapies described are
not U.S. FDA approved in this indication. Referral to a specialist should be considered if the patient remains symptomatic
despite treatment with U.S. FDA-approved doses of second-generation antihistamines. Strength of recommendation:
(A) Category I evidence; (B) Category II evidence, or extrapolated recommendation from Category I evidence; (C) Category
III evidence, or extrapolated recommendation from Category I/II evidence; and (D) Category IV evidence, or extrapolated
recommendation from Category I/II/III evidence. Category of evidence: Ia, meta-analysis of RCTs; Ib, Q1 RCT; IIa, Q1
nonrandomized controlled study; IIb, Q1 other type of quasi-experimental study; III, nonexperimental descriptive studies (e.g.,
comparative studies); IV, expert clinical experience or opinion. AE = adverse event; CIU = chronic idiopathic urticaria;
FDA = Food and Drug Administration; LTRA = leukotriene receptor antagonist; NSAID = nonsteroidal anti-inflammatory drug;
QoL = quality of life; RCT = randomized controlled trial. Reprinted with permission from Bernstein et al., 2014.

VOLUME 8 | NUMBER 4 | JULY/AUGUST 2016 255

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 256
TABLE 2. U.S. Food and Drug Administration-Approved CIU Therapies a
(Apotex, 2001; Sanofi Aventis US LLC, 2007; Merck &
Co., Inc., 2014; Genentech, 2014; UCB, Inc., 2010; Pfizer Inc., 2002)
Administration
Pharmacologic Agents Mechanism Approved/Intended Indication Route Dosing Frequencyb

Nonsedating H1-receptor antagonist;
antihistamines, e.g., reduces the effect of
cetirizine, loratadine, mast cell mediators on
desloratadine, endothelial cells and
fexofenadine, and sensory nerves
levocetirizine
Omalizumab Anti-IgE antibody; binds
to IgE and lowers free IgE
levels. Subsequently, IgE
receptors (FC(RI) on
cells down regulate
Treatment of the uncomplicated PO (tablet/oral Titration: Typically once daily,
skin manifestations of CIU in adults solution) & Initiate starting dose with or without food; the
and children aged 6 months and & If sufficient response time of administration
older (12 years and over for is not obtained, the can be varied to suit
loratadine and 6 years and older dose should be individual patient needs
for fexofenadine) increased as necessary
to the maximum
recommended
daily dose
CIU in adults and adolescents SC & 150 or 300 mg Every 4 weeks
(12 years old and over) who & Dosing is not
remain symptomatic despite dependent on serum
H1-antihistamine treatment IgE level or body weight

CIU = chronic idiopathic urticaria; FC(RI = high-affinity IgE receptor; FDA = Food and Drug Administration; IgE = immunoglobulin E; PO = per os (oral administration); SC = subcutaneous.
a
Other therapies detailed in the step-care approach are not approved by the U.S. FDA for the treatment of CIU. bAlways refer to the relevant prescribing information.

