Dr Susan Leech and Professor Richard Powell describe the classifications, treatments, and a stepwise approach that can help practitioners deal with this common and distressing condition

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Read this article to learn more about:

  • diagnosing and classifying urticaria and angioedema
  • common triggers that exacerbate chronic urticaria
  • management and treatment options, including psychological therapy.

 

Key points

GP commissioning messages

 

Chronic urticaria/angioedema is a common condition, affecting 2–3% of the population.1 It mainly affects adults and, less commonly, children. Although rarely life-threatening, chronic urticaria/angioedema causes misery and embarrassment and adversely impacts on quality of life.2 Regrettably, however, this troublesome condition is often trivialised.1

In February 2015, the Standards of Care Committee of the British Society for Allergy and Clinical Immunology (BSACI) published the BSACI guideline for the management of chronic urticaria and angioedema (2nd edn).1 The guideline is based on evidence as well as expert opinion and is intended for both adult physicians and paediatricians practising in allergy. The majority of cases can be treated in primary care. The process by which BSACI produces its patient management guidelines has been accredited by NICE.

Definitions

Urticaria ('hives' or 'nettle rash') is characterised by red, raised, itchy papules and plaques. Weals vary from a few millimetres to hand-sized lesions and may be either single or numerous.1 Urticarial lesions last less than 24 hours. They are caused by vasodilatation, increased blood flow, and vascular permeability in response to release of histamine and other mediators from mast cells. Urticaria affects the superficial skin layers of the skin. 1

Angioedema (tissue swelling) is due to a local increase in vascular permeability affecting the face, oropharynx, genitalia, and less frequently the gastrointestinal tract. The swellings may be painful rather than itchy and can persist for days. The swellings are deeper and more extensive than in urticaria.1

Urticaria and angioedema often co-exist but can occur independently.1,3

Chronic urticaria is an episode of urticaria and/or angioedema that lasts for more than 6 weeks. Patients may have episodic urticaria/angioedema lasting for hours or days and recurring over months or years.4

Acute urticaria is more common than chronic urticaria. Episodes last for less than 6 weeks. Acute urticaria may be spontaneous or occur in response to a viral infection and may persist for several days. Acute urticaria is not considered further here, or in the updated BSACI guideline. 1

Prognosis

Chronic urticaria usually remits over time; however, 20% of patients still have symptoms 10 years after presentation.5 Persistence is more likely in severe cases, or in the presence of angioedema or positive anti-thyroid antibodies.6 Chronic urticaria in childhood is rarely a severe disease. The majority of children respond to treatment with antihistamines and avoidance of triggers.1,7

Diagnosis and clinical classification

The diagnosis of chronic urticaria/ angioedema is based on the clinical history. It is therefore important that practitioners have a knowledge of the clinical classification, causes, and possible triggers. Investigations may not be necessary. 1

See Table 1 (below) for the clinical classification of chronic urticaria/ angioedema. Some of these classifications may overlap, for example, a patient presenting with spontaneous urticaria may also have elements of dermographism.

Table 1: Clinical classification of chronic urticaria/angioedema1
DescriptionTypeExamples
Spontaneous urticaria Spontaneous Stress, infection, drugs (e.g. non-steroidal anti-inflammatory drugs [NSAIDs])
Autoimmune urticaria Auto-immune None known
Inducible urticaria Aquagenic Contact with hot or cold water
Cholinergic Exercise, emotion
Cold Swimming in cold water, cold wind
Delayed pressure Sitting, lying, tight clothing
Dermographism Minor trauma
Exercise Physical exertion
Heat Hot bath/shower
Solar Sunshine
Vibratory Use of vibrating tools
Angioedema without weals Spontaneous Stress, infection, drugs (e.g. NSAIDs)
C1 inhibitor deficiency Trauma, surgical procedures, stress, infection
C1 inhibitor deficiency related to paraproteinaemia Trauma, surgical procedures, stress, infection
Drugs ACE inhibitors, oestrogens, anti-psychotic drugs, statins, NSAIDs
Vasculitis Urticarial vasculitis
  • Infection, e.g. with hepatitis B/C or streptococcus
  • Drugs, e.g. penicillins, allopurinol, quinolones, or carbamazepine
  • Autoimmune diseases
  • Paraproteinaemia
  • Malignancy
  • Adapted from: Powell R, Leech S, Till S et al. BSACI guideline for the management of chronic urticaria and angioedema. Clin Exp Allergy 2015; 45 (3): 547–565.
  • Available at: onlinelibrary.wiley.com/doi/10.1111/cea.12494/full Reproduced with permission

