10 Chronic Urticaria as an Autoimmune Disease Michihiro Hide, Malcolm W. Greaves Introduction Urticaria is conventionally classified as acute, intermittent and chronic (Grea- ves 2000a). Acute urticaria which frequently involves an IgE-mediated im- munological mechanism, is common, its causes often recognised by the patient, and will not be considered further. Intermittent urticaria – frequent bouts of unexplained urticaria at intervals of weeks or months – will be dis- cussed here on the same basis as ‘ordinary’ chronic urticaria. The latter is conventionally defined as the occurrence of daily or almost daily whealing for at least six weeks. The etiology of chronic urticaria is usually obscure. The different clinical varieties of chronic urticaria will be briefly considered here, and attention will be devoted to a newly emerged entity – autoimmune chronic urticaria, since establishing this diagnosis has conceptual, prognostic and the- rapeutic implications. Contact urticaria and angioedema without urticaria will not be dealt with in this account. Classification of Chronic Urticaria The clinical subtypes of chronic urticaria are illustrated in the pie-chart of Fig. 1. The frequency of these subtypes is based upon the authors’ experience at the St John’s Institute of Dermatology in UK. Whilst there may well be mi- nor differences, it is likely that the frequency distribution of these subtypes will be essentially similar in most centres in Europe and North America (Grea- ves 1995, 2000b). However, our experience suggests that the incidence of angioedema, especially that complicated by ordinary chronic urticaria is sub- stantially lower in Japan and south Asian countries (unpublished observation). 310 Michihiro Hide and Malcolm W. Greaves Fig. 1. Chronic urticaria. Frequency of different subtypes in the authors’ practices. The proportions are probably not very different elsewhere Physical Urticarias These comprise about one third to one fourth of all urticaria patients seen in the authors’ services. The diagnosis is mainly made from careful history tak- ing, appropriate clinical examination, and physical challenge testing is per- formed when necessary. It is important to identify patients in whom a physical urticaria is the main, if not the only, cause of the patient’s symptoms. In this case, further investigation is not indicated, with rare exceptions (see below). Almost invariably, patients with this diagnosis are over-investigated by the time they are referred to the urticaria clinic. Skin prick testing, RAST (radio allergo sorbent tests), food exclusion diets, etc, are not normally indicated in patients with a physical urticaria with the exception of food-dependent exer- cise-induced urticaria, a rare variety of urticaria, which develops following exercise after food ingestion. It is also important to appreciate that different physical urticarias can oc- cur concurrently in the same patient; cold and cholinergic urticarias repre- sent a well recognised example. Furthermore, chronic ‘idiopathic’ urticaria is often associated with dermographism or delayed pressure urticaria. The in- vestigation and management of chronic urticaria should be influenced by es- tablishing the relative contributions of coexisting forms of chronic urticaria to the patient’s overall disability. Symptomatic Dermographism This common physical urticaria presents mainly in teenagers or adults of ei- ther sex. Like most physical urticarias, individual itchy wheals, produced by gentle stroking or rubbing of the skin, last less than 30 minutes before fading (Fig. 2). Angioedema and mucosal whealing do not occur and there are no Chronic Urticaria as an Autoimmune Disease 311 Fig. 2. Symptomatic Dermographism. Upper left hand panel: use of a graduated dermo- grahpometer to test for sensitivity to a dermographic stimulus. Upper right hand panel: graded wheal and flare response to a range of pressures. Lower panel: gentle stroking by round end of a pen rod with a certain pressure may readily disclose abnormal reaction of patients. systemic symptoms but pruritus is troublesome. The etiology is unknown al- though skin reactivity can be passively transferred to non-human primates by intracutaneous injection of donor serum from a dermographic patient (Murphy et al. 1987). As with the majority of physical urticarias, investigations are point- less and any role for food items has not been substantiated. The prognosis is for eventual improvement in two to three years in most patients. Low sedation antihistamines such as loratidine 10 mg, cetirizine 10 mg or fexofenadine 120–180 mg are usually effective in relieving the itch, although additional treat- ment by a sedative antihistamine such as hydroxyzine 25 mg at night may also be useful. Combinations of