urticaria
URTICARIA
Treatment Guideline Chart
Urticaria is characterized by the appearance of wheals (hives) and/or angioedema.
The intensity of the pruritus varies but may be severe enough to disrupt sleep, work or school.
It is classified acute if the urticaria has been present for ≤6 weeks and chronic if >6 weeks. It can be spontaneous (no definite triggering factor) or inducible (a specific definite triggering factor is identified).
It can be triggered by immunological or non-immunological mechanism.

Urticaria Treatment

Principles of Therapy

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

Pharmacotherapy

Antihistamines (Oral)

  • First-line treatment because histamine is an important mediator of symptoms in most types of urticaria
  • Effective in controlling the symptoms of pruritus, reducing the number, size and duration of urticarial lesions
  • Choice of product will depend on adverse effect profile, cost and patient preference
  • Continuous daily use is more efficacious rather than on demand
  • Up-dosing may be done to control symptoms in 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 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
  • Re-assess patients every 3-6 months to evaluate if there is a need to continue or change treatment

Second Generation Antihistamines

  • Eg Bilastine, Cetirizine, Desloratadine, Ebastine, Fexofenadine, Levocetirizine, Loratadine, Rupatadine
  • 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 4-fold only before considering other treatments (considered second-line treatment) 
  • Should be taken regularly rather than as needed for chronic urticaria treatment
  • Preferred over first generation antihistamines because of less adverse effects (eg drowsiness, anticholinergic effects)
  • Not given to children <6 months of age

First Generation Antihistamines

  • Eg Chlorpheniramine, Diphenhydramine, Hydroxyzine, Ketotifen, Promethazine
  • Effective and inexpensive
    • Should no longer be used unless in rare instances where nonsedating antihistamines are not available or in special cases where they are better tolerated than nonsedating 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) which last longer (12 hours) than its antipruritic effects (4-6 hours)
  • Use is not advisable in infants and children <2 years of age

Immunomodulatory Therapy

  • Eg 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 antihistamines
    • Omalizumab should be considered before Cyclosporine A due to the latter's adverse effects 
  • Omalizumab has been proven by several studies 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 antihistamine
    • Prevents 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 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 than placebo, no significant difference was found when compared to Omalizumab
  • Dupilumab, another human monoclonal antibody, is being studied as 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

Corticosteroids (Oral)

  • 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 course may be considered in patients with acute and chronic urticaria (including chronic spontaneous urticaria) of acute exacerbation 
    • 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 applied carefully
  • Topical forms have no part in urticaria except possibly in pressure urticaria on soles

Montelukast

  • A leukotriene receptor antagonist, it may be considered as an additional medication to a second generation antihistamine in patients who are not relieved by initial monotherapy

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)

  • May be used if laryngeal edema accompanies exacerbation of chronic urticaria
    • Not effective for hereditary angioedema

Other Anti-inflammatory Agents

  • Eg Dapsone, intravenous immunoglobulin (IVIG), tumor necrosis factor (TNF)-alpha inhibitors
  • Dapsone is no longer recommended as a standard treatment for urticaria due to low level of evidence for efficacy
  • TNF-alpha inhibitors and IVIG may be last considerations in specialized institutions
  • High doses of IVIG have shown some benefits for patients with chronic urticaria
  • Other anti-inflammatory agents (eg Sulfasalazine, Methotrexate, interferon, IVIG) have only been tested in uncontrolled trials and further studies are needed

Non-Pharmacological Therapy

Knowledge and Removal/Treatment of Underlying Causes

  • Identify potential trigger factors by careful history and selective allergy tests
    • Have patient stop any suspected foods, drinks or medications
    • Also includes physical stimuli and stress
  • Patient 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
    • Usually 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 is 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, are adverse effects; angiotensin II antagonists, dipeptidyl peptidase-4 inhibitors and neprilysin also induce angioedema though less frequently
  • UVA, 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 pseudoallergen (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
    • Must be continued for 2-3 weeks

Inducing Tolerance

  • Lasts for a few days only, hence, exposure to the triggering factor at threshold level on a consistent daily basis is necessary
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