Version May 2024
INTRODUCTION — Chronic spontaneous urticaria (CSU), also called chronic idiopathic urticaria, is defined by the presence of urticaria (hives) on most days of the week for a duration of six weeks or longer [1]. Associated angioedema occurs in approximately 40 percent of patients. Standard management of CSU primarily involves second-generation H1 antihistamines, often at higher-than-usual doses and in combination with H2 antihistamines and leukotriene modifiers. Short courses of systemic glucocorticoids to control severe exacerbations may be needed. This topic discusses the treatment of patients whose symptoms are not controlled over time using these standard therapies.
Therapeutic options for patients with refractory CSU will be reviewed here, as well as the evidence in support of the efficacy of each treatment. Standard management, as well as the diagnosis, pathogenesis, and prognosis of CSU, are reviewed separately. (See "Chronic spontaneous urticaria: Standard management and patient education" and "Chronic spontaneous urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history".)
Urticarial vasculitis and specific physical forms of chronic urticaria, such as delayed-pressure urticaria, cholinergic urticaria, or cold urticaria, are discussed separately. (See "Urticarial vasculitis" and "Physical (inducible) forms of urticaria" and "Cold urticaria".)
REFERRAL — Patients with recurrent urticaria with or without angioedema that continues to recur for a period of six weeks or longer and cannot be adequately controlled with higher doses of second-generation H1 antihistamines should be referred to an allergy or dermatology specialist. These patients are at risk for receiving repeated courses of oral glucocorticoids. However, long-term systemic glucocorticoids have potentially severe side effects and do not appear to induce lasting remission or alter the natural history of CSU. Thus, it is preferable to limit glucocorticoid use to short periods of the minimally effective doses and to refer the patient for consideration of more advanced treatments before they have been exposed to months of glucocorticoid therapy. (See "Major adverse effects of systemic glucocorticoids".)
In some cases, immunosuppressant or antiinflammatory drugs are needed, and it is important for the treating specialist to be knowledgeable about potential adverse effects and monitoring when administering the agents discussed in this topic. Consultation with additional specialists (eg, rheumatologists) may be appropriate, depending on the medication, as well as the experience and comfort level of the treating specialist.
OVERVIEW — Available data indicate that H1 antihistamines at higher-than-standard doses will adequately control CSU symptoms in approximately one-half of patients, and a small number will get additional benefit from the other well-tolerated and low-risk supplementary therapies (eg, H2 antihistamines and montelukast). The efficacy of H1 antihistamine therapy for CSU is reviewed separately. (See "Chronic spontaneous urticaria: Standard management and patient education", section on 'H1 antihistamines'.)
For patients inadequately controlled on high-dose H1 antihistamines, international guidelines recommend treatment with omalizumab [2]. For patients refractory to standard doses of omalizumab, dosing adjustments of omalizumab are recommended prior to consideration of other medications such as cyclosporine and several additional drugs that have either antiinflammatory or immunosuppressant effects. The recommendations in this topic review are generally consistent with guidelines from international societies [1-5]. Deviations from the recommendations in the guidelines are noted.
When introducing these more advanced treatments, antihistamines and other standard agents that were clearly helpful to the patient are typically continued. Any medications of uncertain benefit should be discontinued so that medications do not accumulate.
Goal of therapy — The goal of therapy in patients with refractory CSU is to achieve a level of symptom control and improvement in quality of life that is acceptable to the patient, while minimizing therapy-related side effects. Patients differ in their preferences. Some want to pursue complete control, while others would rather minimize medications and accept a low level of ongoing symptoms. In addition, it should be kept in mind that although CSU can be a disabling disorder, it does not lead to permanent organ damage, and it ultimately resolves in the majority of patients, with or without treatment. Thus, a treatment that appears to be inducing serious adverse side effects is not warranted. The natural history of CSU is reviewed separately. (See "Chronic spontaneous urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history", section on 'Natural history and prognosis'.)
Choice of initial intervention — For patients whose symptoms cannot be adequately controlled by higher-dose antihistamines, international guidelines recommend the addition of omalizumab, a monoclonal antibody against immunoglobulin E (IgE), as the most appropriate next intervention [1]. Omalizumab is preferred because of both proven efficacy and also safety relative to immunosuppressant or antiinflammatory drugs. However, the high cost of omalizumab is a concern in all health care systems and will limit the use of this therapy in many settings. (See 'Omalizumab' below.)
We agree with international guidelines that omalizumab is the most appropriate therapy for patients who do not respond to higher-dose H1 antihistamine therapy [1]. However, we typically give up-dosing of antihistamines a trial period of at least several weeks to fully assess effectiveness, whereas the international guidelines suggest that the trial period for antihistamines can be as short as one month (algorithm 1). Up-dosing of antihistamines is reviewed separately. (See "Chronic spontaneous urticaria: Standard management and patient education", section on 'Up-dosing of second-generation agents'.)
