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INTRODUCTION
Urticaria is a heterogeneous group of diseases that result from a large variety of underlying and potential causes, elicited by a great diversity of factors [1, 2]. For a majority of patients, symptoms can differ by the extent of the areas affected as well as the severity and clinical presentation [1]. Symptoms of chronic urticaria can persist for 6 weeks or more and are frustrating for both patients and caregivers. The aim of treatment is to achieve complete symptom relief. Although the severity of urticaria may fluctuate, spontaneous remission may occur at any time [1, 2]. However, it can take quite a long time to achieve complete remission. Management of chronic urticaria consists of two important approaches. Firstly, the identification and elimination of the underlying cause(s) and/or eliciting trigger(s) [1, 2]. Treating the cause is the most desirable option, but it is, unfortunately, not applicable in the majority of patients, in which urticaria is idiopathic [1]. Secondly, treatment is aimed at providing symptomatic relief [1]. In all cases, unless contraindicated, symptomatic relief should be offered while searching for the underlying cause [1]. Symptomatic treatment is currently the most frequent form of management. It aims to ameliorate or suppress symptoms by inhibiting the release and/or the effect of mast cell mediators and possibly other inflammatory mediators [1, 2].
Health related quality of life is increasingly being recognized as a primary outcome in clinical trials, population studies and public health [1]. In treatment the patient's well-being should be a central focus as chronic urticaria can persist over an extended duration from six weeks to over twenty years.
This guideline is a result of a consensus reached during the 19th Asian-Australasian Regional Conference of Dermatology by the Asian Academy of Dermatology and Venereology (AADV) Study Group in collaboration with the League of Asian Dermatological Societies in 2010.
METHODS
The treatment options available were evaluated by the following methods. Information was sourced from the European and International guidelines for management of chronic urticaria and from Asian journals available from online databases such as MEDLINE from 2000-2010. These guidelines were then discussed in detail by the study group members with review of primary references where applicable. At a final meeting a consensus was obtained by means of a simple voting system. The study group consisted of more than 30 dermatology specialists from 13 countries around Asia including 2 world renowned specialists in urticaria from Europe who are among the authors of the referenced European consensus [1-3]. As there is an existing international consensus on the definition, classification, and routine diagnosis of urticaria [3] which have been generally adopted in Asia, it was not discussed. For reference the recommended diagnostic tests in common urticaria types are shown in Table 1.
Management of chronic urticaria: causes and triggers
In general the management of chronic urticaria begins with the identification and elimination of the underlying cause(s) and/or eliciting trigger(s) [1, 2].
During consultation the information to the patient(s) concerning the symptoms and advice regarding avoidance of potential triggers should be made available such as: alcohol overuse, excessive physical tiredness, mental distress, prolonged pressure on the skin (i.e. tight clothing & bag straps), and hot environments. The provision of symptomatic relief which should always be offered while searching for causes [1]. Avoidance of the eliciting trigger can be instituted for patients with IgE-mediated urticaria. A substantial subset of patients can have a combination of both, e.g. chronic and physical urticaria. These have to be identified in order for adequate prognosis and management. For physical urticaria the impact of physical stimuli can be diminished and symptoms improved by appropriate measures (e.g. cushioning in pressure urticaria) [1, 2]. In spontaneous acute and chronic urticaria, treatment of associated infectious and/or inflammatory processes, including Helicobacter pylori-associated gastritis [4], parasitic diseases [5], or food [6] and drug intolerance may be helpful in selected cases [1, 2]. In addition, it must be noted that some factors, e.g. analgesic drugs, can elicit new wheal formation as well as augment pre-existing urticaria [1, 7].
Chronic urticaria is also recognized as a stress-vulnerable disease in which psychological stress can trigger or increase itching [1]. It is suggested that effective management processes could take into account psychological factors in some of the patients [1]. Many pharmacological and non-pharmacological interventions are available but clinical practice guidelines have created a more unified approach. For these reasons, the treatment regimen should be tailored to the individual patient.
Identification and elimination of the underlying cause / potential trigger
Determining the cause of the symptoms and devising means of protecting the patient from further exposure will help to facilitate recovery. Known triggers include: drugs, food, food additives, infections (bacterial, viral, fungal), parasitic infestations and dermatological disorders [1, 6, 8]. Following elimination of the suspected agent, only recurrence of symptoms in a double-blind provocation test will provide definitive proof [1, 7].
