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Managing CSU

Declaration of sponsorship Novartis Pharma AG and J. Uriach y Compañía S.A
Read time: 370 mins
Last updated:29th Oct 2021
Published:29th Oct 2021

Improve your ability to recognise and manage chronic spontaneous urticaria (CSU). 

  • Explore engaging video content for expert insights into current therapeutic options
  • Delve into real-world efficacy data on treatments
  • Familiarise yourself with the pathophysiology and symptoms of CSU
  • Review national and international guidelines

Developed by EPG Health for Medthority. This content has been developed independently of the sponsor Novartis Pharma AG

Prevalence of CSU

Urticaria is more common than previously thought1

Though there is little epidemiological data for chronic urticaria (CU), a recent meta-analysis reported a point and lifetime prevalence rates of 0.7% and 1.4% respectively1. Interestingly, the results of this study also suggest that CU prevalence is on the rise, though there is substantial variation between geographical regions1.

Overall, chronic spontaneous urticaria (CSU) accounts for over two-thirds of the cases of CU, and most studies show that it is more common among women than men1,2.

Terminology
Lifetime prevalence is the proportion of a population that at some point in their life (up to the time of the assessment) have experienced the condition3

Epi_1July2021.png

Figure 1. CSU as a percentage of chronic urticaria cases and the ratio of male to female CSU sufferers (Adapted2,4). CIndU, chronic inducible urticaria; CSU, chronic spontaneous urticaria.

Although all age groups can be affected, the peak incidence is seen between 20 and 40 years of age5. There is no apparent correlation of prevalence with education, income, occupation, place of residence or ethnic background; although prevalence of chronic urticaria has been noted as higher in Asian studies compared with Europe or the USA1. Interestingly, a Korean study published in 2017 also found that CSU had a greater impact on children and the elderly than was expected6.

The majority of patients have no evidence of any exacerbating factor, however a recognised trigger for CSU is nonsteroidal anti-inflammatory drugs7.

A population-based study on the epidemiology of CSU in Italy over a 12-year period (2002–2013) demonstrated that the risk of CSU was statistically significantly higher in the presence of the following variables8:

  • obesity
  • anxiety
  • dissociative and somatoform disorders
  • malignancies
  • use of immunosuppressive drug
  • schronic use of systemic corticosteroids

CSU duration

CSU has a duration of at least 1 year in most patients and more than 5 years in a considerable proportion. In very rare cases it can last up to 50 years5,9–12.

CSU_Epi_Fig2.png

Figure 2. The percentage of patients with CSU symptoms at 6 months, 3 years, 5 years, and 25 years after their initial diagnosis (Adapted13).

The evolution of CSU is unpredictable, with spontaneous remissions and relapses7. At least 50% of CSU patients will experience at least one recurrence of CSU symptoms after an apparent resolution14

Prognostic factors for the duration of CSU

The duration of CSU is generally longer in patients with:

  • more severe disease5,9
  • concurrent angioedema5,9
  • concurrent inducible urticaria5,15
  • a positive autologous serum skin test (ASST) or autologous plasma skin test (APST)5,16,17

The autologous serum skin test (ASST) is a screening test for autoantibodies in CSU.

Diagnosis is based on a thorough medical history and physical examination as well as diagnostic tests18.

Acute vs. chronic urticaria

While the lifetime prevalence for CSU estimates range from 0.6% to 1.8%19,20, the lifetime prevalence for acute urticaria is thought to be as high as 20%18. Furthermore, acute urticaria accounts for 7–35% of dermatological conditions seen in emergency care21.

Acute urticaria is defined as the occurrence of spontaneous hives, angioedema, or both for <6 weeks18.

Acute urticaria aetiology

The underlying causes of acute urticaria remain idiopathic in 50% of cases, with infections responsible for approximately 40%, and adverse reactions to drugs (9%) and food (1%) responsible for the remaining 10% of cases22.

Managing acute urticaria

For patients with an identifiable trigger, for example a food allergy, patients should be investigated to confirm sensitisation enabling avoidance of the trigger and prevention of future episodes. With acute urticaria being time-limited, treatment is usually focused on symptomatic relief with second-generation H1-antihistamines18. In a study of 100 acute urticaria patients presenting at a French emergency department, 79% of patients treated with levocetirizine were itch free after two days21.

Current guidelines also state that a short course of oral corticosteroids (up to 10 days) may help reduce the duration and activity of acute exacerbations of urticaria18. Interestingly, in the above study, addition of prednisone to levocetirizine treatment did not improve the symptomatic or clinical response compared with levocetirizine plus placebo. This suggests that the addition of a corticosteroid to antihistamine therapy may be unnecessary in acute urticaria patients21.

Sensitisation to insect bites, such as mosquitos, is common and results in immediate hives and pruritic bite papules, although systemic anaphylactic reactions can also occur23. Mosquito-bite hives are a result of antisaliva IgE antibodies and histamine release meaning oral second-generation H1-antihistamines can be an effective option for management of the hives and itch. Placebo-controlled trials have shown cetirizine, ebastine and rupatadine to be effective treatment options in mosquito-bite allergic adult patients. Prophylactically administered rupatadine 10 mg resulted in a 48% decrease in mean hive size and a 21% reduction in itch in these patients. Importantly, for a condition characterised by intense pruritus, rupatadine 10 mg was observed to have a rapid onset of action with a significant reduction versus placebo in hive size and itch reported 15 minutes after administration23. In a separate study, prophylactic cetirizine 10 mg and ebastine 10 mg, but not loratadine 10 mg, resulted in a significant reduction in hive size. While cetirizine had a significantly greater effect on itch than ebastine and loratadine, it also increased the levels of sedation observed, although the clinical significance was uncertain as no patients dropped out23.

