Chronic spontaneous urticaria

Author: Donna Bartlett, Medical Writer, Allori, Melbourne, Victoria, Australia. DermNet Editor in Chief: Adjunct A/Prof Dr Amanda Oakley, Dermatologist, Hamilton, New Zealand. Copy edited by Gus Mitchell. December 2018.

This article was supported by an educational grant from Novartis, distributors of Xolair™ in New Zealand and Australia. Sponsorship does not influence content.


What is urticaria?

Urticaria is a condition characterised by the presence of hives/weals (also spelt wheals) and/or angioedema [1,2].

  • A weal is a superficial red or pale skin swelling, usually surrounded by erythema, which can persist from a few minutes to 24 hours. Weals are usually very itchy, but can also cause a burning sensation.
  • Angioedema is swelling within the deeper dermal layers within the skin or mucous membranes. The swelling is usually skin coloured, but it can be erythematous. Angioedema can be asymptomatic, itchy or cause burning pain. It can take up to 72 hours to resolve.

Weals are accompanied by angioedema in up to 40% of cases, but angioedema may occur on its own in some people [2].

Urticaria affects up to 1 in 4 people at some time in their lives [3] and can be classified by duration (acute or chronic) and by cause (spontaneous or inducible) [1,2]. Two or more different subtypes of urticaria may co-exist in one person [1,2].

Acute urticaria is the daily or episodic occurrence of weals, angioedema or both, that is present for less than 6 weeks [1,2]. There are multiple possible causes including infections or allergies, but it is often idiopathic [2].

Figure 1. Classification of urticaria
Spontaneous urticaria and angioedema

What is chronic urticaria?

Chronic urticaria is the daily or episodic occurrence of weals (hives), angioedema or both, that is present for 6 weeks or more [1,2]. Chronic urticaria can persist for 1–5 years, sometimes longer [2,4].

International guidelines for the classification, diagnosis and management of chronic urticaria have recently been published based on a consensus from multiple national and international societies [1].

Chronic urticaria may be classified as either spontaneous or inducible, and both types may co-exist in one patient [1,2]. This article is about chronic spontaneous urticaria. See DermNet's page on chronic inducible urticaria.

What is chronic spontaneous urticaria?

Chronic spontaneous urticaria refers to chronic urticaria that has no specific cause or trigger. Weals are present on most days of the week for six weeks or more [1,2].

Chronic spontaneous urticaria was previously referred to as chronic idiopathic urticaria. This term is no longer used as many cases have an autoimmune basis [2].

Who gets chronic urticaria?

Estimates of the incidence of chronic urticaria range from 0.05 to 2% of the population in the USA, and up to 20% in Thailand [5].

  • The lifetime prevalence of chronic urticaria is approximately 1.8% [2].
  • Chronic spontaneous urticaria occurs in 0.5–1% of the population at any point in time [3,4].
  • Two out of three cases of chronic urticaria are spontaneous, peaking between 20 and 40 years of age [3].
  • Most studies have reported that women experience urticaria and chronic urticaria almost twice as often as men [2–4].
  • The incidence of urticaria in children has been reported at between 2% and 7% [6] and the incidence of chronic urticaria is between 0.1% and 3% [7].
  • Chronic urticaria is more common in older children and adolescents [2].
  • Spontaneous urticaria is the most common subgroup of chronic urticaria in children [2].

What are the clinical features of chronic spontaneous urticaria?

Chronic spontaneous urticaria is characterised by the presence of weals and/or angioedema [1,2].

Weals can affect any site on the body and tend to be distributed widely [2,8].

  • Weals can be a few millimetres or several centimetres in diameter.
  • They can be coloured white or red, usually with a red flare.
  • Each weal may last a few minutes or several hours, and it may change shape before resolving.
  • Weals may be round or form rings, a map-like pattern, or giant patches.
Urticarial weals

See more images of urticaria and angioedema.

Angioedema is more often localised [8].

  • It commonly affects the face (presenting as swollen lips or eyelids), hands, feet, and genitalia.
  • It may involve the tongue, uvula, soft palate and pharynx.
Angioedema

Chronic spontaneous urticaria is unpredictable and debilitating. The weals are more persistent in chronic spontaneous urticaria than in chronic inducible urticaria, but each has resolved or has altered in shape within 24 hours. They may occur at certain times of the day.

Some patients with chronic spontaneous urticaria report associated systemic symptoms. These may include:

  • A headache and fatigue
  • Joint pain and/or swelling
  • Wheezing, flushing, and palpitations
  • Gastrointestinal symptoms [9].

