Chronic spontaneous urticaria: Treatment of refractory symptoms

Official reprint from UpToDate® www.uptodate.com

©2019 UpToDate®

Chronic spontaneous urticaria: Treatment of

refractory symptoms
Author: David A Khan, MD
Section Editors: Sarbjit Saini, MD, Jeffrey Callen, MD, FACP, FAAD
Deputy Editor: Anna M Feldweg, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Mar 2019. | This topic last updated: Mar 19, 2019.

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Dapsone for refractory chronic spontaneous urticaria (February 2019)

Recent international guidelines for the management of chronic spontaneous urticaria (…

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INTRODUCTION

Chronic spontaneous urticaria (CSU), also called chronic idiopathic urticaria, is defined by the
presence of urticaria (hives) on most days of the week, for a duration of six weeks or longer [1].
Associated angioedema occurs in about 40 percent of patients. Standard management of CSU
primarily involves second-generation H1 antihistamines, often at higher than usual doses and in
combination with H2 antihistamines and leukotriene modifiers. Short courses of systemic
glucocorticoids to control severe exacerbations may be needed. This review discusses the
treatment of patients whose symptoms are not controlled over time using these standard
therapies.

Therapeutic options for patients with refractory CSU will be reviewed here, as well as the
evidence in support of the efficacy of each treatment. Standard management, as well as the
diagnosis, pathogenesis, and prognosis of CSU, are reviewed separately. (See "Chronic
spontaneous urticaria: Standard management and patient education" and "Chronic spontaneous

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Chronic spontaneous urticaria: Treatment of refractory symptoms

urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history".)

Urticarial vasculitis and specific physical forms of chronic urticaria, such as delayed-pressure
urticaria, cholinergic urticaria, or cold urticaria, are discussed separately. (See "Urticarial
vasculitis" and "Physical (inducible) forms of urticaria" and "Cold urticaria".)

REFERRAL

Patients with recurrent urticaria with or without angioedema that continues to recur for a period
of six weeks or longer and cannot be adequately controlled with higher doses of second-
generation H1 antihistamines should be referred to an allergy or dermatology specialist. These
patients are at risk for receiving repeated courses of oral glucocorticoids. However, long-term
systemic glucocorticoids have potentially severe side effects and do not appear to induce lasting
remission or alter the natural history of CSU. Thus, it is preferable to limit glucocorticoid use to
short periods of the minimally effective doses and to refer the patient for consideration of more
advanced treatments before he/she has been exposed to months of glucocorticoid therapy. (See
"Major side effects of systemic glucocorticoids".)

In some cases, immunosuppressant or anti-inflammatory drugs are needed, and it is important

for the treating specialist to be knowledgeable about potential adverse effects and monitoring
when administering the agents discussed in this topic. Consultation with additional specialists
(eg, rheumatologists) may be appropriate, depending on the medication, as well as the
experience and comfort level of the treating specialist.

OVERVIEW

Available data indicate that H1 antihistamines at higher than standard doses will adequately
control CSU symptoms in approximately one-half of patients, and a small number will get
additional benefit from the other well-tolerated and low-risk supplementary therapies (eg, H2
antihistamines and montelukast). The efficacy of H1 antihistamine therapy for CSU is reviewed
separately. (See "Chronic spontaneous urticaria: Standard management and patient education",
section on 'H1 antihistamines'.)

The options for refractory CSU include omalizumab, cyclosporine, and several additional drugs
that have either anti-inflammatory or immunosuppressant effects. The recommendations in this
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topic review are generally consistent with guidelines from international societies [1-4]. Deviations
from the recommendations in the guidelines are noted.

When introducing these more advanced treatments, antihistamines and other standard agents
that were clearly helpful to the patient are typically continued. Any medications of uncertain
benefit should be discontinued so that medications do not accumulate.

Goal of therapy — The goal of therapy in patients with refractory CSU is to achieve a level of
symptom control and improvement in quality of life that is acceptable to the patient, while
minimizing therapy-related side effects. Patients differ in their preferences. Some want to pursue
complete remission, while others would rather minimize medications and accept a low level of
ongoing symptoms. In addition, it should be kept in mind that although CSU can be a disabling
disorder, it does not lead to permanent organ damage, and it ultimately resolves in the majority
of patients, with or without treatment. Thus, a treatment that appears to be inducing serious
adverse side effects is not warranted. The natural history of CSU is reviewed separately. (See
"Chronic spontaneous urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural
history", section on 'Natural history and prognosis'.)

Choice of initial intervention — For patients whose symptoms cannot be adequately controlled
by higher-dose antihistamines, international guidelines recommend the addition of omalizumab,
a monoclonal antibody against immunoglobulin E (IgE), as the most appropriate next
intervention [1]. Omalizumab is preferred because of both proven efficacy and also safety
relative to immunosuppressant or anti-inflammatory drugs. However, the high cost of
omalizumab is a concern in all health care systems and will limit the use of this therapy in many
settings. (See 'Omalizumab' below.)