Burden of disease

The impact on patients’ lives goes beyond effects on skin; currently treated patients experience higher levels of health-related impairment in their functioning in work and non-work activities and quality of life and are more frequent users of healthcare than similar individuals without the condition24

Quality of life

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CSU pathophysiology

Chronic spontaneous urticaria (CSU) is driven by the activation of mast cells, which release histamines and other immune modulators, although the precise mechanism is not fully known42.

Mast cell activation in CSU

Urticaria is a mast-cell-driven disease18.

CSU_Patho_1__FEF5106F-817E-4379-B9F0E04613D42C42.png

Figure 4. Interactions of mast cells on urticaria symptoms (Adapted43,44).

Though the pathophysiology of urticaria is complex and yet to be fully characterised, it is thought that activated mast cells release histamine and other inflammatory mediators, such as platelet-activating factor (PAF) and cytokines45. The mediators cause sensory nerve activation, vasodilatation, and plasma extravasation as well as cell recruitment to urticarial lesions, and form the basis for antihistamines being first-line management12,46,47.

CSU skin lesions show recruitment of mast cells, basophils, neutrophils, eosinophils and T-lymphocytes18,48–52.

CSU_Patho_2__8B460AFD-EDFB-4746-80E0D5FC2E6E373B.png

Figure 5. The recruitment of mast cells, basophils, neutrophils, eosinophils and T-lymphocytes in CSU skin lesions (Adapted18,48–52).

The mast cell activating signals in urticaria are ill-defined and likely to be heterogeneous and diverse18.

Basophils
Basophils, along with mast cells, play an important role in the pathophysiology of CSU. Peripheral blood basophils from CSU patients have unique features that reverse upon remission and in response to therapy7,53:

- basopaenia is typically found in CSU patients

- basophils from CSU patients also tend be less responsive to stimuli that act through the IgE receptor

- basophils from CSU patients are hyperresponsive when stimulated with other sera regardless of source

Immunoglobulin E

Immunoglobulin E (IgE) is key to the release of histamine and other pro-inflammatory mediators from mast cells and basophils and may play a role in the pathogenesis of CSU18.

IgE binds to high-affinity (FcεRI) receptors on mast cells, basophils, eosinophils, alveolar macrophages and antigen-presenting cells54–56. Cross-linking of IgE bound to FcεRI receptors triggers degranulation and release of inflammatory mediators55–57. There is a strong association between IgE and allergic conditions57.

The FcεRI receptor on mast cells plays a key role in activation of these cells and in the pathophysiology of CSU58,59

CSU_Patho_Fig3.png

Figure 6. IgE interactions with mast cells in CSU (Adapted42,60–62). IgE, immunoglobulin E; PAF, platelet-activating factor.

Mast cell activation may either be via autoimmune, allergic or idiopathic mechanisms61–64. It is generally believed that allergy is not an underlying cause of CSU, although total IgE levels are typically higher in CSU patients than in healthy individuals62,65.

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CSU symptoms

The symptoms of chronic spontaneous urticaria (CSU) include itchy hives (wheals) and angioedema18

The symptoms of CSU may appear without warning with a variable intensity5,18 and may profoundly impact patients' day-to-day lives5,27,32,69,70. In CSU, itchy hives, angioedema or both, may occur spontaneously every day, or almost daily for six weeks or more18.

Hives

A hive consists of three typical features18:

  1. Central swelling of variable size, usually surrounded by a reflex erythema (Figure 8)
  2. Associated itching (pruritus), or sometimes a burning sensation
  3. Transient nature, usually resolving within 30 minutes to 24 hours

CSU_HiveCollection.1__62753687-8971-4CE6-A67F873D47C5FB56.png

CSU_HiveCollection.2__D179F990-5247-4F2D-B98912F40E8EB748.png

Figure 8. Hives are superficial swellings with pale centres surrounded by a red flare71 .

Terminology
The terms ‘itch’ and ‘pruritus’ are interchangeable, as are ‘hive’ and ‘wheal’

Reflex erythema describes the redness of the skin due to dilated capillaries that is triggered by local neural reflexes. Erythema typically blanches with pressure

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CSU diagnosis and assessment

Since there is no definitive test for chronic spontaneous urticaria, diagnosis is based on a thorough medical history and physical examination as well as diagnostic tests18.

The importance of earlier diagnosis of CSU

Despite the clear diagnostic algorithm included in international guidelines, evidence suggests that many patients with CSU experience delays in receiving a diagnosis18,40,75,76

The Assessment of the Economic and Humanistic Burden of Chronic Spontaneous/Idiopathic Urticaria Patients (ASSURE-CSU) aimed to provide real-world evidence on the unmet needs of patients with uncontrolled CSU by assessing various aspects of the patient experience. Among the 673 patients included in the study, the mean disease duration was 4.8 years, and the mean (SD) duration of disease from symptom onset to diagnosis was 24.0 (63.36) months, with a median delay of 4.7 months. The authors attributed this delay in diagnosis and specialist referral to a lack of specialist knowledge in the primary and secondary care settings with regard to CSU40.

For patients, these delays in obtaining a diagnosis represent a source of great frustration. Many of them will visit multiple healthcare providers before their diagnosis is confirmed and appropriate treatment is initiated75. For example, in an Italian study published in 2017, three-quarters of the 190 patients included visited ≥3 different physicians before finally receiving a diagnosis of CSU76. Other studies have shown that during this process, patients frequently resort to online resources in search of answers75. This may result in inaccurate self-diagnoses and, alarmingly, attempts to self-medicate are not uncommon. There have even been reports of patients using unprescribed prednisone in a bid to alleviate their symptoms75.

Of the patients included in the Italian study described above, 57% expressed hope for a more rapid and straightforward treatment process, particularly in terms of diagnosis76. Better education for both patients and physicians to help raise awareness of CSU could help spare patients the frustration and anxiety associated with delayed diagnosis and facilitate earlier interventions with appropriate therapeutic agents75.

