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1 How to Treat PULL-OUT SECTION Complete How to Treat quizzes online ( to earn CPD or PDP points. inside Classification Clinical manifestations History and examination Treatment Special considerations The authors Professor Dedee murrell professor and head of dermatology, St George Hospital and school of medicine, University of NSW; executive vice-president, International Society of Dermatology; and chair, World Congress Task Force, American Academy of Dermatology. Introduction URTICARIA is a common, heterogenous group of diseases characterised by the sudden appearance of wheals, angioedema or both. 1 This skin disorder is commonly encountered in dermatology and general practice. The key feature that defines is that the individual lesions resolve within 24 hours without leaving any marks. This article presents an overview of with a focus on the investigation and treatment. The key pathological phenomenon in is vasodilation, and increased permeability of the cutaneous and submucosal microvasculature causing transient intracutaneous oedema. 1 For wheals, the area of oedema involves the entire epidermis, and extends into the upper and middle dermis. There is dilatation of the postcapillary venules and lymphatic vessels in the upper dermal area. 2 These l lesions blanch with pressure and account for the central pallor. In angioedema, swelling occurs in the deeper dermis and subcutaneous region as a result of increased vasopermeability of the microvasculature. Besides skin, the areas of involvement for angioedema may also include the mouth and the bowel. The clinical manifestations of are discussed in greater detail below. The pathogenesis of is complex, involving multiple types of inflammatory cells and cytokines. Regardless of the aetiology, it ultimately involves activation of cutaneous mast cells with subsequent degranulation, resulting in histamines and many other inflammatory cytokines being released. This action induces vasodilation (erythema), increased vascular permeability with plasma extravasation (oedema) and recruitment and subsequent infiltration of neutrophils and other immune cells. The mast-cell mediators also stimulate cutaneous sensory nerves that causes pruritus and the burning sensation that is commonly encountered in. 1 cont d next page Copyright 2013 Australian Doctor All rights reserved. No part of this publication may be reproduced, distributed, or transmitted in any form or by any means without the prior written permission of the publisher. For permission requests, howtotreat@reedbusiness.com.au jaehwan kim medical dermatology fellow, department of dermatology, St George Hospital, Kogarah; and conjoint senior lecturer, school of medicine, University of NSW. clement chee hoou loh medical student, University of NSW. 40 EARN Category 1 CPD POINTS ONLINE N NEW ONLINE EDUCATION MODULE Diabetes in general practice Complete the online interactive learning module and update your knowledge on managing diabetes. This practical and relevant educational activity will help you in your management of patients with type 2 diabetes australiandoctor.com.au/education Sponsored by 15 February 2013 Australian Doctor 25

2 Classification URTICARIA may be classified into three broad categories based on clinical presentation spontaneous, physical and other l syndromes. 1 Depending on duration of symptoms, spontaneous may be further classified as acute symptoms lasting for less than six weeks, and chronic symptoms occurring for most days of the week for more than six weeks. 3 Physical s such as dermatographism, cholinergic and many other subtypes as summarised in table 1, are distinct subtypes of in which symptoms are triggered by specific physical factors. 4 It is clinically important to distinguish from l dermatoses a morphological group that mimics. This group includes l drug eruptions, l vasculitis and even bullous pemphigoid. In these conditions, wheals take more than 24 hours to resolve. Figure 1 shows the relationship between the different classes of. Chronic has a peak prevalence in the middle-aged population, especially females (female to male ratio of 4:1). 5 Spontaneous Pruritic wheals of variable sizes may appear on any part of the body, and resolve within 2-24 hours without residual bruising. Lesions may occur at any time of the day, but more commonly in the evening or just after waking. Systemic symptoms such as sweats, chills, fatigue and arthralgias may be present with severe disease, but the presence of fever or arthritis suggests the possibility of another diagnosis, such as l vasculitis or cryopyrin-associated periodic syndrome. Females may also complain of a premenstrual flare of l lesions. Acute In most cases, spontaneous acute will resolve within days or weeks. It occurs more commonly in children than adults. 1 Patients may describe their symptoms as episodic and attribute them to a preceding event, but most cases of acute are idiopathic, followed by a similar proportion caused by upper respiratory tract infections, and a smaller number caused by drug reactions and food allergy. Drug and food reactions are more common in adults, while streptococcal infections and viral respiratory tract infections are common causes in children. 6 An acute l eruption may be associated with life-threatening angioedema or anaphylaxis. Chronic Chronic refers to l lesions occurring at least twice a week for more than six weeks. 7 Lesions occurring less frequently than this are known as recurrent or episodic. Fifty per cent of patients with chronic (with or without angioedema) become free of lesions within one year, 65% within three years, and 85% within five years. 