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Journal of the Dermatology Nurses’ Association
with anticholinergic effects, including dry mouth and con-
stipation (Goldsobel et al., 1986).
Patients who remain symptomatic despite maximal anti-
histamine therapy (i.e., Step 3) are considered to have
refractory CIU. For these patients, dermatologists may
consider add-on therapy with alternative agents, including
biologics (e.g., omalizumab, interleukin-1 receptor antag-
onists, anti-B-cell therapies, and antitumor necrosis factor
agents), anti-inflammatory agents (e.g., hydroxychloroquine,
dapsone, colchicine, and sulfasalazine), or immunosup-
pressants (e.g., cyclosporine, mycophenolate, tacrolimus,
sirolimus, methotrexate, and cyclophosphamide; Figure 2,
Step 4; Bernstein et al., 2014). The choice of agent should
be based on the potential riskYbenefit of each individual
agent, taking into account a number of factors, including
the rate of onset of the therapeutic effect, potential for
adverse effects, the patient’s medical history including
comorbidities, cost, likely impact of treatment on quality
of life, and the patient’s preference (Bernstein et al., 2014).
Of these agents, omalizumab and cyclosporine are the
most intensively studied in patients with CIU (Bernstein
et al., 2014), hence the focus of the proceeding discussion
on these Step 4 treatment options.
Omalizumab, a monoclonal antibody that targets IgE,
is approved by the FDA for the treatment of adults and
adolescents (aged Q12 years) with CIU who remain symp-
tomatic despite H1-antihistamine treatment (Genentech,
2014; Table 2). Approval of omalizumab (150 and 300 mg)
was based on the findings of three international Phase III,
global, randomized, multicenter, clinical studies (ASTERIA
I, ASTERIA II, and GLACIAL), which showed efficacy and
no unexpected safety concerns in patients with CIU who
remained symptomatic despite H1-antihistamine treatment
(Genentech, 2014; Kaplan et al., 2013; Maurer et al.,
2013; Saini et al., 2014). In ASTERIA I and II, adults
and adolescents who remained symptomatic despite use
of approved doses of H1-antihistamines (ASTERIA I,
N = 319; ASTERIA II, N = 323) were randomized to
receive subcutaneous omalizumab (75, 150, or 300 mg)
or placebo every 4 weeks for 24 and 12 weeks, respectively
(Maurer et al., 2013; Saini et al., 2014). In GLACIAL,
336 patients with CIU, despite treatment with up to
four times the approved dose of H1-antihistamines, plus
H2-antihistamines and/or LTRAs, were randomized to re-
ceive subcutaneous omalizumab 300 mg or placebo every
4 weeks for 24 weeks (Kaplan et al., 2013). In both
ASTERIA I and II, greater decreases from baseline in the
weekly itch severity score and weekly hive count were
observed with omalizumab 150 and 300 mg compared
with placebo (Genentech, 2014). Consistent evidence for
efficacy was not observed with the omalizumab 75-mg dose
(Genentech, 2014). In all three trials, significant improve-
ments with omalizumab 300 mg versus placebo were
observed at Week 12 on quality of life, as measured using
the Dermatological Life Quality Index (Kaplan et al., 2013;
Maurer et al., 2013; Saini et al., 2014). Similar findings
VOLUME 8 | NUMBER 4 | JULY/AUGUST 2016
Copyright © 2016 Dermatology Nurses' Association. Unauthorized reproduction of this article is prohibited.
were also observed for the Chronic UrticariaYQuality of
Life Questionnaire overall score (Kaplan et al., 2013;
Maurer et al., 2013; Saini et al., 2014). On the basis of
pooled data for the three trials (Weeks 1Y12), the most
commonly reported adverse events with omalizumab
were headaches (omalizumab 150 mg, 12.0% [21/175];
omalizumab 300 mg, 6.1% [25/412]; and placebo 2.9%
[7/242]) and nasopharyngitis (omalizumab 150 mg, 9.1%
[16/175]; omalizumab 300 mg, 6.6% [27/412]; and pla-
cebo 7.0% [17/242]; Genentech, 2014). Based on sponta-
neous postmarketing reports, a proportion (at least 0.2%)
of patients with asthma experienced anaphylaxis after
omalizumab treatment (Genentech, 2014), as such
omalizumab carries a box warning from the U.S. FDA
for anaphylaxis. There were two confirmed cases of anaphy-
laxis in patients with CIU in ASTERIA I, of which one
occurred during follow-up and was considered serious;
neither case was attributed to the study drug (Saini et al.,
2014). No episodes of anaphylaxis were observed during
ASTERIA II or GLACIAL (Kaplan et al., 2013; Maurer
et al., 2013). On the basis of the available evidence, a trial
of omalizumab should be considered for refractory CIU,
provided the clinical benefit versus harm/burden and cost
are favorable, and it is consistent with patient preference
(Bernstein et al., 2014). A recent retrospective analysis of
the three pivotal trials in CIU showed dose-dependent re-
sponses to omalizumab treatment with the 300-mg dose
was associated with best control of symptoms (Kaplan
et al., 2016).
Although omalizumab is currently the only drug ap-
proved by the U.S. FDA for use in patients with refractory
CIU (Genentech, 2014), the Practice Parameter notes that
treatment with cyclosporine can also be considered in
this patient population (Bernstein et al., 2014). Cyclo-
sporine is an immunosuppressive agent, approved for
treatment of rheumatoid arthritis; psoriasis; prophylaxis
of organ rejection in kidney, liver, and heart allogeneic
transplants; and treatment of chronic rejection in patients
previously treated with other immunosuppressive agents
(Novartis, 2009, 2013). The exact mechanism of action
of cyclosporine is not known; however, it has been
shown to inhibit T-lymphocytes and affect histamine
release from basophils and mast cells (Novartis, 2009,
