Official reprint from UpToDate www.uptodate.

com 2010 UpToDate

Chronic urticaria: Treatment of refractory symptoms

Author David A Khan, MD Section Editor Sarbjit Saini, MD Deputy Editor Anna M Feldweg, MD

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. Standard management 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 cold urticaria) 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 reviewed elsewhere. (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 glucose6-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 with sulfasalazine 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. Drawbacks include 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 a relatively 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. Hydroxychloroquine was 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 necessary for 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, or hydroxychloroquine. 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 be reduced 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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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. IMMUNOSUPPRESSANT AND IMMUNOMODULATORY AGENTS If an antiinflammatory agent is not successful in controlling the disease, we discontinue it and consider immunosuppressant therapies next, such as cyclosporine, tacrolimus, sirolimus, or mycophenolate. However, in patients who are steroiddependent and already suffering from steroid-induced toxicity, we may elect to use an immunosuppressant prior to antiinflammatory therapy, as immunosuppressants seem to be more reliably effective in our clinical experience. It is important for treating clinicians to be knowledgeable about potential adverse effects and monitoring when administering these medications for CU. 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. Calcineurin inhibitors Calcineurin inhibitors, particularly cyclosporine, have been used successfully in chronic urticaria. These drugs inhibit calcium-dependent release of and responsiveness to histamine, leukotriene C4, and other mediators in mast cells and other cell types [27]. These agents also have anti-T lymphocyte activity [28]. Cyclosporine may also disrupt tumor necrosis factor alpha activity and secondarily inhibit neutrophil accumulation [29]. Tacrolimus has similar therapeutic effects. Cyclosporine Early studies of cyclosporine to treat CU described significant improvement with relatively high doses (6 mg per kg daily), but patients often discontinued therapy because of adverse effects, with relapse of their urticaria [30]. 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 and side effects of cyclosporine and tacrolimus".) Most subsequent studies have used lower doses (eg, 2 to 5 mg per kg daily), as

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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 these patients' 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 two experienced 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 one case 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. 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 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 are needed. 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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mycophenolate next. Mycophenolate mofetil Mycophenolate mofetil is typically started at 1000 mg twice daily and may be increased to 1500 mg twice daily after several weeks if needed. (See 'Mycophenolate' above.) Omalizumab in patients with concomitant asthma In patients with CU refractory to antihistamines and leukotriene modifiers who have concomitant asthma, use of omalizumab earlier in the stepwise approach is reasonable. In most studies, omalizumab has been dosed based on established asthma dosing guidelines (ie, according to IgE level and body weight). Responses to omalizumab typically occur within days of the first dose, but we generally recommend two to three months of omalizumab to determine efficacy. Immune globulin Immune globulin is a reasonable choice of therapy in patients with CU that is refractory to the step wise approach above. It may be an appropriate earlier option in patients in whom an immunodulator would be preferable to an immunosuppressive agent, such as those with a history of malignancy in the past. THERAPIES WITH SIGNIFICANT LIMITATIONS There are additional agents that can be useful in the management of CU, although each has limitations, including one or more of the following: The potential for serious adverse effects Limited evidence of benefit Inconvenience (eg, must be administered in a monitored setting) Intensive monitoring requirements High cost Therapies that show therapeutic promise, but are costly and may not be reimbursed in third-party payer systems, include omalizumab and immune globulin. Therapies with significant side effects include methotrexate, cyclophosphamide, antifibrinolytics and anticoagulants, androgens, and plasmapheresis. Treatments with limited evidence of benefit include colchicine, methylxanthines, phototherapy, and autohemotherapy. 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. Omalizumab Omalizumab, a monoclonal antibody directed against IgE, shows significant promise in the treatment of CU. At the time of this review, omalizumab is only approved in the United States for treatment of asthma, An initial report described successful use in a patient with cold urticaria [53] and was followed by

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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 four weeks 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 cell adhesion, immunoregulatory molecules, complement function, cytokine levels, autoantibody production, and anti-idiotypic networks [60]. It can be administered intravenously (IVIG) or subcutaneously (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 "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 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 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 a favorable 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 alters cytokine 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 failed multiple 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 coagulation and 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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also be reduced [101]. 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 by 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 chronic 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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checking for G6PD deficiency. (See 'Antiinflammatory agents' above.) For patients with evidence of steroid toxicity, we suggest an immunosuppressant or immunomodulatory agent (such as cyclosporine or tacrolimus) in preference to antiinflammatory agents as an initial intervention (Grade 2C). We usually begin with tacrolimus. (See 'Immunosuppressant and immunomodulatory agents' above.) There are a variety of other drugs and therapies for refractory CU, although each has one or more significant limitations. Despite this, there may be situations in which a certain therapy is indicated. As an example, patients with moderate to severe asthma who develop refractory CU are candidates for omalizumab. (See 'Therapies with significant limitations' above.)

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