Approach Considerations
Nonsedating anti-H1 antihistamines remain the mainstay of treatment for chronic urticaria. If these agents are ineffective, higher dosages may be tried (up to four times the standard recommended dosage), or other agents may be substituted (see below). Combined therapy with antihistamines or an immunosuppressive agent (eg, omalizumab, methotrexate) may be required. [33, 34, 35, 36, 37]
Elimination of suspected triggers should be advocated. Avoidance of mental stress, [32] overtiredness, alcohol, nonsteroidal anti-inflammatory drugs (NSAIDs), and tight-fitting garments is recommended. Psychological stress can trigger or increase itching. [32] Nocturnal pruritus may be reduced by lukewarm bathing and keeping the ambient temperature of the bedroom cool. Application of lotions with menthol and phenol provide prompt relief of pruritus for some patients.
Pharmacologic Therapy
Antihistamines
The mainstay of pharmacotherapy for chronic urticaria is the administration of low-sedation anti-H1 antihistamines (eg, loratadine, cetirizine, levocetirizine, and fexofenadine), which have a low incidence of adverse effects. [38, 39] Quality of life appears to be improved more by daily therapy than by therapy administered on an “as needed” basis. [40]
Low-sedation antihistamines decrease the intensity of hives and pruritus in patients with mild chronic urticaria and are considered first-line therapy. Crossover studies comparing the suppression of skin papule and erythema formation induced by intradermal histamine injection after a single antihistamine dose suggest the following order of inhibitory effect: (1) levocetirizine, (2) cetirizine, (3) terfenadine, (4) fexofenadine, and (5) loratadine.
The potency of an antihistamine in inhibiting wheal and erythema formation response to intradermal histamine injection is correlated with the skin concentration of the drug rather than the plasma concentration. Sedation and impairment of performance are concerns when sedating antihistamines are used, but these adverse effects may diminish after 1-2 weeks of therapy.
Many patients find that pruritus is less troublesome during the day but is maximized at night, when there are fewer distractions. An additional nocturnal dose of a sedative antihistamine such as hydroxyzine or doxepin may be added to the morning dose of a low-sedation anti-H1 antihistamine. Doxepin should not be used in patients with glaucoma and should be used with extreme caution in elderly patients or those with heart disease.
Doubling the labeled dose of low-sedation antihistamines may benefit some patients, and increasing the dose of these antihistamines is often the safest therapeutic approach for patients who do not have an adequate response to the conventional doses of these medications. Increasing the dosage up to 4-fold is recommended by expert groups such as the European Academy of Allergy and Clinical Immunology (EAACI). [32]
As many as 75% of patients with chronic urticaria referred to tertiary care centers may require higher than conventional antihistamine doses. [41] These higher nonsedating antihistamine doses improved quality of life but did not increase somnolence. [41]
If high-dose nonsedating antihistamine therapy is not effective, switching to a different nonsedating antihistamine or adding a leukotriene antagonist (see below) to the antihistamine regimen may be considered. [32] Patients who do not respond to 20 mg of desloratadine may benefit from 20 mg of levocetirizine. [41]
Use in pregnant women
Cetirizine and loratadine are category B agents; nevertheless, a first-generation antihistamine such as chlorpheniramine may be considered the drug of choice in pregnant women because the cumulative experience with use of such agents in this population is greater.
Use in patients with kidney or liver impairment
For cetirizine, 60% of an administered dose is eliminated via the kidneys; for levocetirizine, the figure is 85%. Most H1 or H2 antihistamines undergo presystemic metabolism in the liver via cytochrome P-450. Accordingly, reduction of low-sedation antihistamine doses is advised in patients with liver or renal failure.
Use in children
Cetirizine and fexofenadine are approved by the US Food and Drug Administration (FDA) for chronic urticaria in children aged 6 months and older. Desloratadine is approved for chronic urticaria in children aged 1 year and older. Loratadine is approved for chronic urticaria in children aged 2 years and older. Levocetirizine is approved for chronic urticaria in children aged 6 years and older.
Hydroxyzine has been used to alleviate pruritus in children with atopic dermatitis and is an appropriate second-line agent in children with chronic urticaria that is refractory to nonsedating antihistamines.
Leukotriene antagonists
Leukotriene antagonists have been shown to be superior to placebo in the treatment of patients with chronic urticaria but are considered less effective than nonsedating antihistamines [2, 3] ; however, the two classes of agents can be combined. Montelukast 10 mg/day may be particularly helpful for patients experiencing flare-ups due to aspirin or other NSAIDs. Montelukast is approved for treatment of perennial allergic rhinitis in children aged 6 months and older.
