Chronic urticaria – investigations and management Summary Chronic urticaria is a common, debilitating condition. It is frequently accompanied by tissue swelling (angioedema). It is rare to find a specific trigger responsible for the condition and allergy is rarely responsible. Investigations are usually of little benefit. Anti-histamine drugs are the mainstay of treatment and increased dosage of these drugs may be required. Background Urticaria is a very common medical condition. Often, this is an acute, transient problem and may only last a few weeks. Reassurance about its self-limiting nature and the judicious use of anti-histamine drugs is often sufficient treatment for the patient. However, if the urticaria becomes chronic and severe, it can cause considerable distress and alarm to patients. This is particularly so if the skin rash is associated with skin swelling i.e. angioedema. Frequently, urticaria and angioedema co-exist. To keep the language simple in this document, we will refer to the condition as urticaria and occasionally emphasize the angioedema component. Stepwise approach to the investigation of chronic urticaria. In the following paragraphs, steps taken to identify the nature of chronic urticaria are listed [Fig. 1]. Clinical history. As is the case with many medical conditions, a thorough clinical history is essential and may be the single most important step in determining a cause for urticaria. In some instances, patients may be able to identify the circumstances in which they develop urticaria, but quite frequently this is not the case. Hence, in the majority of patients no obvious cause can be identified and the label “chronic spontaneous urticaria” is appropriately used. Various triggers which are sometimes involved are considered in the following paragraphs. Drug triggers. Drugs should always be considered as possible triggers of urticaria. Often the relationship is fairly obvious because of a close temporal relationship between drug ingestion and the urticarial event. In patients in whom angioedema is prominent, non-steroidal anti-inflammatory drugs, including salicylate containing drugs should always be considered. The patient will nearly always recognise the association themselves. Antibiotic allergy is common and can cause urticaria but is unlikely to manifest as chronic disease. When angioedema is the most prominent feature, the involvement of ACE inhibitor drugs must always be considered. The association with ACE inhibitors can be quite subtle, with angioedema sometimes presenting a long time – even years - after the patient commenced these drugs. ACE inhibitor therapy should be discontinued in patients with chronic urticaria. Other drugs which may rarely act as triggers include proton pump inhibitors, codeine and statins. Food triggers. Food allergy can cause urticaria and angioedema. However, as is the case with drugs, patients usually recognise a close temporal relationship between ingestion of a specific food and the development of symptoms. Thus, the symptoms of food allergy nearly always develop within minutes (or at most within 1 hour) of food ingestion. This makes it unlikely that a reaction to an unidentified food is the cause of chronic urticaria. A useful question to ask the patient is whether they awake in the morning with established urticaria/angioedema: if the answer is yes, it effectively rules out allergy as a cause. In particular, since food will not have been ingested for many hours, it excludes food as a trigger. Some patients will describe an apparent relationship between the development of urticaria and eating out, often in Asian food restaurants in which a variety of spices and uncommon ingredients may be used. This situation may require closer evaluation and the potential that spices, preservatives, MSG, colouring reagents or food salicylates are contributing to the situation may need consideration. However, such triggers are involved in less than 1% of cases with chronic urticaria. Physical events as triggers. Some patients will state that in certain physical circumstances urticaria can develop. Thus, patients may note that after a hot shower or on exposure to cold wind, they develop urticaria. Others will describe how the wearing of tight clothing also causes urticaria. These reactions are referred to as “cholinergic urticaria” and they are often of brief duration. In this situation, scratching the patient’s skin may elicit a local reaction referred to as “dermatographism”. Physical exercise can also induce cholinergic urticaria. Patients should be questioned about this possible association. In a few patients, the combination of physical exercise with prior food ingestion can cause marked urticaria and even anaphylaxis. Detergents as triggers? Some patients will describe how they have evaluated many lifestyle changes, including changing their use of detergents. It can be emphatically stated that detergents do not cause chronic urticaria. After the history …….. After careful consideration of the patient’s history, the conclusion may be reached that there are no recognisable triggers causing the patient’s symptoms. This is probably true of 95% of patients with this condition and a diagnosis of “chronic spontaneous urticaria” can be made. The precise aetiology of this form of urticaria is unknown, although some authorities believe that an autoimmune process is involved in up to 50% of patients. In some patients multiple factors may play a role. Some patients are