Find out more about the journey to diagnosis from the patient perspective with our podcast, “All Things Urticaria: The Patient Voice”.

CSU diagnosis

Awareness and understanding of CSU are important to ensure correct diagnosis and appropriate treatment or referral18. Guidelines for diagnosis recommend a thorough patient history and physical examination followed by routine diagnostic tests18,77. Extended diagnostic tests may be needed, based on patient history, to exclude differential diagnoses.

The 2017 International EAACI/GA2LEN/EDF/WAO guidelines recommend a three-step process for the effective diagnosis of urticaria (Figure 10)18.

CSU_Diag_1__05EC90BD-E754-4961-B898B25787749F63.png

Figure 10. The three steps recommended in the 2017 International EAACI/GA2LEN/EDF/WAO guidelines for the effective diagnosis of urticaria (Adapted18). EAACI, European Academy of Allergy and Clinical Immunology; EDF, European Dermatology Forum; GA2LEN, Global Allergy and Asthma European Network; WAO, World Allergy Organization.

Patient history in CSU

Step 1
The first step in the diagnosis of urticaria should be to take a thorough patient history18

Recommended questions should take into consideration a number of different factors including18,77:

  • duration of disease
  • physical symptoms
  • provoking factors
  • family history
  • impact on everyday life
  • previous diagnostic tests/therapy

Duration of disease

  • Time of onset
  • Frequency/duration and provoking factors for hives
  • Diurnal variation
  • Occurrence in relation to weekends, holidays and/or foreign travel

Physical symptoms of CSU

  • Shape, size and distribution of hives
  • Associated angioedema
  • Associated symptoms (e.g. bone/joint pain, fever abdominal pain)

See also Assessment Tools for disease activity and impact in CSU

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Comorbidities in CSU

Unfortunately for many patients with chronic spontaneous urticaria (CSU), the itchy hives and/or angioedema associated with the condition is not all they have to contend with. A substantial number of patients also experience comorbidities associated with the development of CSU94.

Autoimmune diseases in CSU

The pathogenesis of CSU in a subset of patients is believed to be a consequence of an autoimmune response driven by immunoglobulin E (IgE) or immunoglobulin G (IgG) autoantibodies94,95, and a strong association is found between CSU and major autoimmune diseases96, with evidence suggesting potential autoimmune aetiology in up to 50% of CSU patients42. Patients with CSU, therefore, are thought to be at an increased risk of developing other autoimmune disorders. In fact, while the global prevalence of autoimmune diseases is considered to be ≤1%, in patients with CSU it is thought to be ≥1%94,95.

Evidence suggests a potential autoimmune aetiology in up to 50% of patients with CSU42

A large Israeli population study exploring the links between CSU and other autoimmune conditions found that a diagnosis of CU was associated with an increased risk of developing hypothyroidism (9.8% vs. 0.6%; p<0.0005) and hyperthyroidism (2.6% vs. 0.09%; p<0.0005). Interestingly, the presence of autoimmune disease was significantly higher in female patients than male patients. A similar effect was seen with type 1 diabetes (female patients OR, 12.92; 95% CI, 6.53–25.53; p<0.0005 vs. male patients OR, 2.34; 95% CI, 1.15–4.73; p=0.01). Importantly, the onset of type 1 diabetes was observed in the majority (84.8%) of patients in the years after receiving a diagnosis of CU. Meanwhile, a number of autoimmune conditions were only significantly increased in female patients. These included rheumatoid arthritis (OR, 19.88; 95% CI, 10.15–38.92; p<0.0005), Sjögen syndrome (OR, 23.30; 95% CI, 7.31–74.20; p<0.0005), coeliac disease (OR, 57.83; 95% CI, 7.99–418.29; p<0.0005) and systemic lupus erythematosus (OR, 26.71; 95% CI, 6.49–109.90; p<0.0005)96.

More recently, a Korean study utilised their national database to explore the presence of various conditions in patients with CU, patients with CSU and patients without CU/CSU. Similar to Confino-Cohen et al., Korean patients with CU (12.34%) or CSU (11.34%) had a significantly increased rate of autoimmune thyroid diseases (AITD) compared to controls (5.49%)6.

Alopecia areata (AA) is another autoimmune disease with a global prevalence of 0.1–0.2%. However, this differs between populations and studies with an observed prevalence of ~0.7–3% in the USA, and ~2% in the UK. An Israeli study matched 1,751 patients with AA to 3,502 control patients and assessed their respective comorbidities. Interestingly, patients with AA had a significantly increased risk of having comorbid CSU (OR, 6.15; 95% CI, 4.06–9.32; p<0.001) than the control group. Furthermore, patients with both AA and CSU were more likely to also have comorbid allergic rhinitis and atopic dermatitis than patients with CSU but not AA in the control group97.

To gain greater clarity on the association of AITD and CSU, a systematic literature review compared data from 169 identified publications. A strong correlation was seen between CSU and elevated IgG antithyroid autoantibodies, in particular IgG-anti-TPO antibodies. Furthermore, some evidence suggests that patients with CSU typically have higher levels of IgE-anti-TPO autoantibodies than controls. As expected, these changes in autoantibody levels are also associated with elevated rates of AITD. It was identified that patients with CSU are more likely to experience hypothyroidism and Hashimoto’s thyroiditis than hyperthyroidism and Grave’s disease. In addition, and supporting the Israeli population study, thyroid dysfunction was more commonly observed in female than male patients with CSU94,96.

A separate systematic literature review looked at the published rates of a broader spectrum of autoimmune diseases in patients with CSU. The rates of comorbidity in the majority of studies were ≥1% for insulin-dependent diabetes mellitus, rheumatoid arthritis, psoriasis and coeliac disease, ≥2% for Grave’s disease, ≥3% for vitiligo and ≥5% for pernicious anaemia and Hashimoto’s thyroiditis95.