How is the activity and control of urticaria assessed?

There are several validated systems to assess the activity and control of urticaria.

Disease activity in chronic spontaneous urticaria can be assessed with the Urticaria Activity Score (UAS7), a simple, validated scoring system based on the assessment of key urticaria signs and symptoms – weals and pruritus — which are documented by the patient. The daily weal and pruritus scores are added up for 7 days; the maximum score is 42 [1].

The urticaria activity score (UAS7) for assessment of disease activity
ScoreWealsPruritus
0 None None
1 Mild (< 20 weals/24 h) Mild (present but not annoying or troublesome)
2 Moderate (20–50 weals/24 h) Moderate (troublesome but does not interfere with normal daily activity or sleep)
3 Intense (> 50 weals/24 h or large confluent area of weals) Intense (severe pruritus, which is sufficiently troublesome to interfere with normal daily activity or sleep)

The Urticaria Control Test (UCT) [10] is useful in the assessment of the patient’s disease status and is validated to determine the level of disease control in both chronic spontaneous urticaria and chronic inducible urticaria [1]. The UCT has four items with a clear cut-off for a ‘well controlled’ vs a ‘poorly controlled’ disease, making it useful in routine clinical practice.

The Angioedema Activity Score (AAS) [11] allows the patient to score each of five key factors relating to their experience of angioedema from 0 to 3 (giving a daily score of 0–15). Daily AAS can be summed to give 7-day scores (AAS7), 4-week scores (AAS28), and 12-week scores (AAS84) [11].

Assessment of quality of life in chronic urticaria

Current international guidelines recommend validated instruments to assess the emotional impact of chronic urticaria and the effect on the patient’s quality of life (QOL), such as the Chronic Urticaria QOL questionnaire (CU-Q2oL) [12] and the Angioedema QOL questionnaire (AE-QOL) [1,13].

What causes chronic spontaneous urticaria?

Urticaria is a mast cell-driven disease. Activated mast cells release histamine along with other mediators, such as platelet activating factor (PAF) and cytokines, resulting in sensory nerve activation, vasodilatation, plasma extravasation and recruitment of cells to the urticarial lesion. Mast cells can be activated by many different molecules in urticaria, but generally, these are not well defined [1].

By definition, chronic spontaneous urticaria has no known trigger. Causes include:

  • Autoimmunity mediated by functional autoantibodies against the high-affinity IgE receptor
  • IgE autoantibodies to autoantigens
  • Non-allergic reactions to foods or drugs (pseudoallergy)
  • Acute or chronic infections as a result of Helicobacter pylori, streptococci, staphylococci, Yersinia, Giardia lamblia, Mycoplasma pneumoniae, hepatitis viruses, norovirus, parvovirus B19, Anisakis simplex, Entamoeba spp, and Blastocystis spp [1].

Chronic spontaneous urticaria is extremely rarely due to a Type I allergy [1].

There is a strong association between chronic spontaneous urticaria and other immune disorders, in particular, thyroid autoimmune disease. Thyroid autoantibodies are the most common laboratory abnormalities associated with chronic spontaneous urticaria, with most studies reporting elevated levels in ≥ 10% of patients [2,14]. Thyroid dysfunction rates are also increased in people with chronic spontaneous urticaria, with hypothyroidism and Hashimoto thyroiditis observed more commonly than hyperthyroidism and Graves disease [14].

The frequency of underlying causes varies in different studies of chronic spontaneous urticaria, reflecting regional differences in diet or the prevalence of infections [1].

What are the complications of chronic urticaria?

The burden of chronic spontaneous urticaria

Patients with chronic spontaneous urticaria may experience sleep deprivation, anxiety, depression, lack of energy and social isolation [15]. These can result in significant deterioration in the quality of life (see Figure 2) [15]. Chronic spontaneous urticaria is unpredictable and can disrupt the patient’s normal daily activities.

Figure 2. Impact of CSU on QOL, sleep and daily activities

Note: Higher score indicates greater impairment of quality of life.

How is chronic spontaneous urticaria diagnosed?

Chronic urticaria is diagnosed by history and examination and is based on a > 6-week history of daily or episodic weals that last less than 24 hours without physical trigger factors.

