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Clinical characteristics and epidemiology of chronic urticaria: a nationwide, multicentre study on 1091 patients

Introduction Urticaria is one of the most common skin diseases. Depending on the length of symptoms, acute (lasting less than 6 weeks) and chronic urticaria (CU) (> 6 weeks) are distinguished. According to the current European guidelines, CU is divided into inducible urticaria (IU) and chronic spontaneous urticaria (CSU). Aim To assess the epidemiology and clinical characteristics of CU in Poland. Material and methods This was a nationwide, multicentre, cross-sectional, questionnaire-based study performed under the auspices of the Polish Dermatological Society. A total of 102 physicians (dermatologists and allergists) recruited 1091 patients suffering from CU. Results Among 1091 adults with CU, IU was found in 35.1% (n = 383) of patients and CSU was responsible for 61.1% (n = 667) of CU cases. The remaining patients (n = 41, 3.8%) suffered from both, IU and CSU. Persons with CSU were twice more likely to report family history of urticaria than those with IU (12.1% vs. 6.0%, p = 0.001). Generalized eruptions of wheals predominated in CSU (generalized wheals: 57.9%, localized wheals: 42.1%), whereas wheals localized in particular body areas were found more commonly in IU (generalized wheals: 45.2%, localized wheals: 54.8%, p < 0.001). The CU was the cause of absenteeism in almost every fifth patient suffering from this disease. Conclusions The CSU is about twice as frequent cause of CU as compared to IU. The treatment of CU is a major challenge for physicians of various specialties and the treatment choice is closely associated with the specialist knowledge of current treatment guidelines.


Introduction
Urticaria is a common disease characterized by sudden development of wheals, angioedema or both [1]. Chronic urticaria (CU) manifests by reoccurrence of typical lesions for at least 6 weeks or longer and affects up to 1% of general population at any given time [2,3]. According to the latest EAACI/GA 2 LEN/EDF/WAO guidelines, it can be classified either as a spontaneous subtype (CSU) or as an inducible subtype, triggered mostly by physical factors (inducible urticaria -IU) [1]. Epidemiological data on CU, especially its clinical and demographic determinants as well as health care system patterns, are still scarce in the literature.

Aim
The aim of this large, nationwide, multicentre study was to provide more insights regarding the demographic data, clinical manifestations, disease activity/damage, laboratory abnormalities and treatment of urticaria in the Polish population.

Material and methods
This nationwide, multicentre, cross-sectional questionnaire-based study was performed under the auspices of the Polish Dermatological Society. A total of 108 physicians dealing with patients suffering from allergic diseases were invited to participate in the study. All participating physicians were asked to recruit 10 consecutive patients suffering from chronic urticaria. Physicians were invited from different regions of Poland to achieve a good representation of patients from the whole Poland. Six (5.6%) invited physicians refused to participate. The remaining 102 (94.4%) physicians (dermatologists and allergists) recruited a total of 1091 patients with CU. The study was approved by the Ethics Committee at the Wroclaw Medical University and was performed in accordance with the principles of the Declaration of Helsinki. All patients agreed voluntarily to participate in the study.
The 27-item semi-open questionnaire was completed for each patient based on medical history and physical examination during a routine outpatient consultation (Appendix 1). Questions referred to epidemiological data, clinical characteristics of urticaria, as well as management, treatment and outcome of the disease. For the study purpose we used the EAACI/GA 2 LEN/EDF/WAO guidelines for the definition, classification and diagnosis of urticaria (2013 update) [1].

Statistical analysis
Statistical analysis of all data was performed using Statistica 12.0 software (Dell Software, USA). Differences between compared patient groups were verified using χ 2 test with Yates correction, if necessary. Correlation data were analysed by Spearman rank correlations test. Values of p < 0.05 were considered statistically significant.
Among patients with CU, 517 (47.4%) subjects also suffered from other allergic diseases, sometimes having even more than one such disease (allergic rhinitisn = 326, bronchial asthma -n = 138, atopic dermatitisn = 108, nutrition allergy -n = 62). Taking into account the course of the disease we found that the daily occurrence of new wheals was slightly more common in IU than in CSU, but the difference was not significant (p = 0.09). However, the wheals in IU resolved faster than in CSU patients (p < 0.001) ( Table 1). In contrast, the le-sions in CSU were usually more widespread (p < 0.001) and were also more commonly accompanied by angioedema (p < 0.05) (for details see Table 1). An average number of medical consultations/year due to urticaria was 3.0 ±1.7 in CSU and 2.9 ±1.8 in IU (p = 0.36). Patients considered pruritus (75.8%), followed by the presence of skin lesions (35.9%), burning sensations (23.6%) and angioedema (13.3%) to be the most bothersome symptoms of urticaria. Patients with the first episode of urticaria sought help primarily from general practitioners (52.9%), followed by dermatologists (25.5%) and internal medicine specialists (14.1%). Allergists and dermatologists were the most common specialists (38.6% and 33.0%, respectively) to whom patients were referred to by other physicians. The disease diagnosis was established predominantly by dermatologists (52.7%) and allergists (43.1%). Analysing the medication pattern we noticed that the second generation of antihistamines were used most commonly as the first-line treatment, followed by the first generation of antihistamines, regardless of the type of CU (Table 2).
Antihistamines were used significantly more frequently in the registered dose in the IU group, while in the CSU group antihistamines were used significantly more often in higher doses than the registered ones (p < 0.01 for both comparisons). Short-term systemic steroids were used in 53.2% of patients with CSU and in 39.4% with IU, and the difference was statistically significant (p < 0.001). Regarding the treatment outcomes, complete resolution of skin symptoms was observed in 33.4% of CU patients (32.7% in CSU, 36.0% in IU). The CU was the cause of absence from work in 16.3% of patients, of whom 45.5% had the sick leave of between 6 and 14 days, 26.4% of patients were on sick leave for 15 to 30 days and 14.6% of patients were absent from work due to CU for more than a month.