Chronic spontaneous urticaria

This is the commonest form of the disease. There is persistent activation of mast cells in the skin, but the precise mechanism of the mast-cell triggering is unknown.1

Chronic autoimmune urticaria

Functional autoantibodies against the high-affinity immunoglobulin E (IgE) receptor (FceR1) occur in one-third of patients. These patients have more severe symptoms. 1

Inducible urticaria

Urticaria may be induced or triggered by physical factors, for example heat, cold, pressure, vibration, water, ultraviolet light:1

  • dermographism can be demonstrated by applying firm pressure to the skin with a blunt object. It results in blanching, then redness, then a weal
  • delayed-pressure urticaria develops more slowly after physical pressure and lasts several hours or days
  • cold and pressure urticaria are the most commonly diagnosed induced urticarias in children. These may occur in combination with dermographism or cholinergic urticaria
  • cholinergic urticaria is triggered by sweating due to heat, emotion, or exercise.

Inducible urticaria can be more resistant to antihistamines than spontaneous urticaria and follows a protracted course.

Angioedema without weals

Angiotensin-converting enzyme (ACE) inhibitors, hereditary angioedema (HAE), or acquired C1 inhibitor deficiency can induce angioedema without weals.

  • Angioedema with ACE inhibitors. The incidence of angioedema with ACE inhibitors, which is due to reduced bradykinin metabolism, may be as high as 0.7%.1,8 It can occur in the first weeks of treatment or after many years of uneventful drug use. The patient presents with swelling of the tongue; the lips, pharynx, larynx, and viscera may also be involved. Fatalities are reported and it is mandatory that the ACE inhibitor is withdrawn. Symptoms usually disappear or reduce after stopping the ACE inhibitor, although episodes of angioedema may continue for months. The efficacy of antihistamines, corticosteroids, and C1 inhibitor remains unproven.1 ACE inhibitors are contra-indicated in patients with a history of angioedema. People of Afro-Caribbean origin are at increased risk; as ACE inhibitors are less effective in these patients, alternative antihypertensives should be prescribed for them.1
  • Hereditary angioedema. Hereditary angioedema typically involves cutaneous sites, the gut, and larynx. There may be a family history. Types I and II are caused by gene mutations and are associated with deficient levels of C1 inhibitor or dysfunctional C1 inhibitor, respectively.9 In type III HAE, levels of C1 inhibitor remain normal or only slightly reduced; however, oestrogen causes a decrease in C1 inhibitor function, which triggers symptoms. Type III affects women more frequently and more severely because they have higher levels of oestrogen than men and are also more likely to take oestrogen-containing medication, such as combined oral contraceptives and HRT. Combined oral contraception should be avoided in all women with HAE.1

Vasculitis

Urticaria can be a symptom of vasculitic disease, caused by inflammation of small blood vessels. Symptoms suggestive of urticarial vasculitis include:1

  • persistent (rather than evanescent and self-limiting) episodes of urticaria/angioedema
  • individual lesions that last more than 24 hours
  • tender and painful (rather than itchy) urticarial lesions
  • evidence of residual petechial haemorrhage, purpura, or bruising on the skin
  • signs of underlying disease, e.g. fever, significant malaise, arthralgia, hypertension, and blood or protein in urine.

The lesions of urticarial vasculitis last for days rather than hours and leave a brownish stain. People with suspected vasculitis should be referred to secondary care.

Triggers

Common triggers for exacerbations of chronic urticaria are psychological stress10 and respiratory tract infections:11

  • Psychological stress. Urticaria and angioedema can lead to significant stress. Psychological stress aggravates urticaria and stressful events often precede onset of symptoms.12 Patients have high rates of anxiety, depression, life-event stress, perceived stress, and somatoform disorders such as fibromyalgia, which adversely affect quality of life.13,14 An association between post-traumatic stress and urticaria has also been reported.15 Psychological therapies should be considered in patients where stress may be a problem
  • Infections. When present, chronic infections such as dental sepsis, sinusitis, urinary tract infections, and cutaneous fungal infections should be treated. Exhaustive investigations searching for infections are unhelpful.16Candida do not cause chronic urticaria.