Several studies have examined potential biomarkers to predict response to various therapies for refractory CSU, but none can be recommended for routine clinical use [6]. The most promising developments have been in identification of possible biomarkers to predict responsiveness to omalizumab [7-9]. (See 'Predicting responsiveness' below.)
OMALIZUMAB — Omalizumab is a monoclonal antibody directed against IgE, which was approved in the United States in 2014 for the treatment of patients 12 years of age and older with CSU that is not controlled with standard-dose H1 antihistamine therapy [10]. (See "Society guideline links: Urticaria and angioedema (excluding hereditary angioedema)".)
Predicting responsiveness — Studies have identified potential biomarkers that may predict responsiveness to omalizumab therapy, but none predict a response well enough to inform the decision to treat. No specific laboratories are required before omalizumab is initiated for CSU.
A 2022 study of 23 CSU patients treated with omalizumab found that low serum trough concentrations of omalizumab were associated with worse responsiveness [11]. In addition, higher body mass index (BMI) was a significant predictor of low serum omalizumab concentrations, suggesting that some patients with higher BMI may need higher doses or more frequent doses of omalizumab. (See 'Dose adjustment and duration of therapy' below.)
Other possible predictors of a better response include higher baseline serum IgE levels [8,12], a greater than twofold increase in IgE after four weeks of treatment compared with baseline IgE [8], higher baseline levels of high-affinity IgE receptor (Fc-epsilon-RI) on blood basophils, and greater reduction of Fc-epsilon-RI on basophils after four weeks of treatment [9]. However, serum IgE levels predict basophil IgE receptor levels, so these biomarkers are interconnected, and further study is needed.
Efficacy — A meta-analysis of seven randomized trials (1312 patients) demonstrated that omalizumab significantly reduced the weekly itch and wheal scores relative to placebo in patients with CSU not responsive to standard doses of H1 antihistamines (eg, cetirizine 10 mg daily) [13-21]. The most effective dose was 300 mg every four weeks, at which 36 percent of patients had a complete response (urticaria activity score of 0). Adverse event rates and specific events were similar with omalizumab and placebo. Other analyses of multiple studies showed that omalizumab improved sleep beginning after the first dose and provided substantial improvements in quality of life [22,23].
One trial included in the meta-analysis was particularly informative because it closely approximated common clinical practice. The GLACIAL trial evaluated 335 patients whose symptoms were not controlled with H1 antihistamines (up to four times the standard dose) plus H2 antihistamines, antileukotriene agents, or the combination [17]. Subjects were randomized to omalizumab, 300 mg monthly, or placebo. Baseline medications were continued unchanged throughout the study period and the four-month follow-up period. The primary endpoint was a change in mean weekly itch severity scores (on a scale from 0 to 21, with a minimally important difference of 5) at the end of 12 weeks. Clinical efficacy was apparent by one week in the omalizumab group. Mean itch scores decreased a clinically meaningful amount only in the omalizumab group, and the difference between the two groups was statistically significant. A minimally important difference in symptoms was achieved by 70 and 40 percent of subjects in the omalizumab and placebo groups, respectively. At 12 weeks, 34 and 5 percent of subjects were itch and hive free in the omalizumab and placebo groups, respectively. Once omalizumab was stopped, subjects' symptoms gradually returned during the observation period and were similar to placebo at the end of the study. Thus, the addition of omalizumab to the combination of maximally dosed H1 antihistamines (with or without H2 antihistamines, antileukotriene agents, or both) will control symptoms in another 30 to 35 percent of patients, and the combination of maximal antihistamine therapy plus omalizumab will achieve satisfactory control of CSU in approximately 80 percent of patients.
Long-term impact — Omalizumab has not been shown to have a long-term disease-modifying effect, so patients may relapse when omalizumab is tapered or discontinued [24]. However, CSU is a disorder that remits or resolves in the majority of patients within a few years even untreated, so it can be difficult to assess the impact of therapy on natural history. (See "Chronic spontaneous urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history", section on 'Natural history and prognosis'.)
Safety — Among all nonantihistamine therapies with proven efficacy for refractory CSU, omalizumab is the best studied, most widely used therapy and has a very low incidence of serious adverse effects. It has been used safely in pregnant women and is the treatment of choice for refractory CSU during pregnancy [25,26]. The adverse effects of omalizumab are discussed separately. (See "Anti-IgE therapy", section on 'Adverse effects'.)
Monitoring — No specific laboratory monitoring is required for patients receiving omalizumab for CSU.
Our approach
Initial dosing — We initiate omalizumab at a dose of 300 mg injected subcutaneously every four weeks based on studies of efficacy that evaluated different dosing approaches, as well as recommendations from international guidelines [2,13,18]. We continue nonsedating H1 antihistamines initially and then taper as tolerated if the patient responds well to omalizumab. Patients must be prescribed an epinephrine autoinjector because anaphylaxis is reported, although not at rates any higher than with other biologic therapies. (See "Anti-IgE therapy", section on 'Anaphylaxis'.)
