Theodore Rosen, MD, in practice in Houston, TX, discussed the latest treatment options for the management of chronic urticaria with attendees at the Winter Clinical Dermatology Conference Hawaii in January 2015. 
Theodore Rosen, MD, in practice in Houston, TX, discussed the latest treatment options for the management of chronic urticaria with attendees at the Winter Clinical Dermatology Conference Hawaii in January 2015.
Urticaria is a wheal and flare reaction initiated at the level of the small venules of the skin in response to substances that then cause: vasodilation, increased vascular permeability and stimulate type C unmyelinated afferent cutaneous neurons releasing neuropeptides (leading an axon reflex).1
Cases of urticaria can be very challenging to treat, Dr. Rosen noted. There are things that look like urticaria that are not urticaria (Table 1). Numerous characteristics can help yield a diagnosis.
One percent to 25% of the population at some point in their lifetime has had urticaria, he said. Urticaria is often transitory (individual lesions have <24 hour duration). Itching is the predominant symptom and there is no desquamation. “The literature says it’s associated with angioedema in up to 40% of the cases. I don’t think that’s exactly true, at least not in my experience, but it certainly can happen with acute urticaria and chronic urticaria. Most of the cases are acute, less than 6 weeks. Fewer are chronic,” Dr. Rosen explained.2-5
The term urticaria encompasses many variations of the condition. The talk focused on ordinary urticaria, which can be acute or chronic.
Acute Urticaria
About 75% of all cases of urticaria are acute. While the condition is common in children, all ages can be affected. Most cases of acute urticaria have an abrupt onset and are usually pruritic and widespread. Angioedema is also common. Duration usually lasts hours or days.6,7 “There is often, more often than not, a clearly identifiable cause. A good history is the most important thing,” said Dr. Rosen. This includes viral infections, particularly in children, drugs being stopped or started (Figure 1), foods (both on an allergic and a non-allergic basis), following immunization (vaccines) and immediate contactant urticaria. (Table 2).
Lab work is rarely needed for acute urticaria. Instead a good history can be taken and an antihistamine prescribed to be used until it clears, Dr. Rosen said.
Figure 1. Acute urticaria can be caused by medication being stopped or started, such as this patient who received amoxicil- lin. (Pick up from The Consultant boy with hives)
Chronic Urticaria
Urticaria that lasts 6 weeks or more is classified as chronic urticaria. A number of disease states fall under chronic urticaria, however, Dr. Rosen focused on chronic idiopathic urticaria.
About 50% of patients resolve in 6 months, while greater that 50% will resolve in 12 months or less. Another 20% will resolve in 12 to 36 months, while 20% will resolve in 36 to 60 months. Still others may resolve after a very long time — even after 25 years, he noted. The rate of reoccurrence is also high at 25% to 40%.8-11
“It may go away, everybody is happy, and it comes back, like a bad penny. It bounces back,” he said, noting that the majority of cases totally resolve eventually.
Pathophysiology
Most types of urticaria are due to activation of dermal mast cells, although basophils may also be involved, he noted. Release of histamine and other mediators (including eicosanoids, proteases and cytokines) cause local vasodilation and vasopermeability, fibrin deposition and very mild perivascular mixed cellular infiltration. Histologically, there is minimal endothelial swelling and no leukocytoclasis.
Chronic physical urticaria comprises about one-third of chronic urticaria. The most common physical urticaria is dermatographism, which is characterized by generalized pruritus and linear red wheals that are aggravated by scratching, rubbing and wearing of tight, course clothes (Figure 2). Firm stroking of uninvolved skin causes immediate linear red wheal and itch. However, the mucous membrane is unaffected and there is no angioedema. Treatment includes low to minimally sedating H1 antihistamines.12-16
Figure 2. Dermatographism is the most common type of physical urticarial. It is characterized by generalized pruritus and linear red wheals that are aggravated by scratching, rubbing and wearing of tight, course clothes. (Pick up from consultant hives with scratches)
“Interestingly, some patients do not respond to that treatment and a nice alternative narrowband (NB) UVB therapy17 is actually quite effective,” he said noting it is not always available, and can be expensive and inconvenient.
Urticaria is more common in women. For chronic idiopathic urticaria, the ratio is 70/30 women.18
Overall, chronic urticaria is associated with functional thyroid disease. Hypo-hyperthyroidism occurs in about 20% of patients, while Hashimoto’s thyroiditis occurs in about 15%.4,19,20 “One out of 3 chronic idiopathic urticaria patients may have some degree of thyroid dysfunction. You should always ask the appropriate questions.
And, frankly, I think you should do a little thyroid screening on all of these patients,” he said.
