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7/22/2019 Chronic Urticaria Treatment of Refractory Symptoms
Chronic urticaria: Treatment of refractory symptoms
Last literature review version 18.2: May 2010 | This topic last updated:
May 21, 2010
INTRODUCTION — Chronic urticaria (CU) is defined by the presence of urticaria
(hives) on most days of the week, for a duration of longer than six weeks.
Associated angioedema occurs in about 40 percent of patients. Standardmanagement of CU primarily involves H1 antihistamines, often with a short course
of glucocorticoids to control severe exacerbations. Leukotriene modifiers and H2
antihistamines are commonly used adjunctive therapies. (See "Chronic urticaria:
Standard management and patient education".)
Patients whose symptoms are not controlled over time using with these standard
therapy may receive repeated courses of glucocorticoids, or extended periods of
glucocorticoids exposure (ie, months of treatment). In this situation, the clinician
should consider other antiinflammatory, immunomodulatory, or immunosuppressant
agents, as the risks of long-term glucocorticoid therapy are well known. In addition,glucocorticoids are not believed to induce lasting remission or alter the natural
history of CU, while some of the agents discussed in this topic review may have
these properties. (See "Major side effects of systemic glucocorticoids".)
There is no standardized approach to the management of refractory CU, and
therapy must be individualized. The decision to use a certain medication should be
based upon an assessment of risk versus benefit for that specific patient, taking
into account concomitant medical conditions and patient preferences. Typically, the
antihistamines and other standard agents that were clearly helpful to the patient
are continued while these more advanced treatments are tried. Any medications of uncertain benefit should be discontinued, so that medications do not accumulate.
Therapeutic options for patients with refractory CU, as well as the evidence in
support of the efficacy of each treatment, will be reviewed here. Standard
management, as well as the diagnosis, pathogenesis, and prognosis of chronic
urticaria, are reviewed separately. (See "Chronic urticaria: Standard management
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and patient education" and "Chronic urticaria: Diagnosis, theories of pathogenesis,
and natural history".)
TERMINOLOGY — In this review, the term CU refers to patients with isolated
chronic idiopathic urticaria, as well as those with both urticaria and angioedema.
Disorders involving isolated angioedema, urticarial vasculitis, and specific physical
forms of CU (such as delayed pressure urticaria, cholinergic urticaria, or coldurticaria) are discussed separately. (See "An overview of angioedema: Pathogenesis
and causes" and "Urticarial vasculitis" and "Physical urticarias" and "Cold
urticaria".)
Chronic autoimmune urticaria — In the discussion below, the terms chronic
urticaria and chronic idiopathic urticaria are used synonymously. Some studies
distinguish between patients with and without positive autologous serum skin tests
(ASST) or other laboratory indicators of an autoimmune process. This distinction is
mentioned in the text only if a study found a difference between these two patient
groups. The interpretation of a positive ASST in patients with CU is reviewedelsewhere. (See "Chronic urticaria: Diagnosis, theories of pathogenesis, and natural
history", section on 'Autoimmune theory'.)
ANTIINFLAMMATORY AGENTS
Agents — Antiinflammatory agents that have been studied in the treatment of CU
include dapsone, sulfasalazine, and hydroxychloroquine.
Dapsone — Dapsone is a sulfone antimicrobial agent. In CU, it may act by
suppressing prostaglandin and leukotriene activity, interfering with release or
function of neutrophil lysosomal enzymes [1,2], disrupting integrin-mediated
neutrophil adhesiveness [3], inhibiting neutrophil recruitment and activation signals
[4], and scavenging oxygen free radical intermediates [5]. Dapsone has
traditionally been thought to be helpful in cutaneous diseases in which neutrophils
play a prominent role [6]. Some cases of CU have a neutrophil-rich infiltrate on
biopsy, although whether this histopathologic finding predicts response to dapsone
in patients with CU is unproven. Studies of dapsone for the treatment CU include
the following:
A case series of 11 CU patients, refractory to antihistamines alone, reported
clinical improvement in nine subjects within several weeks (ultimately allowing
discontinuation of cetirizine therapy) with a low dose of dapsone (25 mg daily) [7].
In the two remaining patients, the dose was increased to 50 mg daily, which
resulted in a complete response in one subject and partial response in the other.
Seven patients had remission lasting variable periods of time after stopping use of
the drug. We have also observed sustained remission in >50 percent of dapsone
responders in our own practice.