Drugs
Drugs frequently cause acute urticaria, but these can also be associated with chronic urticaria. When such agents are suspected in the course of diagnosis, they should be omitted entirely or substituted by another class of agents. The principle should be to avoid polypharmacy as far as possible, eliminating those which are not absolutely indispensable. Drugs causing non IgE mediated reactions [1] (e.g. aspirin) can not only elicit but also aggravate pre-existing chronic urticaria. Elimination can be expected to improve symptoms. Aspirin may exacerbate chronic urticaria in 30% of patients although patients taking low dose aspirin for its anti-thrombotic properties can usually continue regular treatment [6]. It is advised that in the presence of chronic urticaria, aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) should not be recommended because the potential for aggravation of symptoms [6, 9, 10]. Angiotensin converting enzyme inhibitors (ACEIs) are commonly associated with angioedema but they rarely cause chronic urticaria. However, ACEIs should usually be avoided in chronic urticaria with or without angioedema. Other drugs implicated include alcohol, narcotics (codeine, morphine) and oral contraceptives [6, 11-13].
Physical stimuli
Avoidance of physical stimuli for the treatment of physical urticaria requires detailed information about the physical properties of the respective stimulus [1]. However, in many patients the threshold for the individual eliciting stimulus is low and thus the total avoidance of symptoms is virtually impossible [1, 6]. For dermographic urticaria as well as in delayed pressure urticaria, simple devices (such as broadening of the handle of heavy bags) may be helpful in the prevention of symptoms [1]. When considering prevention in the case of cold urticaria, the impact of the chill factor in cold winds needs to be taken note of [1]. For solar urticaria, the exact identification of the range of eliciting wavelengths may be important for the appropriate selection of sunscreens or for the selection of light bulbs with a UVA filter [1]; although it may be more difficult to prove in Asian countries subject to the availability of such facilities.
Infections and infestations
Among the causal factors associated with chronic urticaria, the following fit into this particular category. Viral infections are known to frequently trigger or aggravate the condition [6]. Bacterial infections such as dental sepsis, sinusitis, gall bladder, urinary tract infections and Helicobacter pylori infection have been implicated in chronic urticaria. Fungal infections such as onychomycosis, tinea pedis and candidiasis were considered as relevant associated treatable conditions [6]. Parasitic infestations such as strongyloidiasis, giardiasis and amoebiasis, are more prevalent particularly in developing and underdeveloped countries of Asia [6]. Intestinal worm infestations, almost exclusively helminthic, elicit eosinophilia, although the absence of eosinophilia does not exclude the presence of a parasite. In tropical environments it is easier to de-worm in all cases [5]. House dust mites are ubiquitous allergens and common sensitizing agents and studies from Japan have implicated house dust mite sensitivity in chronic urticaria based on intradermal skin testing and in-vitro analysis [14].
Inflammatory processes
Apart from infectious diseases, chronic inflammatory processes due to other diverse diseases have been identified as causative for urticaria in the recent past. This holds particularly for gastritis, reflux esophagitis, or inflammation of the bile duct or bile gland [1].
Functional autoantibodies
In some patients with chronic urticaria functional autoantibodies against the α-chain of the high-affinity receptor for IgE (FcεRI) have been found to be relevant. These auto-antibodies are termed conditional as they only recognize unoccupied FcεRI [15]. The same conditional reactivity pattern has also been found in sera of atopic and normal healthy donors. Any condition resulting in accessibility of FcεRI will render these autoantibodies anaphylactogenic [15]. This finding offers a unifying hypothesis for the manifestation of different forms of urticaria. Non-immunologic triggers may thereby influence directly or indirectly the number of accessible FcεRI allowing the conditional autoantibodies to induce urticaria symptoms [15].
Systemic diseases
Chronic urticaria can be a manifestation associated with hyperthyroidism and hypothyroidism (Hashimoto's thyroiditis). In some euthyroid patients with autoantibodies, treatment with thyroxine has been reported to alleviate the urticaria [6].
Dietary management
A practical approach would be removal or avoidance of suspected dietary "pseudoallergens". However, care should be taken to avoid unnecessary recommendation unless backed by reasonable evidence. Although the patient may have reactions to these substances, it is noted that they may not be causative.