8 Figure 1: Classification of. Table 1: Types of physical and other l types Subtypes Triggering factor Physical Other l types Spontaneous Acute Due to mechanical stress Dermatographism Delayed pressure Vibratory Contact Due to temperature changes Cold contact Heat contact Due to sweating or stress Cholinergic Adrenergic Exercise-induced Due to other causes Solar Aquagenic l vasculitis Angioedema without wheals Adapted from: Zuberbier T, et al. 2 and Bolognia 7 As patients with chronic are also at risk for developing autoimmune thyroid disease, they should undergo screening for autoimmune thyroiditis and thyroid dysfunction. Physical - elicted by specific physical factors (see table 1) Chronic Mechanical (scratching/rubbing, etc) Constant pressure on skin Any vibrating force Urticariogenic substance Cold objects/weather Localised heat source Increased core body temperature Stress Physical exercise UV or visible light Contact with water Other l subtypes (see table 1) Chronic has a peak prevalence in the middle-aged population, especially females (with a female to male ratio of 4:1). 5 The mean duration of chronic is four years. Most cases of chronic are characterised by periods of asymptomatic disease lasting days to months. Common causes of chronic are autoreactivity, infection and thyroid disease. Chronic also has a strong association with autoimmune conditions. Autoreactivity. Autoreactivity is the presence of circulating mastcell activating factors in the serum. This form of chronic is also known as chronic autoimmune, in which IgG autoantibodies present in the serum bind onto the alpha-subunit of the highaffinity IgE receptor, and activate mast cell degranulation and release of histamine. 4 Infection. Infections that are known to be associated with chronic spontaneous are viral, bacterial, parasitic and fungal infections including hepatitis, bacterial infections of the nasopharynx, dental infections and gastrointestinal infections including Helicobacter pylori. 1 The role of H. pylori as an aetiological factor in chronic still remains controversial; it may be associated with exacerbation Table 2: Differential diagnoses of 2,3 Condition Distinguishing features pigmentosa(mastocytosis) Brown patches; te on pressure l vasculitis SLE Non-histaminergic angioedema Hereditary angioedema Acquired angioedema with C1 inhibitor deficiency Cryoglobulinemia Polymorphic eruption of pregnancy Associated syndromes Cryopyrin-associated periodic syndrome Muckle Wells syndrome Familial cold Hypereosinophilic syndromes Well s syndrome Schnitzler syndrome of l symptoms. However, a systematic review concluded there is weak evidence of symptom improvement upon eradication of H. pylori. 9 Chronic may be caused or worsened by hypersensitivity reactions to food components such as preservatives, colourants, taste intensifiers and other naturally occurring compounds (aromatic compounds, amines, etc) through non-immunologically mediated mechanisms, known as pseudoallergic hypersensitivity. 1 Thyroid. There is a reasonably significant association between chronic and thyroid disease. Twelve to 30% of patients with have elevated levels of thyroid peroxidase antibodies or anti-microsomal antibodies compared with the general population. 3 There is a positive association between chronic and thyroid autoantibodies, but not with histological thyroiditis or altered thyroid function. 5 Only a small number of patients who are positive for antithyroid antibodies have actual thyroid disease. 5 Patients positive for thyroid autoantibodies have more persistent that is poorly responsive to standard therapies. 3 As patients with chronic are also at risk for developing autoimmune thyroid disease, they should undergo screening for autoimmune thyroiditis and thyroid dysfunction, to enable early identification of these conditions. 5 The prognostic significance of thyroid autoantibodies has been evaluated in a retrospective study that suggests patients who are positive for thyroid autoantibodies have a significantly longer duration of l disease than those patients without thyroid autoantibodies. 10 Thyroxine treatment for patients with thyroid disease may help improve l symptoms, but the efficacy has not been consistent across studies. 5 Lasts >24 hours, leaves bruising/ purpura Longer lasting; sun exposed areas Facial and/or genital areas Usually worse in extremities; purpura Pregnant females Associated features Development of wheals early in life that are resistant to antihistamine treatment; unprovoked attacks of fever, rashes, musculoskeletal and neurologic manifestations Pruritic cellulitis-like eruption occurs, followed by reticular pigmentation/ scarring alopecia. Flame figures on biopsy Nonpruritic l rash with recurrent fever, bone pain, joint pain, organomegaly, and monoclonal IgM gammopathy Less common causes. Other less common causes of chronic include type 1 allergies, which must be considered in chronic with intermittent symptoms. Noninfectious inflammatory processes can also be responsible, such as gastritis, reflux oesophagitis, cholecystitis and cholangitis. Autoimmune disorders such as SLE may also be an underlying cause. Stress, physical exertion and variations in dietary habits such as eating rich or spicy foods are non-specific triggers that may also directly induce or aggravate l symptoms. 1,3 Physical s Physical s are a distinct subtype of that can be induced by an exogenous physical stimulus instead of occurring spontaneously. 7 Physical is classified further based on the physical stimulus heat, cold, pressure, vibration or even sunlight. 11 Physical is usually an acquired condition that typically occurs during adulthood. l lesions develop at sites of exposure within minutes of exposure to the stimulus and resolve within two hours. The exception is for delayed dermatographism and delayed pressure, which take hours to develop after provocation and will persist for more than 24 hours. More than one type of physical may occur in the same patient. Angioedema may be present in all types of physical except for symptomatic dermatographism. The most common type of physical is symptomatic dermatographism, in which linear wheals occur after a shearing force has been applied to the skin, such as stroking or scratching. Patients may first complain of severe itching, which leads to subsequent scratching of the skin that induces the formation of linear wheals. These lesions usually fade within an hour. cont d page Australian Doctor 15 February