To find out more about autoimmune comorbidities in CSU, check out our All Things Urticaria podcast episode ‘Let’s talk comorbidities’ with Professor Marcus Maurer and Dr Simon Francis Thomsen.

Allergic disease

While a link between chronic urticaria and atopic diseases has been suggested, until recently the epidemiological data was lacking98, but some data are starting to clarify the situation. Among a Korean population of patients with CU or CSU, the likelihood or having comorbid allergic rhinitis, drug or other allergies, or asthma was approximately 4.68 times higher than in the control group (Table 4)6.

Table 4. Mean percentage of patients diagnosed with comorbidity between 2010 and 2013 in Korea (Adapted6).CSU, chronic spontaneous urticaria; CU, chronic urticaria.

CSU_Table4_Disease__C5AAB097-8B19-4320-8B697A506AF7FA79.png

In an Israeli population study, 11,271 patients with CU were compared to 67,216 age- and sex-matched controls98. Interestingly, while fewer people experienced allergic comorbidities than observed in the Korean study, they were still significantly more common in patients with CU than in the control group. In this setting, 10.8%, 9.8% and 19.9% of patients with CU had been diagnosed with asthma, atopic dermatitis or allergic rhinitis, respectively compared to 6.5%, 3.7% and 10.1% of patients in the control group98. A multivariate analysis that adjusted for age, sex, body mass index, smoking status and ethnicity revealed that CU was significantly associated allergic rhinitis (OR, 2.03; p<0.001), atopic dermatitis (OR, 2.77; p<0.001) and asthma (OR, 1.62; p<0.001)98. Meanwhile, a comparison of elderly (>60 years of age) and non-elderly patients with CU in Korea revealed that elderly patients with CU were significantly more likely to have comorbid atopic dermatitis than non-elderly patients (37.8% vs. 21.7%, p=0.022)99. However, no difference was seen in the prevalence of asthma or allergic rhinitis99.

The role of allergies and mast cells in irritable bowel syndrome (IBS) has gained increased attention recently. With this possible pathophysiological similarity between IBS and CU, Shalom et al. produced a follow-up study addressing the epidemiological links between the two conditions in Israel98. A total of 1.7% of patients with CU had concomitant IBS versus 0.8% of controls (p<0.001) giving an OR of 1.86 (95% CI, 1.57–2.19; p<0.001). While a pathophysiological explanation remains hypothetical, this study does suggest an association between IBS and CU, warranting further investigation98.

Psychiatric conditions in CSU

Dermatological conditions can have a substantial impact on the mental wellbeing of patients. A UK study reported that 17% of dermatology patients required psychological support while 85% reported that the psychosocial aspects of their skin condition are a major component of their illness100. More recently, a systematic review and meta-analysis including a total of 25 studies revealed that nearly one third of patients with chronic urticaria have one or more psychiatric comorbidity101.

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The Aim of Treatment
The aim of treatment for urticaria is quick and complete symptom control5,18,107

The recommended treatment algorithm

The 2017 European Academy of Allergy and Clinical Immunology (EAACI)/Global Allergy and Asthma European Network (GA2LEN)/European Dermatology Forum (EDF)/World Allergy Organization (WAO) guidelines recommend the following step-wise approach to the treatment of urticaria (Figure 21)18.

CSU_Treatment_1__D673A4E6-CEC6-4807-AF03077631A894AB.png

Figure 21. The 2017 EAACI/GA2LEN/EDF/WAO recommended treatment algorithm for chronic urticaria (Adapted18). EAACI, European Academy of Allergy and Clinical Immunology; EDF, European Dermatology Forum; GA2LEN, Global Allergy and Asthma European Network; WAO, World Allergy Organisation.

A number of additional treatment options are mentioned in the EAACI/GA2LEN/EDF/WAO guidelines but are not included in the recommended treatment algorithm due to limited supporting evidence18.

It is recommended to reassess the need for continued or alternative drug treatment every three to six months, as the severity and symptoms of urticaria may fluctuate and spontaneous remission may occur at any time18.

An urticaria treatment algorithm should serve both patients with easy-to-treat symptoms and those more refractory to treatment and should allow the stepping up or stepping down of treatment depending on requirements over time108.

First-line therapy for CSU

International EAACI/GA2LEN/EDF/WAO guidelines recommend the use of second generation H1-antihistamines, at licensed doses, as first-line treatment for CSU18.

2017 updates to the international CSU guidelines

First generation H1-antihistamines are no longer recommended for the treatment of urticaria due to5,109,110:

- pronounced central nervous system (CNS) and anticholinergic effects/interference with rapid eye movement (REM) sleep (sedating effects)

- drug interactions, particularly with drugs affecting the CNS, e.g., analgesics, hypnotics, sedatives, mood elevating drugs and alcohol

CSU_Treatment_2__B1E6EF48-FF4B-4D5F-81AE0245E9D63125.png

Figure 22. Potential adverse effects of first (old)-generation H1-antihistamines (Adapted111). CNS, central nervous system.

Second generation H1-antihistamines are well tolerated by most patients and are non-sedating or minimally sedating, and free from anticholinergic effects18. However, astemizole and terfenadine, two of the earlier modern second-generation drugs, require hepatic metabolism for full activation and have cardiotoxic effects if this metabolism is blocked18. Due to these safety concerns, these two drugs are no longer available in most countries, and are not recommended in the CSU guidelines18. Despite this setback, newer modern second-generation antihistamines were developed to overcome these issues. Initially, the new generation of antihistamines comprised cetirizine (metabolite of hydroxyzine), loratadine, and fexofenadine but now includes acrivastine, azelastine, bepotastine, bilastine, desloratadine, ebastine, epinastine, levocetirizine, mequitanzine, mizolastine, olopatadine, and rupatadine18.

