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Home , Angioedema, Aquagenic urticaria, Cholinergic urticaria, Cold urticaria, Physical urticaria, Pressure urticaria

clinical Chronic urticaria

Suran Fernando Assessment and treatment Andrew Broadfoot

Episodes of CU typically occur daily or most days Background of the week. If urticaria lasts beyond 6 months, up Chronic urticaria is a common condition encountered in general practice and a frequent to 40% of patients will still experience symptoms source of referral to the clinical immunologist, allergist and dermatologist. at 10 years.2 In contrast to acute urticaria, in CU Objective an external trigger is absent in the vast majority This article discusses the assessment and management of chronic urticaria in the (80%) of patients (Table 1). Approximately 40% general practice setting. of patients with CU have associated , Discussion which typically affects the face, extremities, and Chronic urticaria is defined as the occurrence of transient wheals lasting more than genitals.3 Involvement of the airways is rare. 6 weeks in duration. In 80% of cases, a cause is not identified and this is classified as chronic idiopathic urticaria. A physical trigger, vasculitis or systemic disease Assessment account for a smaller proportion of cases. Allergic causes are rarely responsible. A Careful history taking and physical examination detailed history provides the most useful information in determining the presence are the cornerstone of assessment of CU. Careful of chronic urticaria and a possible aetiology. Apart from thyroid function tests and questioning can help identify triggers if present. thyroid autoantibodies, other investigations should only be performed if clinically Investigations such as physical provocation, indicated. Second generation are the mainstay of treatment and usually laboratory tests, and biopsy should only be twice daily regimens are required for adequate control. H2 antagonists, doxepin and immunomodulation may be necessary in some patients. performed if clinically indicated. Keywords: and ; diseases; urticaria Physical urticaria is responsible for up to 20% of CU cases. If physical triggers are present, they can be identified on history in most cases. Dermographism is the most common form of physical CU and affects 2–5% of the general Urticaria is characterised by the rapid population.4 Dermographism can occur in isolation appearance of transient, pruritic skin swellings (wheals) of variable size surrounded by reflex lasting less than 24 hours and leaving no residual skin changes (Figure 1). Urticaria is a common condition, affecting up to 20% of the population.1 It is broadly classified into acute and chronic forms. Acute urticaria is defined as episodes of less than 6 weeks duration and accounts for over two-thirds of cases. An allergic or infectious trigger is sometimes identified (Table 1). Chronic urticaria (CU) is defined as episodes extending beyond 6 weeks and accounts Figure 1. Urticarial lesions with central wheal and peripheral flare for 30% of cases.

Reprinted from Australian Family Physician Vol. 39, No. 3, march 2010 135 clinical Chronic urticaria – assessment and treatment