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Preliminary, unpublished results from a randomized, crossover study performed
at the author's center showed improvement in 15 of 22 CU patients taking
dapsone, 100 mg daily [8]. Improvement was evident within days in some patients,
whereas others required several weeks.
Dapsone is generally well tolerated, widely available, and inexpensive. However, it
can cause severe hemolytic anemia in patients with glucose-6-phosphate
dehydrogenase (G6PD) deficiency. Therefore, it is our practice to test for G6PD
deficiency before initiating treatment. The various diagnostic tests for G6PD
deficiency are discussed separately. (See "Extrinsic nonautoimmune hemolytic
anemia due to drugs and toxins" and "Diagnosis and treatment of glucose-
6-phosphate dehydrogenase deficiency", section on 'Diagnosis'.)
Dapsone usually causes a small decline in hemoglobin (1 to 2 grams/dL), even in
patients who do not have G6PD deficiency. We follow complete blood counts (CBC)
monthly for the first three months of therapy and then every two to three months
thereafter. We also follow liver function tests because hepatotoxicity is another
uncommon side effect. Peripheral neuropathy, methemoglobinemia, and drug
allergic reactions, such as the drug rash with eosinophilia and systemic symptoms
(DRESS) are rare, but serious reactions that warrant immediate discontinuation of
dapsone [9,10]. (See "Clinical features, diagnosis, and treatment of
methemoglobinemia".)
Sulfasalazine — Sulfasalazine is an antiinflammatory 5-aminosalicylic acid
(5-ASA) derivative. Mechanisms of action with possible relevance in CU include
alteration of adenosine release [11], decreased leukotriene and prostaglandin
synthesis, inhibition of IgE-mediated mast cell degranulation [12], attenuation of neutrophil respiratory burst [13], and inhibition of early-phase events in the
proliferation and differentiation of B-lymphocytes [14]. 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 responsible for its therapeutic activity in patients with
CU.
Limited data are available about the efficacy of sulfasalazine in CU:
In the largest observational series, 19 patients with CU were treated withsulfasalazine and 14 experienced significant improvement, with four others showing
modest benefit and one worsening [15]. Several patients were able to stop taking
other medications, including glucocorticoids. Doses were increased in a stepwise
fashion and response occurred within one month, although doses above 2 g daily
had no additional clinical benefit in this group. Some patients experienced lasting
remission after cessation of therapy.
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Other case reports successfully used doses between 2 and 3 grams daily
[16,17]. Sustained remission was not described.
Treatment failures are also reported [18].
Overall, sulfasalazine is well tolerated by most patients. Side effects include
nausea, headache, mild or transient leukopenia, and transaminitis. Drawbacksinclude the advisability of gradual dose escalation, which may prolong the time to
clinical response, as well as the need for laboratory monitoring. British guidelines
recommend monitoring with CBC, blood urea nitrogen, creatinine, electrolytes, and
liver function tests monthly during the first three months, then every three months
thereafter [19]. Folate supplements should be co-administered to women who are
pregnant or could potentially conceive.
Hydroxychloroquine — Hydroxychloroquine is an antiinflammatory drug and
antimalarial agent. The relative safety and low cost of hydroxychloroquine make it a
reasonable agent in the treatment of refractory CU. The major disadvantage is arelatively slow onset of action. Mechanisms of action include suppression of
T-lymphocyte activation [20] and disruption of antigen processing and other cellular
processes by alkalinization of intracellular vacuoles in macrophages and other
antigen presenting cells [21].
In the best available study, 18 patients with CU were treated with a combination
of therapies for CU (H1 antihistamines, H2 antihistamines, glucocorticoids, and
doxepin) and randomized to receive either hydroxychloroquine (5 mg/kg daily) or
no additional drug [22]. After three months of treatment, patients in the
hydroxychloroquine arm demonstrated improved quality of life. Hydroxychloroquinewas well tolerated and there was a trend toward reduced medication use and
urticarial activity that did not reach significance.
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 used in CU. Opinion
suggests routine ophthalmologic monitoring is not required for patients taking
hydroxychloroquine at lower doses [23], and regular monitoring is not necessaryfor a therapeutic trial in patients with CU. Therefore, we obtain at least a baseline
ophthalmologic examination in patients who show signs of response and are likely
to remain on the agent for some time.