We agree with international guidelines that omalizumab is the most appropriate therapy for
patients who do not respond to higher-dose H1 antihistamine therapy [1]. However, we typically
give up-dosing of antihistamines a trial period of at least several weeks to fully assess
effectiveness, whereas the international guidelines suggest that the trial period for
antihistamines can be as short as one month (algorithm 1). Up-dosing of antihistamines is
reviewed separately. (See "Chronic spontaneous urticaria: Standard management and patient
education", section on 'Up-dosing of second-generation agents'.)

Several studies have examined potential biomarkers to predict response to various therapies for
refractory CSU, but none can be recommended for routine clinical use [5]. The most promising
developments have been in identification of possible biomarkers to predict responsiveness to
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omalizumab [6-8]. (See 'Predicting responsiveness' below.)

OMALIZUMAB

Omalizumab is a monoclonal antibody directed against IgE, which was approved in the United
States in 2014 for the treatment of patients 12 years of age and older with CSU that is not
controlled with standard-dose H1 antihistamine therapy [9]. (See "Society guideline links:
Urticaria and angioedema (excluding hereditary angioedema)".)

Predicting responsiveness — Studies have identified potential biomarkers that may predict
responsiveness to omalizumab therapy, but none predict a response well enough to inform the
decision to treat. No specific laboratories are required before omalizumab is initiated for CSU.

Possible predictors of a better response include higher baseline serum IgE levels [7], a greater
than twofold increase in IgE after four weeks of treatment compared with baseline IgE [7], higher
baseline levels of high-affinity IgE receptor (Fc-epsilon-RI) on blood basophils, and greater
reduction of Fc-epsilon-RI on basophils after four weeks of treatment [8]. However, serum IgE
levels predict basophil IgE receptor levels, so these biomarkers are interconnected, and further
study is needed.

Efficacy — A meta-analysis of seven randomized trials (1312 patients) demonstrated that

omalizumab significantly reduced the weekly itch and wheal scores relative to placebo in
patients with CSU not responsive to standard doses of H1 antihistamines (eg, cetirizine 10 mg
daily) [10-18]. The most effective dose was 300 mg every four weeks, at which 36 percent of
patients had a complete response (urticaria activity score of 0). Adverse event rates and specific
events were similar with omalizumab and placebo. Other analyses of multiple studies showed
that omalizumab improved sleep beginning after the first dose and provided substantial
improvements in quality of life [19,20].

One trial included in the meta-analysis was particularly informative because it closely
approximated common clinical practice. The GLACIAL trial evaluated 335 patients whose
symptoms were not controlled with H1 antihistamines (up to four times the standard dose) plus
H2 antihistamines, antileukotriene agents, or the combination [14]. Subjects were randomized to
omalizumab (300 mg monthly) or placebo. Baseline medications were continued unchanged
throughout the study period and the four-month follow-up period. The primary endpoint was a
change in mean weekly itch severity scores (on a scale from 0 to 21, with a minimally important
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difference of 5) at the end of 12 weeks. Clinical efficacy was apparent by one week in the
omalizumab group. Mean itch scores decreased a clinically meaningful amount only in the
omalizumab group, and the difference between the two groups was statistically significant. A
minimally important difference in symptoms was achieved by 70 and 40 percent of subjects in
the omalizumab and placebo groups, respectively. At 12 weeks, 34 and 5 percent of subjects
were itch- and hive-free in the omalizumab and placebo groups, respectively. Once omalizumab
was stopped, subjects' symptoms gradually returned during the observation period and were
similar to placebo at the end of the study. Thus, the addition of omalizumab to the combination of
maximally-dosed H1 antihistamines (with or without H2 antihistamines, antileukotriene agents, or
both) will control symptoms in another 30 to 35 percent of patients, and the combination of
maximal antihistamine therapy plus omalizumab will achieve satisfactory control of CSU in
approximately 80 percent of patients.

Long-term impact — Omalizumab has not been shown to have a long-term disease-
modifying effect, so patients may relapse when omalizumab is tapered or discontinued [21].
However, CSU is a disorder that remits or resolves in the majority of patients within a few years
even untreated, so it can be difficult to assess the impact of therapy on natural history. (See
"Chronic spontaneous urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural
history", section on 'Natural history and prognosis'.)

Safety — Among all nonantihistamine therapies with proven efficacy for refractory CSU,
omalizumab is the best studied, most widely used therapy and has a very low incidence of
serious adverse effects. It has been used safely in pregnant women and is the treatment of
choice for refractory CSU during pregnancy [22,23]. The adverse effects of omalizumab are
discussed separately. (See "Anti-IgE therapy", section on 'Adverse effects'.)

Monitoring — No specific laboratory monitoring is required for patients receiving omalizumab

for CSU.

Our approach

Initial dosing — We initiate omalizumab at a dose of 300 mg injected subcutaneously every

four weeks based on studies of efficacy that evaluated different dosing approaches [10,15]. We
continue nonsedating H1 antihistamines initially and then taper as tolerated if the patient
responds well to omalizumab. Patients must be prescribed an epinephrine autoinjector because
anaphylaxis is reported, although not at rates any higher than with other biologic therapies. (See
"Anti-IgE therapy", section on 'Anaphylaxis'.)
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Expected response — In an analysis of multiple trials intended to evaluate the extent and
time course of the response to omalizumab, approximately 60 percent of patients had a
meaningful reduction in symptoms by week 12 [24]. Benefit was frequently seen in the first
month, and a majority of patients responded within four months (three doses). Approximately 40
percent of patients became asymptomatic (ie, complete response) by week 12 and about 45
percent by week 24 (in the longer studies). Thus, the analysis suggested that there is a group of
early responders (<1 month) and a smaller group who respond later. Overall, a period of 16
weeks should be sufficient to identify patients who will benefit.