H1- and H2- antihistamines may be useful. Cholinergic Urticaria Cholinergic urticaria is common in children and young adults, although rare in the elderly. Historically, this type of urticaria has been classified as a phys- ical urticaria. However, a recent consensus report for “definition, classification, 312 Michihiro Hide and Malcolm W. Greaves Fig. 3. Cholinergic Urticaria. Typical monomorphic symmetrical maculopapular eruption evoked by heat or exertion or stress and routine diagnosis of urticaria” (Zuberbier et al. 2001) for urticaria and angioedema classified this urticaria as a special type of urticaria, apart from physical urticarias. Symptoms of cholinergic urticaria, typically widespread pruritic monomorphic maculopapular lesions, develop in conditions causing sweating, such as exercise, hot bath taking, or emotional stimuli (Hirschmann et al. 1987) (Fig. 3). If the patient rests, cools off or relaxes, the eruption sub- sides in 15–45 minutes. Typical areas of predilection include the face, neck, fronts of elbows, wrists and popliteal fossae, although almost any area of the body can be involved. It may be accompanied by angioedema and systemic symptoms include wheezing or, rarely, anaphylactoid symptoms. Cholinergic urticaria can be disabling, especially when provoked by occupational or emo- tional triggers. The diagnosis is established by appropriate challenge testing (Commens et al. 1978) (exercise, a hot bath or mental arithmetic) and/or skin test with acetylcholine. No further investigations are indicated. The prognosis is for gradual improvement over the course of months or years in most patients, although the authors have several patients in whom cholinergic urticaria remains unremitting. The condition normally responds reasonably well to avoidance of provoking factors, together with regular daily treatment by an H1-antihistamine, especially in children. Clinical variants include persistent cholinergic urticaria (Murphy et al. 1983), in which the rash is evident even at rest, and exercise-induced angioedema (Lawrence et al. 1981). Rarely patients may give a clear history of food provo- cation – either association of onset non-specifically with food intake, or spe- cifically with certain food items (Zuberbier et al. 1993). The pathomechanisms are incompletely understood. The local wheals can be blocked by atropinisation of the skin indicating involvement of acetylcho- line, and histamine release has also been confirmed – presumably derived from mast cells (Herxheimer 1956). Wheal and flare reaction to autologous sweat and sweat-provoked histamine release from their basophils have been Chronic Urticaria as an Autoimmune Disease 313 Fig. 4. Cold Urticaria. Local whealing response to application of an ice cube for 10 min demonstrated in some populations of patients with cholinergic urticaria (Adachi et al. 1994). These reactions have been suggested to be mediated by specific IgE, but the antigen in human sweat has not been identified yet. Cold Urticaria This less common physical urticaria occurs in children and adults. Whealing is rapidly provoked by exposure to cold fluids or cold surfaces (Fig. 4). Angi- oedema of the oropharynx is common, e.g. after sucking an iced lolly. Sys- temic symptoms are common and may be severe – especially when provoked by extensive body immersion, as in sea-bathing. Cold urticaria is due to his- tamine release (Keahey et al. 1980), and cold-reactivity can be passively transferred to non-human primates by donor serum from affected individu- als (Misch et al. 1983). The transferable factor has been variously attributed to IgE or IgM. Rarely cryoglobulins and cold agglutinin can be identified in sufferers’ serum. These are usually sought routinely but positive results are exceptional. No other investigations are worth while. In adults cold urticaria may be highly disabling especially in outdoor work- ers. It responds rather poorly to antihistamine treatment in all but the mildest cases and in children. Cold tolerance treatment (repeated cold exposure to induce a temporary refractory state) is effective but requires a highly moti- vated patient (Bentley-Phillips et al. 1976). Some remain crippled by cold sensitivity despite all these measures. 314 Michihiro Hide and Malcolm W. Greaves Delayed Pressure Urticaria This common and disabling physical urticaria is arguably not a true urticaria since the wheals characteristically are of more than 24 hours’ duration (Lawlor et al. 1989a). As its name suggests, whealing occurs following a latent period of 2–4 hours after application of pressure perpendicular to the skin. Common examples of triggering factors include a tight waistband, tight footwear and golf club, tennis racquet, or steering wheel grips. Pain is more characteristic