Role in stepwise therapy — The management of refractory CU is not
standardized, as mentioned previously, and published guidelines only list options to
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be considered [24-26]. The approach presented here is that of the author and the
editors of UpToDate.
For patients whose symptoms are resistant to a regimen of H1 antihistamines and
one or more of the other therapies discussed in the standard management topic
review, and are requiring frequent or daily glucocorticoids, we suggest the addition
of an antiinflammatory agent, specifically dapsone, sulfasalazine, orhydroxychloroquine. Any medications that did not appear to be helpful to the
patient should be discontinued before others are added. A baseline CBC and
chemistry panel with liver function tests should be obtained prior to initiation of
these therapies. We consider the following in choosing among these agents:
We most commonly start with dapsone, after additionally checking for G6PD
deficiency. In adults, we start 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 or hematocrit is common and
we do not stop therapy unless the decrease exceeds 25 percent. The dose can bereduced once there is a clear clinical response. A four to six week trial is usually
sufficient to determine effectiveness. (See 'Dapsone' above.)
We choose sulfasalazine instead in patients with underlying anemia or
concomitant delayed pressure urticaria. In adults, we start with a dose of 500 mg
twice a day for one week, then increase to 1 gram twice a day. 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. (See 'Sulfasalazine' above.)
We use hydroxychloroquine in patients who have suboptimal control of their CU,
but only modest impairment in quality of life, as this agent is slow to work and
patients with more severe disease may not be able to tolerate the duration of the
trial. In adults, we start with a dose of 200 mg twice a day. A three month trial is
usually required to determine effectiveness. (See 'Hydroxychloroquine' above.)
Another strategy to circumvent the long latency time of hydroxychloroquine is the
initiation of 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, the other agent (ie, dapsone or
sulfasalazine) may be discontinued and the hydroxychloroquine continued for a
total trial of 12 weeks.
We usually try two antiinflammatory agents before proceeding to
immunosuppressant or immunomodulatory agents.
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well as the strategy of starting high and tapering down to the lowest effective dose
[31-36]. This approach can achieve long-term benefit while minimizing significant
side effects.
Overall, randomized controlled trials support the effectiveness of calcineurin
inhibitors in the treatment of CU, although these studies generally involved subjects
who had failed only standard doses of antihistamines, so the severity of thesepatients' disease may have been overestimated. The following are representative
studies:
Thirty patients with "severe" disease were randomized to cyclosporine (4 mg per
kg daily) or placebo for four weeks [37]. Initial non-responders were offered
open-label cyclosporine for four weeks. Eight of 19 (42 percent) receiving
cyclosporine improved, compared to none receiving placebo. In addition, 11 of 17
initial non-responders responded after an additional four weeks of open-label
treatment. Adverse effects were common in this study (29 of 30 subjects) and
most commonly involved paresthesias, gastrointestinal symptoms, and headache.All 30 patients in this study had positive autologous serum skin tests (ASSTs), but
other studies found no correlation between ASST and cyclosporine response [38].
Another randomized trial evaluated the effects of adding cyclosporine to
cetirizine in 99 patients with CU [36]. The cyclosporine dose was 5 mg per kg daily
for the first 28 days, which was then tapered to 3 mg per kg daily. All subjects were
treated with cetirizine daily, plus either cyclosporine for 16 weeks, cyclosporine for
eight weeks followed by placebo for eight weeks, or placebo for all 16 weeks.
Symptom scores improved significantly in both groups receiving cyclosporine. Two
patients discontinued treatment because of hypertension.
Cyclosporine (5 mg per kg daily) was compared head-to-head with
prednisone (20 mg once daily) in an eight week trial of 20 patients with CU
refractory to antihistamines [39]. Nine of 10 patients receiving cyclosporine were
symptom free within five days of starting therapy, and the last patient cleared
within 15 days. Two patients suffered headache, tremors, and nausea, which
resolved with lowering the dose to 3 mg per kg daily. No patient developed
hypertension or renal function changes. Two patients had recurrent mild symptoms
three months later. In comparison, all patients receiving prednisone also became
symptom free "in a few days." One patient developed hypertension and twoexperienced weight gain. After the treatment period, four prednisone-treated
patients promptly relapsed.