3 from page 26 Differential diagnoses Other non-related systemic diseases may present with wheals and l skin lesions. These include pigmentosa, vasculitis, familial cold and non-histaminergic angioedema. These conditions are not classified as subtypes of as they possess a distinctly different pathophysiological basis that is not largely mediated by histamine. Other associated distinct syndromes that may present with wheals and angioedema are shown in table 2 (page 26). These non-related conditions presenting with l lesions have to be excluded in the routine workup of all patients presenting with l skin reactions. 4 Angioedema without wheals that involve the throat, tongue or lips suggests drug-induced angioedema. Angioedema of the larynx without wheals suggests hereditary angioedema or acquired C1-inhibitor deficiency. Both conditions are characterised by recurrent episodes of angioedema caused by the relative lack of C1 inhibitor, leading to excessive activation of the classical complement pathway. This results in the production of anaphylactic, chemotactic and vasoactive peptides, leading to massive localised oedema. 12 Clinical manifestations Wheal CLINICALLY, a wheal is defined as a transient, well-circumscribed, raised, erythematous plaque often with central pallor (figure 2). It consists of a central area of intracutaneous oedema affecting the epidermis and upper dermis, with a peripheral area of reflex erythema that is fleeting in nature. l lesions are usually associated with an itching or burning sensation. Lesions may be round, annular, or serpiginous (wavy or serpent-like ) in shape. 3 A wheal and flare reaction usually resolves within 1-24 hours. 2,8,13 Lesions lasting longer than 24 hours accompanied with painful or burning sensation or that result in scarring are suggestive of l vasculitis. 3 Angioedema In contrast, angioedema is defined as an abrupt and episodic swelling of the submucosal or subcutaneous tissues, usually affecting the lower dermis and subcutis. It is a non-pitting swelling that develops in minutes or hours, and takes a longer time to resolve, up to 72 hours. The affected areas feel numb, tingling or painful rather than pruritic. Swelling develops in an asymmetrical fashion and frequently involves the facial mucous membranes (figure 3) and those of the genitalia. 1 The oropharynx and Figure 2: Wheals present on anterior aspect of the upper thighs. Figure 3: Angioedema of the face. bowel may be affected in hereditary and acquired angioedema. While almost all other subtypes of manifest as an almost immediate wheal and flare reaction with or without angioedema, some subtypes of have more unique presentations. Delayed-pressure presents as a deeper, more generalised swelling without wheals with a period of latency ( hours), while dermatographism does not present concomitantly with angioedema. 2 Angioedema may also manifest without wheals, which suggests the possibility of hereditary angioedema (C1 inhibitor deficiency) or a drug reaction. 7 Lesions lasting longer than 24 hours accompanied with painful or burning sensation or that result in scarring are suggestive of l vasculitis. History and examination THE diagnosis of is primarily clinical. A detailed history and thorough examination is essential in establishing the diagnosis. 2 Given the heterogeneity of, it is important to identify any causative factors, exclude possible differential diagnoses and assess the impact of disease. Important details that should be elicited in the history include those shown in the box, right. In addition, patients should also be asked about any recent travel, infections, associated atopic conditions, sexual history and systems review. It is estimated that in 80-90% of all chronic cases, the exact cause is unknown. 3 To exclude other systemic causes of, it is important to note any relevant signs and symptoms, including fever, weight loss, arthralgia, arthritis, cold or heat sensitivity, abdominal pain and bone pain. 3 As there is a significant association between chronic and autoimmune thyroid disease, any history of thyroid disease is important. On physical examination, test Key components of the history in evaluation 1. Time of onset and duration of individual lesions 2. Frequency and duration of symptoms 3. Size, shape and distribution of wheals 4. Associated symptoms, eg, pruritus, pain 5. Associated angioedema 6. Previous treatment and response to treatment 7. Previous and/or current allergies, infections, systemic diseases and other comorbidities 8. Past history or symptoms of thyroid disease 9. Correlation of symptoms with food, weekends, holidays, foreign travel 10. Medication history especially NSAIDs, ACEIs 11. Past and family history of atopy or 12. Smoking and alcohol history 13. Correlation of symptoms with weather, exercise or any physical agents 14. Work, hobbies, external stressors 15. Gastrointestinal or psychiatric diseases 16. Surgical implantations and events during surgery Adapted from Zuberbier T, et al. 2 for dermatographism by stroking the affected skin in the areas indicated by the history. Ideally, patients