International guidelines provide a diagnostic algorithm for chronic urticaria (see Figure 3). The diagnosis of chronic spontaneous urticaria relies on compiling a thorough history, covering:

  • Time of onset of disease
  • Shape, size, frequency and distribution of weals
  • Associated angioedema
  • Associated symptoms such as bone/joint pain, fever, and abdominal cramps
  • Personal and family history of weals and angioedema
  • Induction by physical agents or exercise
  • Occurrence in relation to daytime, weekends, menstrual cycle, holidays, and foreign travel
  • Occurrence in relation to food or drugs (NSAIDs, ACE-Inhibitors)
  • Occurrence in relation to infections or psychological stress
  • Previous or current allergies, infections, internal/autoimmune diseases, gastrointestinal problems or other disorders
  • Social and occupational history
  • Leisure activities
  • Previous therapy and response to therapy including dosage and duration
  • Previous diagnostic procedures and results.

The international guidelines recommend limiting investigations in most patients with chronic spontaneous urticaria to differential blood count and ESR and/or CRP. Further diagnostic measures are based on patient history and examination, especially in patients with long-standing and/or uncontrolled disease.

Figure 3. Diagnostic algorithm for chronic urticaria

Notes on diagnostic algorithm for chronic urticaria

open
Accordion: Urticaria

What is the differential diagnosis for chronic spontaneous urticaria?

International guidelines recommend that differential diagnoses be considered in all patients with signs or symptoms suggestive of chronic urticaria based on the diagnostic algorithm. These include:

What is the treatment for chronic urticaria?

There is no ‘cure’ for chronic urticaria. The goal of treatment is to achieve symptom-free control [1,2].

The approach to the management of chronic spontaneous urticaria can involve:

  • Identification and elimination of any underlying causes
  • Avoidance of any known aggravating factors, such as non-steroidal anti-inflammatory drugs
  • Pharmacological treatment to prevent mast cell mediator release, or to prevent the effects of mast cell mediators [1].

Often the management for chronic inducible urticaria and chronic spontaneous urticaria will overlap [2].

Elimination of underlying causes

Chronic spontaneous urticaria is often reported to be associated with a variety of inflammatory or infectious diseases. Any identified infectious diseases (such as H. pylori infection, bacterial infections of the nasopharynx, or bowel parasites), and chronic inflammatory processes (such as gastritis, reflux oesophagitis, and inflammation of the bile duct or gallbladder) should be treated [1].

Plasmapheresis can reduce functional autoantibodies and has shown to provide temporary benefit in some autoantibody-positive patients with chronic spontaneous urticaria who have not responded to any other forms of treatment [1].

Pharmacological treatment of chronic urticaria

About one-third of patients continue to have symptoms despite maximal tolerated daily doses of non-sedating antihistamine [3].

An algorithm for the symptomatic treatment of chronic urticaria is included in the international guidelines (see Figure 4) [1]. The algorithm should be used with caution in children with chronic urticaria and in pregnant/lactating women when drugs contraindicated in pregnancy should not be used [1]. Treatment should be continued until remission occurs.

Figure 4. Pharmacological treatment algorithm

Antihistamines

Many symptoms of urticaria are mediated by the actions of histamine on H1-receptors located on endothelial cells (causing the weals) and on sensory nerves (causing neurogenic flare and pruritus). Continuous treatment with H1-antihistamines is supported by clinical trial data [1,2]. In some forms of physical urticaria, such as cold urticaria, ‘as required’ treatment may be appropriate [1].

Second-generation antihistamines are recommended in preference to first-generation antihistamines, as the latter have anticholinergic effects and sedative actions, and they interact with alcohol and many drugs that affect the central nervous system [1]. Second generation non-sedating antihistamines are the first-line symptomatic treatment for urticaria because of their good safety profile [1]. Those studied in the treatment of chronic urticaria include:

  • Cetirizine
  • Loratadine
  • Fexofenadine
  • Desloratadine
  • Levocetirizine
  • Rupatadine
  • Bilastine.

Terfenadine and astemizole are >no longer available in New Zealand or Australia and should not be used as they are cardiotoxic in combination with ketoconazole or erythromycin [1].

A number of small randomised trials have confirmed the improved efficacy of higher doses of second-generation antihistamines using up to four times the recommended doses of bilastine, cetirizine, desloratadine, ebastine, fexofenadine, levocetirizine and rupatadine (some of these agents are not available and higher doses are not licensed in New Zealand or Australia) [1]. The majority of patients with urticaria not responding to standard doses will benefit from up-dosing of antihistamines [1].

Treatment of refractory chronic spontaneous urticaria

Patients with chronic spontaneous urticaria that have failed to respond to maximum-dose second-generation oral antihistamines taken for 4 weeks should be referred to a dermatologist, immunologist or medical allergy specialist [1].

