Urticaria Management

Principles of Therapy

Goals of Treatment  

The goal is complete symptomatic relief and normalization of quality of life. Good control should be the goal if complete control is not achieved after the utilization of all treatment alternatives.

Urticaria_Management

Pharmacological therapy

Antihistamines (Oral)  

Oral antihistamines are the first-line treatment because histamine is an important mediator of symptoms in most types of urticaria. Effective in controlling the symptoms of pruritus and reducing the number, size and duration of urticarial lesions. The choice of product will depend on the adverse effect profile, cost and patient preference. Continuous daily use is more efficacious than on-demand. Up-dosing may be done to control symptoms in the majority of patients with urticaria, but care must be taken since side effects occur more frequently at higher dosages (especially with sedating antihistamines). It is preferred to up-dose a single antihistamine agent than to combine different antihistamines.  

Simultaneous use of different second generation H₁-antihistamines is not recommended but may be considered as deemed necessary. If one antihistamine fails, another may be tried. It is recommended to wait for 1-4 weeks before changing to alternative treatments (including expert referral) to allow full effectiveness of the antihistamines. Reassess patients every 3-6 months to evaluate if there is a need to continue or change treatment.

Second Generation H₁-Antihistamines  

Example drugs: Bilastine, Cetirizine, Desloratadine, Ebastine, Fexofenadine, Levocetirizine, Loratadine, Rupatadine  

This is a recommended first line of treatment for all types of urticaria at recognized licensed doses and may be increased as necessary. Patients with chronic urticaria, whose symptoms are not relieved by the usual standard dose, may increase it up to fourfold only before considering other treatments (considered second-line treatment). It should be taken regularly rather than as needed for chronic urticaria treatment. Preferred over first generation H₁-antihistamines because of fewer adverse effects (eg drowsiness, anticholinergic effects). It should not be given to children <6 months of age.

First Generation H₁-Antihistamines  

Example drugs: Chlorpheniramine, Diphenhydramine, Hydroxyzine, Ketotifen, Promethazine  

These are effective and inexpensive. They should no longer be used unless in rare instances where non-sedating antihistamines are not available or in special cases where they are better tolerated than non-sedating antihistamines. May be considered if to be taken at bedtime with accompanying patient advice about possible rapid eye movement sleep. Use is limited by side effects (anticholinergic and sedative effects) that last longer (12 hours) than its antipruritic effects (4-6 hours). Use is not advisable in infants and children <2 years of age.

Corticosteroids (Oral)

Oral corticosteroids use should be reserved for severe exacerbations of chronic urticaria that have failed to respond to full-dose antihistamines or when rapid clinical relief is needed. Short courses may be considered in patients with acute and chronic urticaria (including chronic spontaneous urticaria) of acute exacerbation. It may also be required in patients who suffer from delayed pressure urticaria or urticarial vasculitis, which respond poorly to antihistamines. Long-term administration should be avoided. Low-dose alternate-day regimens may be appropriate when used carefully. Topical forms have no part in urticaria except possibly in pressure urticaria on soles.

Leukotriene Receptor Antagonist  

Montelukast may be considered as an additional medication to a second generation H₁-antihistamine in patients who are not relieved by initial monotherapy.

Immunomodulatory Therapy  

Example drugs: Cyclosporine, Ligelizumab, Omalizumab (anti-IgE)  

Omalizumab or Cyclosporine A may be added to the treatment regimen of chronic urticaria patients who are not responding to high doses of second generation H₁-antihistamines. Omalizumab should be considered before Cyclosporine A due to the latter's adverse effects. Omalizumab has been proven to be an effective option for cases of severe chronic spontaneous urticaria, refractory chronic urticaria, cholinergic, cold, heat, solar and delayed pressure urticaria, symptomatic dermographism, or failure with high-dose antihistamines. Prevents the development of angioedema. Suitable for long-term treatment. Effectively treats disease relapse after discontinuation of therapy.  

Cyclosporine may be added only in cases of severe urticaria that are refractory and unresponsive to any dose of antihistamine and Omalizumab in combination. Used with high-dose second generation H₁-antihistamine and Omalizumab as add-on treatment for patients with unresponsive chronic urticaria. Better risk/benefit ratio compared with long-term steroid use. Not recommended as a standard treatment for urticaria due to the high cost and incidence of adverse effects.  