While a total of 16 different second generation H1-antihistamines have featured in review articles and clinical studies focussed on the treatment of CSU, only 10 are widely recognised in current guidelines (acrivastine, bilastine, cetirizine/levocetirizine, ebastine, fexofenadine, loratadine/desloratadine, mizolastine, and rupatadine)112.

Why not combine first- and second-generation H1-antihistamines?

While second-generation antihistamines are the recommended first-line therapy in CSU, many physicians continue to believe that the addition of a sedating, first-generation antihistamine in the evening can aid patient sleep. However, the results from a randomised, double-blind, cross-over study indicated that the addition of hydroxyzine to a second-generation antihistamine did not improve patient sleep, but did increase daytime somnolence, supporting the use of second-generation antihistamines only in the treatment of CSU110,113.

Clinical evidence

Several second-generation H1-antihistamines are used for the management of CSU. Here we review the available clinical data in adults for each.

Bilastine

Bilastine is a second-generation H1-antihistamine that is used for the management of allergic rhinitis and urticaria. A double-blind, randomised, placebo-controlled trial evaluated the efficacy and safety of 20 mg bilastine versus 5 mg levocetirizine and placebo in adult patients with CSU114. Over a 4-week period, 525 patients were assessed with total symptom scores used as the primary endpoint. From day 2 onwards, bilastine showed a significant improvement in the patients’ symptoms compared with placebo. Furthermore, bilastine treatment also resulted in significant improvements compared with placebo in Dermatology Life Quality Index (DLQI) scores, as well urticaria-associated discomfort, and sleep disruption. When considering the levocetirizine group, bilastine was observed to have comparable efficacy and tolerability114. A Japanese study has indicated that the efficacy and tolerability of bilastine is maintained over the course of a year115.

Cetirizine

Clinical data on the efficacy and safety of cetirizine in patients with CSU has been available for 30 years. In 1988, 30 patients with CSU were treated with 10 mg cetirizine or placebo in a double-blind cross-over trial116. This early data indicated that cetirizine significantly reduced the occurrence of hives and pruritus compared with placebo (p<0.001). Of the 30 patients, 26 improved on cetirizine, two on placebo and two discontinued cetirizine due to a lack of efficacy. Meanwhile, mild sedation was observed in two patients receiving cetirizine and one patient given placebo116.

Head-to-head

Cetirizine has also been evaluated in CSU in several head-to-head trials. An early study compared cetirizine with the first-generation antihistamine hydroxyzine and placebo117. While cetirizine was shown to have similar efficacy to hydroxyzine, it had a lower incidence of somnolence and showed levels not significantly different to those observed in the placebo group117.

More recently, the effectiveness and safety of cetirizine was compared to that of rupatadine. In a randomised, double-blind, 6-week trial, 70 patients with CSU were treated with 10 mg of cetirizine or rupatadine once daily118. Evaluations of the mean number of hives (wheals), mean pruritus score and mean total symptom score revealed significantly greater improvements with rupatadine than cetirizine (Figure 23)118.

CSU_Treatment_Fig3-7.png

Figure 23. Mean change from baseline in mean total symptom score (MTSS), mean number of wheals (MNW) and mean pruritus score (MPS) following 6 weeks of treatment with cetirizine (n=31) or rupatadine (n=33) (Adapted118).

The study also used a visual analogue scale (VAS) to assess sedation with participants asked to score themselves on a scale from 0 (alert) to 100 (very sleepy). After six weeks, cetirizine was shown to produce a significant increase in the patients self-reported sedation compared with baseline (p=0.0004). Rupatadine did not induce a significant change in sedation levels after 6 weeks compared with baseline (p=0.2179)118.

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CSU Guidelines

Best practice guidelines for CSU have been developed and published by a number of national and international groups, and those with major significance are described in this section. Broadly speaking they recommend second generation antihistamines of standard and then increased dose, followed by alternative agents such as anti-inflammatories, immunosuppressants or biologics.

CSU presents as wheals and/or angioedema which usually last for less than 24 hours and resolve without leaving a mark. These symptoms occur for six weeks or more18.

The diagnosis of CSU is usually made clinically. Not all possible causative factors need to be investigated in all patients, however, a thorough history should be taken as the first step. The following should be reviewed18:

  • onset of disease
  • frequency of attacks
  • provoking factors
  • diurnal variation
  • shape, size and distribution of wheals
  • angioedema
  • pain, itch, burning, fever
  • family history
  • allergies
  • psychosomatic/psychiatric history
  • surgical implantations
  • gastrointestinal symptoms
  • induction by physical stimulation
  • drugs
  • correlation to food
  • correlation to menstrual cycle
  • smoking 
  • work
  • hobbies
  • quality of life
  • previous therapy (response)
  • previous diagnostic results

Following the patient history, a physical examination of the patient should be made. This should include a diagnostic provocation test including drug, food and physical tests where indicated by the patient’s history. All subsequent diagnostic steps will depend on patient history and the nature of the urticaria subtype18.

EAACI Guidelines recommend only very limited routine diagnostic measures in chronic spontaneous urticaria18.

Routine

  • C-reactive protein (CRP)/erythrocyte sedimentation rate (ESR)
  • Differential blood cell count

Extended

  • Infectious diseases
  • Type I allergy
  • Functional autoantibodies
  • Thyroid hormones
  • Physical tests
  • Pseudo allergen free diet
  • Autologous serum skin test (ASST)

Table 6. Recommended diagnostic tests in frequent spontaneous urticaria subtypes (Adapted18). CIndU, chronic inducible urticaria; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate.

CSU_Table1_Disease_guidelines section__745F0BEC-43E9-498A-B0B09B8205FD58B9.png


Table 7. Recommended diagnostic tests in frequent inducible urticaria subtypes (Adapted18). CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; UV, ultraviolet.