symptoms develop only if exercise takes place conditions includes hepatitis B surface antigen, Table 1. Causes of acute and chronic urticaria within a few hours of eating, and in most cases, hepatitis C , and electrophoretogram/ only if a specific food is eaten in the pre-exercise immunoelectrophoretogram. Beyond these tests, Acute Chronic period. Rarer forms of physical urticaria include the authors recommend further investigation for Food Idiopathic , and vibratory secondary causes only if clinically indicated. Autoimmune angioedema. The various forms of physical Insect sting Physical Systemic disorders urticaria can be confirmed with the appropriate Viral infection Urticarial vasculitis stimulus test if required6 (Table 2). Thyroid functions tests and thyroid autoantibodies Contact Thyroid should be performed to exclude autoimmune disease Urticarial vasculitis Mastocytosis thyroid disease. Autoimmune thyroid disease, Infection Urticarial vasculitis accounts for up to 5% of especially Hashimoto disease, is associated with Hormonal CU cases and is mediated by immune complex CU and angioedema. Up to 26% of patients with deposition in blood vessel walls. The condition has CU have antithyroid compared to 3% or in association with other forms of urticaria. a female preponderance and a peak incidence in of healthy subjects.8 The presence of urticaria Patients describe linear wheals that occur at the fourth decade of life. Patients may describe however, does not necessarily correlate with sites of stroking or scratching. Most patients lesions that are burning or painful rather than thyroid function in these patients. Those patients do not seek medical attention as the lesions pruritic and purpuric or pigmented.7 Individual with CU accompanied by circulating thyroid are not usually pruritic. is lesions may last for up to 72 hours. Patients in autoantibodies and normal thyroid function are characterised by the appearance of small, 1–3 whom CU is suspected, can circle a new lesion and often poorly responsive to standard therapies for mm wheals precipitated by a rise in core body monitor the length of time to its disappearance. urticaria and may have more persistent disease. temperature as occurs with exercise, emotional Systemic features such as , arthritis, chronic The role of these autoantibodies in patients with stress, and heat exposure. obstructive pulmonary disease/asthma, scleritis/ normal thyroid function is not clear. follows exposure to cold air uveitis, glomerulonephritis and abdominal may other systemic diseases are rare causes of and water and can be associated with systemic be present. Skin biopsy for both histopathology and CU and include systemic lupus erythematosis and reactions such as ; fatalities such as direct immunofluorescence reveals leukocytoclastic other connective tissue diseases, mastocytosis, have been reported.5 Cold urticaria is vasculitis and perivascular deposition of (monoclonal gammopathy) usually idiopathic but may be associated with immunogloubulin, complement and fibrin. Laboratory and cryopyrinpathies (autoinflammatory cold dependent serum protein disorders such as investigation may reveal hypocomplementemia syndromes from genetic defects in the cryopyrin or following infections such as (C3, C4), raised inflammatory markers (erythrocyte protein that cause familial cold urticaria). Apart infectious mononucleosis. A familial form with an sedimentation rate and C-reactive protein), and from thyroid stimulating hormone and thyroid autosomal dominant mode of inheritance is rare. positive antinuclear antibody. autoantibodies, further investigations for these This form presents in infancy and is associated with most cases are idiopathic, however systemic manifestations should be performed only a range of specific debilitating systemic symptoms. the condition is associated with a range of if clinically indicated. Delayed involves cutaneous , connective tissue diseases (systemic Infection erythema and swelling that occurs 4–6 hours lupus erythematosis, Sjogren syndrome), after pressure stimulus is applied, such as that infection (hepatitis B, hepatitis C, Epstein-Barr Simple viral infections are common causes of from: constrictive clothing (eg. underwear), shoes, virus), lymphoproliferative disorders, malignancy acute urticaria in children as a result of immune seatbelts, handbags, and from tools used in and physical urticaria. Initial testing for these complex formation but are rarely associated with manual labour. Patients often describe burning and pain instead of, or in addition to, pruritus. Table 2. Testing procedures for physical urticaria The swelling can last several hours to several Physical urticaria Testing method days and may be accompanied by . Dermographism Stroking skin firmly with a narrow pointed object These patients usually have concomitant chronic Cold Ice cube test for 5 minutes idiopathic urticaria and angioedema. Cholinergic Exercise for 15–20 minutes or emersion of leg in a 44ºC bath Exercise induced urticaria and is Delayed pressure Sandbag test using 7 kg of weight for 15 minutes rare. It is characterised by the development of Exercise Exercise for 15–20 minutes +/- skin tests/RASTs for food large wheals, and and particularly if exercise continues, may be accompanied by Solar Specific wavelength light exposure angioedema, gastrointestinal symptoms and Localised heat Test tube of water at 44ºC for 5 minutes hypotension. Food dependent, exercise induced Vibratory Vibration with a laboratory vortex for 4 minutes anaphylaxis is a related condition in which Aquagenic Water compress