Expected response — In an analysis of multiple trials intended to evaluate the extent and time course of the response to omalizumab, approximately 60 percent of patients had a meaningful reduction in symptoms by week 12 [27]. Benefit was frequently seen in the first month, and a majority of patients responded within four months (three doses). Approximately 40 percent of patients became asymptomatic (ie, complete response) by week 12 and approximately 45 percent by week 24 (in the longer studies). Thus, the analysis suggested that there is a group of early responders (<1 month) and a smaller group who respond later. Overall, a period of 16 weeks should be sufficient to identify patients who will benefit.
A meta-analysis was performed on 67 observational studies (randomized trials were excluded) in an effort to describe the "real-world" benefits and risks of omalizumab therapy [28]. In contrast to a meta-analysis of randomized trials, such an analysis provides an estimate of the effects of therapy combined with possible placebo effect (see 'Efficacy' above). Outcomes were expressed as improvement in the weekly Urticaria Activity Score (UAS7), which ranges from 0 to 42, with higher scores indicating more severe symptoms. Omalizumab therapy was associated with a reduction in UAS7 scores of 26 points (95% CI 28-23 points). Approximately 72 percent of patients had a complete response, and approximately 18 percent had a partial response. The rate of adverse events was 4 percent, with three patients experiencing anaphylaxis.
Dose adjustment and duration of therapy — The optimal duration of therapy has not been determined, and patients may relapse when omalizumab is tapered or discontinued [24]. Approaches to tapering therapy have not been studied extensively, although an algorithm has been proposed by one group [29]. The approach of the author and section editors is described here. We consider the severity of disease and duration of CSU, with a more gradual stepdown approach for patients with very severe or long-term CSU as well as those with inducible forms of chronic urticaria. For example, in a patient with a history of refractory CSU for many years (eg, ≥3 years) who responds to omalizumab, we would treat for a minimum of one year before considering tapering.
●If the patient has complete resolution of symptoms and no breakthrough symptoms for two to three months, the dose may be lowered (to 150 mg), and the interval between injections can be gradually lengthened. If a patient has no symptoms for a period of time on 150 mg every eight weeks, therapy can be stopped. Other experts (including the author) maintain a dose of 300 mg monthly, prolong the interval by one week per cycle, and discontinue therapy if the patient's disease remains controlled with eight-week intervals [30].
●If the patient has complete resolution of symptoms and no breakthrough symptoms for two to three months, the approach of the author and other experts is to lengthen the interval between doses by one week per cycle. If the patient's symptoms remain controlled with eight-week intervals, therapy can be discontinued [30]. Another approach is to lower the dose gradually. These two approaches have not been formally compared.
●For patients with partial responses to omalizumab at 300 mg, there is anecdotal evidence that some may have further improvement with higher doses (eg, 450 or 600 mg every four weeks) or more frequent doses (eg, 150 mg every two weeks) [14,15,31]. A response to the increased dose should be evident after three doses. International guidelines recommend a dose increase up to 600 mg given every two weeks [2]. However an observational study did not show improvement in CSU patients not controlled with omalizumab 600 mg every four weeks and then changed to every 600 mg every two to three weeks [32]. The author does not recommend increasing the dose of omalizumab beyond 600 mg every four weeks.
●If the patient has minimal or inadequate control of symptoms despite the higher doses of omalizumab, therapy should be discontinued after a four-month trial and other options explored. Alternatively, the combination of omalizumab and cyclosporine can be tried. (See 'Combined with omalizumab' below.)
●Patients with urticaria who do not show sufficient benefit from treatment with omalizumab in combination with high-dose antihistamines may be treated with cyclosporine (adults dose 3.5 to 5 mg/kg per day), in combination with omalizumab or as monotherapy [2]. (See 'Cyclosporine' below.)
●Patients who were treated in the past and stopped therapy but then had a subsequent recurrence of CSU have been reported to respond to omalizumab again, suggesting that resistance does not develop readily in most patients [24,33,34].
OTHER THERAPIES — For patients who have not achieved adequate relief with the combination of higher-dose H1 antihistamines and omalizumab or do not have access to omalizumab, several other therapies can be tried, including cyclosporine, tacrolimus, mycophenolate, dapsone, sulfasalazine, and hydroxychloroquine [35-37].
Alternative non-US Food and Drug Administration (FDA) approved agents for CSU can be divided into two groups, "immunosuppressant" agents and "antiinflammatory" agents, although there is considerable overlap between the two groups of drugs.
●The term "immunosuppressant" is applied to drugs that have more potent immunosuppression activity and greater potential toxicity, as well as more evidence for efficacy. We have categorized the calcineurin inhibitors and mycophenolate mofetil in this way.
●"Antiinflammatory" denotes a class of agents with predominantly antiinflammatory activities, which have low potential toxicity and less proven efficacy for CSU. We have applied this term to dapsone, sulfasalazine, and hydroxychloroquine.