should stop taking antihistamines and related medications 2-3 days before the examination. Subsequent investigations are guided by clinical impression and findings from the history and physical examination. Acute is typically self-limiting and requires minimal investigation. Most cases are idiopathic or caused by URTI. Allergic reactions to food or drugs may be confirmed as a cause of acute by skin-prick testing or RAST. The diagnostic workup of chronic manifesting as recurrent wheals with or without angioedema is best approached by ascertaining how long it takes for lesions to resolve. Individual wheals lasting less than two hours may suggest physical, and the appropriate physical challenge tests may be indicated. For lesions lasting from 2-24 hours, a trial of antihistamines may first be considered. Nonresponders would require extensive investigations. If lesions persist for more than 24 hours, a skin biopsy should be taken to rule out the possibility of other l syndromes such as l vasculitis. Investigations Chronic or systemic causes of should first be evaluated with a basic blood workup, including an FBC with differential white cell count, ESR or CRP, LFTs and urinalysis. Any medications suspected to be triggering symptoms should be stopped or replaced. If indicated by the history, additional tests to rule out systemic causes include: Hepatitis A, B, C serology. Infectious mononucleosis serology. Thyroid function tests and autoantibodies (antithyroglobulin and antimicrosomal antibodies). Anti-nuclear antibodies (ANA). Helicobacter pylori serology. Autologous serum skin tests. Lesional biopsy. 2 Intensive and expensive general screening to investigate underlying causes is only recommended for individuals with longstanding, persistent l symptoms. 2 A review of laboratory testing for chronic has revealed that only 1.6% of patients were identified as having an underlying systemic condition, and there was no significant association between the cont d page Australian Doctor 15 February

4 from page 28 number of tests ordered and identification of the underlying medical disorder. 14 Allergen testing Skin-prick tests and RAST should be considered in individuals with suspected atopy. Skin biopsies A skin biopsy should be obtained when l lesions persist for more than 24 hours. When obtaining a skin biopsy, patients should ideally stop taking antihistamines, glucocorticoids and leukotriene modifiers (eg, montelukast) for several days. Biopsy samples should be obtained from fresh lesional skin and placed in formalin for haematoxylin and eosin staining. In chronic with episodic features of systemic mast cell mediator release, such as flushing, abdominal cramping and diarrhoea, wheezing, lightheadedness or syncope, a biopsy should be obtained to rule out mastocytosis. 3 If patients present with: Painful rather than pruritic l lesions, associated petechial or purpuric characteristics and residual pigmentation; Elevated ESR or CRP with systemic symptoms; and/or Unresponsiveness to antihistamine therapy, a 3mm punch biopsy of lesional skin, placed in Michel s media or freshly snap-frozen for direct immunofluorescence microscopy with testing for immunoglobulins, may be indicated to rule out l vasculitis. 3 Table 3: Skin provocation tests for different physical. 4,7,16 The triggering threshold, maximal reaction and reaction time should be noted. Types Routine investigations Additional investigations Cold contact Delayed pressure Localised heat contact Solar Dermographism Generalised heat or cholinergic Aquagenic Cold provocation and threshold tests (contact with cold objects) Localised application of an ice cube in a polyethylene bag/hand glove or cold water for five minutes. Use TempTest an electronic device that allows the temperature threshold and time to reactivity to be determined. Positive test: Whealing may take up to 20 minutes or more to develop. Application of localised perpendicular pressure Apply to the back or thigh using a 2.5kg weight to skin for 20 minutes, or use a dermatographometer at 100g/mm 2 for 70 seconds Positive test: Erythematous, painful or burning hard wheal that develops 30 minutes to eight hours after application of pressure; whealing may extend beyond the confines of the test sites in stronger responses. Pressure-bearing areas such as skin under straps, watches, belts and shoes are more commonly affected. Application of localised heat source A source such as a heat cylinder (maximum temperature of 45 C) is applied for up to five minutes Positive test: Whealing occurs immediately (5-10 minutes) or later (6-18 hours) Expose to UV and visible light of different wavelengths Phototesting: Spectrodermograph an xenon arc lamp emitting narrow wavelength bands from 250 to 610nm can be used to diagnose and establish the exact wavelength causing l lesions to develop Positive test: Pruritus developing within seconds of light exposure, followed by development of erythematous wheals 2-3 minutes later, surrounded by a peripheral flare that extends beyond the affected sites Dermatographism tests Lightly stroking the skin of the back with a wooden spatula or by using a dermographometer at 36g/mm 2 Positive test: Koebner s phenomenon linear wheals developing at sites of pressure or shearing forces Heat exposure Immersing in a hot bath at 42 C for 10 minutes or exercising to the point of sweating, such as jogging on a treadmill up to 30 minutes Positive test: Wheals develop after approximately 30 minutes Wheals developing after bath or shower at room temperature, or after application of a wet gauze at room temperature for 20 minutes. Positive test: Wheals developing at sites exposed to contact with water Skin provocation tests In suspected cases of physical, skin provocation tests should be performed to identify Exclude other light-induced dermatoses FBC, ESR or CRP physical triggers. For diagnosis, it is important to identify the trigger and determine its threshold, which is helpful for assessment of disease severity and treatment response. The appropriate diagnostic tests for different subtypes of physical are outlined in table 3. These standardised graded provocation tests for physical can be performed in a general practice setting using office-based methods, so as to facilitate assessment and comparison of disease activity at different times. 