In a subgroup of chronic urticaria patients, pseudoallergic reactions to naturally occurring food ingredients and in some cases to food additives are seen. If identified, the specific food allergens need to be omitted as far as possible but this should only be recommended if causality can be proven [1]. In these cases a diet containing only low levels of natural as well as artificial food pseudoallergens could be instituted and maintained for a prolonged period of at least 3-6 months. As they are aggravating factors during regular intervals of between 3-6 months these items can be re-introduced to the patient's diet [1]. During this time spontaneous remission is achieved in approximately 50% of patients. It should be underlined that avoidance of type I allergens clears urticaria symptoms within 24-48 h if relevant allergens are rapidly eliminated, whereas in pseudoallergy a diet has often to be maintained for 2-3 weeks before beneficial effects can be observed [1]. IgE-mediated food allergy is rare in urticaria. Dietary restrictions should only be recommended if allergens and psuedoallergens are proven to be causative by double-blind, provocation tests [1, 6-8].
Environmental and miscellaneous triggers
Grass pollen, mold, spores, animal dander, house dust mites and even tobacco smoke [16, 17] may aggravate chronic urticaria. Urticaria may worsen during pregnancy and also pre-menstrually. Urticaria has been observed in some instances to be associated with orthopaedic implants, dental prostheses, and with dental amalgams [18, 19]. Stress, depression and anxiety have been found to be associated as a potential causative or aggravating factor for urticaria [6, 20-22].
Management of chronic urticaria: treatment
Symptomatic therapy
These therapies aim at providing symptomatic relief to reduce the effect of mast cell mediators on the target organs.
Mast cell directed therapy
At present, the most efficient drugs inhibiting mast cell mediator release are corticosteroids. Therapies can be mast cell directed or at the receptor of the target organ. They should be avoided for long-term treatment of chronic urticaria, as dosages necessary to suppress symptoms are usually high with significant side-effects [2]. Cyclosporine also has a moderate, direct effect on mast cell mediator release, but this drug cannot be recommended as a standard treatment due to potentially severe adverse effects [2]. Phototherapy with ultraviolet light or photo chemotherapy (PUVA) reduces the numbers of mast cells in the upper dermis. It has been successfully used in mastocytosis and is helpful in treatment-resistant patients with this condition [2].
For the treatment of chronic ur ticaria, UVA and UVB treatment for 1-3 months can be added to the antihistamine treatment. Although there are limited controlled studies with NB-UVB phototherapy, findings have found to be an effective complementary treatment in combination with antihistamines [2]. Tolerance induction may also be considered and is sometimes used for cold urticaria and cholinergic urticaria therapy and as a standard treatment for solar urticaria where even a rush therapy with UVA has been proven to be effective [2].
Therapy at the target organ
Nearly all symptoms of urticaria are mediated by H1-receptors. H1-receptor antagonists are thus of eminent importance in the treatment of urticaria. With the increased availability of this group of substances since the 1950s, urticaria has become one of the diseases that can be treated effectively with a very low adverse effect profile [2]. The development of second-generation non-sedating or low-sedating antihistamines has improved the quality of life of urticaria patients. New generation antihistamines also exert anti-inflammatory effects by controlling that control reactions such as cytokine release from basophils and mast cells [2, 24]. This may be of additional benefit in controlling symptoms in urticaria if these effects occur at a clinically relevant dosage. The possibility of increased adverse cardiac effects of some second generation low-sedating antihistamines should be a consideration in the choice of the specific antihistamine, especially when using higher concentrations than those recommended by the manufacturers [2].
Newer antihistamines such as cetirizine, fexofenadine, and descarboxyloratadine, are cytochrome P450-independent metabolites of earlier antihistamines [2]. The main drug interactions with sedating antihistamines are in association with drugs affecting the central nervous system like analgesics, hypnotics, sedatives, and mood elevating drugs, as well as alcohol [2]. In addition, monoamine oxidase inhibitors can prolong and intensify anticholinergic effects. Some modern antihistamines are also metabolized by cytochrome P450 enzymes, and increased plasma levels are observed when there is concomitant treatment with drugs employing this enzyme system for metabolism such as ketoconazole or erythromycin [2].
Pharmacotherapy
Depending upon the severity of the disease and response to various medicines, drug therapy can be considered at various levels as defined by four levels of therapy as discussed below (Fig. 1).