*for identification of underlying causes or eliciting factors and for ruling out possible differential diagnoses if indicated.
Subtype Routine Diagnostics Tests (Recommended) Extended Diagnostic Program
(Suggested Based on History Only)*
Cold urticaria Cold provocation and threshold test (ice cube, cold water, cold wind) Differential blood count and ESR or CRP, rule out other diseases, especially infections
Heat urticaria Heat provocation and threshold test None
Solar urticaria UV and visible light of different wavelengths Rule out other light-induced dermatoscs
Symptomatic dermographism Elicit dermographism and threshold test (dermatographometer) Differential blood count, ESR or CRP
Vibratory angioedema Test with, for example, vortex None
Aquagenic urticaria Wet cloth at body temperature applied for 20 minutes None
Cholinergic urticaria Provocation testing None
Contact urticaria Cutaneous provocation test. Skin tests with immediate readings
(e.g. prick test)
None

International guidelines

The need for international guidelines in urticaria

Clinical decisions regarding the best diagnostic and therapeutic approaches in patients with urticaria can vary from one allergist or dermatologist to another, and between clinical centres. International guidelines offer clear evidence-based recommendations that18:

  • clarify which interventions are of proven benefit
  • document the quality of the supporting data
  • take into consideration regional differences in causative factors, medical systems and access to diagnosis and treatment worldwide

The 2017 International EAACI/GA2LEN/EDF/WAO Urticaria Guidelines

The only international recommendations for the diagnosis and management of urticaria are provided by the EAACI/GA²LEN/EDF/WAO urticaria guidelines18.

The 2017 International EAACI/GA2LEN/EDF/WAO urticaria guidelines are18:

  • a joint initiative of four societies: the European Academy of Allergy and Clinical Immunology (EAACI), the Global Allergy and Asthma European Network (GA2LEN), the European Dermatology Forum (EDF) and the World Allergy Organization (WAO)
  • the result of a systematic literature review using a modified version of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system and outcomes from a consensus conference on the 1 December 2016, with 44 urticaria experts from 25 countries

The 2017 revision and update to the international EAACI/GA2LEN/EDF/WAO urticaria guidelines include evidence-based recommendations for the definition, classification, diagnosis and management of urticaria18.

Table 8. Summary of the updated 2017 international EAACI/GA2LEN/EDF/WAO urticaria guidelines (Adapted18)

CSU_Table3_Disease_guidelines section__C6303BAC-3FCA-45F8-BBAA61746BC33FA6.png

USA Guidelines

Recommendations for the diagnosis and management of urticaria in the USA are provided by the Joint Task Force on Practice Parameters (JTFPP) 2014 (Figure 41)202. The JTFPP is a 13-member task force consisting of representatives assigned by the American Academy of Allergy, Asthma and Immunology (AAAAI), the American College of Allergy, Asthma and Immunology (ACAAI) and the Joint Council of Allergy and Immunology. 

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Paediatric urticaria

Explore the available data in paediatric urticaria and discover its impact on younger patients, and how diagnosis and management compare to the recommendations for adult patients with CSU.

Epidemiology

Urticaria affects all age groups, however, acute urticaria appears more common in infants and young children while chronic urticaria appears more prevalent in adult patients. Interestingly, a Korean study published in 2018 found an unexpected peak in the prevalence of CU and CSU in subjects aged 0–9 years6. Overall, published data from paediatric patients remains scarce. In the 18-month Early Prevention of Asthma in Atopic Children (EPAAC) study involving 510 atopic children aged between 12 and 24 months, 42% of children receiving placebo experienced urticaria18,211. Outside of this atopic patient population, significant variation in the prevalence of acute and chronic urticaria has been observed (Figure 44).

T2_08.Paeds_Fig45

Figure 44. Prevalence of paediatric urticaria (Adapted63,212–216)

Chronic urticaria is considered less prevalent in children than adults with a point prevalence of 0.1% to 0.3% identified in the UK212, although higher incidences have been observed in other studies215,217. The significant variation that has been observed within the published prevalence of paediatric urticaria around the world is likely to be influenced by different patient populations, clinical settings and diagnostic criteria. However, while the reported prevalence of urticaria within children has been variable, a number of consistencies have also been identified. Unlike the adult population where women are more likely to develop CSU than men, in the paediatric population urticaria appears to be distributed equally between both sexes214,218–220.

Although patient sex may not influence the incidence of paediatric urticaria, it does appear to change with age (Figure 45). A study consisting of 9,088 German new-borns from two prospective birth cohorts identified the incidence of urticaria as approximately 1% per year of age. However, the incidence for both sexes was highest during the second year of life and was typically higher in preschool children than in school-aged children214.

CSU_Paeds_2__80FA14D2-0FFF-48AA-A0D7FBA62CDF5574.png

Figure 45. Incidence of urticaria by age and sex (Adapted214).

Aetiology: acute urticaria

The most common trigger for acute urticaria in children is infection. While these are typically viral infections of the upper respiratory tract, gastrointestinal and urinary infections, as well as bacterial and parasitic infections, have also been implicated221. The association between infection and acute urticaria is underlined by their seasonality with peaks in acute urticaria being observed to coincide with rises in viral respiratory infections222.

Other reported causes of acute urticaria in children include drug hypersensitivity and food allergy. However, detailed workups in two studies suggested that >90% of children with suspected drug hypersensitivity were able to tolerate the medication223,224. Meanwhile, food allergy was cited as the cause of urticaria in 2.7% and 6.3% of paediatric patients225,226.

Aetiology: chronic urticaria

Determining a trigger for paediatric chronic urticaria (spontaneous and inducible) can be difficult with reported identification rates ranging from 21% to 83%227.

While viral infection has been implicated as an exacerbating factor for chronic urticaria in children, it is not believed to play a causal role as has been indicated in acute urticaria228. Meanwhile, the role of bacterial infections in paediatric CSU remains uncertain with many studies suggesting it is unlikely to play a significant role227.