2 Temp-Test is a validated Peltier element-based cold provocation device for testing cold. A dermographometer has been recently developed to measure disease activity in dermatographism, by applying a 36g/mm 2 pressure on the skin surface. 15 Appropriate diagnostic investigations may also be performed for other subtypes of physical as already outlined above. Autologous serum skin tests Autoreactivity is the presence of autoantibodies against IgE or high-affinity IgE receptors, a common cause of chronic. The presence of autoantibodies may be determined by performing the autologous serum skin test (ASST), which detects various types of histamine-releasing factors. In patients with, positive ASST reactivity is achieved in about 40% of adults with allergic or non-allergic respiratory symptoms, and almost 80% of the paediatric population. However, 40-45% of healthy individuals without also achieve positive ASST reactivity. Thus far, the cause of discrepancies in results have remained unclear. 2 Treatment THERE are two approaches to management of. The first approach is to identify and eliminate the underlying cause, and the second approach is to provide symptomatic relief. 17 Table 4 lists the main pharmacological options for treating. Prevention The first line of management is to eliminate triggers such as drugs or chemicals. 7 Drugs that commonly cause non-allergic hypersensitivity reactions are NSAIDs and ACEIs, both of which can elicit and aggravate pre-existing. 17 These drugs should be discontinued or replaced as appropriate. Other suspected triggers should also be avoided to reduce symptoms for patients with inducible. Patients should be educated to recognise and avoid any possible physical stimuli. In delayed-pressure or severe dermatographism, it is important to point out that reducing pressure or friction on the body surface such as broadening the handle of a heavy bag may improve symptoms. Similarly for cold, patients should avoid cold weather outdoors as much as possible. Identifying the eliciting range of wavelengths, avoiding sun exposure, using appropriate sunscreen and selecting light-bulbs with UV-A filters are management options for prevention of solar. 17 Most domestic incandescent light-bulbs, including the ordinary and tungsten-halogen varieties, emit a small amount of UV radiation. Quartz iodide lamps emit significant UV-A and minimal UV-B radiation, which may pose a risk of triggering disease activity. 5 Domestic lightbulbs with UV-A filters are directly available from manufacturers. Antihistamines Antihistamines are the mainstay of symptomatic treatment for. Second-generation nonsedating H1 antihistamines are the preferred first-line treatments because of their efficacy and safety profile. Antihistamines given during or just after the onset of wheals are less effective, hence they need to be taken on a regular basis. The lowest possible dosage should be initiated to minimise side effects, and if not effective, titrating the dose up to a maximum of four times the initial dose is recommended. 17 For severe and severe dermatographism, the use of older first-generation H1 antihistamines may be considered. First-generation H1 antihistamines have profound anti-cholingeric activity and cause prolonged sedative effects (more than 12 hours) on the CNS, as they are able to cross the blood brain barrier. However, their antipruritic effect only lasts for 4-6 hours. Therefore, due to their low safety profile, they are not recommended as first-line agents for chronic. 17 Patients taking these sedating H1 antihistamines must be advised against driving. If the use of non-sedating antihistamines for chronic is ineffective, it is advisable to maximise the dosage of sedating antihistamines before switching to other more potent therapies. Diphenhydramine is an alternative for severe dermatographism but not for cholingeric. Cyproheptadine is particularly effective for cold. Most cases of delayed pressure would require corticosteroid treatment, and cyclosporine is a good alternative. No particular antihistamine regimen is favoured for localised heat. H2 antihistamines have fewer side effects than H1 antihistamines and may be considered as adjunctive therapy. They augment further inhibition of wheal and flare reaction mediated by H1 histamine receptor antagonists once H1 receptor blockade has been maximised. 18 However in the treatment of chronic, this effect is only modest. A Cochrane review on the use of H2 antihistamine based on four previous studies has concluded there is weak and unreliable evidence for the effectiveness of H2 antihistamine therapy for chronic when used alone or in combination with H1 antihistamines. 19 Therefore, their use should be based on clinical judgement and the patient s individual circumstances. Leukotriene receptor antagonists Leukotriene receptor antagonists can be added to existing antihistamine treatment to aid improvement in limited cases of treatment resistant chronic. Montelukast is reported to be effective for NSAID-exacerbated chronic. 6 Tricyclic antidepressants Doxepin is a tricyclic antidepressant with strong antihistamine properties. It exerts antagonistic actions on H1 and H2 histamine receptors with more inhibition on H1 receptors than either hydroxyzine and diphenhydramine. 