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					             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




                           Aspirin,
                           NSAIDs,
Consider       Drugs       ACE
                           inhibitors




                           Additives,
Consider        Food
                           Colours,
                           Preservatives,
                           Salicylates




               Physical    Exercise
Consider       factors     Heat
                           Cold




                          IgE to
Consider       Tests      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