Like adult CSU, autoimmunity appears to be a critical factor in a significant number of patients. In fact, the frequency of autoimmune CSU appears to be similar between paediatric and adult patients227. In a Thai study of 94 paediatric CSU patients, 38% of patients were found to have a positive autologous serum skin test (ASST)229, while in an Italian study, 45% of children with CSU (22 of 49) were identified as having autoimmunity as the underlying cause230.

Chronic inducible urticaria is the most common chronic urticaria subtype in children with dermatographic urticaria and cholinergic urticaria being the two most frequently observed forms221,227. While cold urticaria is less common in paediatric patients, it is important to note that in one study of 30 patients, one-third of patients experienced anaphylactic reactions alongside their urticaria231.

Clinical presentation

As with adult CSU, hives and/or angioedema are the key symptoms in paediatric urticaria. However, the relative ratios of these symptoms at presentation remains less clear in younger patients. An early study indicated that 78.4% of paediatric patients experienced hives alone, while 6.6% suffered from angioedema alone and the remaining 15% had both232. A similar incidence of angioedema was observed in a prospective study that identified concomitant angioedema in 28% of CSU patients younger than 17 years of age220

In contrast, a prospective study of 94 Thai children with CSU revealed that 51% had both hives and angioedema229 while a follow-up study from the same centre revealed 59.8% of children with chronic urticaria to suffer from hives and angioedema218. It is apparent that further research is required to establish the typical clinical presentation ratios within paediatric CSU.

