Urticaria

Abstract

Chronic urticaria (CU) involves release of histamine from mast cells and/or basophils, which in turn promotes the classic inflammatory cascade. The resultant symptoms can severely impact sufferers' quality of life and in severe cases prevent them from leading a normal existence, with consequent burdens on family and society.

Rapid initiation of effective reliable therapy is important in combating CU, together with avoidance of triggers or exacerbating factors, if known. While newer immunologically-based therapies are beginning to be developed, antihistamines remain a cornerstone of effective therapy. Treatment should be tailored to individual patient circumstances, but in principle the choice of antihistamine component should be governed by the availability of evidence of rapid and prolonged efficacy specifically in CU and evidence of good tolerability and safety. Increasingly, evidence of beneficial effects on patient quality of life is also required for rational selection of an antihistamine from amongst those available. Levocetirizine is a new single-isomer antihistamine with a proven efficacy on chronic urticaria as documented in two recent clinical studies, which have included effectiveness and quality of life assessments.

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Introduction

Chronic urticaria (CU) is a relatively common disease in which treatment has often been disappointing (1) and a difficult and often frustrating problem for physicians (2). Consequently, CU has long been a demoralizing disease for patients and their carers. Recent developments, however, have meant that it is no longer a diagnosis of pessimism (3) although it can have a major impact on patient well-being and be a cause of disability severe enough to be equated to that arising from triple coronary artery disease (4). CU certainly has the potential to affect large numbers of patients' quality of life and socioeconomic functioning, since sufferers may be unable to perform normal activities of daily living during an attack.

[FIGURE 1 OMITTED]

According to the recently-agreed consensus classification of urticaria (5), CU is defined as short-lived wheals lasting 12 to 24 hours surrounded by bright red flares occurring daily or near daily for at least 6 weeks with no identifiable cause and sometimes a single patient may exhibit more than one subtype of urticaria (6). Antihistamines are the first-line treatment for CU; with sedation as a side effect for some of them (7). Recent improvements in understanding of the molecular basis for urticaria pathogenesis have made it possible to not only classify the disease into several subtypes but also to develop and test rational therapies for the condition and ensure accurate interpretation of research results. Indeed, some patients formerly classed as having CU may now be demonstrated to have a specific autoimmune trigger so that the description of disease origin as idiopathic in some of these cases may no longer apply (8).

Epidemiology

CU has not had the same full and authoritative epidemiological studies as other dermatological conditions. Even current data for incidence and prevalence are rendered somewhat questionable due to variable diagnostic precision, whereby patients may in fact be suffering from a range of physical urticarias. A fairly accurate lifelong prevalence estimate of 0.5% has been offered and seems to be broadly consistent across all populations studied (3) although prevalence is obviously higher for clinic populations. Another suggestion is the condition may affect from 0.1 to 3% of the general population (9).

All forms of chronic urticaria tend to occur mainly in adults, often being first seen between the third and fifth decades of life (10). CU occurs twice as often in women as in men (11). Triggers for urticaria, such as heat or sunlight or viral infections, may vary across geographical locations but there is no clear pattern of linkage to specific climatic conditions. The natural course of the disease typically involves spontaneous hives daily or at least twice a week. This is called chronic continuous urticaria. However, another chronic urticaria type called chronic recurrent urticaria (formerly chronic intermittent urticaria) exists in which symptom-free intervals ranging from days to weeks can be found (5). Almost half of patients with active chronic urticaria lasting six months or more are likely to have wheals still occurring ten years later (12). The average duration of CU in adults is 3 to 5 years although it may persist for more than 10.

Diagnosis

The cause of true CU is undefined, so its diagnosis requires exclusion of other similar conditions with possibly confounding symptoms requiring different treatment. The condition is considered chronic if persisting more than 6 weeks without an aetiology. There are frequently comorbidities associated with CU such as the physical urticarias (13). The prognosis and treatment for these two very different types of chronic urticaria may also be very different, so it is necessary to take a detailed history of the patient to identify any such issues and find which co-morbidity is contributing most to the patient's disability. However, as almost all patients with CU also show evidence of angioedema, the term CU can be regarded as including these for the purposes of this review.