Colchicine and dapsone
Patients who respond poorly to antihistamine therapy or who are known to have urticaria in which the inflammatory infiltrate is neutrophil-predominant (except those with glucose-6-phosphate dehydrogenase [G6PD] deficiency) may require the addition of colchicine (0.6 mg twice daily) or dapsone (50-150 mg once daily) to the treatment regimen.
Systemic corticosteroids
Systemic corticosteroids are usually effective when antihistamines are not adequate. In the rare situation where systemic corticosteroid treatment is needed to treat chronic urticaria, a low daily dose or alternate-day dosing is advised, and the dose should be titrated to the lowest effective level. In general, long-term systemic corticosteroids are not recommended. [32] Patients receiving long-term corticosteroid therapy should be routinely monitored for bone density changes and adverse ocular effects.
Cyclosporine and methotrexate
Patients with autoimmune urticaria may benefit from administration of methotrexate or cyclosporine. [5, 4] Cyclosporine 4-6 mg/kg/day has been shown in randomized double-blind studies to be effective for chronic urticaria. Cyclosporine has a better risk-to-benefit ratio than systemic corticosteroids. [32]
Cyclosporine is recommended only for patients with severe disease refractory to high doses of oral antihistamines. Cyclosporine therapy for chronic urticaria should be limited to 3 months or less. A sustained remission is observed in approximately one third of patients treated with this medication.
Levothyroxine
Some patients with chronic urticaria and antithyroid antibodies benefit from levothyroxine treatment, perhaps because of suppression of thyroid activity and, possibly, the autoimmune process. The goal of treatment is to suppress thyrotropin maximally without rendering the patient clinically hyperthyroid. The urticaria may respond within 2 weeks of initiation of adequate treatment. Some patients may maintain a sustained remission after 3-6 months of treatment, at which point the levothyroxine can be tapered and then discontinued.
Monoclonal antibodies
Omalizumab (Xolair) was approved by the US Food and Drug Administration (FDA) in March 2014 for chronic idiopathic urticaria in adults and children aged 12 years or older who remain symptomatic despite anti-H1 antihistamine treatment. It is a monoclonal antibody that selectively binds to immunoglobulin E (IgE) and inhibits binding to IgE receptors on the surface of mast cells and basophils. The efficacy and safety of omalizumab for chronic idiopathic urticaria was demonstrated in 2 clinical studies that showed omalizumab significantly improved the mean weekly itch severity score (ISS) from baseline by 9.4-9.6 in the 300-mg treatment arm, by 6.4-6.7 in the 150-mg treatment arm, and by 5.9-6.5 in the 75-mg treatment arm, compared with an improvement of 3.6-5.1 in patients on placebo. [42, 43]
Vitamin D
High-dose vitamin D add-on therapy may provide relief in some patients with chronic urticaria. In a 12-week prospective study of 42 patients with chronic therapy receiving standard triple-drug therapy (cetirizine, ranitidine, and montelukast), those randomized to supplementation with high-dose vitamin D3 (4,000 IU/d) had a trend toward lower total symptom severity scores at the end of the trial (significant reduction in hive body distribution and duration, improved pruritus, and improved sleep quality) compared with patients randomized to low-dose vitamin D3 supplements. [44, 45]
Although baseline total Urticaria Symptom Severity (USS) scores were similar between the 2 groups, and each group had a 33% reduction in total USS scores on triple-drug therapy at 1 week follow-up, by 12 week follow-up, the high-dose vitamin D3 group showed an additional 40% decrease in total USS scores that was not seen in the low-dose group.[2, 3] Despite an increase in levels of serum 25-hydroxyvitamin D with high-dose vitamin D3 supplementation, there was no corresponding association between 25-hydroxyvitamin D levels and USS scores. No adverse events were reported, and medication use in both groups remained similar. [44, 45]
Autologous whole blood injection (AWBI)
AWBI may be an alternative to treat adults with refractory chronic urticaria. In a study of 19 patients in which AWBI was performed on a weekly basis for 8 weeks, a significant improvement was seen in urticaria symptoms and quality-of-life scores. [46]
Consultations
Referral a dermatologist or allergy and immunology specialist should be considered. A consultation with an allergist is recommended when the eliciting factor seems to be food sensitivity.
-
Urticaria developed after bites from an imported fire ant.
-
Urticaria associated with a drug reaction.
