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- Methods and materials
Background: Chronic urticaria is one of the most common and disturbing cutaneous condition. The treatment of chronic idiopathic urticaria (CIU) is still a challenge. Antihistamines are recommended as first-line treatment. Rupatadine is a new potent nonsedative anti-H1.
Objective: To study rupatadine efficacy and safety for moderate to severe CIU treatment.
Methods: This randomized, double-blind, placebo-controlled, parallel-group, multicentre, study was designed to assess primarily mean pruritus score (MPS) reduction with rupatadine, 10 and 20 mg, administered once daily for 4 weeks. Three hundred and thirty-three patients with active episodes of moderate-to-severe CIU were included.
Results: A 57.5% (P < 0.005) and 63.3% (P = 0.0001) significative MPS reduction from baseline, was observed at week 4 with 10 and 20 mg rupatadine, respectively, compared with placebo (44.9%). Both doses of rupatadine were not significantly different at any time point, with respect to their effects on pruritus severity, number of wheals and total symptoms scores. Rupatadine 10 mg had an overall better adverse event profile.
Conclusion: Rupatadine 10 mg is a fast, long-acting, efficacious and safe treatment option for the management of patients with moderate-to-severe CIU.
Chronic urticaria is defined by spontaneous wheals long-lasting more than 6 weeks (1). Conventionally, if any apparent aetiology was considered, chronic urticaria was categorized as idiopathic. Chronic idiopathic urticaria (CIU) is a relatively common skin condition with a 0.5% worldwide lifelong prevalence across different populations, affecting between 0.1% and 3% people in Europe and the USA (1). Some studies show CIU accounts for nearly 75% of all cases of chronic urticaria (2). Besides being severely debilitating and disfiguring, CIU may also be potentially stigmatizing. CIU get worse the Quality of Life (QoL), primarily as a result of sleep disruption, energy loss, fatigue, social isolation and emotional/sexual disturbances (3). This condition follows a chronic course with spontaneous remission and relapses for several years (4). Chronic urticaria aetiology is often unknown (1).
There is increasing evidence for basophil- and mast cell-mediated inflammation in urticaria and angio-oedema. Histamine and other mast cell mediators [including eicosanoids, cytokines, proteases, kinins and platelet activating factor (PAF)] are involved in wheal development (1, 4). Because the symptoms of CIU, including oedema, erythema and pruritus, are primarily associated with histamine release from dermal mast cells, oral H1-receptor inverse agonists (H1 antihistamines) are the treatment of choice (4, 5).
Among specific pathological chronic urticaria triggers some pathogenic mechanisms have been suggested. In up to 50% of patients the disease could be explained by an underlying autoimmune mechanism involving antihigh-affinity immunoglobulin (Ig) E receptor antibodies or less frequently, anti-IgE antibodies. The importance of these autoantibodies is now widely recognized (6). The association between thyroid autoimmunity and chronic urticaria has long been recognized as significant in spite of the pathogenic mechanism is still unknown. Recently, thrombin generation has been suggested as relevant cause of mast cell activation but further studies are needed (7).
A recently published International Consensus guideline on the management of urticaria has recommended nonsedating H1 antihistamines as first-line treatment for chronic urticaria (8).
There is evidence that PAF and histamine have mutually complementary activities in vivo. Each mediator is able to promote the release of the other by different tissues and cells (9, 10). Dual blockade of these mediators is likely to be a more effective treatment strategy for CIU.