A meta-analysis was performed on 67 observational studies (randomized trials were excluded) in

an effort to describe the "real-world" benefits and risks of omalizumab therapy [25]. In contrast to
a meta-analysis of randomized trials, such an analysis provides an estimate of the effects of
therapy combined with possible placebo effect (see 'Efficacy' above). Outcomes were expressed
as improvement in the weekly Urticaria Activity Score (UAS7), which ranges from 0 to 42, with
higher scores indicating more severe symptoms. Omalizumab therapy was associated with a
reduction in UAS7 scores of 26 points (95% CI 28-23 points). Approximately 72 percent of
patients had a complete response, and approximately 18 percent had a partial response. The
rate of adverse events was 4 percent, with three patients experiencing anaphylaxis.

Dose adjustment and duration of therapy — The optimal duration of therapy has not been
determined, and patients may relapse when omalizumab is tapered or discontinued [21].
Approaches to tapering therapy have not been studied extensively, although an algorithm has
been proposed by one group [26]. The approach of the author and section editors is described
here. We consider the severity of disease and duration of CSU, with a more gradual step-down
approach for patients with very severe or long-term CSU. For example, in a patient with a history
of refractory CSU for many years (eg, ≥3 years) who responds to omalizumab, we would treat
for a minimum of one year before considering tapering.

● If the patient has complete resolution of symptoms and no breakthrough symptoms for two
to three months, the dose can be lowered (to 150 mg) or the interval between injections can
be gradually lengthened. If a patient has no symptoms for a period of time on 150 mg every
eight weeks, therapy can be stopped.

● For patients with partial responses to omalizumab at 300 mg, there is anecdotal evidence
that some may have further improvement with higher doses (450 or 600 mg every four
weeks) or more frequent doses (eg, 150 mg every two weeks) [11,12,27]. A response to the

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increased dose should be evident after three doses.

● If the patient has minimal or inadequate control of symptoms despite the addition of
omalizumab, therapy should be discontinued after a four-month trial and other options
explored.

● Patients who were treated in the past and stopped therapy but then had a subsequent
recurrence of CSU have been reported to respond to omalizumab again, suggesting that
resistance does not develop readily in most patients [21,28,29].

OTHER THERAPIES

For patients who have not achieved adequate relief with the combination of higher-dose H1
antihistamines and omalizumab or do not have access to omalizumab, several other therapies
can be tried, including cyclosporine, tacrolimus, mycophenolate, dapsone, sulfasalazine, and
hydroxychloroquine [30-32].

Alternative non-US Food and Drug Administration (FDA)-approved agents for CSU can be
divided into two groups: "immunosuppressant" agents and "anti-inflammatory" agents, although
there is considerable overlap between the latter two groups of drugs.

● The term "immunosuppressant" is applied to drugs that have more potent

immunosuppression activity and greater potential toxicity, as well as more evidence for
efficacy. We have categorized the calcineurin inhibitors and mycophenolate mofetil in this
way.

● "Anti-inflammatory" denotes a class of agents with predominantly anti-inflammatory

activities, which have low potential toxicity and less proven efficacy for CSU. We have
applied this term to dapsone, sulfasalazine, and hydroxychloroquine.

With the immunosuppressant and anti-inflammatory drugs described in this section, therapy is
generally continued for a period of several months once control of symptoms has been
achieved. We favor a longer duration of therapy before attempting to taper for patients with
longstanding CSU.

In the author's experience, serious adverse effects that require discontinuation of therapy are
rare, and he has not observed any permanent complications from use of these agents [30].
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Choice of agent — Of the drugs that have been studied in CSU, some have the advantage of a
rapid onset of action, such as cyclosporine and tacrolimus, which can be helpful for patients with
significant impairment in quality of life or side effects from glucocorticoids. The international
guidelines emphasize cyclosporine over other agents, but the authors and editors of this topic
consider a wider range of options [1,30]. There is insufficient evidence on which to base a strong
preference for one drug over another.

Cyclosporine — Cyclosporine (and tacrolimus) has several desirable properties, including rapid
onset (sometimes within days) [33-36], a degree of efficacy comparable with prednisone [4,37],
and the possibility of lasting remission after treatment is discontinued [36,38,39]. Cyclosporine
has the most supporting data. However, cyclosporine has potentially serious adverse effects (ie,
hypertension and renal insufficiency) as well as unpleasant cosmetic effects with long-term use
(ie, hirsutism and gingival hyperplasia), although these are less common at the doses used for
CSU, which are significantly lower than the doses used for most other indications [40].
Cyclosporine should be avoided in patients with chronic kidney disease or poorly controlled
hypertension.

