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"Medical Journeys" is a set of clinical resources reviewed by physicians, meant for the medical team as well as the patients they serve. Each episode of this journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease."

The reflects worldwide consensus on the classification, diagnosis, and treatment of urticaria, with the expert advice updated every 4 years.

Many of the recommendations in this 2021 document -- a joint initiative of the European Academy of Allergology and Clinical Immunology; the Global Allergy and Asthma European Network; the European Dermatology Forum; and the Asia Pacific Association of Allergy, Asthma and Clinical Immunology -- have not changed from the 2018 version. The overall treatment goal remains complete control of urticaria -- i.e., "treat urticaria until it is gone" -- while keeping in mind the safety and quality of life of each individual patient. The mainstay of treatment for both children and adults continues to be the avoidance and elimination of triggers.

Several key revisions have implications for routine clinical practice and for the management of chronic spontaneous urticaria (CSU) in particular. The therapeutic algorithm has been streamlined from 4 steps to 3, and for the first time physicians are advised to make treatment decisions based on continuous assessment of urticaria activity, quality-of-life impairment, and disease control.

"In this area, the newest version of the international urticaria guideline is more precise and comprehensive than previous versions," noted the authors of a .

"Patients should be assessed for disease activity, impact, and control at the first and every follow-up visit, and six validated patient-reported outcome measures are recommended," wrote Torsten Zuberbier, MD, of Charité–Universitätsmedizin in Berlin, and colleagues.

Control Tests

Physicians are strongly encouraged to take an "as much as needed and as little as possible' approach to achieve complete disease control based on results of the urticaria control test (UCT), the review notes. "This implies stepping up or stepping down the treatment algorithm according to the course of disease following the principle assess, adjust, act, and reassess."

The angioedema control test (AECT) is now recommended for patients with CSU who develop angioedema, with or without wheals, and both the UCT and the AECT should be used in patients with wheals and angioedema, the guideline notes. It also emphasizes the importance of "good counseling" to help patients understand the need for continuous treatment, and the use of tools such as the urticaria activity score (UAS) and the 7-day urticaria activity score (UAS7) to reinforce this message.

First-line Treatment

Second-generation histamine type 1 (H1) antihistamines (sgAHs), which are non-sedating, remain the recommended first-line therapy for all types of urticaria.

At standard doses, the evidence supports the effectiveness and safety of daily rather than on-demand use of bilastine (Blexten), cetirizine (Zyrtec), desloratadine (Clarinex), ebastine (Ebast), fexofenadine (Allegra), levocetirizine (Xyzal), loratadine (Claritin), and rupatadine (Rupafin).

Short-term prophylactic antihistamine treatment prior to trigger exposure is also useful in patients with chronic inducible urticaria (CIndU).

"These are preferred over first-generation antihistamines for they selectively block peripheral receptors, therefore causing fewer side effects, including sedation and anticholinergic effects," wrote the authors of a 2023 .

CSU Unresponsive to Standard Second-Generation Antihistamines Dosing

In patients with CSU unresponsive to standard sgAH dosing, the guideline recommends up to a fourfold increase in dose. The addition of a different sgAH is not recommended, and there is no recommendation for or against the combined use of H1 and H2 antihistamines. In patients with acute urticaria or acute exacerbations of CSU, the guideline acknowledges that a short course of oral corticosteroids, up to a maximum of 10 days, may reduce disease duration.

"Antihistamines are considered safe overall, but they don't control urticaria in a large subset of patients," said Jonathan I. Silverberg, MD, PhD, MPH, director of clinical research at George Washington University School of Medicine and Health Sciences in Washington, D.C. Most of the novel targeted therapies for urticaria currently under investigation are focused on antihistamine-refractory and/or omalizumab (Xolair)-refractory CSU, he told MedPage Today.

Some patients with CSU respond incompletely to antihistamine updosing. In a 2016 , only 63.2% of CSU patients had complete remission of symptoms following a 2- to 4-fold sgAH dose escalation. Although control of pruritus was significantly improved, the number of wheals was not.

Omalizumab

For incomplete disease control (UCT<12) after 2-4 weeks on a high-dose sgAH, the guideline recommends adding second-line omalizumab at a starting dose of 300 mg every 4 weeks. Omalizumab, a humanized monoclonal anti-immunoglobulin E (IgE) delivered by subcutaneous injection, was approved by the FDA for antihistamine-resistant CSU in 2014. Since then, the agent has been widely used for off-label treatment of all subtypes of chronic urticaria.