Rupatadine is a novel selective long-acting histamine H1-receptor inverse agonist (H1 antihistamine), which is currently approved as a once daily dose of 10 mg, for the treatment of allergic rhinitis (11). Rupatadine has recently been shown to have a higher affinity for the H1-receptor than fexofenadine and levocetirizine (12). Although some antihistamines have shown PAF antagonist properties (13), these effects cannot be attributed to specific interactions with PAF receptors. Rupatadine has shown both anthistamine and anti-PAF effects through its interaction with specific receptors and not due to physiological antagonism (11). Studies in seasonal allergic rhinitis with patients exposed to allergen in a controlled exposure chamber showed that rupatadine 10 mg compared with placebo has a fast onset of action, as indicated by significant decrease of allergen-induced nasal and non-nasal symptoms within 15 min of exposure to allergen (14). Several randomized double-blind, multicentre studies demonstrated that rupatadine 10 and 20 mg once daily are highly efficacious attenuating the symptoms of rhinitis in adult and adolescent patients with moderate-to-severe allergic rhinitis (15–17).
A previous dose-ranging study demonstrated that rupatadine 10 and 20 mg once daily for 4 weeks significantly decreased the severity of pruritus, the number of wheals and the total symptom score in patients with CIU, compared with placebo (18). Furthermore, both doses investigated were well tolerated and safe, with no untoward cardiac effects.
The aim of the present study was to assess efficacy and safety on CIU symptoms treatment and patients QoL improvement with rupatadine, 10 and 20 mg.
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- Methods and materials
This study was designed to evaluate the efficacy of rupatadine 10 and 20 mg in the treatment of CIU symptoms, by primarily assessing the change in MPS over a 4-week treatment period in patients with active CIU. The study demonstrated that rupatadine 10 and 20 mg were significantly better than placebo over the 4-week treatment period and decreased the MPS from baseline, the primary outcome, by 57.5% and 63.3%, respectively, compared with a 44.9% reduction with placebo. Moreover, the superiority of rupatadine 10 and 20 mg over placebo, in reducing the MPS, was evident from week 1 and maintained over an extended treatment period of 6 weeks. Similarly, rupatadine 10 and 20 mg were also significantly better than placebo in reducing the MNW and MTSS from week 1 onwards over 6 weeks. The two doses of rupatadine were not significantly different with respect to their efficacy in attenuating the symptoms of CIU over 4- or 6-week treatment periods and were both safe and well tolerated in this moderate-to-severe CIU patient cohort. However, rupatadine 10 mg led to nearly half the incidence of headache and about a third the incidence of somnolence, than rupatadine 20 mg. The significantly greater efficacy of rupatadine in attenuating the symptoms of CIU was reflected by a finding for greater reductions in general discomfort and improvement in the QoL from the first week of treatment. Indeed, by the end of the 6-week treatment period a larger number of the investigators (63–75%) judged there to be an overall good or excellent improvement in disease symptoms in rupatadine 10 and 20 mg-treated patients, than the number of investigators (50%) making a similar judgement for placebo-treated patients. In contrast, a greater number of investigators (11.8%) judged the symptoms to be worse by the end of 6-weeks’ treatment with placebo, compared with rupatadine 10 and 20 mg (8.3% and 5.6% of investigators, respectively). Collectively, these results confirm the findings of a previous dose-finding study (17) and re-enforce the proposition that rupatadine 10 mg should be used as the preferred normal dose for the management of patients with moderate-to-severe CIU.
The findings of this study are in accordance with studies documenting the effect of other H1 antihistamines in CIU. Studies with fexofenadine have shown that fexofenadine 20–240 mg twice daily for 4 weeks, significantly reduced the MPS, MNW and MTSS from baseline as well as QoL indices in patients with moderate-to-severe CIU symptoms over the 4-week period (21, 22). Similarly, studies investigating the effect of desloratadine 5 mg once daily for 6 weeks in patients with moderate-to-severe CIU have shown that this agent was also significantly more effective than placebo in improving total symptoms/MTSS and QoL indices, compared with placebo (23, 24). Unlike these studies, however, the present study used the validated DLQI and demonstrated that rupatadine 10 and 20 mg to significantly improved most of the subdomain scores after 2 weeks, compared with placebo, suggesting that rupatadine is likely to provide rapid and meaningful overall QoL benefits in affected individuals.