Calcineurin inhibitors block the calcium-dependent release of and responsiveness to histamine,

leukotriene C4, and other mediators in mast cells and several cell types [41]. These agents also
have anti-T lymphocyte activity [42]. Cyclosporine may also disrupt tumor necrosis factor-alpha
activity and secondarily inhibit neutrophil accumulation [43].

Efficacy — A 2018 systemic review identified 18 studies, including two randomized-

controlled trials of cyclosporine for CSU [44]. Early studies described significant improvement
with relatively high doses (5 to 6 mg per kg daily), but patients often discontinued therapy
because of adverse effects, with relapse of their urticaria [37,45]. Most subsequent studies have
used lower doses (eg, 2 to 4 mg per kg daily), as well as the strategy of starting high and
tapering down to the lowest effective dose [34,35,38,46-50]. Pediatric studies also used the
lower dose range [51].

In a representative trial, 30 patients with CSU refractory to standard doses of antihistamine were
randomized to cyclosporine (4 mg per kg daily) or placebo for four weeks [52]. Initial
nonresponders were offered open-label cyclosporine for four weeks. Eight of 19 (42 percent)
receiving cyclosporine improved, compared with none receiving placebo. In addition, 11 of 17
initial nonresponders responded after an additional four weeks of open-label treatment. Mild
adverse effects were common in this study (29 of 30 subjects).
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Dosing — The optimal dose of cyclosporine for CSU has not been determined. As
recommended by the authors of the aforementioned systematic review, we also suggest starting
with a dose of 3 mg per kg, divided into two doses. For most adults, this is 100 to 150 mg twice
daily. Cyclosporine is available in modified and nonmodified formulations. We prefer using
modified cyclosporine, as it exhibits increased bioavailability and less erratic absorption. Some
patients respond within one week or two, and most patients who will respond improve within
three months.

Blood pressure, blood urea nitrogen, and creatinine should be monitored monthly, and fasting
lipids should be monitored initially and yearly for patients who remain on therapy. [53]. Serum
levels may be followed to ensure that the dose is not excessive, although we do not find this
useful, because the optimal therapeutic level for CSU has not been defined, high levels are rare
with the low doses we suggest, and drug levels do not seem to correlate with effectiveness in
CSU.

Mild adverse effects include paresthesias, gastrointestinal symptoms, and headache and are
dose-related. Dose reduction may eliminate these. Severe side effects are uncommon and
should prompt discontinuation. These include hypertension and renal insufficiency. Cyclosporine
is contraindicated in patients with uncontrolled hypertension. (See "Pharmacology of
cyclosporine and tacrolimus".)

The optimal duration of therapy with cyclosporine is not known. We typically treat patients at a
dose required for complete or near-complete control of urticaria for three months and then taper
the dose over several months, as tolerated. In the majority of patients, six to nine months of
treatment is adequate, although some require long-term therapy (two or three years) at the
lowest effective dose [54].

Tacrolimus — Data in support of the use of tacrolimus in CSU are limited [55,56]. Despite this,
the author prefers tacrolimus over cyclosporine because of an apparent lower rate of
problematic side effects with it. In particular, tacrolimus does not cause the hirsutism and
gingival hyperplasia that can be seen with cyclosporine. However, like cyclosporine, it should be
avoided in patients with chronic kidney disease or poorly controlled hypertension. Baseline
laboratories including renal function are required prior to starting calcineurin inhibitors.

We start tacrolimus at a dose of 1 mg twice daily for one to two weeks and then increase by 1 to
2 mg increments every few weeks, up to a maximum of 3 mg twice daily. In our experience, most

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patients respond to doses ≤4 mg daily of tacrolimus. Higher doses with monitoring of drug levels
can be used in patients who partially respond or have no response to lower doses. Similar to
cyclosporine, monitoring of renal function is recommended to avoid renal toxicity [57-62].

The largest study of tacrolimus was a retrospective review of 36 patients treated with 45 distinct
courses [56]. Remission (ie, no urticaria for >1 month after treatment was discontinued, with no
need for other medications) occurred in 25 percent of courses, complete response occurred (no
symptoms >1 month while on tacrolimus) in 30 percent of courses, and partial response was
seen in 23 percent of courses. An additional 23 percent of courses had no improvement with
tacrolimus. The mean length of therapy was 9.2 months. Therapy was generally well-tolerated,
with gastrointestinal symptoms in eight patients, mild hypertension in three patients and
reversible elevations in serum creatinine in four patients.

Mycophenolate — Mycophenolate mofetil acts as an antimetabolite selectively for lymphocytes

and also impairs expression of adhesion molecules and secondary leukocyte migration [63].
Although unrelated to the calcineurin inhibitors, mycophenolate has some of the same properties
with fewer reported adverse effects. However, it works more gradually than the calcineurin
inhibitors, and it is rare to see an effect within days.

Mycophenolate mofetil is typically started at 1000 mg twice daily and may be increased by 500
mg twice daily at monthly intervals if needed, up to a maximal dose of 2000 mg twice daily. We
rarely exceed 4000 mg daily. If there has been no improvement after one month of 2000 mg
twice daily, we discontinue it.

It is generally well-tolerated. The most common problems are gastrointestinal symptoms and
leukopenia. Complete blood counts (CBCs) should be performed after the first one to two weeks
of therapy and then once every six to eight weeks thereafter if no cytopenias are noted. (See
"Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases".)