The main clinical finding, which differentiates CU from other dermatological inflammatory disorders, is the frequent development of erythematous skin wheals, lasting < 24 hours and accompanied by itching. They can range in size from a few millimetres to several centimetres, being smooth oedematous pink or red wheals surrounded by a bright red flare (11). Wheals may merge into larger areas of affected skin and may be found in many areas from the soles of the feet to the scalp. The wheals resolve spontaneously and leave no skin marks or permanent changes. The occasionally intense itchiness can often be relieved by rubbing (not scratching) (14) and unlike urticarial vasculitis there is no pigmentation or pain associated with these wheals. The differential diagnosis of urticaria includes insect sting cutaneous reactions, scabies, and autoimmune diseases, including erythema multiforme and vasculitis. Particularly, if hives persist in loco for more than 24 hours, a biopsy is indicated to exclude an underlying disease, most often a systemic vasculitis. But most of all, it is important to exclude physical urticaria in the first step of the workup of chronic urticaria.

Pathophysiology

It has been known for some time that the typical inflammatory signs of CU are caused by the degranulation of mast cells in the dermis, leading to release of a cascade of histamine and other mediators, including prostaglandins, proteases and other cytokines (15). However, the nature of the precipitating allergen or antigenic stimulus or stimuli that initiate the cascade of inflammatory mediators has not been defined yet. Helicobacter pylori, viral infections, food allergies and aspirin have all been investigated as possible triggers and all have been cleared of involvement in CU aetiology (16-19).

It has been suggested that an antibody-mediated reaction is involved (20,21). Indirect evidence of CU having an autoimmune basis is that autoimmune thyroid disease is more common in these patients (22). Studies of patients with severe CU have shown that about 25% of them possess functional antibodies against the high-affinity receptor epsilon (Fc[epsilon]R1) of dermal mast cells and basophils and a further 5% had evidence of functional anti-IgE autoantibodies (23). The link with CU lesions is confirmed by the ability of these autoantibodies to cause release of histamine from healthy volunteer mast cells and basophils and also generate wheals or hives following intradermal injection into healthy volunteers (24). In addition, it has been clearly shown that the serum does not only result in histamine release but also in de novo production of cysteinyl leukotrienes and basophil activation by means of CD63 expression (25,26). Histamine release results in, amongst other things, activation of histamine receptors in the blood vessels of the skin. This leads to increased vascular permeability and vasodilation, followed by local edema, erythema and direct stimulation of cutaneous nerves to precipitate occasionally intense itching. However, histamine is not the only mediator, prostaglandins/eicosanoids, proteases, proteoglycans, tumour necrosis factor, interleukin-4 and certain leukotrienes also appear to play a role in cell recruitment that promote the immune response. There is debate over the role of basophils, although they are known to express high-affinity IgE receptors and release leukotriene C4. Preferential migration of basophils to urticaria lesions has been proposed but to date the quantitative evidence is inconclusive (27,28). Overall, the percentage of patients with CU and anti-Fc[epsilon]R1 autoantibodies seems to fall in the region of 35% to 55% of the total, leaving probably at least 50% of patients with an initial diagnosis of CU who appear to have no detectable autoantibodies and therefore represent "idiopathic" urticaria.

Therapeutic rationale

Successful treatment of CU can present a significant challenge for both patients and doctors alike. There is no single catch-all therapy that offers success in every case and several pharmacological and non-pharmacological approaches to management are used to relieve the symptoms and prevent recurrence where possible.

The therapy mainly consists of:

* avoiding triggering stimuli if known

* inhibiting mast cell mediator release

* treating the inflammatory response and mediator target tissues

Trigger avoidance

Individuals with CU may be unable to conduct normal daily activities; therefore, prompt initiation of effective treatment is essential and should be aimed at eliminating or minimizing the effect of disturbing symptoms. This can be at least partly brought about by avoidance of precipitating factors and unhelpful conditions in general, such as elevated room temperatures or excessive alcohol ingestion and, where possible, avoiding use of non-steroidal anti-inflammatory and related drugs such as aspirin, which may interfere with mast cell dynamics. Good sleep hygiene, loose clothing, avoidance of pressure points, and a balanced diet are advisable, although significant dietary restrictions are rarely helpful. Topical antipruritic lotions and creams and frequent tepid showers may also bring temporary relief (31).

CU is also known to have a significant psychological component but there are as yet no definitive studies confirming or quantifying an association between stress, anxiety, or depressive symptoms and CU. Various psychotropic drugs (mainly tricyclic antidepressants) have been considered, partly because of their anti-H1 activity, but there are as yet no persuasive results. It may be that psychological symptoms are a consequence of living with a debilitating condition and may resolve spontaneously once the underlying illness is successfully treated.