Food and food additives

Food allergy is rarely the cause of chronic urticaria and is usually excluded on the clinical history.1 The following questions may assist practitioners in excluding allergy as a possible trigger:1

  • does the urticaria occur within 60 minutes (usually 20 minutes) of eating a particular food (with the exception of meat and crustaceans, e.g. prawn)?
  • does it occur only if a particular food (e.g. wheat) has been eaten followed by exercise?
  • does it occur after contact with an allergen to which the patient is sensitised (animals, grass, food, latex, etc.)?
  • could it be caused by any drugs the patient has taken (ACE-inhibitor/aspirin/non-steroidal anti-inflammatory [NSAID])?

In IgE-mediated food allergy, symptoms occur within 60 minutes of exposure and resolve within 24 hours, rather than coming on overnight or being present first thing in the morning. Oropharyngeal itching, wheezing, vomiting, or abdominal pain are usually present. Food additives, preservatives, and dyes rarely cause urticaria.

Investigations

Investigations may not be necessary, although the following may be indicated:1

Allergy tests

Patients are often referred to allergy clinics in the mistaken belief that food is responsible. Atopy can be excluded by measuring serum-specific IgE or skin-prick testing to aeroallergens and suspect foods. Negative allergy tests may reassure the patient that their symptoms are not due to allergy and improve adherence to long-term antihistamines.

Full blood count

The eosinophil count is elevated in some drug-induced reactions. An elevated neutrophil count may be present in urticarial vasculitis.

Acute phase proteins

The erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP) is elevated in chronic infection and vasculitis. A high ESR with normal CRP may indicate paraproteinaemia.

Thyroid function and autoantibodies

Patients with chronic urticaria may have anti-thyroid autoantibodies. Patients are often euthyroid but require monitoring.

Complement studies

C4 and C1 inhibitor should be measured in patients with angioedema without weals. Complement studies are not indicated in patients with urticaria. C4 is usually low in types I and II HAE.

Urinalysis

Haematuria and proteinuria are present in urinary tract infections and renal vasculitis.

Challenges

Cold-induced urticaria can be diagnosed by placing an ice cube in a sealed plastic bag over the forearm for up to 10 minutes (allow skin to re-warm subsequently). Dermographism can be confirmed by lightly scratching the skin, with weals appearing within 10 minutes. The water test for aquagenic urticaria involves immersing a body part into water at 37ºC or placing wet towels for a few minutes on to the area of skin most affected.

Further investigations

Skin biopsy

A patient with an unusual presentation, or where vasculitis is suspected, should be referred for skin biopsy, particularly if there are:1

  • systemic symptoms (fever, arthralgia, or arthritis)
  • lesions lasting for more than 24 hours or associated with tenderness, petechiae, purpura, or skin staining as the lesions fade.

Nasendoscopy

Patients with unexplained pharyngeal obstruction should be referred for nasendoscopy. During an attack, direct visualisation of the pharynx/larynx establishes or excludes angioedema of the throat. Important differential diagnoses of 'swelling, lump, or discomfort in the throat' include globus, gastro-oesophageal reflux, and vocal cord dysfunction.

Treatment and management of chronic urticaria

[NB At time of publication, not all treatments detailed below are licensed for this indication; the prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council's Good practice in prescribing and managing medicines and devices for further information.17]

Management of chronic urticaria includes the identification and exclusion of triggers, treatment of symptoms, patient education, and a personalised management plan (see Figure 1, below).

Figure 1. Stepwise management of chronic urticaria (adults and children)1
Stepwise management of chronic urticaria adults and children
  • Adapted from: Powell R, Leech S, Till S et al. BSACI guideline for the management of chronic urticaria and angioedema. Clin Exp Allergy 2015; 45 (3): 547–565.
  • Available at: onlinelibrary.wiley.com/doi/10.1111/cea.12494/full Reproduced with permission

For patients with confirmed urticaria:1

  • check that symptomatic episodes have not followed ingestion of an NSAID
  • explain the symptoms and that histamine-induced chronic urticaria symptoms do not involve the (upper and/or lower) respiratory tract or cardiovascular system—as occurs in anaphylaxis
  • give a once-daily dose of a long-acting, non-sedating antihistamine (as needed [prn] if symptoms are infrequent)
  • if necessary, double the dose of antihistamine (usually given at night)
  • consider:
    • further increase in dose of antihistamine up to 4 times the recommended dose
    • adding a leukotriene receptor antagonist
    • the need for psychological referral
    • short-term oral corticosteroid rescue treatment.

