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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.

In a 1954 in the Journal of Allergy and Clinical Immunology, a trio of specialists referred to the management of urticaria, hives, as "the vexing problem."

Recognizing and treating the symptoms is "usually quite simple," wrote John M. Sheldon, MD, Kenneth P. Mathews, MD, and Robert G. Lovell, MD, all then at the University of Michigan Medical School in Ann Arbor. "However, good long-term results require the physician to exert every effort to determine the etiology of the hives in each individual case."

Now, almost 70 years later, the cause of urticaria -- characterized by the sudden eruption of itchy raised wheals on the skin, with or without angioedema -- remains unknown in 50% of acute cases, and 80-90% of chronic urticaria. The classifies acute urticaria as daily or almost daily symptoms lasting 6 weeks or less, and chronic urticaria as symptoms that wax and wane for longer than 6 weeks.

"It's a puzzle and we're constantly trying to fit the pieces together," said Jenny Murase, MD, of the University of California, San Francisco.

The diagnosis of urticaria is clinical, with a clinical presentation that is similar across age groups, ethnicities, and genders. However, identifying the cause is tricky, and certainly not a "one-visit thing," warned Alison Ehrlich, MD, MHS, of Foxhall Dermatology and Research Center in Washington, D.C.

"We have to be careful about dismissing cases as chronic idiopathic," Ehrlich told MedPage Today. "Taking a good history is essential and it's really important to see patients for follow-up. You may never identify the trigger, or it might turn up later. What's important is continuing to listen to your patients and working with them. Think of 'zebras,' too."

In 40% of cases, urticaria is accompanied by angioedema, and the risk of life-threatening anaphylaxis must be ruled out. Clinicians must also differentiate urticaria from other conditions and diseases that present with wheals and angioedema, including autoinflammatory syndromes, urticarial vasculitis, and bradykinin-mediated hereditary angioedema.

Different subtypes of chronic urticaria can be present in the same patient, and in 1% of cases, urticaria can be a sign of serious underlying autoimmune disease. So-called chronic spontaneous urticaria (CSU) related to COVID vaccinations has also been in a number of studies.

Although second-generation, non-sedating, histamine type 1 (H1)-receptor antihistamines are standard first-line therapy for all types of urticaria, a significant proportion of patients with chronic urticaria are refractory to antihistamines, and some to second-line therapy with omalizumab (Xolair), a monthly injectable.

"There are still a lot of unmet needs for sure," said Jonathan I. Silverberg, MD, PhD, MPH, of George Washington University School of Medicine and Health Sciences in Washington, D.C. "We don't have anything [for urticaria] that is curative or remittive, and even when patients do well on current therapies, they come off and go back to square one."

In patients with severe refractory hives, the recommends the off-label use of cyclosporine rather than long-term steroids until a complete response is achieved.

"We need alternate options for second- or even third-line treatment, including more oral options that are safe and effective," Silverberg told MedPage Today. Of the many new targeted therapies for urticaria currently in the pipeline, most are focused on antihistamine-refractory and/or omalizumab-refractory CSU.

"I think there should be a paradigm of 'treat to clear,' not just 'treat to control,'" said Ehrlich. "You want your patients to be free of hives. Maybe then they won't have to be on medication for hives for the rest of their lives."

The pathogenesis of urticaria is complex, but the principal driver is the activation of skin mast cells by exacerbating factors such as infection, drugs, foods, and immune system alterations. Mast cell degranulation and the release of histamine and other inflammatory mediators result in the rapid development of raised, round, papules, often with erythema in the surrounding skin. These lesions multiply and coalesce into annular wheals ranging in size from several millimeters to 10-20 centimeters, and can migrate, cropping up in one area only to disappear and reappear in another.

"Mast cells are like firecrackers under the microscope," said Murase. "They're full of packets of histamines, and when they are triggered, degranulate, and explode, the membrane stays twitchy for about 3 months."

Acute urticaria -- thought to be associated with to foods, drugs, and other allergens -- is most often seen in children 5 years of age and younger. It tends to have a benign, self-limited course, and two-thirds of cases resolve within 1 week. Risk factors include high population density and a personal and family history of allergic disease. Infection, mainly of the upper respiratory tract, is the most common comorbidity as well as the cause in 30-40% of cases.

Acute idiopathic urticaria becomes chronic in 5-39% of cases. Chronic urticaria is twice as prevalent in women compared with men, and the incidence peaks between the ages of 20 and 40 years. Symptoms continue daily or almost daily or take an intermittent/recurrent course for 1-5 years, often with devastating impact on quality of life.

"The quality-of-life impact of urticaria, if you consider severe chronic pruritus alone, is somewhere between undergoing a kidney transplant and having cystic fibrosis," said Murase.

Ehrlich herself experienced a severe allergic reaction to alpha-gal (galactose-α-1,3-galactose), a sugar found in red meat, that lasted for 72 hours. She recalls being covered in hives and exhausted from lack of sleep. When new patients report feeling miserable, she gets it. "The impact of urticaria is enormous and needs to be taken seriously," she said, adding, "I think we miss cases."

The two major subtypes of chronic urticaria -- chronic spontaneous urticaria (CSU) and chronic inducible urticaria (CIndU) -- have an estimated incidence of 0.5%–1% in the U.S. and Europe. CSU accounts for 60% to 90% of all chronic urticaria cases, with driven by a series of mast cell-activating events that involve autoantibodies, cell infiltration, coagulation factors, and complement.

The signs and symptoms of CSU arise without definite triggers, but aggravating factors such as stress may increase risk in some patients. About 57% of patients with CSU present with wheals, 37% with wheals and angioedema, and 6% with angioedema alone.

By contrast, the pathogenesis of CIndU is largely unknown, but the signs and symptoms are driven by definite, subtype-specific triggers. Within the broad CIndU subcategory of chronic physical urticaria, the subtypes include:

• Symptomatic dermographism (previously known as urticaria factitia or dermographic urticaria)

• Cold/cold contact urticaria

• Delayed pressure/pressure urticaria

• Solar urticaria

• Heat/heat contact urticaria

• Vibratory angioedema urticaria

Other CIndU subtypes are cholinergic urticaria, contact urticaria, and aquagenic urticaria.

The duration of chronic urticaria varies significantly by subtype, with a median of 1-4 years to clinical remission in CSU vs 20 years in 73% of CIndU cases. However, diagnostic delays are common in CSU, and while half of untreated patients go into remission within the first 12 months, as many as 11% struggle with symptoms for more than 5 years prior to diagnosis. CSU can also recur years after remission.

Urticaria is linked to a number of comorbidities, including sleep disturbance, social isolation, and anxiety and depression. Recently, the American Academy of Dermatology (AAD) acknowledged urticaria as a comorbidity of atopic dermatitis in adults. The authors of the noted that the pruritus associated with chronic urticaria may potentiate the itch-scratch cycle in atopic dermatitis, resulting in worsened dermatitis.

"It can go both ways," said Silverberg, one of the guideline authors. "This is not to necessarily say that they're causing each other, but that they can co-occur in patients as well."