18 It may be considered in patients with chronic refractory to conventional treatment with antihistamines. It is also appropriate for treating anxiety and depression associated with chronic. Corticosteroids A short course of corticosteroids may be considered for patients with chronic or severe refractory to aggressive treatment with antihistamines and leukotriene antagonists. They should only be used for acute and in the treatment of acute flares of chronic spontaneous. Dosing should not exceed 25mg every other day or 10mg daily, and should be tapered over 2-3 weeks. Chronic improves with time and can eventually be managed without corticosteroids. 18 Immunotherapy If a patient fails to respond to any of the above-mentioned approaches, various immunotherapeutic approaches may be considered. 6 A low dose of cyclosporine is effective against that is refractory to conventional treatment and is corticosteroid sparing. 18 Double-blind randomised controlled trials have demonstrated that cyclosporine is a safer alternative to prednisone if used appropriately. The dosage can be started at 100mg bd and titrated up to no more than 100mg tds. 7 Dapsone exerts an immunomodulatory effect and demonstrates excellent clinical response, is rapid in small doses, but in some 30 Australian Doctor 15 February

5 Severity of disease Mild to moderate Severe Adjunctive Table 4: Pharmacological treatments for Treatment option Initial dose Side effects Drug use in pregnancy (Category) Non-sedating H1 antihistamines Cetirizine Loratadine Desloratadine Adults: 10mg once daily. Children (6-12): 5mg bd. 10mg once daily Not recommended for children below 12 years of age Adults: 5mg daily years old: 2.5mg daily. 1-5 years old: 1.25mg daily Somnolence, dry mouth and fatigue. Headache, sedation, fatigue, dry mouth. In children taking loratadine syrup 10mg once daily: nervousness, hyperkinesia, sedation and headache Headache, fatigue, dizziness or drow s- iness and nausea Fexofenadine 180mg daily Headache, fatigue, dizziness or drowsiness and nausea Sedating H1 antihistamines Hydroxyzine mg PO or IM tds-qid. REM sleep interference, learning difficulties, sedation Diphenhydramine Adults, children>12 years: 10mL or Drowsiness and somnolence A 50mg tab daily 25-75mg nocte or 10-20mg bd/tds Promethazine C Cyproheptadine 4mg tds, not exceeding 32mg tds A H2 antihistamines Cimetidine Ranitidine Famitodine Nizatidine 20mg-50mg daily Itching, swelling, lightheadness, drowsiness, dizziness, feeling flushed, throat tightness, nausea, palpitations, metallic taste, headache, tongue swelling, blurry vision, rash,, exfoliative dermatitis, pruritis B3 Leukotriene antagonists Montelukast Adults: 10mg daily Fatigue, fever, abdominal pain Sodium cromoglycate (mast cell stabiliser) 20mg bd PO Throat irritation, cough and transient bronchospasm Tricyclic antidepressants B2 B2 A - Monitoring/preventive measures If persistent symptoms, may titrate dose up to four times normal dosage. Not to be coadministered with CYP3A4/CYP2D6 drugs Interacts with alcohol and many drugs including sedatives, hypnotics, analgesics and monoamine oxidase inhibitors. Patients must be advised against driving. Inhibits P-450 CYP enzymes and potentiates effects of drugs metabolised by this pathway. Doxepin 30mg daily PO Sedation, xerostomia and constipation C May be considered for refractory chronic can also interacts with other drugs metabolised via the cytochrome P-450 pathway(eg, erythromycin, ketoconazole) Corticosteroids Prednisone 10mg daily PO Hyperglycaemia, hypertension A Not recommended for long-term use Immunotherapy Cyclosporine 100mg bd PO Anaemia, toxic hepatitis, jaundice, pancreatitis, vertigo - Monitor blood pressure, serum creatinine, blood urea nitrogen level, FBC, LFTs and urinalysis should be performed every 6-8 weeks Dapsone 100mg daily PO B2 FBC, LFTs, G6PD levels Methotrexate 10-15mg weekly D FBC, LFTs, EUC Topical measures Topical antipruritic As needed - lotion (pramoxine lotions) Cooling lotions (Sarna - lotion) Tepid showering or tepid oatmeal baths patients it can take several weeks to take effect. This drug is generally well tolerated and can maintain disease remission even after stopping treatment. It is necessary to monitor for a predictable drop in haemoglobin levels in all patients, and to check G6PD levels to avoid anaemia in G6PD-deficient patients. Methotrexate may also be used, but its efficacy for resistant chronic has only been anecdotal. Use of methotrexate for intractable chronic has only been reported in several case reports that state response may be achieved within 1-2 weeks. However, there may be significant adverse effects that warrant frequent monitoring. A retrospective case review of 16 patients concluded that methotrexate may be useful for refractory chronic as a alternative or substitute for third-line treatments (such as cyclosporine) when such treatments are ineffective or contraindicated. 20 IV immunoglobulin can achieve rapid responses ranging from transient partial relief to long-lasting complete remission. However, treatment with IV immunoglobulin has only been reported in limited case reports and short series on patients, therefore the optimum dose and number of infusions is unclear. Adrenaline Adrenaline may be indicated for severe or life-threatening l eruptions and angioedema leading to anaphylaxis. Injectable adrenaline solutions have rapid onset but limited duration of action. They are usually administered as 10 μg/ kg (0.01mL) to a maximum of 500μg (0.5mL) doses in 1:1000 solution IM or IV every five minutes if necessary. Adrenaline and intubation may be necessary for patients who demonstrate little response to antihistamines and corticosteroids. This is particularly so in patients with angioedema presenting with oedema of the larynx, pharynx or tongue. Acute onset of hereditary angioedema requires immediate adrenaline, intubation and transfusion with fresh frozen plasma or C1 inhibitor concentrate to abort acute episodes. 