With the immunosuppressant and antiinflammatory drugs described in this section, therapy is generally continued for a period of several months once control of symptoms has been achieved. We favor a longer duration of therapy before attempting to taper for patients with longstanding CSU.
In the author's experience, serious adverse effects that require discontinuation of therapy are rare, and he has not observed any permanent complications from use of these agents [35].
Choice of agent — Of the drugs that have been studied in CSU, some have the advantage of a rapid onset of action, such as cyclosporine and tacrolimus, which can be helpful for patients with significant impairment in quality of life or side effects from glucocorticoids. The international guidelines emphasize cyclosporine over other agents, but the authors and editors of this topic consider a wider range of options [1,35]. There is insufficient evidence on which to base a strong preference for one drug over another.
Cyclosporine — Cyclosporine (and tacrolimus) has several desirable properties, including rapid onset (sometimes within days) [38-41], a degree of efficacy comparable with prednisone [5,42], and the possibility of lasting remission after treatment is discontinued [41,43,44]. Cyclosporine has the most supporting data. However, cyclosporine has potentially serious adverse effects (ie, hypertension and kidney insufficiency), as well as unpleasant cosmetic effects with long-term use (ie, hirsutism and gingival hyperplasia), although these are less common at the doses used for CSU, which are significantly lower than the doses used for most other indications [45]. Cyclosporine should be avoided in patients with chronic kidney disease or poorly controlled hypertension.
Calcineurin inhibitors block the calcium-dependent release of and responsiveness to histamine, leukotriene C4, and other mediators in mast cells and several cell types [46]. These agents also have anti-T lymphocyte activity [47]. Cyclosporine may also disrupt tumor necrosis factor alpha activity and secondarily inhibit neutrophil accumulation [48].
Efficacy — A 2018 systemic review identified 18 studies, including two randomized, controlled trials of cyclosporine for CSU [49]. Early studies described significant improvement with relatively high doses (eg, 5 to 6 mg per kg daily), but patients often discontinued therapy because of adverse effects, with relapse of their urticaria [42,50]. 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 [39,40,43,51-55]. Pediatric studies also used the lower dose range [56]. A 2022 network meta-analysis noted better outcomes with omalizumab than cyclosporine and a higher odds of adverse effects with cyclosporine than other treatment options [57].
In a representative trial, 30 patients with CSU refractory to standard doses of antihistamine were randomized to cyclosporine, 4 mg per kg daily, or placebo for four weeks [58]. Initial nonresponders were offered open-label cyclosporine for four weeks. Eight of 19 (42 percent) receiving cyclosporine improved compared with none receiving placebo. In addition, 11 of 17 initial nonresponders responded after an additional four weeks of open-label treatment. Mild adverse effects were common in this study (29 of 30 subjects).
Combined with omalizumab — The effectiveness of combining cyclosporine at 3 mg/kg per day with omalizumab at 300 mg every four weeks was evaluated in 21 CSU patients who had not responded to a trial of either therapy for four months [59]. After six months of combined therapy, 16 of 21 patients had control of their CSU. Importantly, the majority of patients had improvement after two months, suggesting that it may take longer to see a response with this combined approach in patients refractory to omalizumab. The author has noted similar effectiveness using tacrolimus and omalizumab in patients with inadequate control on omalizumab alone.
Dosing — The optimal dose of cyclosporine for CSU has not been determined. As recommended by the authors of the aforementioned systematic review, we also suggest starting with a dose of 3 mg per kg, divided into two doses [49]. For most adults, this is 100 to 150 mg twice daily. Cyclosporine is available in modified and nonmodified formulations. We prefer using modified cyclosporine as it exhibits increased bioavailability and less erratic absorption. Some patients respond within one week or two, and most patients who will respond improve within three months.
Blood pressure, blood urea nitrogen, and creatinine should be monitored monthly, and fasting lipids should be monitored initially and yearly for patients who remain on therapy. [60]. Serum levels may be followed to ensure that the dose is not excessive, although we do not find this useful, because the optimal therapeutic level for CSU has not been defined, high levels are rare with the low doses we suggest, and drug levels do not seem to correlate with effectiveness in CSU.
Mild adverse effects include paresthesias, gastrointestinal symptoms, and headache and are dose related. Dose reduction may eliminate them. Severe side effects are uncommon and should prompt discontinuation. They include hypertension and kidney insufficiency. Cyclosporine is contraindicated in patients with uncontrolled hypertension. (See "Pharmacology of cyclosporine and tacrolimus".)
The optimal duration of therapy with cyclosporine is not known. We typically treat patients at a dose required for complete or near-complete control of urticaria for three months and then taper the dose over several months as tolerated. In the majority of patients, six to nine months of treatment is adequate, although some require long-term therapy (two or three years) at the lowest effective dose [61].