Mast cell inhibition

Since CU is a chronic condition, long-term use of corticosteroids should be avoided because of side effect risks, despite their undoubted ability to resolve symptoms rapidly and effectively. For very severe episodes, however, a short course of systemic therapy such as prednisone or methylprednisolone can be administered for a few days (7-14) if antihistamines do not control symptoms of urticaria and a rapid clinical response is needed. In cases of relapse after corticosteroid suspension, leukotriene receptor antagonists, such as montelukast and zafirlukast, could be tried.

Cyclosporin A is known to damp down mast cell mediator release but it is also normally ruled out for long term treatment because of cost and side effect disadvantages. Light therapy with UV-A and UV-B has sometimes been used as add-on therapy for exacerbations of CU but practical problems exist for long term use, as well as the risks of harm from over-exposure. Drugs such as nifedipine and terbutaline used primarily in other conditions have been tried in CU but the results were equivocal at best and they are no longer considered appropriate. The same applies, perhaps more surprisingly, to topical formulations of steroids, antihistamines and local anaesthetics, which are no longer recommended (29).

Mediator target tissue therapy

By contrast, given the pivotal role of histamine in the inflammatory cascade, treatment with H1 receptor antagonist (antihistamine) drugs is both logical and often effective. The goal is to minimize the problematic effects of histamine and other cytokines on cutaneous vasculature and inflammatory cells that participate in the pathogenesis of the urticaria lesions and symptoms. The most common approach is the twin-track strategy of avoiding all aggravating factors and blocking histamine. The central role of antihistamines for the treatment of CU was recently confirmed in a survey of dermatologist, allergist, and general practitioner clinical practices (30).

General practitioners perform few diagnostic investigations and usually prescribe an antihistamine as first line therapy. When symptoms persist, they refer to dermatologists or allergy specialists for a specialist opinion, both of whom normally follow broadly similar treatment strategies although investigations may differ in scope and number between the two specialities. For all physicians, non-sedating and/or sedating antihistamines are the principal treatment, sometimes associated with others drugs in case of resistance. Most physicians perceive psychological factors as important but are less often able to suggest a specific therapy for these aspects (31).

Antihistamines and CU

Nearly all the direct symptoms of CU are mediated via H1 receptors on the various target tissues. The development of second generation non- or low-sedating antihistamines has largely improved quality of life for CU patients (6). The newer antihistamines, also called third generation antihistamines, have additional anti-inflammatory effects such as inhibition of cytokine release from mast cells and basophils (31).

Modern antihistamines, such as cetirizine, fexofenadine, loratadine, mizolastine, and, more recently, levocetirizine, desloratadine, and ebastine, are the mainstay of therapy for all chronic urticaria patients and as a group do not penetrate the blood-brain barrier as well, leading to fewer central effects (7). Older sedating antihistamines, such as hydroxyzine and diphenhydramine, may be used for more severe symptoms or if they are associated with angioedema--especially if the patient is anxious and disturbed by symptoms at night (32). Corticosteroid therapy with prednisone or methylprednisolone can be administered for a few days, as previously mentioned, if urticarial symptoms are not controlled by antihistamine alone and a rapid clinical response is required. If patients relapse following cessation of steroid treatment it is logical to try co-medication with a leukotriene receptor antagonist, such as montelukast and zafirlukast but this may be more appropriate under specialist supervision.

In all cases, CU treatment should follow an individualized plan and the goal of therapy and priorities agreed with the patient, whose lifestyle may dictate elements of the treatment strategy. Failure to take patients fully into account heightens the risk of non-compliance, which in turn leads inexorably to higher rates of treatment failure. First generation antihistamines might be preferred in some patients for whom a night-time dose of a more sedating drug is preferred to overcome troublesome nocturnal symptoms. However, the fact of the matter is that there is often a "hangover effect" that would interfere with their work or social commitments the next morning.

To be considered for treatment of CU, any antihistamine must be licensed for this indication, based on positive results from randomized, controlled, clinical trials. The chosen compound should preferably demonstrate rapid onset of relief, extended duration of response and efficacy across a range of symptoms--ideally with additional convincing anti-inflammatory features. Although useful to compare various antihistamines, the wheal and flare model features mimic early-phase allergic reactions rather than the late-phase condition typical of chronic disorders such as CU (33).