Avoidance of triggers

Symptom diaries help determine the frequency, duration, and severity of urticaria. 18 Patients who fail to uncover a consistent trigger are advised to discontinue the search for an external cause. 1

The patient should be given advice on avoiding triggers, for example, cold or pressure (see Table 1, above). If the patient is taking a drug associated with chronic urticaria or angioedema (e.g. NSAID or ACE inhibitor), they should have a trial off treatment for several weeks. ACE inhibitors are contraindicated in angioedema.

Treatment of underlying infections and malignancies may lead to resolution of symptoms. Alcohol aggravates chronic urticaria by the effect of vasodilation.1

Symptom control

A stepwise approach to the treatment of chronic urticaria should be employed (see Figure 1, above). The starting point and rate of progression between steps depends on clinical severity and response.

H1-antihistamines

H1-antihistamines remain the mainstay of treatment; second generation antihistamines should be prescribed and are less sedating. Once-daily dosage improves adherence. To rapidly achieve optimal blood levels and relief of symptoms, the patient may take two tablets as the first dose, reverting to a single daily tablet thereafter. Individual responses and side-effects to antihistamines vary.

In urticaria that is difficult to treat, levocetirizine and desloratadine are effective at up to four times the conventional doses and incremental updosing is advised (see Figure 1, above). 1,19 Up-dosing with a single antihistamine is preferable to mixing different antihistamines. Once symptom control is accomplished, daily treatment for 3–6 months is advised.1,20

For individuals with a long history of symptoms at presentation, treatment for 12 months is advised with gradual withdrawal over a period of weeks. Antihistamines should be withdrawn gradually rather than stopped abruptly. For patients with infrequent symptoms, treatment may be taken as required or prophylactically.

First generation antihistamines (e.g. chlorphenamine) should be avoided because of sedation and interference with psychomotor performance. Although this may still occur with second generation antihistamines, it is less severe. Sedating antihistamines at night may help sleep.

The long half-life of hydroxyzine causes daytime somnolence, so should be avoided. 1,21

There is little evidence for the addition of H2-antihistamines and this should not be routine practice.1

Tranexamic acid

Tranexamic acid (15–25 mg/kg [maximum 1.5 g] 2–3 times per day) may benefit some patients who have problematic angioedema, particularly those without weals.1

Leukotriene receptor antagonists

Leukotriene receptor antagonists (LTRAs) may be a useful addition in some patients, particularly those who react adversely to aspirin and NSAIDs, and in individuals with delayed-pressure or autoimmune urticaria.1

Topical preparations

Two percent menthol in aqueous cream is antipruritic and can be soothing. Topical steroids should not be used.1

Psychological interventions

Psychological problems are common in people with chronic urticaria, arising before and following onset of symptoms.10 Psychotherapeutic treatments and behavioural interventions, such as cognitive behavioural therapy, may be beneficial.

Treatment and management of angioedema

In patients with angioedema, without urticaria, C1 inhibitor deficiency should be excluded.1 Management of angioedema follows that of urticaria as detailed above; however, the following steps should also be considered:1

  • tranexamic acid if the patient is unresponsive to high-dose antihistamines
  • stop ACE inhibitors
  • avoid prescribing ACE inhibitors in the future
  • an adrenaline auto-injector only if there is significant angioedema (in the presence of urticaria) affecting the upper airway. The patient should be shown how to use the device and provided with a written self-management protocol
  • short-term oral corticosteroid rescue treatment.

Further treatment

Patients unresponsive to high-dose antihistamines +/– LTRAs or tranexamic acid should be referred to secondary care. Patients with unexplained pharyngeal obstruction, patients with angioedema without weals and a family history of HAE or low levels of C4 or C1 inhibitor, and adults with suspected urticarial vasculitis should all be referred to secondary care for further assessment.

Low-dose ciclosporin may be considered in patients with severe, unremitting disease. Monthly omalizumab injections are effective and well tolerated in patients with spontaneous and autoimmune chronic urticaria. Icatibant and C1 inhibitor are effective in treating acute attacks of HAE. Icatibant may improve angioedema induced by ACE inhibitors. Long-term corticosteroids may be needed to control urticarial vasculitis.1

Rescue medication

Rescue medication may be needed in severe cases; details are listed below.