The limited amount of information available on the putative mechanisms involved in the pathophysiology of chronic urticaria, and to some extent CIU, point towards the roles of histamine and PAF as important and complimentary mediators (1, 4, 9, 10). While intradermal injections of PAF and histamine cause vasodilatation and increased vascular permeability, leading to a wheal and flare response that is accompanied by pruritus (25, 26), a comparison of PAF- and histamine-induced cutaneous reactions in the skin of patients with atopic dermatitis (26) and chronic urticaria (27) suggests that the inflammatory response to these agents may be different. One study in patients with atopic dermatitis demonstrated that intradermal PAF resulted in the opening of endothelial gaps and extravasation of predominantly neutrophils, followed by eosinophils after 4 h (26). Similarly, another study in patients with chronic urticaria showed that intradermal PAF led to increased eosinophils at all injection sites, while intradermal histamine lead to increased eosinophils at only a limited number of sites (27). One study of patients with cold-induced urticaria reported that there was an association between urticaria and the release of histamine, PAF and neutrophilic chemotactic activity (NCA) in these patients (28). Collectively, these results suggest that dual blockade of the histamine and PAF receptor may provide rupatadine with an overall greater treatment advantage.
Some other pathogenic mechanisms in chronic urticaria have been evidenced and suggest that in up to 50% of patients the disease could be explained by an underlying autoimmune mechanism involving, i.e. antihigh-affinity IgE receptor antibodies and the importance of these autoantibodies is now widely recognized (6).
In the absence of a specific measure for pruritus severity, the assessment of this measure in the present study, like all other studies documenting the use of this efficacy measure in CIU, was reliant on a subjective assessment. It is nevertheless important to emphasize that the mean pruritus severity was evaluated from the patient's perspective, and that significant decreases in this primary outcome measure, and indeed the secondary outcome measures assessing symptoms (i.e. MNW and MTSS), were detected with rupatadine treatment very early (just after 7 days of treatment) and then maintained over a period of 6 weeks.
The present study provides important information, which enlarges the currently small scientific database on treatment of patients with CIU.
It is important to mention that recent recommendations from the EAACI/GA (2) LEN/EDF guidelines for urticaria management and diagnosis, suggest to treat the patients with new generation antihistamines, with a very low AE effect profile and good patient compliance, In addition, it is also suggested that for nonresponding patients, higher dosage (up to fourfold) should be tried (6, 29).
The responder analyses we performed may assist clinicians in evaluating the impact of rupatadine in a relevant clinical scenario, i.e. in patients with CIU previously stabilized on a second-generation antihistamine. The current results indicate that in this setting, rupatadine produce improvement of symptoms, across multiple outcomes, and thus provide a clinically important treatment benefit for patients with moderate-to-severe CIU. Based on current expert opinion, a 40–50% in symptoms reductions after 4-week treatment could be considered as a meaningful clinical response for patients suffering from CIU and are under a nonsedating anti-H1 treatment.
In particular, this study clearly demonstrates that rupatadine 10 and 20 mg are effective in providing rapid and long-lasting relief from pruritus, which is possibly the most bothersome symptom of CIU, and wheals in affected individuals. Furthermore, rupatadine appears to be efficacious in improving the QoL in these patients, which from the patient's perspective is likely to be a major aspect of their condition.
A recent publication from Asero (30), did suggests that the proportion of patients with severe CIU that may gain a better control of their disease with high, off-label doses of antihistamines is probably small, and that most patients will eventually have to undergo more aggressive treatments. In effect this finding is in keeping with the results of the present study that did not show a marked difference between rupatadine at 10 or 20 mg/day.
In view of the finding that rupatadine 10 and 20 mg were not significantly different at any time point, with respect to their effects on pruritus severity, number of wheals and total symptom scores, but that rupatadine 10 mg has an overall better AE profile than rupatadine 20 mg, particularly with respect to headache and somnolence, it is evident that rupatadine 10 mg is the preferred dose of choice that is likely to be recommended for the management of patients with CIU.