Ligelizumab has been granted a breakthrough therapy designation for the treatment of patients with chronic spontaneous urticaria inadequately controlled by H₁-antihistamines. Phase III clinical trials for the investigation of the safety and efficacy of Ligelizumab compared with Omalizumab in patients with chronic spontaneous urticaria found that while Ligelizumab is superior to placebo, no significant difference was found when compared to Omalizumab.  

Dupilumab, another human monoclonal antibody, is being studied as a treatment for refractory chronic spontaneous urticaria unresponsive to Omalizumab therapy and in cholinergic urticaria. Mepolizumab and Reslizumab have shown efficacy in the treatment of chronic spontaneous urticaria and chronic inducible urticaria. Rituximab is a monoclonal antibody that has been proposed as an alternative treatment for chronic spontaneous urticaria because of its potential ability to inhibit IgG autoantibodies against FcεRIα or IgE. Other immunomodulatory agents undergoing clinical trials for urticaria include Benralizumab, Fenebrutinib, GSK2646264, Lirentelimab (Antolimab), LY3454738, Remibrutinib, Secukinumab, Bruton tyrosine kinase inhibitors, Tezepelumab, AZD1981 and Barzolvolimab.

Other Agents  

If adequate control is not obtained by 18 weeks after the addition of Omalizumab in patients with chronic urticaria, consider the following alternative agents:

• Anti-inflammatory agents: Dapsone, Hydroxychloroquine, Methotrexate, Sulfasalazine
• Immunosuppressive agents: Mycophenolate, Sirolimus, Tacrolimus
• Immunomodulatory biologic agents: Tumor necrosis factor (TNF)-alpha inhibitor, IL-1 antagonist
• Alternative therapy: Intravenous immunoglobulin (IVIG)

H₂ Antagonists (Oral)  

Cimetidine, Ranitidine and Famotidine have been used in combination with H₁-antihistamines. The addition of H₂ antagonist may reduce pruritus and wheal formation among patients with chronic urticaria. Monotherapy with H₂ antagonists has not shown benefit.  

Epinephrine IM/SC  

Epinephrine may be used if laryngeal edema accompanies exacerbation of chronic urticaria. It is not effective for hereditary angioedema.

Nonpharmacological

Knowledge and Removal/Treatment of Underlying Causes  

Identify potential trigger factors by careful history and selective allergy tests. Have the patient stop any suspected foods, drinks or medications, which also include physical stimuli and stress. Patients should avoid the potential allergens/trigger factors. Known or suspected chronic inflammatory and infectious diseases should be treated. Decreasing functional autoantibodies by means of plasmapheresis is usually done for chronic spontaneous urticaria patients who are autoantibody positive and refractory to all other types of therapy.

Chronic Urticaria  

Counsel the patient to avoid aggravating factors (eg heat, tight clothing, emotional/physical stress, alcohol) and trigger stimuli (eg sun in solar urticaria). Provide information and advice about preventive measures (eg cool showers for cholinergic urticaria, covering of exposed skin in patients with cold urticaria). Medications suspected to trigger urticaria attacks should be substituted if maintenance is a must.  

Avoidance of Aspirin and other NSAIDs is usually recommended since these drugs aggravate chronic urticaria in approximately 30% of patients. Avoidance of Codeine and other opiates may also be recommended since there are enhanced skin test reactions to these drugs found in chronic urticaria patients. Angiotensin-converting enzyme (ACE) inhibitors should be avoided since angioedema and rarely, urticaria have adverse effects; angiotensin II antagonists, dipeptidyl peptidase-4 inhibitors and neprilysin also induce angioedema, though less frequently.

Ultraviolet (UV) A, Psoralen plus UVA (PUVA), and UVB may be used for 1-3 months as add-on therapy to antihistamine treatment for chronic spontaneous urticaria and symptomatic dermographism. Restrictive dietary measures such as avoidance of dietary pseudoallergens (eg food coloring, preservatives, etc) have no role in most forms of chronic urticaria but may provide symptomatic relief in patients with pseudoallergic reactions to natural food ingredients and additives. These must be continued for 2-3 weeks.

Inducing Tolerance  

Inducing tolerance lasts for a few days only; hence, exposure to the triggering factor at a threshold level on a consistent daily basis is necessary.  

Patient Education  

Explain to the patient the nature of urticaria and convey a realistic expectation from available treatment options. Reassure the patient that the majority of acute urticaria cases resolve spontaneously, with most causes of urticaria resolving within 6 weeks and chronic urticaria is benign (except in cases of angioedema, where life-threatening airway closure can be a risk). The application of cooling lotions with menthol may be done to control itchiness.