136 Reprinted from Australian Family Physician Vol. 39, No. 3, march 2010 Chronic urticaria – assessment and treatment clinical the chronic form.9 Human virus, Reassurance possible. Avoidance of excessive heat, spicy foods bacterial infection and parasitic infestation are It is important to reassure the patient that, in the or alcohol may also be useful in some patients. rare causes of CU. vast majority of cases, CU is not associated with Pharmacological treatment malignancy and is not usually life threatening. Hormonal Except for those patients with cold or exercise In most cases of CU a specific cause is not found Progesterone containing oral contraceptives, induced anaphylaxis, most patients with CU are and hence the primary objective is the relief of hormone therapy, or endogenous progesterone not at risk of airway obstruction or anaphylaxis. symptoms. Pharmacological therapy may not may be rarely associated with cyclic urticaria, Information for patients with urticaria and completely relieve symptoms and this should be with or without other types of skin . Lesions angioedema can be downloaded from the conveyed to the patient. appear before menses and resolve following its Australasian Society of Clinical Immunologists Oral antihistamines completion.10 Skin testing +/- oral challenge to and Allergists website (see Resource). progesterone can be performed to confirm the Symptoms of urticaria are predominantly Nonpharmacological treatment diagnosis. Pruritic urticarial papules and plaques mediated by H1 receptors on cutaneous nerves of is an urticarial, pruritic eruption that Physical triggers should be avoided. Patients with and endothelial cells as a result of develops in and around the abdominal striae in cold urticaria should be warned never to swim release from mast cells. This means that second about 0.5% of . alone and similarly, those with exercise induced generation, nonsedating antihistamines are the first anaphylaxis, never to exercise alone. These line treatment of CU.12 Drugs in this class include Less well established causes patients should also be prescribed an loratidine, desloratidine, and . The association between Helicobacter pylori, auto-injector. Certain medications such as , Comparative data regarding the relative efficacy of candidal infection, malignancy, related nonsteroidal anti-inflammatory agents and these antihistamines show similar benefits. Often and CU have been reported but not well opiates, which can cause or exacerbate urticaria patients require more than the recommended single substantiated. Investigation for these conditions in some patients, should also be stopped if daily dose, however, in the authors’ experience, is not routinely recommended. In contrast to acute urticaria, IgE mediated is rare Chronic urticaria in the chronic form and skin testing is futile and can lead to an inaccurate diagnosis of a food allergy and unnecessary dietary restriction. An Urticarial vasculitis Urticarial vasculitis elimination diet to exclude the remote possibility Not present Present of an intolerance to food chemicals should ideally be performed by a specialist in close collaboration with a dietician that has expertise Avoid physical triggers Antihistamines in the area. Caution with aspirin/ Prednisone NSAIDs/opiates Immunomodifiers Chronic idiopathic urticaria Treat co-existent systemic Monitoring of systemic disease manifestations (eg. In the majority of cases no cause can be found, articular, renal, respiratory, and hence, the diagnosis of chronic idiopathic gastrointestinal, ocular disease) urticaria is made. A subset of patients have Nonsedating autoantibodies to the high affinity IgE receptor, daily to twice daily or rarely, anti-IgE antibodies.11 Autologous serum Incomplete response skin testing for these autoantibodies is performed Nonsedating antihistamine daily to in a few specialised centres using an intradermal twice daily injection of a patient’s serum and observing for a H2 antagonist daily to twice daily wheal and flare reaction. More recently, in vitro Incomplete response tests measuring basophil and mast cell activation Doxepin 10–25 mg initially have been introduced in a few specialist up to 75 mg at night laboratories as a means of detecting surrogate markers of autoimmune urticaria. Incomplete response Leukotriene inhibitor plus Treatment antihistamines An approach to the treatment of CU is outlined in Immunomodifiers Figure 2. Approach to treatment of chronic urticaria Figure 2.

Reprinted from Australian Family Physician Vol. 39, No. 3, march 2010 137 clinical Chronic urticaria – assessment and treatment

