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Chronic urticaria: Treatment of refractory symptoms
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Chronic urticaria: Treatment of refractory symptoms
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Nov 2016. | This topic last updated: Aug 28, 2014.

INTRODUCTION — Chronic urticaria (CU) or chronic spontaneous urticaria 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.

Standard management of CU primarily involves H1 antihistamines, sometimes at higher than usual doses and in combination with H2 antihistamines and leukotriene modifiers or other adjunctive agents. 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 CU 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 CU, are reviewed separately. (See "Chronic urticaria: Standard management and patient education" and "Chronic urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history".)

DEFINITION OF CHRONIC URTICARIA — In this review, the term "chronic urticaria" (CU) refers to patients with chronic idiopathic urticaria, also called chronic spontaneous urticaria, with or without intermittent angioedema. Disorders involving isolated angioedema, urticarial vasculitis, and specific physical forms of CU, such as delayed pressure urticaria, cholinergic urticaria, or cold urticaria, are discussed separately. (See "An overview of angioedema: Pathogenesis and causes" and "Urticarial vasculitis" and "Physical urticarias" and "Cold urticaria".)

The terms "chronic urticaria" and "chronic idiopathic urticaria" are used synonymously in this discussion. Some studies distinguish between patients with and without positive autologous serum skin tests (ASSTs) 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 reviewed elsewhere. (See "Chronic urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history", section on 'Autoimmune theory'.)

OVERVIEW — Patients whose symptoms are not controlled over time using standard therapy may receive repeated courses of glucocorticoids, or have extended periods of glucocorticoids exposure (eg, months of treatment). However, long-term oral glucocorticoids have potentially severe side effects and do not appear to induce lasting remission or alter the natural history of the disorder. Thus, it is preferable to use oral glucocorticoids for short periods and at the minimally effective dose necessary to achieve control, and to consider other treatment options before the patient has been exposed to months of glucocorticoid therapy. (See "Major side effects of systemic glucocorticoids".)

The options for refractory chronic urticaria (CU) include omalizumab, as well as several drugs that have either antiinflammatory or immunosuppressant effects. There is no standardized approach to the management of refractory CU, and published guidelines only list options to be considered [1-3]. Therefore, the approach of the author, which is based on clinical experience, is presented here to provide additional guidance, although 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.

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.

Terminology — In this discussion, omalizumab is considered separately, and the other agents are divided into two groups: "antiinflammatory" agents and "immunosuppressant" agents, although there is considerable overlap between the latter two groups of drugs.

"Antiinflammatory" denotes a class of agents with predominantly antiinflammatory activities, which have low potential toxicity and less proven efficacy for CU. We have applied this term to dapsone, sulfasalazine, and hydroxychloroquine.

The term "immunosuppressant" is applied to drugs that have more potent immune suppression activity and greater potential toxicity, as well as more evidence for efficacy. We have categorized the calcineurin inhibitors, sirolimus, and mycophenolate mofetil in this way.

Goal of therapy — The goal of therapy in patients with refractory CU 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 CU 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 CU is reviewed separately. (See "Chronic urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history", section on 'Natural history and prognosis'.)

Choice of initial intervention — Omalizumab, a monoclonal antibody against immunoglobulin E (IgE), was approved for CU refractory to H1 antihistamines by the US Food and Drug Administration (FDA) in 2014. However, the high cost of omalizumab is a concern in all healthcare systems and will limit the use of this therapy in many settings. (See 'Omalizumab' below.)

Since most patients have received extended courses of glucocorticoids by the time the treatments discussed in this topic review are considered, our approach has been to stratify patients by the presence or absence of glucocorticoid toxicity (eg, significant weight gain, hypertension, gastritis, hyperglycemia, etc) (table 1). This approach is based largely on expert opinion, because studies comparing these agents with each other are lacking and guidelines for CU have not yet incorporated omalizumab.

For patients without glucocorticoid toxicity, we begin with either omalizumab or one of the antiinflammatory agents (dapsone, sulfasalazine, or hydroxychloroquine). Omalizumab is safe and effective for most patients, but it is very costly, requires regular visits to a clinic for administration, and does not appear to induce lasting remission. In addition, in the United States, there is usually an initial delay in therapy as the necessary administrative work is completed.