Omalizumab

Omalizumab (Xolair®) is a fully human monoclonal antibody that selectively binds to free immunoglobulin E (IgE), reducing the amount of IgE available in the blood and subsequently the skin [16]. This leads to down-regulation of surface IgE receptors, decreasing downstream signalling and resulting in suppressed activation of mast cells and basophils and in reduced inflammatory responses [16].

Omalizumab has been shown to be effective and well-tolerated in the treatment of chronic spontaneous urticaria [17–20]. Phase III studies have demonstrated efficacy at doses from 150–300 mg every 4 weeks independent of total serum IgE levels or body weight. Omalizumab improves angioedema [21,22], improves quality of life [21–23], is suitable for long-term use [24], and treats relapse after discontinuation [25].

The recommended dose for the treatment of chronic spontaneous urticaria is 300 mg by subcutaneous injection every 4 weeks. Some patients may achieve control of their symptoms with a dose of 150 mg every 4 weeks [16].

Omalizumab is indicated in New Zealand and Australia for adults and adolescents (≥ 12 years of age) with chronic spontaneous urticaria who remain symptomatic despite H1 antihistamine treatment [16]. It is currently listed on the Pharmaceutical Benefits Scheme in Australia [August 2018] for patients with severe chronic spontaneous urticaria provided specific criteria are met [26]. Xolair is funded for use in chronic spontaneous urticaria in New Zealand under Special Authority criteria (refer to PHARMAC for details) [27].

Ciclosporin

Ciclosporin is a calcineurin inhibitor and has a moderate direct effect on mast cell mediator release. The efficacy of ciclosporin in combination with an H1 second-generation antihistamine has been shown in placebo-controlled trials in chronic spontaneous urticaria [1]. It is not recommended as standard treatment due to the risk of significant adverse effects [1]. Ciclosporin should be reserved for patients with severe refractory chronic spontaneous urticaria [1].

Corticosteroids

  • Systemic corticosteroids have not been studied in randomised controlled trials and evidence for their use in chronic urticaria is limited [1,2].
  • Long-term use of systemic corticosteroids should be avoided as high doses are often required to reduce the symptoms of urticaria with associated potentially serious adverse effects [1,2].
  • A short course of systemic steroids may be considered for severe exacerbation of chronic urticaria [1,2].

Other treatments

Other agents have been used off-label for the treatment of chronic spontaneous urticaria but have little evidence to support them. These include:

These treatments may be of value to individual patients in particular clinical situations.

What is the outcome for chronic spontaneous urticaria?

Chronic spontaneous urticaria has a high rate of remission, which was up to 80% in 12 months in one population study [4]. However, symptoms were reported to last for longer than one year in up to 20% of patients and for more than 5 years in 11.3% of patients in another study [2,4].

Self-skin examination
New smartphone apps to check your skin
Learn more
(Sponsored content)

 

Related information

 