atopic, making them more prone to mast cell activation. Others have features of cholinergic urticaria and nerve activation of mast cells may be involved. Emotional stress can also contribute significantly to the disorder. Tests in patients with chronic urticaria If the history has led you to the conclusion that the patient has chronic spontaneous urticaria, then there is no need or benefit in carrying out laboratory or other investigations. However, if there is a legitimate concern that the patient may have a food allergy, it is reasonable to perform a limited amount of food allergy blood testing. The appropriate test is to measure the level of IgE to the suspected food (previously termed the RAST test). Clearly, if there is no hint as to the likely identity of an involved food, this is a worthless exercise. Treatment of chronic urticaria If a diagnosis of chronic spontaneous urticaria is made, various steps can be taken to treat the condition. The two most important steps are reassurance of the patient and appropriate use of anti-histamine drugs [Fig. 2]. Studies have revealed that quality of life can be severely adversely affected by unremitting chronic urticaria. The stress of living with this condition is likely to act as a contributing factor to its severity and continuation. Patients should be reassured that with drug therapy, the urticaria will be largely controlled and that in more than 80% of patients, the condition will spontaneously remit over a one year period. Patients should also be advised that endless searching for a cause of their urticaria should be avoided because it is unrewarding and can cause its own anxieties. In some patients, fear of life-threatening respiratory difficulties or anaphylaxis may be a significant concern; reassurance that this is highly unlikely in chronic spontaneous urticaria/angioedema is important. In the majority of patients, chronic spontaneous urticaria can be controlled by appropriate use of anti-histamine medication. These drugs are considered in the next section. Antihistamines. A series of so-called second generation anti-histamines are now available. These drugs contrast with the early anti-histamines, such as chlorpheniramine (Piriton), which although effective, often cause sedation. It is preferable to use the newer anti-histamines, since they are long acting and are less likely to cause sedation. Examples of these include cetirizine (Zirtek), levocitirizine (Xyzal), desloratadine (Neoclarityn) and fexofenadine (Telfast). If urticaria is present on a persistent, recurrent basis, it is best to take these drugs daily, with eventual weaning when the urticaria starts to remit. However, if the urticaria is only intermittently present, the anti-histamine can be used for these individual episodes. Not infrequently, a single anti-histamine tablet is insufficient to control the patient’s rash. In this instance, it is permissible to increase the dose of the drug, to double or triple the normal recommended amount. Although, the use of higher amounts of anti-histamines is an “off label” practice, it is the recommendation of leading authorities in this field of medical practice. A second option is to add a second anti-histamine, e.g. levocitirizine (Xyzal) with fexofenadine (Telfast). Individual patients may respond better to certain anti-histamines or combinations of these drugs. In patients in whom stress is playing a significant role, if the anti-histamines listed above are not effective, the drug doxepen can be usefully employed for its combined anti-histamine and psychotropic effects. Other drug therapies. A further option, which can be used in particularly resistant cases is to add the anti-leucotriene receptor drug montelukast (Singulair) to the anti-histamine medication. Some practitioners may also prescribe a H2 antagonist drug, such as cimetidine (Tagamet) but there is little evidence that these drugs are of benefit. Corticosteroid drugs such as prednisolone are best avoided in the treatment of urticaria/angioedema. However, in certain situations a rapidly reducing “crash” course may be a reasonable option. If corticosteroids are the only effective treatment of chronic urticaria in a patient, it suggests that other inflammatory pathways are involved in the disease process. In this situation, other investigations including skin biopsy may be warranted. Self-injectable adrenaline is sometimes prescribed for patients with chronic urticaria. This treatment should only be employed if a patient has evidence of anaphylaxis, with for example severe angioedema causing respiratory difficulties. This is an exceedingly rare complication of chronic spontaneous urticaria. Internet information. A good source of information is the webpage of the British Association of Dermatologists which provides guidelines for doctors and patient information leaflets. Many other internet sites may be helpful. The journal Allergy published an important European expert consensus paper on the management of urticaria in 2009 (volume 64, 1427-1443). Conleth Feighery Consultant Immunologist St. James’s Hospital, Dublin. June 2010 CLINICAL HISTORY Consider Drugs Consider Food Consider Physical factors Consider Tests Aspirin, NSAIDs, ACE inhibitors Additives, Colours, Preservatives, Salicylates Exercise Heat Cold IgE to suspected food allergens Treatment Re-assurance Eliminate triggers Non-sedating antihistamines Antihistamines - increase dose up to x 4 fold Combination of antihistamines Referral to specialist centre