6 Phototherapy Narrowband UV-B phototherapy may be useful for patients with chronic resistant to standard therapies. In a recent randomised controlled trial, narrowband UV-B phototherapy combined with antihistamine was superior to antihistamine therapy alone in reducing l symptoms, and these reductions in disease activity were maintained for three months after finishing phototherapy. 21 Treatment of associated infections Chronic is often associated with several infectious diseases, such as H. pylori-associated gastritis, bacterial infection of the nasopharynx and other bowel parasitic infections. Treatment of these infections has been shown to be beneficial in the management of limited cases. 17,22 Intestinal candidiasis has recently been discounted as a significant cause of chronic. 17 Other chronic inflammatory disease such as gastritis, reflux oesophagitis, cholecystitis or cholangitis have been associated with chronic, but it still remains unclear if they are causative or only a chance association. 17 Topical measures Itching may be relieved by applying topical pramoxine lotions, cooling lotions (such as Sarna lotion), and by taking tepid showers and tepid oatmeal baths. cont d next page 15 February 2013 Australian Doctor 31

6 Special considerations Children THE diagnostic workup and management of in children should be the same as that in adults, as the differences in the underlying causes of chronic between children and adults are small. Pregnancy There has been a lack of evidence for treatment of in pregnant women. As several antihistamines have been associated with teratogenic effects, it is important to assess the risk of teratogenicity and benefits of using antihistamine therapy during pregnancy. 24 First-generation sedating H1 antihistamines such as chlorpheniramine and diphenhydramine, and second-generation non-sedating H1 antihistamines loratadine, levocetirizine and cetirizine, are all US Food and Drug Administration category B drugs that do not have a major teratogenic effect. 25,26 Fexofenadine, desloratadine, terfenadine and astemizole are classified as category C drugs that may be teratogenic, hence their use is contraindicated in pregnancy. 27 The Australian classification of these drugs for use during pregnancy is shown in table 4 (page 31). Use of large doses of first-generation H1 antihistamines just before parturition may exert an oxytocin-like effect resulting in premature contractions, and the neonate may have withdrawal symptoms, including irritability. Recent studies have ruled out loratadine as a possible causative factor of hypospadias in infants whose mothers have previously taken loratadine during pregnancy, and suggest that loratadine does not represent a major teratogenic risk. 24 l symptoms during the first trimester are preferably managed with bland topical emollients, and use of systemic antihistamine therapy is best avoided to minimise the risk of teratogencity. 24 First-generation H1 antihistamines are recommended for treating during pregnancy, as they are more widely used and have well-established data on their safety and side effects. 28 In the patient who is intolerant or non-responsive to first-generation H1 antihistamines, the use of second-generation H1 antihistamines loratadine or cetirizine is recommended for use, preferably after the first trimester. These drugs are best avoided during early pregnancy when organogenesis is taking place. 24 Algorithm for treatment of chronic THE most recent international treatment algorithm for was published by the GA2LEN, Global Allergy and Asthma Network in In summary, non-sedating H1 antihistamines should be initiated as the first-line treatment, and the dosage may be titrated up to four times the baseline amount to achieve symptomatic control. If required, leukotriene antagonist, cyclosporine, H2-antihistamines, dapsone, omalizumab may be added as adjunctive therapy to achieve symptom control. Acute exacerbation of symptoms may be controlled with a tapering course of corticosteroids for 3-7 days. 17 Online resources MedicineNet Hives ( and Angioedema) article.htm Royal Children s Hospital Melbourne Clinical Practice Guidelines guideline_index/ Therapeutic Goods Administration Prescribing medicines in pregnancy database References Available on request from howtotreat@reedbusiness.com.au How to Treat Quiz 15 February 2013 Instructions Complete this quiz online and fill in the GP evaluation form to earn 2 CPD or PDP points. We no longer accept quizzes by post or fax. The mark required to obtain points is 80%. Please note that some questions have more than one correct answer. GO ONLINE TO COMPLETE THE QUIZ 1. Which THREE statements regarding the pathophysiology of are correct? a) The key feature that defines is that the individual lesions, wheals and/or angioedema are present for at least one week b) The pathological phenomenon in is vasodilation and increased permeability of the cutaneous and submucosal microvasculature, causing transient intracutaneous oedema c) The area of oedema of a wheal involves the entire epidermis and extends into the upper and middle dermis d) Wheals blanch with pressure, which causes central pallor in the lesion 2. Which THREE statements regarding the pathogenesis of are correct? a) Increased vasopermeability of the microvasculature occurs in the lower dermis and subcutaneous region in angioedema b) The pathogenesis of involves activation of cutaneous mast cells and their