"Pre-Xolair, we really had very few treatments," Silverberg said. "Immunosuppressants didn't really work, antihistamines were inadequate, and topical medications didn't have a great role."

Omalizumab is highly effective and safe for treating CSU, preventing the development of wheals and angioedema, and markedly improving quality of life. Omalizumab is also effective for treating disease relapse after discontinuation, as well as for treating different subtypes of CIndU, including cholinergic urticaria, cold urticaria, solar urticaria, heat urticaria, symptomatic dermographism, and delayed pressure urticaria.

In CSU patients who have an incomplete response to omalizumab, the dose can be increased to a maximum of 600 mg every 2 weeks at intervals of 2-4 weeks, or sooner if symptoms become unbearable. Alternatively, the guideline recommends shortening the interval between doses.

A 2020 review of studies on showed improved clinical response with a good safety profile when dose adjustment was based on UAS and UCT results. Patients with a high body mass index may benefit the most from omalizumab updosing, and real-life experience has shown that the associated adverse events are no more severe or frequent compared with those in patients taking the recommended starting dose.

Alternative Treatments

Still, some experts caution that alternative treatment options are needed, including safer and more effective oral therapies for second- and even third-line use. "Omalizumab is certainly a good therapy, but it's also associated with an inadequate response in a number of patients, and there's a theoretical concern about anaphylaxis," Silverberg noted.

"Although antihistamines and omalizumab are recommended, many patients tend to be refractory to these therapies and continue to experience hives and pruritus," the authors of the 2023 review noted. They added that other treatments such as oral dapsone, dupilumab (Dupixent), and tumor necrosis factor alpha inhibitors have also been helpful for some patients.

In patients with severe CSU refractory to any dose of antihistamine in combination with any dose of omalizumab, the guideline recommends the addition of third-line cyclosporine, up to 5 mg/kg, to an sgAH until there is a complete response.

"Treatment of urticaria with cyclosporine has shown positive outcomes in case studies and clinical studies, including double-blind placebo-controlled studies," the review authors said. "It should be noted, however, that there are potential risks associated with cyclosporine."

In a 2017 review of , that drug was effective at low and moderate doses, but adverse events such as nephrotoxicity and hypertension appeared to be dose-dependent, occurring in more than half of patients on moderate doses. The guideline recommends monitoring blood pressure and renal function every 6 weeks during treatment with cyclosporine.

The long-term use of systemic glucocorticosteroids in chronic urticaria is not recommended, but the guideline suggests that a short course of rescue systemic glucocorticosteroids may be considered in patients with an acute exacerbation.

Treatment step-down and assessment of spontaneous remission is recommended in patients treated with high-dose antihistamines who have complete disease control (UCT=16 or UAS7=0) for at least 3 consecutive months. "Step-down protocols should bring on board individual patient needs and, in general, be implemented with prudence and patience," Zuberbier and co-authors said.

When treatment step-down interferes with disease control, the guideline recommends reinstating antihistamines at the last dose that provided complete disease control.

In a, published shortly after the new guideline, Marcus Maurer, MD, of Charité–Universitätsmedizin Berlin, and colleagues wrote that "the guideline provides a step-up algorithm for achieving complete disease control, but not a step-down algorithm."

"Currently, no clear consensus exists on how to step down and discontinue CSU treatments," the team explained.

The authors of a 2023 review of the in CSU agreed: "As of now, it is unclear over which period, with what intervals, and with which dosages CSU treatment should be stepped down."

Based on a 2024 of 103 physicians in 34 countries, most national guidelines don't provide detailed information on when or how to discontinue treatment for CSU either. Information was lacking on antihistamines and cyclosporine; nearly all respondents step down omalizumab within 6 months from the first controlled status.

"This [lack of guidance] needs to change," the researchers said, noting that they have now designed their own step-up/step-down CSU treatment algorithm. "We call on the guideline expert panel to consider including guidance on stepping down the treatment in the next update and revision of the guideline," the team wrote.

Read previous installments in this series:

Part 1: Urticaria/Hives: The Search Continues for Causes

Part 2: Keys to Diagnosis of Urticaria

Part 3: Chronic Spontaneous Urticaria and Autoimmunity

Part 4: Case Study: Terrible Recurrent Itchy Wheals All Over This Woman's Body

Part 5: Managing Comorbidities in Chronic Urticaria