Tacrolimus — Data in support of the use of tacrolimus in CSU are limited [62,63]. Despite this, the author prefers tacrolimus over cyclosporine because of an apparent lower rate of problematic side effects with it. In particular, tacrolimus does not cause the hirsutism and gingival hyperplasia that can be seen with cyclosporine. However, like cyclosporine, it should be avoided in patients with chronic kidney disease or poorly controlled hypertension. Baseline laboratories including kidney function are required prior to starting calcineurin inhibitors.
We start tacrolimus at a dose of 1 mg twice daily for one to two weeks and then increase by 1 to 2 mg increments every few weeks, up to a maximum of 3 mg twice daily. In our experience, most patients respond to doses ≤4 mg daily of tacrolimus. Higher doses with monitoring of drug levels can be used in patients who partially respond or have no response to lower doses. Similar to cyclosporine, monitoring of kidney function is recommended to avoid kidney toxicity [64-69].
The largest study of tacrolimus was a retrospective review of 36 patients treated with 45 distinct courses [63]. Remission (ie, no urticaria for >1 month after treatment was discontinued, with no need for other medications) occurred in 25 percent of courses; complete response occurred (no symptoms >1 month while on tacrolimus) in 30 percent of courses; and partial response was seen in 23 percent of courses. An additional 23 percent of courses had no improvement with tacrolimus. The mean length of therapy was 9.2 months. Therapy was generally well tolerated, with gastrointestinal symptoms in eight patients, mild hypertension in three patients, and reversible elevations in serum creatinine in four patients.
Mycophenolate — Mycophenolate mofetil acts as an antimetabolite selectively for lymphocytes and also impairs expression of adhesion molecules and secondary leukocyte migration [70]. Although unrelated to the calcineurin inhibitors, mycophenolate has some of the same properties with fewer reported adverse effects. However, it works more gradually than the calcineurin inhibitors, and it is rare to see an effect within days.
Mycophenolate mofetil is typically started at 1000 mg twice daily and may be increased by 500 mg twice daily at monthly intervals if needed, up to a maximal dose of 2000 mg twice daily. We rarely exceed 4000 mg daily. If there has been no improvement after one month of 2000 mg twice daily, we discontinue it.
It is generally well tolerated. The most common problems are gastrointestinal symptoms and leukopenia. Complete blood counts (CBCs) should be performed after the first one to two weeks of therapy and then once every six to eight weeks thereafter if no cytopenias are noted. (See "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases".)
Very few studies are available on the use of mycophenolate in CSU:
●An open series evaluated nine patients with "severe" CSU, defined as symptoms unresponsive over a six-week period to antihistamines and/or more than two week-long courses of oral glucocorticoids. Patients were treated with mycophenolate, 1000 mg twice daily, for 12 weeks without dose escalation [71]. 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 whom had not benefitted from other alternative therapies, doses ranging from 1 to 6 grams (divided into twice-daily dosing) were administered [72]. 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 occurred in 53 percent of subjects.
Sulfones (uncommonly used) — The sulfone medications dapsone and sulfasalazine have both been studied in CSU. Dapsone is a sulfone antimicrobial agent. Sulfasalazine is an antiinflammatory 5-aminosalicylic acid (5-ASA) derivative. The author rarely uses sulfones since the approval of omalizumab for CSU. However, if omalizumab is not available, the author prefers dapsone over sulfasalazine but prefers sulfasalazine for patients with underlying anemia.
Dapsone — Dapsone may provide benefit in CSU by suppressing prostaglandin and leukotriene activity, interfering with release or function of neutrophil lysosomal enzymes [73,74], disrupting integrin-mediated neutrophil adhesiveness [75], inhibiting neutrophil recruitment and activation signals [76], and scavenging oxygen-free radical intermediates [77]. Dapsone has traditionally been thought to be helpful in cutaneous diseases in which neutrophils play a prominent role [78]. Some cases of CSU have a neutrophil-rich infiltrate on biopsy, although whether this histopathologic finding predicts response to dapsone in patients with CSU is unproven.
Prior to initiating dapsone therapy, we check a CBC, liver function tests, and glucose-6-phosphate dehydrogenase (G6PD) levels. Dapsone can cause severe hemolytic anemia in patients with G6PD deficiency, and it is contraindicated in patients with this disorder. We also avoid this agent if the patient is already anemic or has any abnormalities in hepatic function. The various diagnostic tests for G6PD deficiency are discussed separately. (See "Drug-induced hemolytic anemia" and "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency", section on 'Diagnostic evaluation'.)
In adults, dapsone can be initiated at a dose of 100 mg daily. CBC and liver function tests should be checked in two weeks and repeated 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 it is not necessary to stop therapy unless the decrease exceeds 25 percent. The dose can be reduced once there is a clear clinical response. A four-week trial is usually sufficient to determine effectiveness.
Peripheral neuropathy, clinically significant methemoglobinemia, agranulocytosis, and drug-allergic reactions, such as drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome (DRESS/DiHS), are rare but serious reactions that warrant immediate discontinuation of dapsone [79,80]. (See "Methemoglobinemia".)