Corticosteroids

A short course of prednisolone (e.g. up to 40 mg daily for 7 days) may be prescribed for severe exacerbations of chronic urticaria, especially when accompanied by angioedema. 1

Intramuscular adrenaline

Patients with severe angioedema affecting the upper airway, or cardiovascular symptoms resulting from urticaria, should have an adrenaline autoinjector prescribed for intramuscular self-administration in an emergency. Adrenaline does not need to be prescribed for patients with nonhistaminergic angioedema, such as HAE and angioedema due to ACE inhibitors.1

Chronic urticaria in pregnancy and breastfeeding

Chronic urticaria usually improves in pregnancy; however, it sometimes worsens. Most antihistamines should be avoided; there is considerable clinical experience with cetirizine and loratadine in pregnant women, with no increase in congenital abnormalities.1 Hydroxyzine is specifically contraindicated in early pregnancy. 1

Antihistamines are excreted in breast milk. Although not known to be harmful, they should be avoided while breastfeeding. Chlorphenamine may cause drowsiness and poor feeding. Loratadine and cetirizine appear safer, with low levels found in breast milk.1

Chronic urticaria in childhood

Chronic urticaria is less common in children than in adults, and its management is very similar. The majority of children respond to treatment with antihistamines and avoidance of triggers. 22 Most cases are spontaneous and cold urticaria is the most commonly diagnosed induced urticaria. The physical appearance of weals and angioedema may cause concern to parents and carers, who perceive that the child is infectious or allergic, and keep them off school.

The diagnosis is usually based on a detailed history and examination. Investigations are rarely required. There is little evidence to support the suggestion that urticaria is due to a reaction to foods or food additives.

Families often find it helpful to see a lack of atopy demonstrated by skin tests or specific IgE. Avoidance of known provoking stimuli, and drug treatment (see Figure 1, above) are the mainstay of treatment. Parents need reassurance that this is not a severe disease and it remits over time.1 A quarter of children with chronic spontaneous urticaria are disease free 3 years after presentation, and 96% are asymptomatic after 7 years.1 Children with physical urticaria should be advised to avoid triggers and the condition usually spontaneously regresses after 2–3 years.1

Conclusion

Chronic urticaria is a common condition which reduces the patient's quality of life. Diagnosis is based on the clinical history. Angioedema occurring in the absence of weals has a separate aetiology, and drugs and HAE should be considered in the differential diagnosis.

Management involves identification and exclusion of triggers and management of symptoms, initially using antihistamines, the dose of which can be escalated. Treatment needs to be modified according to response and development of side-effects.

Severe cases, suspected vasculitis or HAE should be referred to secondary care for further assessment. Symptoms in the majority of patients resolve over time and the majority of cases can be effectively managed in primary care.

Key points

  • Chronic urticaria/angioedema is defined as daily or almost daily symptoms lasting for more than 6 weeks. Symptoms may be episodic, lasting for hours or days and recurring over months or years. Urticaria and angioedema commonly occur together, but may also occur separately
  • Chronic urticaria affects approximately 2–3% of individuals and significantly reduces quality of life
  • Diagnosis is based primarily on the clinical history. Investigations may not be necessary
  • Food allergy can usually be excluded if there is no temporal relationship to a particular food. Food additives, preservatives, and dyes rarely cause chronic urticaria
  • Certain drugs, such as ACE inhibitors, NSAIDs and antibiotics, can cause or aggravate chronic urticaria and/or angioedema. ACE inhibitors:
    • can cause angioedema without urticaria, resulting in airway compromise
    • are contraindicated in individuals with a history of angioedema and should be withdrawn
  • Autoimmune and some inducible urticarias are more resistant to treatment and can follow a protracted course
  • Angioedema without urticaria is a cardinal feature of HAE and typically involves subcutaneous sites, gut, and larynx. In type I and II HAE, levels of C4 and C1 inhibitor (functional and/or antigenic) are low
  • Management involves identification and exclusion of possible triggers, patient education, and management of symptoms. Pharmacological treatment should be started with a standard dose of a non-sedating H1-antihistamine. Treatment should be modified according to response and development of side-effects. Higher than normal doses of antihistamines may be required to control severe symptoms
  • In pregnancy, the lowest dose of chlorphenamine, cetirizine, or loratadine should be used. During breastfeeding, either cetirizine or loratadine should be taken at the lowest dose. Chlorphenamine should be avoided during breastfeeding
  • The majority of patients can be managed in primary care. Patients requiring referral to secondary care include those with:
    • symptoms unresponsive to high-dose antihistamines
    • family history of HAE or low levels of C4 or C1 inhibitor in a patient with angioedema without weals
    • suspected urticarial vasculitis in an adult patient
    • unexplained pharyngeal obstruction.