A study of 54 children (9 to 16 years of age) with CU evaluated the use of
cyclosporine for refractory symptoms [40]. Of the 54, 7 children had symptoms
that were not controlled with high dose antihistamines plus alternate-day
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prednisone and required daily oral prednisone. In these seven, cyclosporine (3
mg/kg/day divided into two doses per day) was added, and attempts were made to
taper glucocorticoids. Cyclosporine levels were maintained ≤200 ng/mL to avoid
adverse effects. Hives were completely controlled in all patients. This was achieved
in one to four weeks for six subjects, and eight weeks for one. Once symptoms
were controlled for one month, cyclosporine doses were reduced every two to four
weeks and then discontinued. Four patients had relapses that again responded to
cyclosporine, but all were eventually able to discontinue all medications with
apparent remission of the disease. No children had significant side effects.
Thus, cyclosporine appears to have several desirable properties, including rapid
onset (sometimes within days) [32,34,41], a degree of efficacy comparable to
prednisone [26], and the possibility of lasting remission [35,41,42]. Some
authorities advocate the addition of cyclosporine for patients with prohibitive or
persistent glucocorticoid requirements or who develop significant glucocorticoid side
effects [43].
The optimal duration of therapy with cyclosporine is not known. Some studies
indicate that a longer duration of therapy is more likely to induce sustained benefit,
but this is not certain [44]. Blood pressure, blood urea nitrogen, and creatinine
should be monitored monthly and fasting lipids periodically [19]. Serum levels may
be followed to ensure that the dose is not excessive, although the optimal
therapeutic level for CU has not been defined. In our experience, drug levels of
calcineurin inhibitors have a poor correlation with overall effectiveness, and
therefore we do not pursue a specific target drug level.
Tacrolimus — Experience with the use of tacrolimus in CU is limited. In onecase series, 19 patients with severe CU were treated with low-dose tacrolimus [45].
Two patients discontinued tacrolimus due to side effects. At 12 weeks, 71 percent
(12 patients) had responded to a significant degree, nine of whom were able to
stop antihistamines, and three were able to stop glucocorticoids. One responder
had a lasting drug-free remission and had previously failed cyclosporine, so there
may be important differences between the calcineurin inhibitors in the treatment of
CU. The monitoring suggested with tacrolimus is similar to that with cyclosporine.
Sirolimus — Sirolimus (rapamycin) was reported to be effective in two of three
patients in a case report [46]. The patients had previously failed multiple
alternative therapies including montelukast, dapsone, hydroxychloroquine,
colchicine, olsalazine, and mycophenolate mofetil. Of note, sirolimus and the
related agent everolimus have been implicated in causing isolated angioedema
[47-50].
Mycophenolate — Mycophenolate acts as an antimetabolite selectively for
lymphocytes and also impairs expression of adhesion molecules and secondary
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leukocyte migration [51]. Although unrelated to the calcineurin inhibitors,
mycophenolate has some of the same properties with fewer reported adverse
effects. The most common problems are gastrointestinal symptoms and leukopenia.
(See "Mycophenolate mofetil: Pharmacology and adverse effects when used in the
treatment of rheumatic diseases".)
Very few studies are available on the use of mycophenolate in chronic urticaria. Anopen series evaluated nine patients with "severe" CU, 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 (1 g twice daily) for 12 weeks [52]. Six patients experienced
marked improvement in urticaria scores, and the authors noted a steroid-sparing
effect, since all patients were able to discontinue glucocorticoids by the end of the
12 week trial and improvement persisted for at least six months after
discontinuation. No adverse effects or laboratory abnormalities were reported. If
these findings are confirmed by future studies, mycophenolate would represent a
highly attractive alternative to the calcineurin inhibitors, although further data areneeded.
Use in stepwise therapy and dosing — Most patients with CU have relatively
rapid responses (within days) to immunosuppressants. However, given the inherent
variability of CU, a trial of one-month is typically adequate to determine efficacy.
The following is one approach to administering these agents to patients with CU.
Tacrolimus — We prefer tacrolimus as an initial immunosuppressant. Although
there are more data in support of cyclosporine, we prefer tacrolimus because most
of our patients are women, and cyclosporine can cause hirsutism and gingival
hyperplasia. Anecdotally, we have observed more frequent problematic side effects
with cyclosporine than tacrolimus. 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 week, and increase to 2 mg twice daily if no therapeutic
benefit is seen within one to two weeks.
In our experience, most patients will respond to doses ≤4 mg daily of tacrolimus.
Higher doses can be used in patients who partially respond or have no response to
lower doses and monitoring of tacrolimus levels and renal function is recommended
to avoid renal toxicity. (See 'Tacrolimus' above.)