The antiinflammatory agents, on the other hand, may have long-term disease modifying effects, are less expensive, and do not require visits to a clinic for administration (they are all oral medications). However, they are less reliably effective, may have a slower onset of action, and have side effects in some patients (albeit a minority).

For patients who already display evidence of glucocorticoid toxicity, there is a more urgent need to control symptoms so that glucocorticoids can be reduced or discontinued. For this group, we suggest either omalizumab or an immunosuppressant agent (in preference to an antiinflammatory drug), as these therapies produce a more rapid effect and appear to be more reliably effective (although comparative studies are lacking).

It is important for treating clinicians to be knowledgeable about potential adverse effects and monitoring when administering the antiinflammatory and immunosuppressant agents discussed in this topic. Consultation with other specialists (eg, dermatologists, rheumatologists) may be appropriate depending on the medication, as well as the experience and comfort level of the treating clinician.

ANTIINFLAMMATORY AGENTS — The antiinflammatory agents that are best studied in chronic urticaria (CU) are dapsone, sulfasalazine, and hydroxychloroquine.

Treatment strategies — Any standard CU therapies that did not appear to be helpful to the patient should be discontinued before antiinflammatory agents are added. A baseline complete blood count (CBC) and chemistry panel with liver function tests should be obtained prior to initiation of any of these therapies. We consider the following in choosing among these agents:

We most commonly start with dapsone, after additionally checking for glucose-6-phosphate dehydrogenase (G6PD) deficiency. Efficacy, dosing, and adverse effects are reviewed below. (See 'Dapsone' below.)

We choose sulfasalazine instead for patients with underlying anemia. Efficacy, dosing, and adverse effects are discussed below. (See 'Sulfasalazine' below.)

We choose hydroxychloroquine for patients with uncontrolled CU, but only modest impairment in quality of life, as this agent is slow to work and patients with more severe impairment may not be able to tolerate the duration of the trial. Efficacy, dosing, and adverse effects are reviewed below. (See 'Hydroxychloroquine' below.)

A strategy 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, the other agent (dapsone or sulfasalazine) may be discontinued and the hydroxychloroquine continued for a total trial of 12 weeks.

Agents

Dapsone — Dapsone is a sulfone antimicrobial agent, which is generally well tolerated, widely available, and inexpensive. The author prefers this agent over sulfasalazine and hydroxychloroquine, or sometimes uses the combination of dapsone and hydroxychloroquine, as mentioned above. (See 'Treatment strategies' above.)

In CU, dapsone may act by suppressing prostaglandin and leukotriene activity, interfering with release or function of neutrophil lysosomal enzymes [4,5], disrupting integrin-mediated neutrophil adhesiveness [6], inhibiting neutrophil recruitment and activation signals [7], and scavenging oxygen-free radical intermediates [8]. Dapsone has traditionally been thought to be helpful in cutaneous diseases in which neutrophils play a prominent role [9]. 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 of 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) [10]. 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.

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 [11]. Improvement was evident within days in some patients, whereas others required several weeks.

Prior to initiating dapsone therapy, we check a CBC and liver function tests, because we do not use this agent in a patient with anemia or abnormal liver function. Dapsone can also cause severe hemolytic anemia in patients with G6PD deficiency, so we test for G6PD deficiency before initiating treatment. The various diagnostic tests for G6PD deficiency are discussed separately. (See "Hemolytic anemia due to drugs and toxins".)

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 (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- to six-week trial is usually sufficient to determine effectiveness. Efficacy and adverse effects are reviewed below.

Peripheral neuropathy, clinically significant methemoglobinemia, agranulocytosis, 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 [12,13]. (See "Clinical features, diagnosis, and treatment of methemoglobinemia".)

Sulfasalazine — Sulfasalazine is an antiinflammatory 5-aminosalicylic acid (5-ASA) derivative. We choose sulfasalazine instead of dapsone for patients with underlying anemia, and sometimes initiate therapy with the combination of sulfasalazine and hydroxychloroquine, as described above. (See 'Treatment strategies' above.)

Mechanisms of action with possible relevance in CU include alteration of adenosine release [14], decreased leukotriene and prostaglandin synthesis, inhibition of immunoglobulin E (IgE)-mediated mast cell degranulation [15], attenuation of neutrophil respiratory burst [16], and inhibition of early-phase events in the proliferation and differentiation of B lymphocytes [17]. 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.