Very few studies are available on the use of mycophenolate in CSU:

● An open series evaluated nine patients with "severe" CSU, defined as symptoms
unresponsive over a six-week period to antihistamines and/or more than two week-long
courses of oral glucocorticoids. Patients were treated with mycophenolate (1000 mg twice
daily) for 12 weeks, without dose escalation [64]. Six patients experienced marked
improvement in urticaria scores, all patients were able to discontinue glucocorticoids by the
end of the 12-week trial, and improvement persisted for at least six months after
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discontinuation.

● In another series of 19 patients, the majority of whom failed other alternative therapies,
doses ranging from 1 to 6 grams (divided into twice daily dosing) were administered [65].
Time to initial response ranged from 1 to 9 weeks, and complete control of symptoms was
achieved in 60 percent, after a mean treatment period of 14 weeks. Subjects who tapered
off the drug subsequently had remissions lasting between 2 and 16 weeks at the conclusion
of the study. Gastrointestinal adverse effects occurred in 53 percent of subjects.

Sulfones (dapsone and sulfasalazine) — The sulfone medications dapsone and sulfasalazine
have both been studied in CSU. Dapsone is a sulfone antimicrobial agent. Sulfasalazine is an
anti-inflammatory 5-aminosalicylic acid (5-ASA) derivative. The author prefers dapsone over
sulfasalazine but prefers sulfasalazine for patients with underlying anemia. Both dapsone and
sulfasalazine can be combined with hydroxychloroquine. (See 'Combined with a sulfone' below.)

Dapsone — Dapsone may provide benefit in CSU by suppressing prostaglandin and

leukotriene activity, interfering with release or function of neutrophil lysosomal enzymes [66,67],
disrupting integrin-mediated neutrophil adhesiveness [68], inhibiting neutrophil recruitment and
activation signals [69], and scavenging oxygen-free radical intermediates [70]. Dapsone has
traditionally been thought to be helpful in cutaneous diseases in which neutrophils play a
prominent role [71]. Some cases of CSU have a neutrophil-rich infiltrate on biopsy, although
whether this histopathologic finding predicts response to dapsone in patients with CSU is
unproven.

Prior to initiating dapsone therapy, we check a CBC, liver function tests, and glucose-6-
phosphate dehydrogenase (G6PD) levels. Dapsone can cause severe hemolytic anemia in
patients with G6PD deficiency, and it is contraindicated in patients with this disorder. We also
avoid this agent if the patient is already anemic or has any abnormalities in hepatic function. The
various diagnostic tests for G6PD deficiency are discussed separately. (See "Hemolytic anemia
due to drugs and toxins" and "Diagnosis and management of glucose-6-phosphate
dehydrogenase (G6PD) deficiency", section on 'Diagnostic evaluation'.)

In adults, we start dapsone with a dose of 100 mg daily. In two weeks, we obtain a CBC and liver
function tests and repeat these monthly for three months and then less often. A 10 to 20 percent
decline in hemoglobin (1 to 2 grams/dL) or hematocrit is common, even in patients who do not
have G6PD deficiency, and we do not stop therapy unless the decrease exceeds 25 percent.
The dose can be reduced once there is a clear clinical response. A four-week trial is usually
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sufficient to determine effectiveness.

Peripheral neuropathy, clinically significant methemoglobinemia, agranulocytosis, and drug-

allergic reactions, such as drug reaction with eosinophilia and systemic symptoms/drug-induced
hypersensitivity syndrome (DRESS/DiHS), are rare but serious reactions that warrant immediate
discontinuation of dapsone [72,73]. (See "Clinical features, diagnosis, and treatment of
methemoglobinemia".)

Studies indicating that dapsone is effective for the treatment of CSU include two small,
randomized trials [74,75]. In the more rigorous trial, 22 patients with antihistamine refractory
CSU showed improvement in itch and urticaria scores in patients taking dapsone, 100 mg daily
[74]. In all responders, efficacy was apparent within the first week. Three patients had complete
resolution of CSU with dapsone [75].

A larger retrospective review included 79 patients with CSU refractory to four times the standard
dose of nonsedating antihistamines [76]. Some had additionally failed one or more other agents
(ie, glucocorticoids, omalizumab, cyclosporine, mycophenolate mofetil, leukotriene inhibitors, H2
antagonists, and/or nifedipine). Improvement was seen in 62 patients in a mean of 1.1 months,
with the mean maximal dose of 118 mg daily. In addition, 29 of these individuals had complete
resolution after a mean of 5.2 months. Dapsone was tapered down after 2 months of controlled
symptoms, and 10 patients had sustained remission, for periods up to 16 months. However, two
patients developed serious adverse effects (DRESS/DiHS and methemoglobinemia).

The optimal duration of treatment is unknown. If the patient is on sedating antihistamines or did
not respond significantly to antihistamines in the past, we taper these first, and then the dapsone
is reduced over a period of several months, as tolerated.

Sulfasalazine — We choose sulfasalazine instead of dapsone for patients with underlying

anemia and sometimes initiate therapy with the combination of sulfasalazine and
hydroxychloroquine. (See 'Combined with a sulfone' below.)