References

  1. Zuberbier T, Aberer W, Asero R et al. The EAACI/GA²LEN/EDF/WAO Guideline for the Definition, Classification, Diagnosis and Management of Urticaria. The 2017 Revision and Update. Allergy 2018; 73: 1392–1414. PubMed
  2. Australasian Society of Clinical Immunology and Allergy (ASCIA) CSU Working Party. Chronic Spontaneous Urticaria (CSU) Guideline. 2015. Available at: https://allergy.org.au/images/stories/pospapers/ASCIA_Guidelines_Chronic_Urticaria_2015.pdf [accessed 15/5/2018].
  3. Maurer M, Weller K, Bindslev-Jensen C, et al. Unmet clinical needs in chronic spontaneous urticaria. A GA2LEN task force report. Allergy 2011; 66: 317–30. PubMed
  4. Gaig P, Olona M, Munoz Lejarazu D, et al. Epidemiology of urticaria in Spain. J Investig Allergol Clin Immunol 2004; 14: 214–20. PubMed
  5. World Allergy Organisation. Urticaria and angioedema: Global overview. 2017. Available at: http://www.worldallergy.org/education-and-programs/education/allergic-disease-resource-center/professionals/urticaria-and-angioedema-global-overview [accessed 23/5/2018].
  6. Greaves MW. Chronic urticaria in childhood. Allergy 2000; 55: 309–20. PubMed
  7. Zitelli KB, Cordoro KM. Evidence-based evaluation and management of chronic urticaria in children. Pediatr Dermatol 2011; 28: 629–39. PubMed
  8. Kaplan AP. Chronic urticaria and angioedema. N Engl J Med 2002; 346: 175–9. PubMed
  9. Doong JC, Chichester K, Oliver ET, Schwartz LB, Saini SS. Chronic Idiopathic Urticaria: Systemic Complaints and Their Relationship with Disease and Immune Measures. J Allergy Clin Immunol Pract 2017; 5: 1314–18. PubMed
  10. Weller K, Groffik A, Church MK, et al. Development and validation of the Urticaria Control Test: a patient-reported outcome instrument for assessing urticaria control. J Allergy Clin Immunol. 2014; 133: 1365–72. doi:10.1016/j.jaci.2013.12.1076. PubMed
  11. Weller KG, M. Magerl, M. Tohme, et al. Development, validation and initial results of the Angioedema Activity Score. Allergy 2013; 68(9): 1185–1192. PubMed
  12. Baiardini I, Pasquali M, Braido F et al. A new tool to evaluate the impact of chronic urticaria on quality of life: chronic urticaria quality of life questionnaire (CU-QoL). Allergy. 2005; 60(8): 1073–8. PubMed
  13. Weller K, Groffik A, Magerl M, et al. Development and construct validation of the angioedema quality of life questionnaire. Allergy. 2012; 67: 1289–98. doi: 10.1111/all.12007. PubMed
  14. Kolkhir P, Metz M, Altrichter S, Maurer M. Comorbidity of chronic spontaneous urticaria and autoimmune thyroid diseases: A systematic review. Allergy 2017; 72: 1440–60. PubMed
  15. Maurer M, Abuzakouk M, Berard F et al. The burden of chronic spontaneous urticaria is substantial: real-world evidence from ASSURE-CSU. Allergy 2017; 72: 2005–16. PubMed
  16. Xolair® Approved Product Information, March 2017.
  17. Saini S, Rosen KE, Hsieh HJ et al. A randomized, placebo-controlled, dos-ranging study of single dose omalizumab in patients with H1-antihistamine-refractory chronic idiopathic urticaria. J Allergy Clin Immunol 2011; 128: 567–73. PubMed
  18. Saini SS, Bindsley-Jensen C, Maurer M, et al. Efficacy and safety of omalizumab in patients with chronic idiopathic/spontaneous urticaria who remain symptomatic on H1 antihistamines: a randomized placebo-controlled study. J Invest Dermatol 2015; 135: 67–75. PubMed
  19. Maurer M, Rosen K, Hsieh HJ, et al. Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria. N Engl J Med 2013; 368: 924–35. Journal
  20. Kaplan A, Ledford D, Ashby M, et al. Omalizumab in patients with symptomatic chronic idiopathic/spontaneous urticaria despite standard combination therapy. J Allergy Clin Immunol 2013; 132(1): 101–9. PubMed
  21. Staubach P, Metz M, Chapman-Rothe N, et al. Effect of omalizumab on angioedema in H1-antihistamine-resistant chronic spontaneous urticaria patients: results from X-ACT, a randomized controlled trial. Allergy 2016; 71: 1135–44. PubMed
  22. Maurer M, Sofen H, Ortiz B, Kianifard F, Gabriel S, Bernstein JA. Positive impact of omalizumab on angioedema and quality of life in patients with refractory chronic idiopathic/spontaneous urticaria: analyses according to the presence or absence of angioedema. J Eur Acad Dermatol Venereol 2017; 31: 1056–1063. PubMed
  23. Finlay AY, Kaplan AP, Beck LA et al. Omalizumab substantially improves dermatology-related quality of life in patients with chronic spontaneous urticaria. J Eur Acad Dermatol Venereol 2017; 31: 1715–21. PubMed
  24. Maurer M, Kaplan A, Rosén K et al. The XTEND-CIU study: long term use of omalizumab in chronic idiopathic urticaria. J Allergy Clin Immunol 2017; 141: 1138–39. PubMed
  25. Metz M, Ohanyan T, Church MK, Maurer M. Retreatment with omalizumab results in rapid remission in chronic spontaneous and inducible urticaria. JAMA Dermatol 2014; 150: 288–90. PubMed
  26. Schedule of Pharmaceutical Benefits. Pharmaceutical Benefits Scheme. July 2018. Available at: www.pbs.gov.au
  27. PHARMAC New Zealand. Omalizumab. Available at: https://www.pharmac.govt.nz/wwwtrs/ScheduleOnline.php?osq=omalizumab
  28. Antia C, Baquerizo K, Korman A, Alikhan A, Bernstein JA. Urticaria: A comprehensive review: Treatment of chronic urticaria, special populations, and disease outcomes. J Am Acad Dermatol. 2018; 79: 617–33. doi: 10.1016/j.jaad.2018.01.023. Review. PubMed

On DermNet NZ

Other websites

Books about skin diseases

See the DermNet NZ bookstore.