2013; Stellato et al., 1992). Data from one 8-week and
two 16-week clinical trials provide evidence for efficacy
of cyclosporine alone or in combination with H1-antihis-
tamines in patients with CIU (N = 30Y99; Di Gioacchino
et al., 2003; Grattan et al., 2000; Vena et al., 2006);
however, treatment may be associated with adverse
effects on blood pressure and renal function (Bernstein
et al., 2014; Kaplan, 2014) and therefore should be
monitored closely. On the basis of the perceived
riskYbenefit, cost, limitations of the randomized clinical
trials in this indication, and the low level of evidence
supporting cyclosporine from these trials, there is a weak
recommendation for its use in refractory CIU (Bernstein
257
et al., 2014). These factors should be taken into consideration
and discussed openly with patients when considering cyclo-
sporine as a potential treatment option (Bernstein et al.,
2014).
Systemic corticosteroids are frequently used for patients
with refractory CIU, but clinical trial data supporting their
use are lacking (Bernstein et al., 2014). Short-term use
(e.g., 1Y3 weeks) of systemic corticosteroids may be con-
sidered for patients with acute exacerbation of symptoms
until control is achieved with other therapies (Bernstein
et al., 2014). However, long-term use of corticosteroids
is discouraged, because of tolerability concerns and poten-
tial complications, including avascular necrosis of the bone
and development of cataracts and osteoporosis (Bernstein
et al., 2014; Clarke, 2012; Urban & Cotlier, 1986; Weldon,
2009; Zuberbier et al., 2014). The risk of developing
adverse events is reportedly enhanced with increased cu-
mulative exposure to oral corticosteroids in patients with
CIU (Ledford et al., 2015).
PRACTICAL CONSIDERATIONS AND SUMMARY
CIU places considerable economic burden on society, par-
ticularly considering a disease duration typically ranging
from 1 to 5 years, with some patients suffering for much
longer (Maurer et al., 2011; Toubi et al., 2004). A study
of the burden of CIU found that patients were regular
users of healthcare resources (Sun, Raimundo, Antonova,
Chang, & Broder, 2014). Annually, it has been estimated
that per-patient CIU-specific costs amount to a mean of
US$997 (Sun et al., 2014). CIU is predominantly an out-
patient disease, with outpatient services reported to be the
biggest contributor to the total annual cost (66.0%). A
smaller study estimated that prescription medication use
accounted for 62.5% of the total annual cost, whereas
indirect costs, including loss of income because of out-
patient visits or absence from work because of diminished
quality of life, accounted for 15.7% (Delong, Culler, Saini,
Beck, & Chen, 2008).
A recent Internet survey conducted in 321 European
adults diagnosed with chronic urticaria revealed that ap-
proximately one third of people with chronic urticaria do
not use any kind of prescription medication for their condi-
tion (Maurer et al., 2009b). Patient education is clearly
essential to help patients manage CIU more effectively
(Maurer et al., 2009a, 2009b), with physicians under-
standing a patient’s individual health behavior, symptom
pattern, and unmet needs also being key to the long-term
effective management of CIU. Through close patientY
dermatologist cooperation, the ultimate goal of prompt,
systematic treatment management is to achieve complete
resolution of the symptoms of CIU, thereby vastly improv-
ing overall patient quality of life. Referral to a specialist
should be considered if a patient remains refractory to first-
line treatment with U.S. FDA-approved doses of antihista-
mines (Zuberbier et al., 2014). Omalizumab has the
greatest level of evidence for a positive riskYbenefit profile
258
Copyright © 2016 Dermatology Nurses' Association. Unauthorized reproduction of this article is prohibited.
in patients who remain symptomatic beyond Step 3 care
(i.e., nonresponsive to antihistamine treatment; Figure 2).
Some studies have shown efficacy with cyclosporine; how-
ever, potential renal toxicity and hypertension are a risk
and require regular monitoring. A brief course of cortico-
steroids may be helpful in cases of nonresponsiveness to
antihistamines; however, longer-term use is not recom-
mended. It should be noted that, with the exception of
standard doses of antihistamines and omalizumab for pa-
tients who remain symptomatic on H1-antihistamines, all
other therapies described in the step-care approach for the
treatment of CIU are not U.S. FDA approved for this
indication. h
BOX 3. Practical recommendations for
patients with CIU
 Assessment of impact of CIU on quality of life
and understand unmet needs (Box 1)
 Efficient recognition and diagnosis of CIU (Box 2)
 Expeditious, systematic approach to CIU treatment
management (Figure 2), including timely referral
to a specialist
Acknowledgments
Medical writing and editorial assistance in the develop-
ment of this manuscript were provided by Katy Tucker
at Fishawack Communications, Oxford, UK, and this
service was supported by Novartis Pharmaceuticals
Corporation, East Hanover, NJ, and Genentech, Inc.,
South San Francisco, CA. The authors would like to
acknowledge Meryl Mendelson, Novartis Pharmaceuticals
Corporation, East Hanover, NJ, for medical expertise
and editorial contributions to this manuscript. Novartis
Pharmaceuticals Corporation jointly market omalizumab
(Xolair ) with the manufacturers, Genentech Inc. The
A
authors did not receive any financial funding or benefits
from Novartis Pharmaceuticals Corporation for the
preparation of this manuscript.
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