Chronic ordinary urticaria impacts quality of life and is economically costly due to absenteeism and cost of medications. One study found that the impairment of quality of life due to the condition was equal to the magnitude to that experienced by patients with triple coronary artery disease waiting for by pass surgery.21-23
Dr. Rosen noted that patients with chronic urticaria are over-investigated. One study with 356 patients included 1,872 lab tests and only 1 patient had a significant abnormality that modified or affected the therapy.24 He recommended complete blood count, SMAC and in some cases a chest x-ray. For thyroid function, the thyroid-stimulating hormone screening test can be done as well as the thyroid antibody screen.
“If patients have arthralgia and their SED rate is very high you might want to consider a biopsy for urticarial vasculitis,” he said.
Management of Chronic Urticaria
Patients should avoid triggers that worsen hives, which can be varied. These can include opiate narcotics, non-steroidal anti-inflammatory drugs, alcohol, overtiredness or stress, strenuous physical exercise and overheated ambient temperatures.25,26
Although there is a significant difference between European and American recommendations for published guidelines for pharmacotherapy, a stepwise approach is agreed upon. In the United States, the recommendations for treatment include monotherapy with H1 antagonists at standard dose (non-sedated, or minimally sedated). If that is unsuccessful, the dose is increased or a second H1 or H2 is added, or on the way to H1, a leukotriene antagonist is added.
“For antihistamines, the dose can be increased, up to 3 to 4 times the standard dose. For example, if the standard dose is 10 mg of cetirizine give them up to 40 mg. They are safe, even in that high a dose. The H2 antihistamines are not good monotherapy because there aren’t a whole lot of H2 receptors in the skin,” he said.
A standard dose of sedating antihistamine could be added at night. Dose advancement of sedating antihistamine at bedtime, as tolerated, is also recommended. Sedating antihistamines require a patient warning concerning operating machinery in the morning, he added.
The next line of therapy would be alternate agents, such as cyclosporine-A or omalizumab (Xolair, Genentech Inc.). “Cyclosporine does a much better job for autoimmune urticaria than it does for chronic idiopathic urticaria,” he said.
Finally, alternative immunomodulators, like methotrexate or mycophenolate, can be considered.27 “Methotrexate is usually given in a single week. We dose 1 mg to 25 mg. Mycophenolate is dosed at about 2 g. They are add-ons in addition to your standard dose of antihistamine to try to get control,” he said.
“Along the way if it’s absolutely intolerable for the patient, and nothing seems to be working, you can consider short courses of corticosteroids, which can be given for 7 to 10 days,” he said.
European guidelines are more streamlined. “Patients are given a second-generation agent (the modestly sedating or non-sedating antihistamines, at standard doses). If that isn’t effective, increase the dose and if that doesn’t work go to omalizumab, cyclosporine or montelukast,” he said noting that if this treatment fails then the patient could do a short course of steroids if needed.
One small head-to head treatment study,18 compared antihistamines, steroids and cyclosporine treatments for chronic idiopathic urticaria, and found that antihistamines and steroids work better than cyclosporine. “If you look at autoimmune urticaria, a very small and unusual subset of chronic urticaria, steroids work better than the antihistamines. Cyclosporine works the best,” he noted.
New Treatment
The newest drug for chronic idiopathic urticaria is omalizumab, a monoclonal antibody direct anti-IgE. It binds to the spot where the IgE would normally bind to its receptor on mast cells. Omalizumab is administered as monthly subcutaneous injections and is indicated for the treatment of chronic idiopathic urticaria in adults and adolescents 12 years of age or older when H1 antihistamine therapy has failed.
A risk of anaphylaxis exists but was not observed in chronic idiopathic urticaria trials; however, it has been observed in conjunction with asthma, said Dr. Rosen. “Therefore, after the first dose the patient should stay and be observed for several hours. This medication is administered in the healthcare provider setting; it’s not self-injection. And after that 30 minutes there’s the warning,” he said.
Dr. Rosen noted that anaphylaxis includes a wide spectrum of symptoms, such as flushing, heat and nausea as well as not being able to breathe. “Not all people get the worst and in the chronic idiopathic urticaria studies there were none.”
Three major studies28-30 have been published regarding treatment of chronic idiopathic urticaria with omalizumab. Several of the studies include standard H1 antihistamines, and 1 study29 included patients who had chronic idiopathic urticaria for 6 to 7 years and were on 4 to 6 drugs, and they had a very high score for itching and hives over 7 days.
In the study,29 omalizumab was well-tolerated and reduced the signs and symptoms of chronic idiopathic urticaria/chronic spontaneous urticaria in patients who remained symptomatic despite the use of H1-antihistamines (up to 4 times the approved dose) plus H2-antihistamines, leukotriene receptor antagonists or both. Treatment might continue passed 24 weeks, the duration of the study, he said. “With the higher dose, in particular the longer you give it you have up to 40% of patients who achieve a score of zero on itching and hives,” he added.
In summary, a stepwise approach to treatment can help most patients find relief. Omalizumab is a positive addition to the other therapy options for the worst urticaria patients.
Disclosure: Dr. Rosen is a consultant for Genentech.
References
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