25 October 2017

Skin deep – an update for chronic spontaneous urticaria

Clinical Dermatology

The term urticaria describes an uncomfortable skin condition characterised by wheals of variable size, almost invariably surrounded by erythema. It is usually associated with pruritus, and occasionally, a burning sensation. Urticarial lesions are fleeting in nature with the skin returning to normal appearance, usually within one to 24 hours.1

Urticaria is caused by mast cell degranulation in superficial layers of the dermis.

Angioedema is characterised by a sudden, pronounced swelling of the deeper dermis and subcutis. It frequently involves mucous membranes and resolution is slower than for wheals, taking up to 72 hours.1 Angioedema represents swelling in deeper dermal layers, triggered by mast cells or bradykinin.2

Urticaria is classified as acute, when lasting for less than six weeks, or chronic, when lasting longer. Acute urticaria is common and can develop as part of an IgE mediated allergic reaction, but there are other causes including infection.

In chronic cases, urticaria develops on most days of the week, but may also develop daily. Unlike acute urticaria, an underlying cause is often not found in chronic urticaria.3 Chronic urticaria is often not related to allergy, a concept that can be difficult for some patients to accept.

Chronic urticaria can be broadly categorised into three forms: urticarial vasculitis, inducible urticaria, and chronic spontaneous urticaria.

Urticarial vasculitis is responsible for 5% of chronic urticaria cases and may be associated with systemic features including fever and arthritis. It is more common in women with a peak incidence between 30 to 40 years of age. The urticarial lesions may be described as painful or burning, instead of pruritic.

Single urticarial lesions can last for days and cause pigmentation/bruising of the skin when they resolve, features not seen with other forms of urticaria. Skin biopsy is necessary to confirm the diagnosis and will typically reveal leukocytoclastic vasculitis.Inflammatory markers (C-reactive protein and erythrocyte sedimentation rate) may be elevated while complement C3 and C4 levels may be depressed. The majority of cases are idiopathic but associations with a number of systemic autoimmune conditions, infections and malignancies have been described.3

Inducible urticaria accounts for 20% of chronic urticaria cases. Of the inducible urticarias, dermatographism is the most common form and describes the formation of wheals that develop after scratching the skin. Other inducible urticarias include cold urticaria, delayed pressure urticaria, solar urticaria, heat urticaria, vibratory angioedema/urticaria, cholinergic urticaria, contact urticaria and aquagenic urticaria.

Individuals with chronic urticaria who do not have an inducible or vasculitic form are described as having chronic spontaneous urticaria, previously known as chronic idiopathic urticaria.

It should be noted that inducible forms of urticaria can coexist with chronic spontaneous urticaria. Chronic spontaneous urticaria is a common condition that has a lifetime prevalence rate of around 1.8% of the general population, with a point prevalence rate in adults of 0.6% to 0.8% and affects females more often than males.4,5 The prevalence of urticaria in children is 2% to 7% while the prevalence of chronic urticaria is 0.1% to 3%.6-9

The majority of infants and young children presenting with urticaria have acute urticaria while less than 10% develop chronic urticaria. Recurrent acute urticaria is reported in 10% to 30% of young children. Chronic urticaria is more common among adolescents and older children.10-14

Chronic spontaneous urticaria is by far the commonest subgroup of chronic urticaria in children15 while inducible urticaria (most commonly dermatographism) accounts for the next most common subgroup.8 There is a higher incidence of autoimmune thyroid disease in patients with chronic spontaneous urticaria and those with thyroid autoantibodies may have more resistant disease.3,18 Emotional stress, alcohol, non-steroidal anti-inflammatory medications, and opiates can exacerbate symptoms in some patients.

In approximately 40% of cases, angioedema accompanies chronic spontaneous urticaria.16,17 Angioedema affecting the airway is rarely observed in patients suffering from chronic spontaneous urticaria.3 Recurrent angioedema in the absence of urticaria should be considered a separate disorder.2

Chronic spontaneous urticaria is usually a self-limiting disease which resolves within 12 weeks in approximately 52% of patients. It can last for more than one year in 20% of patients, and more than five years in 11% of patients.5 The presence of angioedema is associated with an increased duration of disease.18 In children chronic spontaneous urticaria may also persist for months to years.7-9

Chronic spontaneous urticaria is diagnosed by history and examination. There is no single investigation to confirm the diagnosis. There is no underlying or associated disease in the vast majority of cases and so extensive routine investigations are not required or recommended for chronic spontaneous urticaria unless concomitant disorders are suggested by the history.1,2,19,20 Treatment of chronic spontaneous urticaria should begin with a non-sedating H1 antihistamine such as cetirizine or loratadine. If symptoms do not improve after two weeks, up-titrating to four times the recommended daily dose may be necessary to control symptoms. Exceeding this dose is unlikely to confer any additional benefit and so an alternative agent should be added.1,3

In the 10 to 15% of patients who are unresponsive to H1 antihistamines, the addition of a H2 antihistamine such as ranitidine may help to control symptoms.

If this combination is inadequate, or if sleep is disturbed because of nocturnal symptoms, doxepin can be added if there are no contraindications to its use. Doxepin has strong H1 and H2 antihistamine properties and also acts as a sleeping aid.

While oral corticosteroids are very effective for treating chronic spontaneous urticaria, long-term use can result in significant side effects and their regular use is not recommended.

In addition, withdrawal of corticosteroids usually results in an exacerbation of symptoms.