Mechanisms of action with possible relevance in CSU include alteration of adenosine release
[77], decreased leukotriene and prostaglandin synthesis, inhibition of IgE-mediated mast cell
degranulation [78], attenuation of neutrophil respiratory burst [79], and inhibition of early-phase
events in the proliferation and differentiation of B lymphocytes [80]. Sulfasalazine is metabolized
to sulfapyridine and 5-ASA within the gastrointestinal tract, and most of the 5-ASA is degraded
locally in the colon without much systemic distribution. Thus, the sulfapyridine may be largely
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responsible for its therapeutic activity in patients with CSU.

In adults, sulfasalazine therapy can be initiated with 500 mg once or twice per day for one week
and then gradually increased to 1 gram twice per day.

Overall, sulfasalazine is well-tolerated by most patients. Side effects include nausea, headache,
mild or transient leukopenia, and transaminitis. Rare reports of agranulocytosis exist. Folate
supplements should be coadministered to women who are pregnant or could potentially
conceive. Drawbacks include the advisability of gradual dose escalation, which may prolong the
time to clinical response, as well as the need for laboratory monitoring.

Laboratory monitoring with a CBC, liver function tests, and urinalysis is performed every month
for the first three months and then less often. A four- to six-week trial is usually sufficient to
determine effectiveness. British guidelines recommend monitoring with CBC, blood urea
nitrogen, creatinine, electrolytes, and liver function tests monthly during the first three months
and then every three months thereafter [53]. Other guidelines suggested weekly or every other
week blood counts and transaminases during the first month. Monitoring in patients with
rheumatologic diseases is reviewed in greater detail elsewhere. (See "Sulfasalazine:
Pharmacology, administration, and adverse effects in the treatment of rheumatoid arthritis",
section on 'Dosing and monitoring'.)

Observational studies suggest that sulfasalazine is useful as an add-on to standard therapies for
patients with refractory symptoms [81-85]:

The largest study was a retrospective chart review of 39 patients with CSU refractory to
antihistamines and other therapies treated with sulfasalazine as an add-on therapy [81]. These
patients had relatively recalcitrant disease and had CSU on average for 5.5 years prior to
starting sulfasalazine, during which one-third required daily glucocorticoids and 10 percent had
received other immunomodulators (dapsone, cyclosporine, mycophenolate). Sulfasalazine
treatment was added to existing therapies starting with 500 mg daily and increased by 500 mg
per week to 2000 mg daily (and up to 3000 mg daily in 15 patients) if tolerated, and laboratories
remained normal. Using this approach, 84 percent of patients improved within three months. The
percentage becoming asymptomatic on sulfasalazine on the background of antihistamines was
32 and 51 percent by three and six months, respectively. The average duration of sulfasalazine
therapy was 74 weeks. Nine of 10 steroid-dependent patients were able to discontinue
glucocorticoids. Once the patient's symptoms were controlled, sulfasalazine was gradually

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withdrawn, while antihistamines were continued throughout in most patients and withdrawn last.
Eleven patients remained asymptomatic after sulfasalazine was discontinued, requiring only

antihistamine therapy. Five patients (16 percent) failed therapy, either due to a drug adverse
effect (one) or lack of improvement. There were two serious adverse events (neutropenia and
leukopenia and rhabdomyolysis of uncertain association), although both patients recovered fully
after the drug was discontinued.

The optimal duration of treatment is unknown. If the patient is on sedating antihistamines or did
not respond significantly to antihistamines in the past, we taper these first, and then the
sulfasalazine is reduced over a period of several months, as tolerated.

Hydroxychloroquine — Hydroxychloroquine is an anti-inflammatory drug and antimalarial

agent. The relative safety and low cost of hydroxychloroquine makes it a reasonable agent in the
treatment of refractory CSU. The major disadvantage is a relatively slow onset of action. This
can be countered by starting hydroxychloroquine in combination with dapsone or sulfasalazine.
(See 'Combined with a sulfone' below.)

Mechanisms of action include suppression of T lymphocyte activation [86] and disruption of

antigen processing and other cellular processes by alkalinization of intracellular vacuoles in
macrophages and other antigen-presenting cells [87]. Hydroxychloroquine has not been shown
to induce lasting remission [32].

In adults, we start with a dose of 200 mg twice per day. A three-month trial is usually required to
determine effectiveness. Hydroxychloroquine rarely causes serious side effects. The most
common adverse reactions are related to the gastrointestinal tract (nausea), skin (various
macular lesions), and central nervous system (headache).

Ophthalmologic problems, including corneal deposits (reversible) and retinopathy (potentially

vision threatening), are possible but rare with the low daily doses of hydroxychloroquine used in
CSU. The issue of ophthalmologic screening is reviewed separately. (See "Antimalarial drugs in
the treatment of rheumatic disease", section on 'Ocular health'.)

There are limited data on efficacy. In the best available study, 18 patients with CSU were treated
with a combination of therapies for CSU (H1 antihistamines, H2 antihistamines, glucocorticoids,
and doxepin) and randomized to receive either hydroxychloroquine (5 mg/kg daily) or no
additional drug [88]. After three months of treatment, patients in the hydroxychloroquine arm
demonstrated improved quality of life. Hydroxychloroquine was well-tolerated, and there was a
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Chronic spontaneous urticaria: Treatment of refractory symptoms

trend (not reaching significance) toward reduced medication use and urticarial activity.