Cyclosporine — Cyclosporine may be started at 100 mg twice daily and
increased to 5 mg per kg daily, given in divided doses. (See 'Cyclosporine' above.)
Certain patients appear to respond better to either tacrolimus or cyclosporine,
although if one of these agents has not helped, we generally try
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several more positive reports in patients with various types of refractory CU,
including other physical urticarias and urticarial vasculitis, as well as patients with
both positive and negative ASSTs [54-59]. Whether omalizumab has any disease
modifying effects remains unclear. (See "Anti-IgE therapy".)
A single-blind, controlled trial of 12 patients with CU with autologous antibodies
involved a four-week placebo phase followed by omalizumab every two or fourweeks for 16 weeks [55]. Seven patients had complete resolution, four had partial
improvement, and one had no response.
Expense, approval by third party payers, and inconvenience remain barriers to
widespread application. However, patients with CU and concomitant asthma would
be candidates for omalizumab.
Immune globulin — Immune globulin is an immunomodulatory agent that alters
autoantibody production, and anti-idiotypic networks [60]. It can be administered
intravenously (IVIG) or subcutaneously (SCIG), although the higher doses used insome studies of CU can only be administered intravenously. Adverse effects are
generally predictable and manageable. Similar to omalizumab, barriers to use
include expense, approval by insurance carriers, and inconvenience. (See "General
principles in the use of immune globulin" and "Intravenous immune globulin:
Adverse effects".)
Success in CU was first reported in an open trial of 10 patients who were treated
with five days of IVIG (0.4 grams per kilogram per day) [61]. All had positive
autologous serum skin test (ASST) and basophil histamine-release test results and
many had failed glucocorticoids and various other agents. Responses occurredwithin days, ranged from modest transient benefit to complete and lasting
remission. The three patients who exhibited complete remission (one after a second
course) were symptom-free at least three years after the last course of IVIG.
IVIG may be dosed in a several ways, and the optimal dose, number of infusions to
administer, and schedule are unknown [62-68]:
The lowest dose described was 0.15 grams per kg, given once every four weeks,
in 29 patients [63]. Treatment duration ranged from 6 to 51 months. Twenty-six
patients improved, including 19 who experienced complete remission.
Another patient was treated with a 10-fold higher (2 grams per kg), infused
once, and responded within 48 hours with improvement that lasted seven months
[64]. However, repeating the infusion produced only moderate benefit that failed to
persist.
In two other reports representing a total of four patients, five-day infusions
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resulted in two complete responses, one partial benefit, and one failure [65,66].
Other failures have also been reported [67,68].
Colchicine — Colchicine may act to relieve CU by suppressing leukotriene
generation or by decreasing leukocyte adhesiveness and migration [69,70].
However, evidence for effectiveness is lacking. Despite this, colchicine has afavorable safety profile at recommended doses, minimal requirements for
monitoring, low cost, and a generally rapid onset of action.
The single available randomized controlled trial evaluated 12 patients with delayed
pressure urticaria, and failed to demonstrate any effect compared to placebo [71].
Evidence of benefit in patients with chronic idiopathic urticaria is limited to
anecdotal reports [72,73]. Our clinical experience with colchicine in CU has been
disappointing in that only a small number of patients seem to respond.
Androgens — Androgens, which are effective in the treatment of hereditary
angioedema, have been studied in chronic idiopathic urticaria and angioedema[74,75]. A randomized trial of 58 patients with CU refractory to cetirizine compared
stanozolol, 2 mg twice daily, with placebo over a 12-week period [75]. The
stanozolol group had a greater clinical response with respect to frequency of
marked improvement (65 percent versus 29 percent) and mean reduction in clinical
scores. Short-term adverse effects were reported as "infrequent," with two patients
having transient elevations in transaminases that normalized without treatment
cessation. This study was criticized because both treatment groups showed
continued reduction in urticarial activity that had not plateaued by the end of the
study.
The long-term adverse effects of androgens include hypercholesterolemia,
hypertension, acne, mood disorders, and transaminitis, and monitoring is
recommended. Although androgens may compare favorably with glucocorticoids in
many patients, these side effects limit their use in children, women, and some
men. (See "Prevention of attacks in hereditary angioedema", section on 'Attenuated
androgens'.)
