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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.

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.