Resource increasing the dose beyond a twice daily regimen Table 3. Treatments for refractory is rarely beneficial. Prophylactic therapy rather than The Australasian Society of Clinical Immunologists urticaria and Allergists (ASCIA): www.ascia.org.au. symptomatic therapy may better stabilise mast cells Leukotriene modifiers +/- and hasten resolution of CU. Sedation at higher antihistamines Authors Suran Fernando MBBS, BSc(Med), PhD, doses may be evident in some patients. Sulfasalazine Data regarding the safety of antihistamines FRACP, FRCPA, is Head, Department of Clinical Dapsone Immunology, Royal North Shore , St during pregnancy reveals that chlorpheniramine Hydroxychloroquine Leonards, New South Wales. sfernando@nsccahs. is the first generation antihistamine of choice and Colchicine health.nsw.gov.au or cetirizine as the second generation Cyclosporin Andrew Broadfoot MBBS, FRACP, FRCPA, is visiting 13 antihistamine of preference. The reassuring Mycophenolate mofetil medical officer, Department of Allergy, Royal North human data for loratadine and cetirizine in a (anti-IgE monoclonal Shore Hospital, St Leonards, New South Wales. large number of patients and the potential for antibody) Conflict of interest: none declared. sedation or performance impairment with first Plasmapheresis generation antihistamines suggest that these References second generation antihistamines are a feasible replacement.15 Some reports suggest that 1. Champion RH, Roberts SO, Carpenter RG, Roger alternative for pregnant women. euthyroid patients with CU and thyroid JH. Urticaria and angio-oedema. A review of 554 patients. Br J Dermatol 1969;81:588–97. the addition of an H2 receptor antagonist autoantibodies should also be treated with 2. sibbald RG, Cheema AS, Lozinski A, Tarlo S. Chronic may be effective when added to H1 receptor thyroxine.16 The authors advise against this urticaria. Evaluation of the role of physical, immuno- logic, and other contributory factors. Int J Dermatol antagonists in the 10–15% of patients who because of the potential risk of osteoporosis. 1991;30:381–6. are unresponsive to H1 receptor antagonists 3. Kaplan AP. Chronic urticaria: pathogenesis and treat- Treatments for histamine resistant ment. J Allergy Clin Immunol 2004;114:465–74. alone. The options include ranitidine, nizatidine, disease 4. Kirby JD, Matthews CN, James J, Duncan EH, famotidine and at daily to twice daily Warin RP. The incidence and other aspects of dosing. The side effect profile of cimetidine, factitious wealing (dermographism). Br J Dermatol A number of medications have been used 1971;85:331–5. including its numerous drug interactions, limits its to treat CU unresponsive to high dose 5. Fernando SL. Cold-induced anaphylaxis. J Pediatr utility in this setting. antihistamines. They act as anti-inflammatory 2009;154:148–148.e1. 6. Khan DA. Chronic urticaria: diagnosis and manage- First generation antihistamines have a agents and/or immunomodulators, ment. Allergy Asthma Proc 2008;29:439–46. limited role in CU because of excessive sedation. immunosuppressives (Table 3). A review of 7. mehregan DR, Hall MJ, Gibson LE. Urticarial vasculi- tis: a histopathologic and clinical review of 72 cases. However, is especially useful in other agents is beyond the scope of this article. J Am Acad Dermatol 1992;26:441–8. cold urticaria, and first generation antihistamines Patients who require these medications should 8. Verneuil L, Leconte C, Ballet JJ, et al. Association between chronic urticaria and thyroid autoim- are useful when nocturnal symptoms interfere be reviewed by a specialist. munity: a prospective study involving 99 patients. with sleep. Patients should be specifically warned 2004;208:98–103. of impairment of fine motor and driving skills. Summary of important points 9. mortureux P, Leaute-Labreze C, Legrain-Lifermann V, Lamireau T, Sarlangue J, Taieb A. Acute urticaria Doxepin has very potent H1 and H2 • Chronic urticaria is relatively common and in infancy and early childhood: a prospective study. antihistamine activity and initiated at doses of causes distressing pruritus that can last from Arch Dermatol 1998;134:319–23. 10. Poole JA, Rosenwasser LJ. Chronic idiopathic urti- 10–25 mg at night and increased to up to 75 mg/ weeks to years. caria exacerbated with progesterone therapy treated day in patients unresponsive to combined H1 and • Careful history taking and physical with novel desensitization protocol. J Allergy Clin Immunol 2004;114:456–7. 14 H2 blockade. Its utility is restricted by sedation examination is the cornerstone of assessment. 11. Boguniewicz M. The autoimmune nature of chronic and weight gain. High doses may prolong the QT • Apart from thyroid stimulating hormone and urticaria. Allergy Asthma Proc 2008;29:433–8. 12. Zuberbier T, Bindslev-Jensen C, Canonica W, et al. interval. thyroid autoantibodies, further evaluation EAACI/GA2LEN/EDF guideline: management of urti- of CU with provocation tests, laboratory caria. Allergy 2006;61:321–31. Oral 13. Gilbert C, Mazzotta P, Loebstein R, Koren G. Fetal investigation and skin biopsy should only be safety of drugs used in the treatment of allergic rhini- Prednisone is often prescribed for short term relief performed if clinically indicated. tis: a critical review. Drug Saf 2005;28:707–19. of severe urticaria that is unresponsive to high • Allergy is very rarely a cause of CU; skin tests/ 14. smith PF, Corelli RL. Doxepin in the management of pruritus associated with allergic cutaneous reactions. dose antihistamines. However, the side effects of RASTs are rarely indicated. Ann Pharmacother 1997;31:633–5. corticosteroids preclude their use in the long term • First line treatment involves reassurance, 15. Rumbyrt JS, Katz JL, Schocket AL. Resolution of chronic urticaria in patients with thyroid autoimmu- management of CU. avoidance of exacerbating factors and nity. J Allergy Clin Immunol 1995;96:901–5. nonsedating antihistamines. 16. Aversano M, Calazzo P, Iorio G, Ponticiello L, Lagana Treatment of underlying systemic B, Leccese F. Improvement of chronic idiopathic • Patients with urticarial vasculitis, associated disease urticaria with L-thyroxine: a new TSH role in immune systemic diseases or refractory disease may response? Allergy 2005;60:489–93. Patients with thyroid autoantibodies and hypo- require further evaluation and alternative thyroidism may benefit from thyroid hormone treatments by a specialist. correspondence [email protected]

138 Reprinted from Australian Family Physician Vol. 39, No. 3, march 2010