First line therapy
When symptoms present themselves, the first line treatment should be a non-sedating second generation H1-AH. Histamines are the main mediator of ur ticaria and non-sedating H1 antihistamines represent the initial and mainstay treatment of all urticarias. These agents are reasonably effective for many patients [1, 6]. The newer generation less sedating H1 antihistamines and less cholinergic effects are preferred over the older generation H1 antihistamines as the initial choice of therapy and different studies on role of antihistamines in chronic urticaria showed 44 to 91% response rate [6]. Antihistamines should be taken on regular basis, not as and when required to get consistent results [6]. Antihistamines should be given with due regard to age, pregnancy, state of health, and individual response. In summary, considering their good safety profile, second-generation antihistamines must be considered as first line symptomatic treatment for urticaria [6].
Second line therapy
If symptoms persist after 2 weeks, the treatment regimen should be adjusted and non-sedating second generation H1-AH can be up dosed up to 4 times [1]. Even though there is available evidence for increased dosing [25, 26] it should be noted that up dosing is not a part of current labelling for non-sedating second generation H1-AH in Asia.
The general consensus of the group is that Asians, being generally of smaller physical build, dosing of antihistamines can be continued in smaller increments and this was believed to be a successful approach. Other treatment options or combination therapy should be attempted for best response.
Third line therapy
If symptoms persist after a further 1-4 weeks, the treatment regimen of the nsAH dosage can be changed to a 1st generation sedating antihistamine or an alternative 2nd generation non-sedating antihistamine with the option of adding a leukotriene antagonist. Should exacerbation of symptoms occur, in addition the patient can be put on systemic corticosteroid for 3-7 days [1]. The use of systemic corticosteroids in the treatment of urticaria is a controversial issue. Short courses of systemic steroids can be given in resistant cases of chronic urticaria that have not responded to H1 antihistamine [1, 6]. The efficacy of corticosteroid therapy is high, but long term therapy cannot be proposed because of known adverse effects, such as diabetes mellitus, hypertension, osteoporosis and gastrointestinal bleeding. Prolonged treatment of chronic urticaria with oral corticosteroids should usually be avoided except in disabling delayed or pressure urticaria and urticarial vasculitis, which are usually nonresponsive to antihistamines [1, 6]. Leukotriene receptor antagonists, zafirlukast (20 mg twice daily) and montelukast (10 mg once daily) have been shown to have beneficial effect in treatment of chronic urticaria especially in cases which were aggravated by the NSAIDs and food additives. Zileuton, a 5-lipooxygenase inhibitor, which inhibits leukotriene generation has been found to be effective in improving chronic urticaria [6].
Fourth line therapy
If symptoms persist after a further 1-4 weeks, the treatment regimen of the nsAH dosage can be continued as a combination with the addition of a cyclosporine, second generation non-sedating H2-antihistamine, dapsone, or omalizumab. Should exacerbation of symptoms occur, in addition the patient should be put on systemic corticosteroid for another 3-7 days [1]. Therapy with immunomodulating properties could be tried in patients with severe refractory autoimmune urticaria. Cyclosporine has been shown to be effective in severe unremitting urticaria that had a poor response to conventional treatment with antihistamines [1, 6]. However, it cannot be recommended as standard therapy due to the high incidence of adverse events [1].
High dose of intravenous immunoglobulin (IVIG) has been found to be associated with some apparent benefits in the treatment of chronic urticaria. Plasmapheresis has been used to treat some patients with autoantibody positive severe chronic urticaria [6]. According to some case reports oral tacrolimus, low dose methotrexate, hydroxychloroquine, sulfasalazine, and dapsone, which also have immunomodulatory properties, have demonstrated some efficacy in the treatment of chronic urticaria. However in the case of oral tacrolimus, plasmapheresis and IVIG access may be an issue due to availability and costs and thus not readily as available throughout Asia. Warfarin therapy may be considered in a subgroup of patients with autologous serum skin test negative chronic urticaria and angioedema unresponsive to antihistamine [6, 27].
Prolonged corticosteroid treatment should generally not be given for chronic urticaria [1, 8]; it can, however, be used in urticarial vasculitis and then often in combination with colchicine or dapsone. Cyclosporine up to 5 mg per kg per day has been proven effective in patients with severe chronic urticaria.