Discussion
Our study provides a number of new epidemiological data concerning CU. As to the aetiology, CSU represents more than 60% of all cases of CU. These results are consistent with data published previously (70-82% of the cases) [4][5][6][7]. Inducible urticaria occurred in approximately one third of patients, however, its prevalence varies greatly among the studies from 10% even to almost 100% [8][9][10][11]. As has been previously reported, we observed a significantly higher prevalence (65%) of urticaria in women, which can be partially explained by a higher incidence of autoimmune diseases in women than in men [8,12]. On the other hand, cholinergic urticaria was significantly more common in men. Other studies provide inconsistent data concerning the sex in this subset of urticaria. The study of Kim et al. [13] showed a male predominance, while others have reported that both sexes were affected to the same degree [14,15].  Compared to the general population, wherein the average prevalence of allergic rhinitis is approximately 25%, the prevalence of allergic rhinitis in CU patients seems to be higher [16]. Food allergy was reported in 5.7% of patients. Similarly, in Kulthanan's paper food allergy was found in 4% of the patients with CU [17]. The impact of nutrients on chronic urticaria is not entirely understood. It is believed that pseudoallergic reactions or aspirin idiosyncrasy are more likely to occur in CU, whereas IgEmediated reactions may play a role in acute urticaria.
Chronic urticaria significantly impairs quality of life of the patients. In the analysed group the most trouble-some symptom of the disease was pruritus, followed by the presence of skin lesions. Other studies confirm our results showing itching as the leading bothersome symptom of CU [12].
In our report we also examined the utilization of the healthcare system pattern. In the analysed group more than a half of all patients sought help from the general practitioners in the first place. However, in order to establish the precise diagnosis and treatment, 71.6% of the patients were subsequently referred to allergists and dermatologists. These data reflect the mechanism of functioning of the health care system in Poland, where the family doctor does not have the appropriate tools for detailed diagnosis of urticaria. In addition, patients need a referral to a specialist and the time to see a specialist is much longer than to see a family doctor. A similar proceeding pattern was observed in Spanish population, but in contrast to our study, a large proportion of Spanish patients were treated in emergency departments [8].
The treatment of CU is a major challenge for physicians of various specialties. Numerous studies pointed the usefulness of the second-generation H1-antihistamines as the first-line treatment of CU and, as also shown in our study, this was the therapy of choice for the majority of physicians, regardless of the specialty. Surprisingly, more than one-third of physicians choose the sedative first-generation H1-antihistamines and systemic steroids alone or in combination as the initial therapy. A similar drug administration pattern was reported by Weller et al. [18] who found that approximately 20% of German specialists (mainly dermatologists and allergists) were using the first-generation H1-antihistamines or steroids as the first-line treatment for CU. On the other hand, according to a large multicentre study conducted among Italian specialists (dermatologists and allergists) it was demonstrated that second-generation H 1 -antihistamines in the registered dose were the most common treatment of choice in Italy [19]. The authors of both studies indicated that the treatment choice was closely associated with the specialist knowledge of current treatment guidelines.
Taking into account the type of CU, we noticed that both, the second-generation H1-antihistamines in higher than registered doses as well as systemic steroids were prescribed significantly more often in CSU than in IU, which may mirror the physicians' conviction that this variant of urticaria is more difficult to control by standard regimen. In our study, the applied treatment induced complete remission of skin lesions in up to 40% of patients and significant remission of the symptoms was observed in further 47.5%. However, in CU, treatment results are frequently unsatisfactory, both for doctors and patients [20]. In our study, 16.6% of patients demonstrated no improvement after the treatment or the remission was inconsiderable.

Conclusions
Chronic urticaria constitutes a significant economic burden on society in terms of the absence from work and production lost. According to our data, urticaria was the cause of absenteeism in almost every fifth patient suffering from CU. In contrast, in Spanish population, only 8.7% of patients seeking medical attention due to urticaria, required an absence from work [8]. Numerous data indicated that the use of antihistamines in the registered doses allows symptom reduction in less than 50% of CSU patients, and increased dosage of these drugs increases the proportion of responders [18,21,22]. However, there is a group of patients in whom it is difficult to obtain satisfactory improvement. In our study there were no patients treated with omalizumab, because the drug is still difficult to obtain in Poland and it is not routinely used, but we suspect that the wider use of omalizumab in selected patients could further improve the treatment results.