Randomized trials of sulfasalazine for CU have not been performed, although observational studies suggest that sulfasalazine is useful as an add-on to standard therapies for patients with refractory symptoms [18-22]. The largest study was a retrospective chart review of 31 patients with CU refractory to antihistamines and other therapies treated with sulfasalazine as an add-on therapy [18]. These patients had relatively recalcitrant disease. The average duration of CU prior to starting sulfasalazine was 5.5 years, 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 percent 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 withdrawn, while antihistamines 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 in the group (neutropenia and leukopenia, and rhabdomyolysis of uncertain association), although both patients recovered fully with drug discontinuation.

In adults, therapy can be initiated with 500 mg once or twice a day for one week, and then gradually increased to 1 gram twice a 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 co-administered 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, then every three months thereafter [23]. 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 in the treatment of rheumatoid arthritis", section on 'Dosing and monitoring'.)

Hydroxychloroquine — Hydroxychloroquine is an antiinflammatory drug and antimalarial agent. The relative safety and low cost of hydroxychloroquine makes it a reasonable agent in the treatment of refractory CU. The major disadvantage is a relatively slow onset of action. This can be countered by starting hydroxychloroquine in combination with dapsone or sulfasalazine, as mentioned previously. (See 'Treatment strategies' above.)

Mechanisms of action include suppression of T lymphocyte activation [24] and disruption of antigen processing and other cellular processes by alkalinization of intracellular vacuoles in macrophages and other antigen presenting cells [25].

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 [26]. After three months of treatment, patients in the hydroxychloroquine arm demonstrated improved quality of life. Hydroxychloroquine was well tolerated and there was a trend (not reaching significance) toward reduced medication use and urticarial activity.

In adults, we start with a dose of 200 mg twice a 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 CU. The issue of ophthalmologic screening is reviewed separately. (See "Antimalarial drugs in the treatment of rheumatic disease", section on 'Ocular health'.)

Maintenance of successful therapy — If the patient's symptoms are controlled, we usually maintain the effective dose of antiinflammatory agent while tapering and discontinuing glucocorticoids. If symptoms remain controlled on the antiinflammatory agent and antihistamines for a period of months, we then gradually begin reducing medications. If the patient is on sedating antihistamines or has not responded significantly to antihistamines, we taper these first and then the antiinflammatory is reduced over a period of several months, as tolerated. No studies have evaluated the ideal length of treatment.

OMALIZUMAB — Omalizumab, a monoclonal antibody directed against immunoglobulin E (IgE), has been shown in randomized trials to be effective for chronic urticaria (CU) [27-29]. Omalizumab was approved in the United States in 2014 for the treatment of patients 12 years of age and older with CU that is not controlled with H1 antihistamine therapy [30].

Efficacy — Efficacy was initially suggested in case reports and small series of patients with both positive and negative autologous serum skin tests (ASSTs), those with physical urticarias, and urticarial vasculitis [31-39].

Subsequent randomized trials have demonstrated efficacy of omalizumab in CU not responsive to standard doses of H1 antihistamines (eg, cetirizine 10 mg daily) [27-29,40]:

In a randomized multicenter trial, 323 patients (ages 12 to 75 years) with persistent moderate to severe CU symptoms were treated with three monthly injections of either placebo or omalizumab at doses of 75, 150, or 300 mg subcutaneously, and observed for an additional four months [29]. The primary endpoint was a change in mean weekly itch severity scores (on a scale from 0 to 21, with a minimally important difference of 5) at the end of 12 weeks. Mean itch scores decreased in all groups (-5, -6, -8, -10 points in placebo, 75, 150, and 300 mg groups, respectively). The improvement in scores was statistically significant only in the groups receiving 150 and 300 mg doses. Clinical efficacy was apparent by one week in the 300 mg group. The percentages of subjects with complete resolution of urticaria were 10, 18, 23, and 53, respectively. Following the active treatment stage of the study, subjects' symptoms gradually returned during the four months of observation, but did not reach the severity at the start of the study.

A subsequent randomized trial evaluated the effect of omalizumab (300 mg monthly) or placebo in 335 CU patients with persistent symptoms despite H1 antihistamines plus H2 antihistamines, antileukotriene agents, or both, treated for six months [40]. Subjects were permitted to receive as much as four times the standard dose of H1 antihistamines prior to beginning the trial. In the omalizumab group, 73 percent and 27 percent of subjects were receiving one to two times and three to four times standard doses, respectively. These 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 difference of 5) at the end of 12 weeks, as in the study discussed previously. Clinical efficacy was apparent by one week in the 300 mg group. Mean itch scores decreased in both the omalizumab and placebo groups (-8.6 versus -4.0), but was clinically meaningful 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. As in other trials, subjects' symptoms gradually returned during the observation period.