The risk/benefit profile should be demonstrably unambiguous with few, if any, significant adverse events and no cardiac or anticholinergic effects. The lack of adverse effects should extend to its use in combination with commonly used therapies for other conditions, whether related to CU comorbidity or not, and of course to drug-food interactions.

Apart from excellent clinical and technical credentials, the candidate drug ought to be able to demonstrate substantive "real world" benefits in terms of patient quality of life in CU. These should be demonstrable by means of validated instruments and significant improvements as ranked by both patients and investigators. A detailed analysis of each new generation antihistamine is beyond the scope of this brief review, but two recent studies for levocetirizine provide an example of some of the key points that should emerge from a clinical development program for agents designed for use in CU.

Levocetirizine in CU

Levocetirizine (Xyzal[TM], UCB Pharma) is a new-generation H1-antagonist. It is the single R-isomer of the racemic mixture cetirizine dihydrochloride, a potent second generation antihistamine. Levocetirizine has twice the affinity of cetirizine for the H1 receptor and a better pharmacokinetic profile (34). In a recently published study using the wheal and flare model, levocetirizine has been shown to be more active than all currently marketed antihistamines (34).

Two studies were conducted in CU. These studies were both randomized, double-blind and controlled multicenter designs. The first was a 4-week dose-ranging study comparing the efficacy and safety of 2.5 mg, 5 mg and 10 mg of levocetirizine once daily in 258 CU patients randomized to one of the active arms or placebo. The second study compared the efficacy of 5 mg once daily levocetirizine to placebo in 166 CU patients. Both studies were approved by the Local Ethics Committee and patients gave their informed consent.

Levocetirizine dose in CU

In the dose-ranging study 303 patients were screened and 258 progressed to randomization. With one drop-out due to noncompliance, the intent-to-treat (ITT) population analyzed for efficacy and safety comprised 70, 65, and 59 patients in the levocetirizine 2.5 mg, 5 mg and 10 mg dose arms respectively, with a further 63 in the placebo group.

The primary study objectives were to demonstrate that at least one dose of levocetirizine was superior to placebo in CU after one week and after the total 4-week treatment period--as measured by the mean pruritus severity score computed from daily diary cards. The method used for the statistical analysis was an Analysis of Covariance, with treatment and center as factors and baseline as covariates. Each dose of levocetirizine was compared to placebo using a t-test at an alpha error of 2% (Dunnett adjustment for multiple treatment comparisons). The linear and quadratic nature of the relationship between the dose and the treatment effect were tested by means of a linear combination of adjusted means.

Statistically-significant improvements were seen in the primary efficacy variables compared to placebo for all three doses of levocetirizine over the first treatment week and the total treatment period (p<0.001).

During the first treatment week the differences in adjusted means compared with the placebo group were 0.93 [98% CI (0.63; 1.23)] for the levocetirizine 2.5 mg group, 1.10 [98% CI (0.80; 1.40)] for the levocetirizine 5 mg group and 1.14 [98% CI (0.83; 1.46)] for the levocetirizine 10 mg group. This supported the concept of a dose response relationship but not to a statistically significant extent. However, over the total treatment period the differences in adjusted means compared with the placebo group were 0.82 [98% CI (0.53; 1.11)] for the levocetirizine 2.5 mg group, 0.91 [98% CI (0.62; 1.21)] for the levocetirizine 5 mg group and 1.11 [98% CI (0.81; 1.41)] for the levocetirizine 10 mg group. There was a statistically significant linear dose-response relationship between the three dosages (p=0.02) with benefit increasing with dose (Figure 2).

The primary efficacy results were supported by secondary efficacy variable results, i.e., pruritus severity (>24 hours), number and size of wheals and pruritus duration over week one and during the total treatment period. All levocetirizine doses were statistically significantly superior to placebo (p<0.001). These results were also confirmed by patient global evaluation of the disease evolution at the end of treatment--there being a higher proportion with marked or moderate improvement in all three levocetirizine groups than in the placebo group. The most common adverse events were somnolence and headache. Somnolence was highest in the levocetirizine 10 mg group (16.9%) and headache was highest in the placebo group (12.7%).