Combined with a sulfone — A treatment strategy used successfully by the author to

circumvent the long latency time of hydroxychloroquine is to start either dapsone or
sulfasalazine at the same time. If the patient responds within a few weeks, the
hydroxychloroquine can be discontinued, as it was unlikely to have been responsible for the
improvement. If no benefit is apparent with dual therapy after four to six weeks, then the
hydroxychloroquine is likely responsible for the improvement, and the other agent (dapsone or
sulfasalazine) may be discontinued. This approach has not been formally studied.

RARELY USED THERAPIES

There are additional agents that have been reported to be useful in the management of CSU,
although each has significant limitations, including one or more of the following:

● High cost combined with limited evidence of benefit (eg, immune globulin)

● Limited evidence of benefit (eg, colchicine, methylxanthines, phototherapy)

● The potential for serious adverse effects (eg, methotrexate, tumor necrosis factor [TNF]-
inhibitors, cyclophosphamide, antifibrinolytics, anticoagulants, androgens)

Phototherapy — Phototherapy (eg, either psoralen plus ultraviolet A [PUVA] or narrow band
UVB and UVA) have been shown to have modest clinical benefit in CSU [89-92]. In a
randomized trial of 50 patients with CSU refractory to H1 antihistamines (escalated to fourfold
the standard dose for at least three months) and requiring repeated courses of oral
glucocorticoids, subjects received either PUVA or narrow band UVB for 90 days [93]. There was
no placebo group. Subjects in both treatment groups had statistically and clinically significant
improvement, with greater improvement in the UVB group, and the authors noted that most
responders had continued benefit for up to one year. However, very few patients had complete
control of hives, and adverse effects included tanning and xerosis of the skin. In addition, the
mean IgE was quite high in this population of patients from India (403 to 721 international
units/mL), raising questions regarding the generalizability of the findings.

Phototherapy is a reasonable option for patients able to commit to frequent visits or for those
intolerant to systemic medications. Skin that is directly irradiated improves most dramatically,
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Chronic spontaneous urticaria: Treatment of refractory symptoms

suggesting local mediators and cells as primary targets. Histamine release from mast cells may
also be reduced [94]. It has also been used in the management of solar urticaria and other

physical urticarias. Phototherapy and its longer-term adverse effects are discussed in greater
detail separately. (See "Psoralen plus ultraviolet A (PUVA) photochemotherapy" and "Physical
(inducible) forms of urticaria", section on 'Solar urticaria'.)

Others — There are several other agents with weak evidence of efficacy in CSU.

● Sirolimus (rapamycin) was reported to be effective in two of three patients in a case report
[95]. The patients had previously failed multiple alternative therapies, including montelukast,
dapsone, hydroxychloroquine, colchicine, olsalazine, and mycophenolate mofetil.

● Immune globulin (given intravenously or subcutaneously) may be an option in patients in

whom an immunomodulator would be preferable to an immunosuppressive agent, such as
those with a history of malignancy. It is an immunomodulatory agent that alters cell
adhesion, immunoregulatory molecules, complement function, cytokine levels, autoantibody
production, and anti-idiotypic networks [96]. Dosing has varied in past trials. The optimal
dose, number of infusions to administer, and schedule for CSU are unknown and have
ranged from a single dose of 2 grams per kg to 0.15 grams per kg, given monthly [97-104].
Similar to omalizumab, barriers to use include expense, approval by insurance carriers, and
inconvenience. (See "Overview of intravenous immune globulin (IVIG) therapy" and
"Intravenous immune globulin: Adverse effects".)

● Tumor necrosis factor (TNF)-inhibitors, including etanercept, adalimumab, and infliximab,

have been studied in the treatment of CSU because TNF-alpha has been shown to be
upregulated in the epidermis in lesional and nonlesional skin of CSU patients relative to
controls [105]. We would consider TNF-inhibitors in patients who have failed omalizumab,
calcineurin inhibitors, and anti-inflammatory agents. Reports of effectiveness are limited
[106,107]. In the largest series, 25 patients with CSU refractory to omalizumab,
cyclosporine, prednisone, and azathioprine were treated with adalimumab or etanercept for
3 to 35 months, with responses in 10 of 17 and 5 of 8, respectively [107]. Sixty percent
obtained complete or near-complete control of symptoms. One patient experienced a
severe adverse effect (polyneuropathy).

Optimal dosing of TNF-inhibitors for CSU is unknown, but doses similar to those for other
cutaneous diseases have been used. As with omalizumab, barriers to use include expense
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Chronic spontaneous urticaria: Treatment of refractory symptoms
and inconvenience. TNF-inhibitors have several adverse effects, including injection-site or
infusion-related reactions, infectious complications, and others. (See "Tumor necrosis
factor-alpha inhibitors: An overview of adverse effects".)
● Methotrexate reduces neutrophil accumulation in inflamed skin [108], diminishes activated
leukocyte adhesiveness and other adenosine-mediated anti-inflammatory properties [109],
decreases leukotriene synthesis [110], and alters cytokine activity [111]. Adverse effects can
be serious, and frequent monitoring is advised. These issues are reviewed elsewhere. (See
"Major side effects of low-dose methotrexate".)