A smaller randomized multicenter trial included 49 patients with persistent CU [28]. All subjects had demonstrable IgE autoantibodies to thyroid peroxidase (a test not commercially available), although the role of this antibody in the pathogenesis of CU, if any, has not been demonstrated. Omalizumab was dosed according to weight and total IgE level, based upon dosing for asthma. The primary endpoint was the change in weekly urticaria activity scores (UAS7) after 24 weeks of therapy. Compared with placebo, omalizumab therapy was associated with a significantly greater reduction in UAS7 scores from baseline (-18 versus -8 points) and a significantly higher rate of complete control of CU (70 versus 5 percent).

Dosing — Two doses were approved by the US Food and Drug Administration (FDA) for CU refractory to H1 antihistamines: 150 mg or 300 mg every four weeks. Based upon the studies reviewed above, it is reasonable to start omalizumab with a dose of 300 mg every four weeks, and if the response is adequate, taper to a lower dose (eg, 150 mg every four weeks) or less frequent injections (every six weeks). An algorithm for dose individualization has been proposed [41].

Safety of omalizumab is discussed separately. (See "Anti-IgE therapy", section on 'Adverse effects'.)

Assessing response — The available data suggest that omalizumab has a rapid effect in the majority of patients [41]. Benefit is usually seen in the first month, in the author's experience. Therefore, until more data are available, we suggest the following approach:

If the patient was started at the 300 mg dose and there is no apparent effect, a second dose of 300 mg should be given in two to four weeks. If there is no response after a second dose, the patient is unlikely to respond and the drug can be discontinued.

If the patient was started at the 150 mg dose and there is no apparent effect, a second dose of 300 mg should be given in two to four weeks. If there is no response after the second higher dose, the patient is unlikely to benefit.

Some patients may have complete resolution of symptoms, and if this persists for two to three months, the dose can be lowered or the interval between injections lengthened. An algorithm for dose individualization has been proposed [41]. If a patient has no symptoms for a period of time on 150 mg every eight weeks, therapy can be withheld beyond the next doing interval to see if symptoms come back.

The optimal duration of therapy has not been determined and long-term disease modifying effects have not been demonstrated, so patients may relapse when it is discontinued [42]. We suggest that dose adjustment be individualized based upon severity of disease and duration of CU, with a more gradual step-down approach for patients with very severe or long-term CU. Patients who were treated in the past, stopped therapy, but had a subsequent recurrence of CU, have been reported to respond to omalizumab again, suggesting that resistance does not develop readily in most patients [42].

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

IMMUNOSUPPRESSANT AGENTS — In patients who are glucocorticoid dependent and already suffering from toxicity, immunosuppressants may be effective. In addition, we use immunosuppressant therapies in patients with inadequate or no response to antiinflammatory agents or omalizumab, after discontinuing those agents. (See 'Choice of initial intervention' above.)

Agents — Immunosuppressant agents used in the treatment of chronic urticaria (CU) include cyclosporine, tacrolimus, sirolimus, and mycophenolate.

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

Calcineurin inhibitors — Calcineurin inhibitors, particularly cyclosporine, have been used successfully to treat CU, and are the preferred treatment for severe symptoms according to some experts [43]. These drugs inhibit calcium-dependent release of and responsiveness to histamine, leukotriene C4, and other mediators in mast cells and other cell types [44]. These agents also have anti T lymphocyte activity [45]. Cyclosporine may also disrupt tumor necrosis factor (TNF)-alpha activity and secondarily inhibit neutrophil accumulation [46]. Tacrolimus has similar therapeutic effects.

Cyclosporine — Cyclosporine has several desirable properties, including rapid onset (sometimes within days) [47-49], a degree of efficacy comparable with prednisone [3,50], and the possibility of lasting remission [49,51,52].

The following studies provide information about efficacy of cyclosporine at different doses. 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 [53]. Mild adverse effects are frequent and dose related, and dose reduction may eliminate these. Severe side effects are uncommon, but include hypertension and renal insufficiency. (See "Pharmacology of cyclosporine and tacrolimus".)