Studies indicating that dapsone is effective for the treatment of CSU include two small, randomized trials [81,82]. In the more rigorous trial, 22 patients with antihistamine-refractory CSU showed improvement in itch and urticaria scores in patients taking dapsone, 100 mg daily [81]. In all responders, efficacy was apparent within the first week. Three patients had complete resolution of CSU with dapsone [82].
A larger retrospective review included 79 patients with CSU refractory to four times the standard dose of nonsedating antihistamines [83]. Some had additionally not improved with one or more other agents (ie, glucocorticoids, omalizumab, cyclosporine, mycophenolate mofetil, leukotriene inhibitors, H2 antagonists, and/or nifedipine). Improvement was seen in 62 patients in a mean of 1.1 months, with the mean maximal dose of 118 mg daily. In addition, 29 of these individuals had complete resolution after a mean of 5.2 months. Dapsone was tapered down after two months of controlled symptoms, and 10 patients had sustained remission for periods up to 16 months. However, two patients developed serious adverse effects (DRESS/DiHS and methemoglobinemia).
The optimal duration of treatment is unknown. If the patient is on sedating antihistamines or did not respond significantly to antihistamines in the past, we taper them first, and then the dapsone is reduced over a period of several months as tolerated.
Sulfasalazine — Sulfasalazine is preferable to dapsone in patients with underlying anemia. In adults, sulfasalazine therapy can be initiated with 500 mg once or twice per day for one week and then gradually increased to 1 gram twice per day.
Mechanisms of action with possible relevance in CSU include alteration of adenosine release [84], decreased leukotriene and prostaglandin synthesis, inhibition of IgE-mediated mast cell degranulation [85], attenuation of neutrophil respiratory burst [86], and inhibition of early-phase events in the proliferation and differentiation of B lymphocytes [87]. 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 CSU.
Overall, sulfasalazine is well tolerated by most patients. Side effects include nausea, headache, mild or transient leukopenia, and transaminitis. Rare reports of agranulocytosis exist. Folate supplements should be coadministered to females who are pregnant or could potentially conceive. Drawbacks include the advisability of gradual dose escalation, which may prolong the time to clinical response, as well as the need for laboratory monitoring.
Laboratory monitoring with a CBC, liver function tests, and urinalysis is performed every month for the first three months and then less often. A four- to six-week trial is usually sufficient to determine effectiveness. British guidelines recommend monitoring with CBC, blood urea nitrogen, creatinine, electrolytes, and liver function tests monthly during the first three months and then every three months thereafter [60]. 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 separately. (See "Sulfasalazine: Pharmacology, administration, and adverse effects in the treatment of rheumatoid arthritis", section on 'Dosing and monitoring'.)
Observational studies suggest that sulfasalazine is useful as an add-on to standard therapies for patients with refractory symptoms [88-92].The largest study was a retrospective chart review of 39 patients with CSU refractory to antihistamines and other therapies treated with sulfasalazine as an add-on therapy [88]. These patients had relatively recalcitrant disease and had CSU on average for 5.5 years prior to starting sulfasalazine, during which one-third required daily glucocorticoids and 10 percent had received other immunomodulators (dapsone, cyclosporine, mycophenolate). Sulfasalazine treatment was added to existing therapies starting with 500 mg daily and increased by 500 mg per week to 2000 mg daily if tolerated (and up to 3000 mg daily in 15 patients), and laboratories remained normal. Using this approach, 84 percent of patients improved within three months. The percentage becoming asymptomatic on sulfasalazine on the background of antihistamines was 32 and 51 percent by three and six months, respectively. The average duration of sulfasalazine therapy was 74 weeks. Nine of 10 steroid-dependent patients were able to discontinue glucocorticoids. Once the patient's symptoms were controlled, sulfasalazine was gradually withdrawn, while antihistamines were continued throughout in most patients and withdrawn last. Eleven patients remained asymptomatic after sulfasalazine was discontinued, requiring only antihistamine therapy. Five patients (16 percent) failed therapy, either due to a drug adverse effect (one) or lack of improvement. There were two serious adverse events (neutropenia and leukopenia and rhabdomyolysis of uncertain association), although both patients recovered fully after the drug was discontinued.
The optimal duration of treatment is unknown. If the patient is on sedating antihistamines or did not respond significantly to antihistamines in the past, we taper them first, and then the sulfasalazine is reduced over a period of several months as tolerated.
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 CSU. The major disadvantage is a relatively slow onset of action.
In adults, we start with a dose of 200 mg twice per day. A three-month trial is usually required to determine effectiveness. Hydroxychloroquine rarely causes serious side effects. The most common adverse reactions are related to the gastrointestinal tract (nausea), skin (various macular lesions), and central nervous system (headache).
Mechanisms of action include suppression of T lymphocyte activation [93] and disruption of antigen processing and other cellular processes by alkalinization of intracellular vacuoles in macrophages and other antigen-presenting cells [94]. Hydroxychloroquine has not been shown to induce lasting remission [37].