subsequent degranulation, resulting in histamines and many other inflammatory cytokines being released c) Neutrophils have no role in the pathogenesis of d) The mast-cell mediators stimulate cutaneous sensory nerves that produce the pruritus and burning sensation that is commonly encountered in 3. Jane, 45, presents after many episodes over summer of sudden-onset, itchy, raised, red skin lesions on her trunk and limbs, lasting several hours after dipping in the ocean. Which TWO statements are correct? a) Jane has pityriasis rosea b) Jane is in the group with the highest prevalence of chronic c) Jane is likely to have the l subtype of cold d) Jane s would be classified as acute 4. Which TWO statements are correct regarding acute and chronic? a) Drug or food reactions are common causes of acute spontaneous in adults b) The mean duration of chronic is 10 years c) Chronic autoimmune occurs when IgG autoantibodies present in the serum bind onto the alpha-subunit of the highaffinity IgE receptor, and activate mast cell degranulation and release of histamine d) Helicobacter pylori has been proven to be a cause of chronic 5. Which TWO statements regarding chronic and thyroid disease are correct? a) Three per cent of patients with chronic have elevated levels of thyroid peroxidase antibodies or anti-microsomal antibodies as compared with the general population b) There is a positive association between chronic and histological thyroiditis c) Patients with thyroid autoantibodies have more persistent that is poorly responsive to standard therapies d) Patients with chronic are at risk of developing autoimmune thyroid disease and should undergo screening for autoimmune thyroiditis and thyroid dysfunction 6. Which THREE statements are correct regarding wheals and angioedema? a) A wheal is a well-defined erythematous plaque that is usually associated with intense pruritus or a burning sensation b) Wheals lasting longer than 24 hours accompanied by a painful or burning sensation or that result in scarring are suggestive of l vasculitis c) Angioedema is a gradually developing pitting oedema that resolves within 1-2 hours d) The swelling of angioedema develops in an asymmetrical fashion and frequently involves the facial mucous membranes and those of the genitalia 7. Which TWO statements are correct regarding investigations in patients with? a) All patients who have an episode of should have extensive testing to exclude associated systemic diseases including hepatitis and Epstein Barr virus serology and a lesional biopsy b) Antihistamines, glucocorticoids and other relevant medications should ideally be discontinued before skin biopsy c) Skin provocation tests should be performed to identify physical triggers when physical is suspected d) The autologous serum skin test (ASST) is a highly sensitive and specific test to diagnose chronic autoimmune 8. Which THREE statements regarding medication are correct? a) Drugs that commonly cause non-allergic hypersensitivity reactions are NSAIDs and ACEIs, both of which can elicit and aggravate pre-existing b) The older, first-generation H1 antihistamines are considered first-line treatment for c) Montelukast is reported to be an effective treatment for NSAID-exacerbated chronic d) Corticosteroids can be used for acute and for the treatment of acute flares of chronic spontaneous 9. Which THREE statements are correct regarding immunotherapy treatment in? a) A low dose of cyclosporine is effective against that is refractory to conventional treatment b) Dapsone is an immune modulator that has a small but immediate response in patients with chronic c) Methotrexate may be useful for refractory chronic as an alternative or substitute for third-line treatments when such treatments are ineffective or contraindicated d) Acute onset of hereditary angioedema (HAE) requires immediate adrenaline, intubation and transfusion with fresh frozen plasma or C1 inhibitor concentrate to abort acute episodes 10. Jane s niece, Julia, has chronic and is planning a pregnancy. She is concerned about using medication for the condition during her pregnancy. Which THREE statements are correct regarding treatment of in pregnant women? a) It would be safe for Julia to use the antihistamine fexofenadine b) Chlorpheniramine is a sedating H1 antihistamine that may be used in pregnancy c) l symptoms during the first trimester are preferably managed with bland topical emollients d) Loratidine and cetirizine are secondgeneration, less-sedating H1 antihistamines, the use of which can be considered in pregnancy, preferably after the first trimester CPD QUIZ UPDATE The RACGP requires that a brief GP evaluation form be completed with every quiz to obtain category 2 CPD or PDP points for the triennium. You can complete this online along with the quiz at Because this is a requirement, we are no longer able to accept the quiz by post or fax. However, we have included the quiz questions here for those who like to prepare the answers before completing the quiz online. how to treat Editor: Dr Barbara Tink barbara.tink@reedbusiness.com.au Next week Pertussis or whooping cough affects all age groups, but is most serious in infants, who are at risk of dying from it. The next How to Treat gives an up-to-date account of managing this concerning condition in the Australian context. The authors are Dr Briony Hazelton, advanced trainee in paediatric infectious diseases and microbiology, Centre for Infectious Diseases and Microbiology, Westmead Hospital; and Professor Gwendolyn Gilbert, director, Centre for Infectious Diseases and Microbiology Public Health, Westmead Hospital, and clinical professor, Sydney Emerging Infectious Diseases and Biosecurity Institute, University of Sydney, NSW. 32 Australian Doctor 15 February