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 [50]. 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 two experienced weight gain. After the treatment period, four prednisone-treated patients promptly relapsed. Thus, cyclosporine appeared to induce a longer lasting remission.

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 [47,48,51,54-58]. This approach can achieve long-term benefit while minimizing significant side effects.

A study of 16 children (9 to 18 years of age) with CU evaluated the use of cyclosporine for symptoms refractory to higher dose cetirizine or hydroxyzine [59]. Cyclosporine (3 mg/kg/day divided into two doses per day) was added to antihistamines. Cyclosporine levels were measured at two weeks and every four weeks after a dose increase, and maintained ≤200 ng/mL to avoid adverse effects. Hives were completely controlled in all patients, with a median time to response of seven days. Once symptoms were controlled for one to three months (depending upon how long CU had been present), cyclosporine doses were reduced every two to four weeks and then discontinued. Median duration of treatment was 5.5 months. No children had significant side effects. One-third relapsed after treatment was discontinued, and all responded to resumption of cyclosporine.

A case series described 120 patients with CU refractory to high-dose antihistamines who were treated with cyclosporine, beginning with 3 mg/kg/day for two months [57]. If the patient responded after two months, cyclosporine was tapered and discontinued during the next month and the patient was followed for relapse. Symptoms and safety measures (blood pressure and creatinine) were monitored every two months. Patients responded as follows:

17 percent did not tolerate cyclosporine due to early emergence of side effects (gastrointestinal upset, peripheral neuropathy, or headache).

15 percent had no improvement after at least one month of cyclosporine and were considered treatment failures.

25 percent had complete remission of disease and were able to stop cyclosporine after three months. They were followed thereafter and did not relapse for at least three years.

27 percent had some improvement and were able to manage their CU on antihistamines alone after finishing three months of cyclosporine.

17 percent improved, but were unable to discontinue cyclosporine, and required extended treatment with 1 to 2 mg/kg/day and antihistamines. Eight were able to stop cyclosporine after 8 to 14 months, while the other 12 continued for 5 to 10 years with no blood pressure elevation, laboratory abnormalities, or malignancies. This group provided reassuring data about long-term safety.

A small number of randomized controlled trials of cyclosporine for CU have been published, although these generally involved subjects who had failed only standard doses of antihistamines, so the severity of these patients' disease may have been overestimated. The following are representative studies:

Thirty patients were randomized to cyclosporine (4 mg per kg daily) or placebo for four weeks [60]. 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. 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), although other studies have found no correlation between ASST and cyclosporine response [61].

Another randomized trial evaluated the effects of adding cyclosporine to cetirizine in 99 patients with CU [56]. 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 8 weeks followed by placebo for 8 weeks, or placebo for all 16 weeks. Symptom scores improved significantly in both groups receiving cyclosporine. Two patients discontinued treatment because of hypertension.

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 [62], but other studies have found that the majority of patients respond within three months [57]. Blood pressure, blood urea nitrogen, and creatinine should be monitored monthly and fasting lipids periodically [23]. 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. Issues that may arise with long-term cyclosporine use are reviewed separately. (See "Secondary immunodeficiency induced by biologic therapies".)

Tacrolimus — Experience with the use of tacrolimus in CU is limited. In one case series, 19 patients with severe CU were treated with low-dose tacrolimus [63]. 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 [64]. 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 [65-68].

Mycophenolate — Mycophenolate acts as an antimetabolite selectively for lymphocytes and also impairs expression of adhesion molecules and secondary leukocyte migration [69]. 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:

An open 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 gram twice daily) for 12 weeks [70]. 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 discontinuation.

In another series of 19 patients, the majority of who failed other alternative therapies, doses ranging from 1 to 6 grams were administered, divided into two daily doses [71]. Time to initial response ranged from one to nine 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 were common, occurring in 53 percent of subjects.

No serious adverse effects or laboratory abnormalities were reported in either series. If these findings are confirmed by future studies, mycophenolate would represent a highly attractive alternative to the calcineurin inhibitors, although further data are needed.

Choice of agent and dosing — With cyclosporine, tacrolimus, and sirolimus, a trial of one month is typically adequate to determine efficacy. Most patients with CU have relatively rapid responses (within days). Mycophenolate is slower to work and may require increasing the dose every two to four weeks to determine efficacy. The optimal duration of immunosuppressant therapies is unknown. We typically treat patients at a dose required for complete or near complete control of urticaria for three months, then taper the dose over several months as tolerated. The majority of patients are able to be treated for six- to nine-month periods, although some require long-term therapy (years) at the lowest effective dose.

