Urticaria: An Elusive Disorder With 'a High Unmet Need for Treatment'

Doug Brunk

March 03, 2022

In the clinical experience of Adam Friedman, MD, when patients present with acute urticaria, the culprit is usually food, a drug, or a bug.

Dr Adam Friedman

But in some cases, the trigger remains elusive. "We don't always find the source, but don't beat yourself up about it," Friedman, professor and chair of dermatology at George Washington University, Washington, said at the ODAC Dermatology, Aesthetic, and Surgical Conference. "The basic rule is to treat patients to clearance and keep them clear."


Chronic urticaria is characterized by plaques with a burning/itch sensation that often "move" to different locations on the body over minutes to hours, and they typically last for less than 24 hours. The plaques are often oval, round, or irregular in shape and they typically leave no postinflammatory pigmentary alteration or scarring other than from scratching.

Urticaria affects an estimated 20% of the population, Friedman said, and is more common in females than males. More than two-thirds of cases are self-limiting but 10% can persist longer than 5 years. Acute episodes are more likely to have an identifiable trigger, while chronic episodes, which last more than six weeks, typically do not. The longer the duration, the lower the chance of identifying the root cause. The foods/food products most commonly affecting children with acute urticaria include milk, egg, peanut, wheat, and soy, while the common culprits in adults are tree nuts, peanuts, and shellfish. Other triggers include the yellow food dye annatto, the red food dye carmine, contact with raw fruits or vegetables, animal saliva, and certain detergents or perfume.

"When you have no idea what the cause is for acute urticaria, I think about viral or bacterial infections, especially in children," Friedman said, particularly mycoplasma, adenovirus, enterovirus, rotavirus, respiratory syncytial virus, Epstein-Barr virus, and cytomegalovirus. COVID-19 has also been a new etiologic source for a recent rise in acute urticaria cases.

Other causes include certain medications such as antibiotics, opiates, muscle relaxants, salicylates, and NSAIDs; stinging insects; and exposure to latex products, which can cross react with passion fruit, banana, avocado, chestnut, and kiwi. Alcohol consumption can also trigger urticaria.

"Ask patients if they have joint discomfort or pain," Friedman advised, referring to urticaria arthritis syndrome that is typically seen more often in women than in men. "It's rare but important, because that may distinguish for you what is needed to get those patients under control."

Chronic urticaria develops in 20%-45% of patients who present with acute urticaria. One form of chronic urticaria is inducible urticaria, which spontaneously occurs after an exposure to an external force. "The distinguishing feature here is that it doesn't last long – 30 minutes or so – and is typically unresponsive to corticosteroids," Friedman said. "It comes on quickly but disappears quickly whereas with chronic spontaneous urticaria, someone might be getting those wheals of flare for hours and hours."

The most common form of physical urticaria is dermatographism, while other examples include physical urticaria resulting from exposure to cholinergic agents, heat, exercise, cold, water, sunlight, and pressure on the skin.

About half of patients with chronic urticaria are disease free within 1 year, but 20% continue to experience episodes for more than 10 years. One study found that patients with chronic spontaneous urticaria who were diagnosed at a younger age trended toward a longer disease course, and rates were higher in women, compared with men. "Perceived stress can make this worse," Friedman added.

According to Friedman, it's more important to ask patients targeted questions during office visits than it is to do a full workup. "I ask patients to keep a diary, which can help them identify triggers if there are any," he said. "I also ask them to take a picture of the papules with their smartphone. There can be a genetic association, so it's important to ask if anyone else in the family has urticaria. No routine lab tests are required unless there's something in the history that suggests it's worthwhile. Let the patient guide the diagnostic workup; don't just order a million tests."

That said, known comorbidities associated with urticaria include autoimmune disease, atopy, infections, metabolic conditions, and neoplastic disorders. "Biopsies are typically useless because this is an invisible dermatosis," he said. "They're useful when it's urticarial, not urticaria, when you're trying to figure out what it is."

According to recently published international guidelines on urticaria, published in September 2021, the recommended first line of treatment for urticaria is with second-generation nonsedating antihistamines such as cetirizine and loratadine, up to four times the recommended dose.

Second-generation derivatives include desloratadine, levocetirizine, and fexofenadine. "I like using fexofenadine in the morning for folks who don't tolerate cetirizine, then I'll recommend something a little more sedating at night," Friedman said. "We max out [the dose] by week 4. If it works, great. If not, we move on to something else."

In late 2021, the British Association of Dermatologists also published guidelines on the treatment of chronic urticaria.

As for markers of treatment success, a study of 240 children with chronic spontaneous urticaria found that risk factors for a poor response included longer duration of disease, higher treatment step until initial disease control, and food sensitization.

Vitamin D supplementation may also add some benefit. One study of 42 adults with urticaria found that low and high doses of vitamin D added to antihistamine therapy can boost effectiveness. "This may be because vitamin D could be a marker of severity," Friedman said. "The reality is, however, that a lot of patients don't do well."

Data from the large, prospective study known as AWARE (A World-Wide Antihistamine-Refractory Chronic Urticaria Patient Evaluation) found that 23% patients treated with nonsedating H1-antihistamines and 42% patients treated with up-dosed nonsedating H1-antihistamines had uncontrolled chronic spontaneous urticaria at month 24.

A second-line treatment option for patients aged 6 and older is the anti-IgE antibody omalizumab, 150-300 mg by subcutaneous injection every 4 weeks. Friedman typically uses only the 300-mg dose. "You do not need to take pretreatment serum IgE levels," he said. "The most significant adverse event is anaphylaxis, which only affects 0.2% of patients."

A third-line option is cyclosporine A. A dose of 3-5mg/kg per day appears to benefit about two-thirds of patients with antihistamine recalcitrant chronic urticaria. "It works fast but you can't keep patients on it for very long," he said.

Another third-line option is mycophenolate mofetil, which may work by inhibiting the production of autoantibodies to the high-affinity IgE receptor and/or IgE. "It does work well, especially in conjunction with antihistamines; it's kind of a softer immunosuppressant," he said. Methotrexate can also be used as an add-on therapy to H1 antihistamine therapy in difficult-to-treat cases.

"It's great we have [a Food and Drug Administration]–approved biologic therapy in omalizumab and access to over-the-counter antihistamines, but there is a high unmet need for treatment," and a need for new therapies, Friedman said. "Only about 39% achieve symptomatic control with conventional dosing of antihistamines, and 63% of nonresponders achieve symptom control with a fourfold increased dosing of antihistamines." In addition, about 20% of patients will not respond to either standard or increased doses of antihistamines and are eligible for treatment with omalizumab. However, more than 50% of such patients experience a delay or lack of response to omalizumab. "We need innovation; we need to understand the disease better," he said.

Friedman disclosed that he serves as a consultant and/or adviser for Loreal, La Roche Posay, Cerave, Galderma, Aveeno, Microcures, Pfizer, Novartis, Dermira, Brickell Biotech, Incyte, UCB, Janssen, Pfizer, Bristol-Myers Squibb, Almirall, Zylo Therapeutics, Hoth Therapeutics, Corbus, Greenway Therapeutics, TruPotency, and Dermavant. He is a speaker for Regeneron/Sanofi, AbbVie, Janssen, Brickell Biotech, and Incyte, and has received grants from Pfizer, the Dermatology Foundation, Incyte, and Galderma.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.


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