Evidence of efficacy in CSU is limited to case reports and small series [112-117]. The doses
of methotrexate required ranged from 5 to 25 mg/week. Effects were typically observed after
four weeks of therapy. The authors do not state whether patients could be removed from
therapy. Negative studies also exist [103].

● Colchicine may act to relieve CSU by suppressing leukotriene generation or by decreasing

leukocyte adhesiveness and migration, but our clinical experience with it has been
disappointing [118,119]. It has a favorable safety profile at recommended doses, minimal
requirements for monitoring, and a generally rapid onset of action. However, evidence of
benefit in patients with CSU is limited to anecdotal reports and retrospective series [120-
122]. The single available randomized-controlled trial evaluated 12 patients with delayed-
pressure urticaria and failed to demonstrate any effect compared with placebo [123].

● Cyclophosphamide has generally been reserved for patients in whom multiple other
alternative agents have failed. It is believed to act on plasma cells to reduce autoantibody
production in autoimmune CSU [124]. Evidence of efficacy is limited to case reports of
patients with positive autologous serum skin tests who had failed multiple other therapies,
including cyclosporine [125-127]. In one report, improvement began four weeks into the
initial infusions and continued to complete resolution by six months [125]. The patient
continued to be asymptomatic 12 months after the last infusion. Cyclophosphamide use is
limited by expense, inconvenience, need for monitoring, and risk of serious adverse effects
(including delayed secondary neoplasia and hemorrhagic cystitis).

● Several anticoagulants and antifibrinolytic agents have been studied in CSU because the
inflammatory pathways believed relevant to urticaria/angioedema are interconnected with
pathways of coagulation and fibrinolysis [128,129]. Agents acting on different points in these
pathways theoretically shunt mediators along altered routes and reduce prourticarial factors.

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Chronic spontaneous urticaria: Treatment of refractory symptoms
Antifibrinolytic agents (aprotinin and tranexamic acid) have long been used to treat
disorders of angioedema, and their utility in some patients with CSU was first noted in the
1970s [130-133]. The anticoagulants warfarin and heparin were also studied in CSU
[129,134-140]. However, the risks of these agents generally outweigh the potential benefits.

● Methylxanthines have also been used to treat CSU [141,142]. A double-blind, placebo-
controlled study of 134 CSU patients evaluated theophylline 200 mg twice daily for six
months followed by 200 mg once daily for six months, as add-on therapy to cetirizine [142].
Both groups experienced large improvements in all symptoms assessed, and the
theophylline group had statistically significant improvement in overall urticaria scores.
However, pruritus did not improve.

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Urticaria and
angioedema (excluding hereditary angioedema)".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade
reading level, and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and who prefer
short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more
sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading
level and are best for patients who want in-depth information and are comfortable with some
medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print
or e-mail these topics to your patients. (You can also locate patient education articles on a
variety of subjects by searching on "patient education" and the keyword(s) of interest.)

● Basics topic (see "Patient education: Chronic hives (The Basics)")

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Chronic spontaneous urticaria: Treatment of refractory symptoms

SUMMARY AND RECOMMENDATIONS

● Chronic spontaneous urticaria (CSU) is considered refractory when symptoms are not
controlled by higher-dose, nonsedating H1 antihistamines in combination with other
standard therapies (ie, additional H1 antihistamines, H2 antihistamines, and/or
antileukotriene drugs). (See "Chronic spontaneous urticaria: Standard management and
patient education".)

● Patients with refractory CSU should be referred to an allergy or dermatology specialist for
consideration of advanced therapies, rather than receiving repeated courses of oral
glucocorticoids. (See 'Referral' above.)

● With the exception of omalizumab, the effectiveness of the other therapies discussed in this
review is supported by low-quality evidence, and the approach presented is largely based
on clinical experience. In addition, there are no biomarkers or clinical features that are
useful in selecting one therapy over another for a specific patient. (See 'Overview' above.)

● For patients with CSU who have significant symptoms despite maximal doses of
nonsedating H1 antihistamines in combination with other standard therapies (additional H1
antihistamines, H2 antihistamines, and/or antileukotriene drugs), we recommend adding
omalizumab therapy in preference to other agents, with the understanding that the cost of
this medication may be prohibitive in many settings (Grade 1A). We initiate omalizumab at
a dose of 300 mg injected subcutaneously every four weeks. (See 'Omalizumab' above.)

● For patients who have not achieved adequate relief with the combination of higher-dose H1
antihistamines and omalizumab or do not have access to omalizumab, we suggest a
calcineurin inhibitor (ie, cyclosporine or tacrolimus) (Grade 2C). We start cyclosporine at a
dose of 3 mg per kg, divided into two doses daily and tacrolimus at 1 mg twice per day.
Blood pressure, blood urea nitrogen, and creatinine should be monitored. (See
'Cyclosporine' above and 'Tacrolimus' above.)

● Other generally well-tolerated therapies include mycophenolate, dapsone, sulfasalazine,

and hydroxychloroquine. (See 'Other therapies' above.)

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