Methotrexate — Methotrexate reduces neutrophil accumulation in inflamed skin
[76], diminishes activated leukocyte adhesiveness and other adenosine-mediated
antiinflammatory properties [77], decreases leukotriene synthesis [78], and alterscytokine activity [79]. 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 CU is limited to case reports and small series [80-83], and
negative studies also exist [67]. To our knowledge, the largest series described
seven patients with CU, all of whom improved within one to two weeks of starting
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methotrexate therapy [82]. The authors did not comment on whether drug-free
remission was seen, but the drug was well tolerated.
Cyclophosphamide — Cyclophosphamide has generally been reserved for patients
in whom multiple other alternative agents have failed. It is believed to act on
plasma cell to reduce autoantibody production in autoimmune CU [84]. Evidence of
efficacy is limited to case reports of patients with positive ASSTs who had failedmultiple other therapies, including cyclosporine [85-87]. In one report,
improvement began four weeks into the initial infusions and continued to complete
resolution by six months [85]. 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).
Antifibrinolytics and anticoagulants — The inflammatory pathways believed
relevant to urticaria/angioedema are interconnected with pathways of coagulationand fibrinolysis [53]. Agents acting on different points in these pathways
theoretically shunt mediators along altered routes and reduce pro-urticarial factors.
Antifibrinolytic agents (aprotinin and tranexamic acid) have long been used to treat
disorders of angioedema, and their use in chronic urticaria was evaluated in the
1970s [88-90]. The anticoagulants warfarin and heparin were also studied in CU
[91-96]. However, the risks of these agents generally outweigh the potential
benefits.
Methylxanthines — The use of methylxanthines to treat CU has also been
considered [97,98]. A double-blind, placebo-controlled study of 134 CU patients
evaluated theophylline 200 mg twice a day for six months followed by 200 mg once
a day for six months, compared to placebo, as add-on therapy to cetirizine [98].
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.
Non-drug therapies — Non-drug treatments that have been studied in CU include
phototherapy, autohemotherapy, and plasmapheresis.
Phototherapy — Phototherapy has been administered to patients with CU[99,100], although it has been applied more often to the treatment of solar
urticaria and other physical urticarias. 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, suggesting
local mediators and cells as primary targets. Histamine release from mast cells may
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A small randomized trial of 19 patients with CU compared two forms of
phototherapy (PUVA and UV-A) and found that both modalities provided modest
clinical benefit [100]. Phototherapy is discussed in greater detail separately. (See
"Physical urticarias", section on 'Solar urticaria'.)
Autohemotherapy — Autohemotherapy involves parenteral injection of
autologous blood in an attempt to desensitize patients to pro-urticarial factors in
the patient's own serum. An initial report of this was promising [102]. Following
that report, a single-blind placebo-controlled trial of 56 patients randomized to
weekly subcutaneous injections of either autologous, whole, untreated blood, (2.5
mL the first week and 5 mL thereafter), or isotonic sodium chloride solution for
eight weeks [103]. Patients with ASST positivity experienced some reduction in
urticarial lesions, decreased antihistamine use, and improved quality of life,
although the differences were not statistically significant. The ASST-negative
patients did not have appreciable benefit. We do not use this treatment.
Plasmapheresis — Plasmapheresis removes a variety of proteins and other
substances from plasma, and may have immunomodulatory effects through one of
several mechanisms [104,105]. One study described eight patients with severe CU
who underwent plasmapheresis. Two had complete resolution, two improved, and
two did not change [106].
SUMMARY AND RECOMMENDATIONS
CU should be considered refractory when symptoms are not controlled byantihistamines in combination with other standard therapies. (See "Chronic
urticaria: Standard management and patient education".)
Patients who require frequent and repeated courses of oral glucocorticoids, or
extended periods of glucocorticoid treatment (ie, months at a time) are candidates
for the other therapies presented in this review. The most effective combination of
antihistamines and the lowest possible dose of glucocorticoids for that patient
should be continued while trials of other agents are conducted. (See
'Introduction' above.)
There is no standardized approach to the management of severe refractorychronic urticaria (CU), and therapy must be individualized. The effectiveness of the
therapies discussed in this review is supported by low quality evidence in all cases.
For patients without evidence of steroid toxicity, we suggest antiinflammatory
agents (ie, dapsone, sulfasalazine, or hydroxychloroquine) in preference of other
drugs as an initial intervention (Grade 2C). We usually begin with dapsone, after
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