Further therapeutic possibilities
Whereas antihistamines at higher concentrations will control symptoms in probably more than 95% of patients with urticaria, alternative treatments are needed for the remaining unresponsive patients (Table 3) [2]. Many of the alternatives are based on open trials or case reports. More recent approaches include leukotriene antagonists, interferon, or immunoglobulins [28]. On the other hand some treatment alternatives formerly proposed have been shown to be ineffective in double-blind, placebo-controlled studies and should no longer be used [2]. These include tranexamic acid and sodium cromoglycate in chronic urticaria, nifedipine in dermographicurticaria, and colchicine and indomethacin in delayed pressure urticaria [2, 29].
More selective immunotherapies are possibilities. The extracellular part of the subunit of FcεRIa or shorter peptide sequences containing the autoantibody epitopes could be used to bind to circulating FcεRIa auto antibodies, thereby inhibiting their attachment to receptors on mast cells or basophils [30].
First-generation H1-antihistamines: history & caveats
First-generation H1-antihistamines have been in clinical use since the 1940s and 1950s this class of drugs are still widely available and is the most frequent form of over-the-counter self-medication widely used for the treatment of allergic rhinitis, allergic conjunctivitis, urticaria, coughs, colds and insomnia.
Based on the European paper published by the GA2LEN task force [31], their findings reveal that these drugs pose a considerable level of risk to the self-medicating general public and to special patient groups that are purchased over-the-counter in the absence of appropriate medical supervision.
The primary reason for their choice and usage by adults has been their availability for decades, patient's familiarity with them and their self-intuitive considerations that, "they must be both effective and safe". "In fact, patients believe them to be so safe that the warnings on the label that the drugs may cause drowsiness often go unheeded, or even unread even though they have potentially dangerous unwanted effects [31]."
Documented adverse effects associated with the sedating nature of first-generation H1-antihistamines include the following:
Special patient groups who are particularly at risk with first-generation H1-antihistamines are:
It is in the opinion of the Asian Academy of Dermatology and Venereology Study Group that second generation non-sedating antihistamines should be prescribed as first-line treatment. But based on extenuating circumstances where availability, costing, coupled with proper medical advice providing warnings about the adverse effects of sedation or somnolence in environments where the patient may be subject to harm or may be causal in harming others, prescription of first-generation H1-antihistamines can be carried out (Table 4).
Non-pharmacological and alternative approaches
Similar with many other therapeutically challenging disorders, chronic idiopathic urticaria has seen an abundance of fad therapies, including ayurvedic and homeopathic medications and naturopathy. Frequent tepid showers and application of soothing lotions can be prescribed as cooling agents when wheals erupt and are pruritic. These include 0.5-1% menthol or calamine in aqueous cream/lotion and 10% crotamiton lotion [32].
PUVA has been used for treating chronic urticaria, but the reported results have been inconclusive. A complementary psychological treatment of patients suffering from chronic idiopathic urticaria seems necessary, because of the high prevalence of psychological symptoms. Relaxation under hypnosis has produced a decrease in itching, but not in the number of hives [33].
Limitations
Data regarding the racial differences of chronic urticaria in Asia, its epidemiology, socio-economic impact and outcomes of management was not covered as part of this consensus. However it is recognized as an important area for further investigation. Future editions of this consensus will endeavour to address this knowledge gaps where possible.
CONCLUSION
The quality of life with chronic urticaria is severely affected and management of the disease should therefore be prompt and with close cooperation between patient and physician. Due to the high variability of disease severity, an individual approach is necessary for each patient. As a first line, triggering factors should be avoided as far as possible and any associated diseases should be treated. In the majority of patients, symptomatic pharmacologic treatment is possible with new generation antihistamines, with a very low adverse effect profile and good patient compliance.
In rare, non-responding patients higher dosages and alternative medication should be tried. Most of these, such as corticosteroids or cyclosporine, should be reserved for severely affected patients because of their unfavourable adverse effect profile. These treatment options exist and are discussed in detail in the text: second generation antihistamines (including up to four-fold higher; corticosteroids in severely affected patients; cyclosporine for patients refractory to other modalities).
First generation sedating antihistamines should no longer be used as initial therapy except in those few countries where second generation antihistamines are not available or where their use outweigh their risks. Since the severity of urticaria may fluctuate and spontaneous remission may occur at any time, it is also important that the necessity for continued or alternative drug treatment is re-evaluated every 3-6 months.
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