[FIGURE 2 OMITTED]

Having selected 5 mg as the dose for CU, a second study was performed to measure the impact of 5 mg levocetirizine on the duration and severity of pruritus and confirm its superiority over placebo. Results were also gathered for number and size of wheals and mean pruritus duration. The study was again a 4-week treatment study. It used a 1-week selection period, results gathered after one week and at the end of the 4-week treatment, and with a further week's follow up.

During the first week of treatment, the mean pruritus severity decreased significantly more in the levocetirizine group than in the placebo group, with a difference in adjusted means of 0.78 [95% CI (0.53;1.04)] demonstrating the efficacy of levocetirizine 5 mg in treating this condition (p<0.001). The difference over placebo in mean pruritus severity was sustained during the total treatment period (p<0.001) (Figure 3). Levocetirizine also showed a significant improvement in secondary parameters compared to placebo (p[less than or equal to]0.001) for the mean number of wheals, the mean size of wheals and the mean pruritus duration both after 1 week and over the total treatment period.

Effects of levocetirizine on health-related quality of life in CU

Both studies assessed quality of life issues using the DLQI, a skin-disease specific 10-item questionnaire in which summed item scores gave values ranging from 0 (no impairment) to 30 (very highly impaired quality of life).

For the dose-ranging study, baseline scores in all groups were comparable, with a mean score of 8.5 units in the placebo group and 8.0, 7.7 and 7.8 units in the 2.5 mg, 5 mg and 10 mg levocetirizine groups respectively. After treatment the improvements in all three active groups were similar, with the three levocetirizine group scores improving with 4.4, 4.2 and 5.1 units respectively while the improvement in placebo group score was limited to 0.9 units. In the 5 mg study, the baseline values were also similar, albeit in a slightly more impaired study population (scores of 11.5 in the placebo group and 11.1 in the levocetirizine arm). On treatment, the scores decreased by 2.4 units in the placebo group and 7.3 units in the levocetirizine 5 mg group.

From the results of this development program and other work, levocetirizine was confirmed to provide rapid relief of the most worrisome symptoms of CU: pruritus and wheals (size and number). According to patients' global evaluation, "marked improvement" was twice as common in levocetirizine patients as in the placebo group. Symptomatic relief also delivered an improved quality of life in the levocetirizine group. Accordingly, levocetirizine was licensed for use in CU and its use appears to substantiate the place of antihistamines as first-line therapy in this condition.

Other treatments

The knowledge that CU is frequently autoimmune in origin has encouraged a more aggressive and varied therapeutic approach, particularly in serious or refractory cases. This includes the use of immunomodulatory drugs such as interferon, sulphasalazine and immunoglobulins (35). Guidelines for the management of CU are constantly being developed but for the foreseeable future these and other potential biological response modifier therapies remain for use in specialist settings only.

Conclusions

Five decades after the earliest examples came into use; antihistamines remain a key therapy in allergic diseases, including treatment of CU. The disease is not trivial and dosage of the chosen therapy may need to be increased in serious cases, or additional therapies may need to be prescribed for exacerbations. There are interesting theoretical and potential practical developments underway, based on increased understanding of CU pathophysiology and the term "idiopathic" may be less applicable to a number of cases where an autoimmune or other cause can now be determined. In the meantime, however, the advent of new powerful and minimal or non-sedating antihistamines have given both general practitioners and specialists more options for keeping CU sufferers symptom free and enjoying an improved quality of life. A typical example of a modern potent antihistamine of clinical interest in CU is levocetirizine. Recent studies confirm that this isomer of cetirizine appears to maintain the potency of the parent compound while offering reduced unwanted effects and thereby delivering a rapid therapeutic response combined with a beneficial impact on quality of life.

The studies described in this paper were supported by an unrestricted grant from UCB Farchim, Chemin de Croix Blanche, CH-1630 Bulle, Switzerland.

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A KAPP MD PHD, B WEDI MD PHD

DEPARTMENT OF DERMATOLOGY AND ALLERGOLOGY HANNOVER MEDICAL UNIVERSITY, HANNOVER, GERMANY

ADDRESS FOR CORRESPONDENCE:

Alexander Kapp MD PhD

Professor and Chairman

Director of the Department of Dermatology and Allergology

Hannover Medical University

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D-30449 Hannover

Germany

Phone: +49 511 9246232

Fax: +49 511 9246234

Email: Kapp.Alexander@mh-hannover.de

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