ACE=angiotensin converting enzyme; NSAID=non-steroidal anti-inflammatory drug; HAE=hereditary angioedema

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GP commissioning messages

written by Dr David Jenner, NHS Alliance GMS contract/PBC Lead

  • The BSACI guideline for chronic urticaria and angioedema is helpful in defining effective management of people with this condition and indicating points for referral and investigation
  • CCGs with local immunology specialists could adapt these guidelines into local care pathways to assist GPs with managing patients with this condition effectively and in primary care where possible
  • CCGs should ensure they commission sufficient specialist services to manage people who need specialist referral and the necessary immunological tests that can inform the correct diagnosis and treatments
  • These specialists services could be provided in part by community specialist nurses who can work with local primary care practices and provide ongoing advice, guidance, and education to primary care teams, as well as direct access support to patients
  • Local formularies should identify appropriate medications and their licensed doses and indications as well as where specialists advise their use out of normal licensed dose ranges (e.g. antihistamines).

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References

  1. Powell R, Leech S, Till S et al . BSACI guideline for the management of chronic urticaria and angioedema. Clin Exp Allergy 2015; 45 (3): 547–565.
  2. Maurer M, Ortonne JP, Zuberbier T. 2009. Chronic urticaria: a patient survey on qualityof- life, treatment usage and doctor–patient relation. Allergy 2009; 64 (4): 581–588.
  3. Kaplan A. Clinical practice. Chronic urticaria and angioedema. N Engl J Med 2002; 346 (3): 175–179.
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  7. Leech S. Recurrent urticaria. Paediatrics and Child Health 2012; 22 (7): 281–286.
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  9. Kaplan A. C1 inhibitor deficiency: hereditary and acquired forms. J Investig Allergol Clin Immunol 2001; 11 (4): 211–219.
  10. Ben-Shoshan M, Blinderman I, Raz A. Psychosocial factors and chronic spontaneous urticaria: a systematic review. Allergy 2013; 68 (2): 131–141.
  11. Ricci G, Giannetti A, Belotti T et al. Allergy is not the main trigger of urticaria in children referred to the emergency room. J Eur Acad Dermatol Venereol 2010; 24 (11): 1347–1348.
  12. Özkan M, Oflaz S, Kocaman N et al. Psychiatric morbidity and quality of life in patients with chronic idiopathic urticaria. Ann Allergy Asthma Immunol 2007; 99 (1): 29–33.
  13. Staubach P, Dechene M, Metz M et al. High prevalence of mental disorders and emotional distress in patients with chronic spontaneous urticaria. Acta Derm Venereol 2011; 91 (5): 557–561.
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  17. General Medical Council. Good practice in prescribing and managing medicines and devices. GMC, 2013. Available at: www.gmc-uk.org/ Prescribing_guidance.pdf_59055247.pdf
  18. Jariwala S, Moday H, de Asis M et al. The Urticaria Severity Score: a sensitive questionnaire/index for monitoring response to therapy in patients with chronic urticaria.Ann Allergy Asthma Immunol 2009; 102 (6): 475–482.
  19. Staevska M, Popov T, Kralimarkova T, Lazarova C et al. The effectiveness of levocetirizine and desloratadine in up to 4 times conventional doses in difficult-to-treat urticaria. J Allergy Clin Immunol 2010; 125 (3): 676–682.
  20. Grob J, Auquier P, Dreyfus I, Ortonne J. How to prescribe antihistamines for chronic idiopathic urticaria: desloratadine daily vs PRN and quality of life. Allergy 2009; 64 (4): 605–612.
  21. Staevska M, Gugutkova M, Lazarova C et al. Night-time sedating H1-antihistamine increases daytime somnolence but not treatment efficacy in chronic spontaneous urticaria: a randomized controlled trial. Br J Dermatol 2014; 171 (1): 148–154.
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