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 anecdotally, we have observed more frequent problematic side effects with cyclosporine than tacrolimus. Most of our patients are women, and cyclosporine can cause hirsutism and gingival hyperplasia. 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 – The optimal dose of cyclosporine for CU has not been determined. Until more definitive studies are available, we suggest starting with a dose of 3 mg per kg, divided into two doses. Most patients respond within three months, after which the dose can be gradually reduced and in many cases, treatment discontinued. (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 mycophenolate next.

Mycophenolate mofetil – Mycophenolate mofetil is typically started at 1000 mg twice daily and may be increased by 500 mg twice daily after two to four weeks if needed, up to a maximal dose of 2000 mg twice daily.

THERAPIES WITH SIGNIFICANT LIMITATIONS — There are additional agents that can be useful in the management of chronic urticaria (CU), although each has 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, cyclophosphamide, antifibrinolytics, anticoagulants, androgens)

Inconvenience/intensive monitoring requirements (eg, plasmapheresis)

Glucocorticoids remain the standard comparator for these therapies. Glucocorticoids have the advantages of high efficacy and low cost, and the disadvantages of predictable long-term toxicity and lack of disease modifying effect. Studies comparing the therapies in this section with each other are needed.

Immune globulin — Immune globulin may be an appropriate earlier option in patients in whom an immunomodulator would be preferable to an immunosuppressive agent, such as those with a history of malignancy.

Immune globulin is an immunomodulatory agent that alters cell adhesion, immunoregulatory molecules, complement function, cytokine levels, autoantibody production, and anti-idiotypic networks [72]. It can be administered intravenously (intravenous immune globulin [IVIG]) or subcutaneously (subcutaneous immune globulin [SCIG]), although the higher doses used in some 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 "Overview of intravenous immune globulin (IVIG) therapy" 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) [73]. All had positive autologous serum skin test (ASST) and basophil histamine-release test results and many had failed glucocorticoids and various other agents. Responses occurred within 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 several ways, and the optimal dose, number of infusions to administer, and schedule are unknown [74-80]:

The lowest dose described was 0.15 grams per kg, given once every four weeks, in 29 patients [75]. 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 [76]. 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 resulted in two complete responses, one partial benefit, and one failure [77,78].

Other failures have also been reported [79,80].

TNF-inhibitors — Tumor necrosis factor (TNF)-alpha has been shown to be upregulated in the epidermis in lesional and nonlesional skin of CU patients, but not controls [81]. TNF-inhibitors, including etanercept, adalimumab, and infliximab, have been studied in the treatment of CU. Reports of effectiveness are limited. A single patient with delayed pressure urticaria and psoriasis had improvement with etanercept (25 mg subcutaneously twice weekly) and maintained improvement with infliximab [82]. A case series of three patients with CU and three with urticarial vasculitis who were refractory to numerous alternative agents showed all six patients responded to therapy, some with complete resolution. Etanercept, adalimumab, and infliximab were used in this series and some patients had preferential responses to one agent over another.

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".)

Optimal dosing of TNF-inhibitors for CU is unknown, but doses similar to those for other cutaneous diseases have been used. As with omalizumab and IVIG, barriers to use include expense, approval by insurance carriers, and inconvenience.

Colchicine — Colchicine may act to relieve CU by suppressing leukotriene generation or by decreasing leukocyte adhesiveness and migration [83,84]. However, evidence for effectiveness is lacking. Despite this, colchicine has a favorable safety profile at recommended doses, minimal requirements for monitoring, and a generally rapid onset of action. Since colchicine is no longer available as a generic drug, its cost is higher than other antiinflammatory agents.

The single available randomized-controlled trial evaluated 12 patients with delayed pressure urticaria, and failed to demonstrate any effect compared with placebo [85]. Evidence of benefit in patients with chronic idiopathic urticaria is limited to anecdotal reports and retrospective series [86-88]. 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 [89,90]. A randomized trial of 58 patients with CU refractory to cetirizine compared stanozolol, 2 mg twice daily, with placebo over a 12-week period [90]. 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 "Hereditary angioedema: General care and long-term prophylaxis", section on 'Attenuated androgens'.)