If symptoms persist despite using a combination of H1 and H2 antihistamines, omalizumab, cyclosporin or montelukast can be added.1

Omalizumab has few side effects, is not immunosuppressive and is the most efficacious option for the management of antihistamine resistant disease. Omalizumab is an IgE monoclonal antibody, which was developed for the treatment of severe asthma. It has been shown to be very effective for the treatment of chronic spontaneous urticaria.1

Omalizumab was listed on the pharmaceutical benefits scheme in September this year. To be eligible for this medication, affected patients must be treated by a clinical immunologist, allergist, dermatologist, or general physician with expertise in the management of CSU, and have failed to respond to standard therapy, which is defined as a combination of therapies that includes H1 antihistamines at maximally tolerated doses in accordance with clinical guidelines, and one of the following:

• a H2 receptor antagonist (150 mg twice per day), or

• a leukotriene receptor antagonist (10 mg per day), or

• doxepin (up to 25mg three times a day).

A failure to achieve an adequate response to standard therapy is defined as a current Urticaria Activity Score 7 (UAS7) score of equal to or greater than 28 with an itch score of greater than eight, as assessed while still on standard therapy. The UAS7 is a disease activity score, which takes in to account the number of hives present each day and the severity of pruritus over a period of one week, and is recorded by the patient.1

Omalizumab 300mg is administered subcutaneously every four weeks for 12 weeks. Those who respond will be eligible for ongoing supply under the supervision of their treating physician.

Side effects include injection site reactions, headache and pyrexia. Anaphylaxis may rarely develop and so patients are usually observed for a period of time following their first dose.

Omalizumab has significantly improved the lives of patients with chronic spontaneous urticaria, a disease, which for many years, lacked effective and safe treatment options in those with antihistamine resistant disease.

Dr Ali Murad is a consultant immunologist and allergist practising in Castle Hill, Sydney  

References: 

1. Zuberbier T, Aberer W, Asero R, et al. European Academy of Allergy and Clinical Immunology; Global Allergy and Asthma European Network; European Dermatology Forum; World Allergy Organization. The EAACI/GA(2) LEN/EDF/WAO Guideline for the definition, classification, diagnosis, and management of urticaria: the 2013 revision and update. Allergy. 2014 Jul;69(7):868-87. 

2. Katelaris CH, Smith W, Choi J, Frith K, Lau WY, Nolan R, Randall K, Stirling R, Wainstein B. ASCIA Chronic Spontaneous Urticaria (CSU) Guidelines 2015.  

3. Fernando S, Broadfoot A. Chronic urticaria–assessment and treatment. Aust Fam Physician. 2010 Mar;39(3):135-8. 

4. Zuberbier T, Balke M, Worm M, Edenharter G, Maurer M. Epidemiology of Urticaria; a representive cross-sectional population survey. Clin Exp Dermatol 2010; 869-73.

5. Gaig P, Olona M, Munoz Lejarazu D, et al. Epidemiology of urticaria in Spain. J Investig Alergol Clin Immunol, 2004; 14:214-20.

6. Greaves MW. Chronic urticaria in childhood. Allergy. 2000; 55: 309-20.

7. Kaplan AP. Clinical practice. Chronic urticaria and angioedema. The New England journal of medicine. 2002; 346: 175-9.

8. Khakoo G, Sofianou-Katsoulis A, Perkin MR, Lack G. Clinical features and natural history of physical urticaria in children. Pediatric allergy and immunology: official publication of the European Society of Pediatric Allergy and Immunology. 2008; 19: 363-6.

9. Zitelli KB, Cordoro KM. Evidence-based evaluation and management of chronic urticaria in children. Pediatric dermatology. 2011; 28: 629-39.

10. Legrain V, Taieb A, Sage T, Maleville J. Urticaria in infants: a study of forty patients. Pediatric dermatology. 1990; 7: 101-7.

11. Mortureux P, Leaute-Labreze C, Legrain-Lifermann V, Lamireau T, Sarlangue J, Taieb A. Acute urticaria in infancy and early childhood: a prospective study. Archives of dermatology. 1998; 134: 319-23.

12. Sackesen C, Sekerel BE, Orhan F, Kocabas CN, Tuncer A, Adalioglu G. The etiology of different forms of urticaria in childhood. Pediatric dermatology. 2004; 21: 102-8.

13. Konstantinou GN, Papadopoulos NG, Tavladaki T, Tsekoura T, Tsilimigaki A, Grattan CE. Childhood acute urticaria in northern and southern Europe shows a similar epidemiological pattern and significant meteorological influences. Pediatric allergy and immunology: official publication of the European Society of Pediatric Allergy and Immunology. 2011; 22: 36-42.

14. Liu TH, Lin YR, Yang KC, et al. Significant factors associated with severity and outcome of an initial episode of acute urticaria in children. Pediatric allergy and immunology: official publication of the European Society of Pediatric Allergy and Immunology. 2010; 21: 1043-51.

15. Sahiner UM, Civelek E, Tuncer A, et al. Chronic urticaria: etiology and natural course in children. International archives of allergy and immunology. 2011; 156: 224-30.

16. Kaplan JACI 2004;114:465

17. Maurer M, Rosen K, Hsieh HJ et al. Omalizumab for the treatment of chronic idiopathic or spontaneous urticarial. N Engl J Med 2013; 368: 924-35

18. Toubi E, Kessel A, Avshovich N, Bamber E, Sabo E, Nusem D, Panasoff J. Clinical and laboratory parameters in predicting chronic urticaria duration: a prospective study of 139 patients. Allergy 2004; 59:869-73

19. Bernstein JA, Lang DM, Khan DA, et al. The diagnosis and management of acute and chronic urticaria: 2014 update. The Journal of allergy and clinical immunology. 2014; 133: 1270-7.

20. Powell RJ, Du Toit GL, Siddique N, et al. BSACI guidelines for the management of chronic urticaria and angio-oedema. Clinical and experimental allergy: journal of the British Society for Allergy and Clinical Immunology. 2007; 37: 631-50.