Ophthalmologic problems, including corneal deposits (reversible) and retinopathy (potentially vision threatening), are possible but rare with the low daily doses of hydroxychloroquine used in CSU. The issue of ophthalmologic screening is reviewed separately. (See "Antimalarial drugs in the treatment of rheumatic disease", section on 'Routine eye examinations'.)
There are limited data on efficacy. In the best available study, 18 patients with CSU were treated with a combination of therapies for CSU (H1 antihistamines, H2 antihistamines, glucocorticoids, and doxepin) and randomized to receive either hydroxychloroquine, 5 mg/kg daily, or no additional drug [95]. 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.
A 2022 retrospective study reported outcomes in 111 antihistamine-resistant CSU patients treated initially with hydroxychloroquine and 134 treated with omalizumab [96]. After three months of therapy, 82 percent of omalizumab patients had a complete response versus 38 percent of those on hydroxychloroquine. At 12 months, a sustained complete response was seen in 82 percent for omalizumab and 66 percent for hydroxychloroquine. There were 12 patients who had partial or no response to omalizumab who were treated with hydroxychloroquine, and 8 of 12 had a complete response by 12 months. Duration of CSU was not reported in this study, and, given the observational nature of the data, it is unclear if the higher responses observed at 12 months may be due to natural remission of disease.
INVESTIGATIONAL AGENTS — Other biologics are under investigation for the treatment of refractory CSU, including the high-affinity anti-IgE monoclonal antibody ligelizumab [97-99], the anti-interleukin (IL) 4 and IL-13 monoclonal dupilumab [100,101], the anti-IL-5 receptor alpha monoclonal antibody benralizumab [102,103], the Bruton tyrosine kinase inhibitor remibrutinib [104], and several novel drugs that are still in development [105].
RARELY USED THERAPIES — There are additional agents that have been reported to be useful in the management of CSU, although each has significant limitations, including one or more of the following:
●High cost combined with limited evidence of benefit (eg, immune globulin)
●Limited evidence of benefit (eg, colchicine, methotrexate [106], methylxanthines, phototherapy)
●The potential for serious adverse effects (eg, methotrexate, tumor necrosis factor [TNF] inhibitors, cyclophosphamide, antifibrinolytics, anticoagulants, androgens)
Phototherapy — Phototherapy (eg, either psoralen plus ultraviolet A [PUVA] or narrowband ultraviolet B [UVB] and ultraviolet A [UVA]) have been shown to have modest clinical benefit in CSU [107-110]. In a randomized trial of 50 patients with CSU refractory to H1 antihistamines (escalated to fourfold the standard dose for at least three months) and requiring repeated courses of oral glucocorticoids, subjects received either PUVA or narrowband UVB for 90 days [111]. There was no placebo group. Subjects in both treatment groups had statistically and clinically significant improvement, with greater improvement in the UVB group, and the authors noted that most responders had continued benefit for up to one year. However, very few patients had complete control of hives, and adverse effects included tanning and xerosis of the skin. In addition, the mean IgE was quite high in this population of patients from India (403 to 721 international units/mL), raising questions regarding the generalizability of the findings.
Phototherapy is a reasonable option for patients able to commit to frequent visits or for those intolerant to systemic medications. Skin that is directly irradiated improves most dramatically, suggesting local mediators and cells as primary targets. Histamine release from mast cells may also be reduced [112]. It has also been used in the management of solar urticaria and other physical urticarias. Phototherapy and its longer-term adverse effects are discussed in greater detail separately. (See "Psoralen plus ultraviolet A (PUVA) photochemotherapy" and "Physical (inducible) forms of urticaria", section on 'Solar urticaria'.)
Other — There are several other agents with weak evidence of efficacy in CSU.
●Sirolimus (rapamycin) was reported to be effective in two of three patients in a case report [113]. The patients had previously not improved with multiple alternative therapies, including montelukast, dapsone, hydroxychloroquine, colchicine, olsalazine, and mycophenolate mofetil.
●Immune globulin (given intravenously or subcutaneously) may be an option in patients in whom an immunomodulator would be preferable to an immunosuppressive agent, such as those with a history of malignancy. It is an immunomodulatory agent that alters cell adhesion, immunoregulatory molecules, complement function, cytokine levels, autoantibody production, and anti-idiotypic networks [114]. Dosing has varied in past trials. The optimal dose, number of infusions to administer, and schedule for CSU are unknown and have ranged from a single dose of 2 grams/kg to 0.15 grams/kg, given monthly [115-122]. 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".)
●TNF inhibitors, including etanercept, adalimumab, and infliximab, have been studied in the treatment of CSU because TNF-alpha has been shown to be upregulated in the epidermis in lesional and nonlesional skin of CSU patients relative to controls [123]. We would consider TNF inhibitors in patients who have not improved with omalizumab, calcineurin inhibitors, and antiinflammatory agents. Reports of effectiveness are limited [124,125]. In the largest series, 25 patients with CSU refractory to omalizumab, cyclosporine, prednisone, and azathioprine were treated with adalimumab or etanercept for 3 to 35 months, with responses in 10 of 17 and 5 of 8, respectively [125]. Sixty percent obtained complete or near-complete control of symptoms. One patient experienced a severe adverse effect (polyneuropathy).
