The Evidence-based Management of Chronic Urticaria

A review of the various guidelines on the treatment of chronic urticaria shows there is limited evidence demonstrating the efficacy of many commonly used medications, with the strongest evidence supporting the use of one or more second-generation antihistamines.

During a session at the 2014 Annual Meeting of the American Academy of Allergy, Asthma & Immunology, held February 28 — March 4, 2014, in San Diego, CA, Javed Sheikh, MD, from the Kaiser Permanente Los Angeles Medical Center, reviewed several stepwise (three-step and four-step) treatment algorithms that have developed for chronic urticaria with (CUA) or without (CU) angioedema and published in recent guidelines.

Sheikh covered several guidelines in his presentation, including the 2007 British Society for Allergy and Clinical Immunology guidelines for the management of chronic urticaria and angio-oedema, the guidelines on the diagnosis and therapy of chronic urticaria that were developed at the 4th International Consensus Meeting on Urticaria in 2012, and the Urticaria Practice Parameter Update 2014, edited by Bernstein, Lang and Khan and submitted to the Journal of Allergy and Clinical Immunology (JACI).

Both GRADE criteria and Categories of Evidence (from I through IV) have been employed for these guidelines but the evidence base for treatment of urticaria is based on limited data and lack of FDA and other regulatory agency approval for the various treatments available. Unfortunately, much of the evidence falls in the level IV category, meaning the quality of evidence is low and the strength of recommendation weak. This type of evidence is derived from recognized expert opinions or consensus reports rather than from the ideal based on data from one or more randomized clinical trial.

The criteria for the GRADE system for rating quality of evidence and strength of recommendations are evolving. They now include not only the category and quality of evidence but also incorporate risk assessment and cost-benefit evaluations, as well as patient values and preferences.

Sheikh noted that many treatment options for urticaria are supported by only low-to-moderate strength evidence demonstrating efficacy. For example, in the WAO Journal position paper, “Diagnosis and Treatment of Urticaria and Angioedema: A Worldwide Perspective,” Sanchez-Borgez et al, made only two recommendations for which the quality of evidence was rated as “high” by the GRADE system. They issued a strong positive recommendation for the use of second-generation antihistamines “at licensed doses” in the treatment of urticaria, noting that “A number of high-quality, randomized, controlled trials have been carried out with these drugs in patients with mild/moderate urticaria. Evidence of their effectiveness is very high. They are also safe and well-tolerated.” The authors issued a strong negative recommendation against the use of first-generation antihistamines in the treatment of urticaria, noting that although first-generation antihistamines have been recommended as add-on therapy to chronic urticaria patients who have had inadequate control on second-generation antihistamines, “studies to demonstrate efficacy of this approach are lacking.” They concluded that “first-generation antihistamines do not provide additional benefits to those obtained with nonsedating antihistamines.”

In addition, Sanchez-Borgez et al noted that there is only low to moderate-strength evidence supporting the use of cyclosporine and other immunosuppressive agents, IGIV, and omalizumab and thus these agents were only weakly recommended.

The proposed stepwise algorithm submitted to the JACI in 2014 was summarized by Sheikh as follows:

Step 1: Monotherapy with second-generation antihistamine, avoidance of triggers (eg, NSAIDs) and physical factors if relevant.

Step 2: One or more of the following -- dose advancement of second-generation antihistamine used in Step 1, add another second-generation antihistamine, add an H2-antagonist, add a leukotriene receptor agonist, and/or add a first-generation antihistamine to be taken at bedtime.

Step 3: Dose advancement of a potent antihistamine (hydroxyzine or doxepin) as tolerated.

Step 4: If the patient is refractory to treatments up to Step 3, add an alternative agent such as an anti-inflammatory drug (dapsone, hydroxychloroquine, sulfasalzone), an immunosuppressant (cyclosporine, mycophenylate, tacrolimus, methotrexate), or a biologic (omalizumab and others).

Alternative procedures or agents include phototherapy, theophylline, beta-agonists, cromolyn, and plasmapheresis.

With respect to cyclosporine, the quality of the evidence supporting its use in this context, even though there is data from several randomized clinical trials, is not considered robust and the treatment is therefore weakly recommended. Systemic steroids are only recommended for the short-term treatment of urticaria. Sheikh also noted there is a lack of high-quality evidence for the efficacy of thyroid hormone supplementation for euthyroid chronic urticaria patients in the absence of thyroid autoimmunity.

Finally, Sheikh reviewed data from two phase III clinical trials on omalizumab treatment for uritcaria. He said the evidence suggests a dose of 300 mg appeared to show sustained efficacy with low incidence of severe adverse events that are comparable to those seen in the control cohorts.