Methotrexate — Methotrexate reduces neutrophil accumulation in inflamed skin [91], diminishes activated leukocyte adhesiveness and other adenosine-mediated antiinflammatory properties [92], decreases leukotriene synthesis [93], and alters cytokine activity [94]. 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 [95-100]. One of the larger series described 16 patients, 10 with CU, 4 with urticarial vasculitis, and 2 with angioedema without urticaria [99]. Three of the CU patients also had delayed pressure urticaria. Of the 16 treated patients, there were 12 that noted some benefit along with steroid-sparing effects. 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 [79].

Cyclophosphamide — 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 CU [101]. Evidence of efficacy is limited to case reports of patients with positive ASSTs who had failed multiple other therapies, including cyclosporine [102-104]. In one report, improvement began four weeks into the initial infusions and continued to complete resolution by six months [102]. 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 coagulation and fibrinolysis [39,105]. Agents acting on different points in these pathways theoretically shunt mediators along altered routes and reduce prourticarial factors.

Antifibrinolytic agents (aprotinin and tranexamic acid) have long been used to treat disorders of angioedema, and their utility in some patients with CU was first noted in the 1970s [106-109]. The anticoagulants warfarin and heparin were also studied in CU [105,110-116]. However, the risks of these agents generally outweigh the potential benefits.

Methylxanthines — The use of methylxanthines to treat CU has also been considered [117,118]. 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 with placebo, as add-on therapy to cetirizine [118]. 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.

Nondrug therapies — Nondrug treatments that have been studied in CU include phototherapy, autohemotherapy, and plasmapheresis.

Phototherapy Phototherapy has been administered to patients with CU [119,120], 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 also be reduced [121].

Several types of phototherapy (eg, psoralen plus ultraviolet A [PUVA], narrow band UV-B and UV-A) have been shown to have modest clinical benefit [120,122]. Phototherapy is discussed in greater detail separately. (See "Psoralen plus ultraviolet A (PUVA) photochemotherapy" and "Physical urticarias", section on 'Solar urticaria'.)

Autohemotherapy – Autohemotherapy involves parenteral injection of autologous blood in an attempt to desensitize patients to prourticarial factors in the patient's own serum. An initial report of this was promising [123]. Following that report, a single-blind placebo-controlled trial of 56 patients randomized subjects 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 [124]. 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. A second randomized trial compared weekly injections of autologous whole blood or autologous serum with placebo in 88 patients and reported improvement in both active treatment groups, but not greater than that in the placebo group [125]. 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 [126,127]. One study described eight patients with severe CU who underwent plasmapheresis. Two had complete resolution, two improved, and two did not change [128].

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 info" and the keyword(s) of interest.)

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

SUMMARY AND RECOMMENDATIONS

Chronic urticaria (CU) should be considered refractory when symptoms are not controlled by higher dose H1 antihistamines 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 refractory CU, and therapy must be individualized. 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 upon clinical experience. (See 'Overview' above.)

Omalizumab, a monoclonal antibody against immunoglobulin E (IgE), is safe and effective for many patients, but it is very costly and does not appear to have long-term disease modifying effects. Studies directly comparing omalizumab with other therapies for refractory CU are lacking. (See 'Omalizumab' above.)

For patients with CU who have significant symptoms despite maximal doses of nonsedating H1 antihistamines in combination with other standard therapies, we suggest adding omalizumab therapy over other antiinflammatory or immunosuppressant drugs, with the understanding that the cost of this medication may be prohibitive in many settings (Grade 2B). (See 'Choice of initial intervention' above.)

If omalizumab is not effective or not available:

We suggest one of the antiinflammatory agents (ie, dapsone, sulfasalazine, or hydroxychloroquine) in preference of other drugs as an initial intervention for patients without evidence of glucocorticoid toxicity (Grade 2C). We usually begin with dapsone, after checking for glucose-6-phosphate dehydrogenase (G6PD) deficiency. (See 'Antiinflammatory agents' above.)

We suggest one of the immunosuppressant or immunomodulatory agents (such as cyclosporine, tacrolimus, or methotrexate) in preference to antiinflammatory agents as an initial intervention for patients with signs and symptoms of glucocorticoid toxicity. (Grade 2C). (See 'Immunosuppressant agents' above.)

There are a variety of other drugs and therapies for refractory CU, although each has one or more significant limitations. (See 'Therapies with significant limitations' above.)

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