Optimal dosing of TNF inhibitors for CSU is unknown, but doses similar to those for other cutaneous diseases have been used. As with omalizumab, barriers to use include expense and inconvenience. TNF inhibitors have several adverse effects, including injection-site or infusion-related reactions, infectious complications, and others. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects".)
●A meta-analysis of two randomized trials found that methotrexate had no significant benefit as an add on to antihistamines in difficult-to-treat CSU [126]. Methotrexate reduces neutrophil accumulation in inflamed skin [127], diminishes activated leukocyte adhesiveness and other adenosine-mediated antiinflammatory properties [128], decreases leukotriene synthesis [129], and alters cytokine activity [130]. Adverse effects can be serious, and frequent monitoring is advised. These issues are reviewed elsewhere. (See "Major side effects of low-dose methotrexate".)
●Colchicine may act to relieve CSU by suppressing leukotriene generation or by decreasing leukocyte adhesiveness and migration, but our clinical experience with it has been disappointing [131,132]. It has a favorable safety profile at recommended doses, minimal requirements for monitoring, and a generally rapid onset of action. However, evidence of benefit in patients with CSU is limited to anecdotal reports and retrospective series [133-135]. The single available randomized, controlled trial evaluated 12 patients with delayed-pressure urticaria and failed to demonstrate any effect compared with placebo [136].
●Cyclophosphamide has generally been reserved for patients in whom multiple other alternative agents have failed. It is believed to act on plasma cells to reduce autoantibody production in autoimmune CSU [137]. Evidence of efficacy is limited to case reports of patients with positive autologous serum skin tests who had not improved despite multiple other therapies, including cyclosporine [138-140]. In one report, improvement began four weeks into the initial infusions and continued to complete resolution by six months [138]. The patient continued to be asymptomatic 12 months after the last infusion. Cyclophosphamide use is limited by expense, inconvenience, need for monitoring, and risk of serious adverse effects (including delayed secondary neoplasia and hemorrhagic cystitis).
●Several anticoagulants and antifibrinolytic agents have been studied in CSU because the inflammatory pathways believed relevant to urticaria/angioedema are interconnected with pathways of coagulation and fibrinolysis [141,142]. 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 CSU was first noted in the 1970s [143-146]. The anticoagulants warfarin and heparin were also studied in CSU [142,147-153]. However, the risks of these agents generally outweigh the potential benefits.
●Methylxanthines have also been used to treat CSU [154,155]. A double-blind, placebo-controlled study of 134 CSU patients evaluated theophylline 200 mg twice daily for six months followed by 200 mg once daily for six months, as add-on therapy to cetirizine [155]. Both groups experienced large improvements in all symptoms assessed, and the theophylline group had statistically significant improvement in overall urticaria scores. However, pruritus did not improve.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Urticaria and angioedema (excluding hereditary angioedema)".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Chronic hives (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Indications for specialist referral – Patients with chronic spontaneous urticaria (CSU) that is not controlled by higher-dose, nonsedating H1 antihistamines in combination with other standard therapies (additional H1 antihistamines, H2 antihistamines, and/or antileukotriene drugs) should be referred to an allergy or dermatology specialist for consideration of advanced therapies rather than receiving repeated courses of oral glucocorticoids. (See 'Overview' above and 'Referral' above.)
●Omalizumab – For patients with CSU who have significant symptoms despite maximal doses of nonsedating H1 antihistamines, we recommend adding omalizumab therapy in preference to other agents, with the understanding that the cost of this medication may be prohibitive in many settings (Grade 1A). We initiate omalizumab at a dose of 300 mg injected subcutaneously every four weeks. (See 'Omalizumab' above.)
●Other therapies – With the exception of omalizumab, the effectiveness of the other therapies discussed in this review is supported by low-quality evidence, and the approach presented is largely based on clinical experience. In addition, there are no biomarkers or clinical features that are useful in selecting one therapy over another for a specific patient. (See 'Other therapies' above.)
●Cyclosporine or tacrolimus – For patients who have not achieved adequate relief with the combination of higher-dose H1 antihistamines and omalizumab or do not have access to omalizumab, we suggest a calcineurin inhibitor (ie, cyclosporine or tacrolimus) (Grade 2C). We start cyclosporine at a dose of 3 mg per kg, divided into two doses daily, or tacrolimus at 1 mg twice per day. Blood pressure, blood urea nitrogen, and creatinine should be monitored. (See 'Cyclosporine' above and 'Tacrolimus' above.)
●Additional options – Other generally well-tolerated therapies include mycophenolate, dapsone, sulfasalazine, and hydroxychloroquine. (See 'Other therapies' above.)
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