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References

  1. Fricke J, Ávila G, Keller T, Weller K, Lau S, Maurer M, et al. Prevalence of chronic urticaria in children and adults across the globe: Systematic review with meta-analysis. Allergy Eur J Allergy Clin Immunol. 2020;75(2):423–432.
  2. Watanabe J, Shimamoto J, Kotani K. The effects of antibiotics for helicobacter pylori eradication or dapsone on chronic spontaneous urticaria: A systematic review and meta-analysis. Antibiotics. 2021;10(2):1–14.
  3. NIH. What is Prevalence? https://www.nimh.nih.gov/health/statistics/what-is-prevalence. Accessed 5 July 2021.
  4. Alen Coutinho I, Regateiro FS, Fernandes RA, Pita JS, Gomes R, Coelho C, et al. Refractory chronic urticaria in adults: clinical characterization and predictors of severity. Allergy, Asthma Clin Immunol. 2020;16(1):1–9.
  5. Maurer M, Weller K, Bindslev-Jensen C, Giménez-Arnau A, Bousquet PJ, Bousquet J, et al. Unmet clinical needs in chronic spontaneous urticaria. A GA2LEN task force report. Allergy Eur J Allergy Clin Immunol. 2011;66(3):317–330.
  6. Kim BR, Yang S, Choi JW, Choi CW, Youn SW. Epidemiology and comorbidities of patients with chronic urticaria in Korea: A nationwide population-based study. J Dermatol. 2018;45(1):10–16.
  7. Ferrer M, Bartra J, Giménez-Arnau A, Jauregui I, Labrador-Horrillo M, Ortiz de Frutos J, et al. Management of urticaria: Not too complicated, not too simple. Clinical and Experimental Allergy. 2015;45(4):731–743.
  8. Lapi F, Cassano N, Pegoraro V, Cataldo N, Heiman F, Cricelli I, et al. Epidemiology of chronic spontaneous urticaria: Results from a nationwide, population-based study in Italy. Br J Dermatol. 2016;174(5):996–1004.
  9. Toubi E, Kessel A, Avshovich N, Bamberger E, Sabo E, Nusem D, et al. Clinical and laboratory parameters in predicting chronic urticaria duration: A prospective study of 139 patients. Allergy Eur J Allergy Clin Immunol. 2004;59(8):869–873.
  10. Młynek A, Magerl M, Hanna M, Lhachimi S, Baiardini I, Canonica GW, et al. The German version of the chronic urticaria quality-of-life questionnaire: Factor analysis, validation, and initial clinical findings. Allergy Eur J Allergy Clin Immunol. 2009;64(6):927–936.
  11. Gattey N, Bahrani B, Hull PR. Chronic spontaneous urticaria: A questionnaire survey. J Cutan Med Surg. 2016;20(3):241–243.
  12. Beck LA, Bernstein JA, Maurer M. A review of international recommendations for the diagnosis and management of chronic urticaria. Acta Dermato-Venereologica. 2017;97(2):149–158.
  13. Curto-Barredo L, Riba Archilla L, Roura Vives G, Pujol RM, Giménez-Arnau AM. Clinical features of chronic spontaneous urticaria that predict disease prognosis and refractoriness to standard treatment. Acta Derm Venereol. 2018;98(7):641–647.
  14. Hellgren L. The Prevalence of Urticaria in the Total Population. Allergy. 1972;27(3):236–240.
  15. Kozel MMA, Mekkes JR, Bossuyt PMM, Bos JD. Natural course of physical and chronic urticaria and angioedema in 220 patients. J Am Acad Dermatol. 2001;45(3):387–391.
  16. Staubach P, Onnen K, Vonend A, Metz M, Siebenhaar F, Tschentscher I, et al. Autologous whole blood injections to patients with chronic urticaria and a positive autologous serum skin test: A placebo-controlled trial. Dermatology. 2006;212(2):150–159.
  17. Boonpiyathad T, Sangasapaviliya A. Autologous serum and plasma skin test to predict 2-year outcome in chronic spontaneous urticaria. Asia Pac Allergy. 2016;6(4):226–235.
  18. Zuberbier T, Aberer W, Asero R, Abdul Latiff AH, Baker D, Ballmer-Weber B, et al. The EAACI/GA2LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. Allergy Eur J Allergy Clin Immunol. 2018;73(7):1393–1414.
  19. Gaig P, Olona M, Muñoz Lejarazu D, Caballero MT, Domínguez FJ, Echechipia S, et al. Epidemiology of urticaria in Spain. J Investig Allergol Clin Immunol. 2004;14(3):214–220.
  20. Zuberbier T, Balke M, Worm M, Edenharter G, Maurer M. Epidemiology of urticaria: A representative cross-sectional population survey. Clin Exp Dermatol. 2010;35(8):869–873.
  21. Barniol C, Dehours E, Mallet J, Houze-Cerfon CH, Lauque D, Charpentier S. Levocetirizine and Prednisone Are Not Superior to Levocetirizine Alone for the Treatment of Acute Urticaria: A Randomized Double-Blind Clinical Trial. Ann Emerg Med. 2018;71(1):125-131.e1.
  22. Kathuria PC. Urticaria and its management. Indian J Allergy Asthma Immunol,. 2011;25(1):33–37.
  23. Karppinen A, Brummer-Korvenkontio H, Reunala T, Izquierdo I. Rupatadine 10 mg in the treatment of immediate mosquito-bite allergy. J Eur Acad Dermatology Venereol. 2012;26(7):919–922.
  24. Balp MM, Vietri J, Tian H, Isherwood G. The Impact of Chronic Urticaria from the Patient’s Perspective: A Survey in Five European Countries. Patient. 2015;8(6):551–558.
  25. Carne E. Managing chronic spontaneous urticaria (hives) in primary care. Nurs Stand. 2018;33(7):78–82.
  26. Gonçalo M, Gimenéz-Arnau A, Al-Ahmad M, Ben-Shoshan M, Bernstein JA, Ensina LF, et al. The global burden of chronic urticaria for the patient and society*. Br J Dermatol. 2021;184(2):226–236.
  27. Kang MJ, Kim HS, Kim HO, Park YM. The impact of chronic idiopathic urticaria on quality of life in Korean patients. Ann Dermatol. 2009;21(3):226–229.
  28. Silvares MRC, Fortes MRP, Miot HA. Quality of life in chronic urticaria: A survey at a public university outpatient clinic, Botucatu (Brazil). Rev Assoc Med Bras. 2011;57(5):565–569.
  29. Staubach P, Eckhardt-Henn A, Dechene M, Vonend A, Metz M, Magerl M, et al. Quality of life in patients with chronic urticaria is differentially impaired and determined by psychiatric comorbidity. Br J Dermatol. 2006;154(2):294–298.
  30. Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)—a simple practical measure for routine clinical use. Clin Exp Dermatol. 1994;19(3):210–216.
  31. Młynek A, Zalewska-Janowska A, Martus P, Staubach P, Zuberbier T, Maurer M. How to assess disease activity in patients with chronic urticaria? Allergy Eur J Allergy Clin Immunol. 2008;63(6):777–780.
  32. Engin B, Uguz F, Yilmaz E, Özdemir M, Mevlitoglu I. The levels of depression, anxiety and quality of life in patients with chronic idiopathic urticaria. J Eur Acad Dermatology Venereol. 2008;22(1):36–40.
  33. Staubach P, Dechene M, Metz M, Magerl M, Siebenhaar F, Weller K, et al. High prevalence of mental disorders and emotional distress in patients with chronic spontaneous urticaria. Acta Derm Venereol. 2011;91(5):557–561.
  34. Maurer M, Raap U, Staubach P, Richter-Huhn G, Bauer A, Oppel EM, et al. Antihistamine-resistant chronic spontaneous urticaria: 1-year data from the AWARE study. Clin Exp Allergy. 2019;49(5):655–662.
  35. Maurer M, Giménez-Arnau AM, Sussman G, Metz M, Baker DR, Bauer A, et al. Ligelizumab for Chronic Spontaneous Urticaria. N Engl J Med. 2019;381(14):1321–1332.
  36. Savic S, Leeman L, El-Shanawany T, Ellis R, Gach JE, Marinho S, et al. Chronic urticaria in the real-life clinical practice setting in the UK: results from the noninterventional multicentre AWARE study. Clin Exp Dermatol. 2020;45(8):1003–1010.
  37. Thomsen SF, Pritzier EC, Anderson CD, Vaugelade-Baust N, Dodge R, Dahlborn AK, et al. Chronic urticaria in the real-life clinical practice setting in Sweden, Norway and Denmark: baseline results from the non-interventional multicentre AWARE study. J Eur Acad Dermatology Venereol. 2017;31(6):1048–1055.
  38. Itakura A, Tani Y, Kaneko N, Hide M. Impact of chronic urticaria on quality of life and work in Japan: Results of a real-world study. J Dermatol. 2018;45(8):963–970.
  39. DeLong LK, Culler SD, Saini SS, Beck LA, Chen SC. Annual direct and indirect health care costs of chronic idiopathic urticaria: A cost analysis of 50 nonimmunosuppressed patients. Arch Dermatol. 2008;144(1):35–39.
  40. Maurer M, Abuzakouk M, Bérard F, Canonica W, Oude Elberink H, Giménez-Arnau A, et al. The burden of chronic spontaneous urticaria is substantial: Real-world evidence from ASSURE-CSU. Allergy Eur J Allergy Clin Immunol. 2017;72(12):2005–2016.
  41. Maurer M, Houghton K, Costa C, Dabove F, Ensina LF, Giménez-Arnau A, et al. Differences in chronic spontaneous urticaria between Europe and Central/South America: Results of the multi-center real world AWARE study. World Allergy Organ J. 2018;11(1):32.
  42. Bracken SJ, Abraham S, MacLeod AS. Autoimmune theories of chronic spontaneous urticaria. Frontiers in Immunology. 2019;10(MAR):627.
  43. Giménez-Arnau AM, DeMontojoye L, Asero R, Cugno M, Kulthanan K, Yanase Y, et al. The Pathogenesis of Chronic Spontaneous Urticaria: The Role of Infiltrating Cells. J Allergy Clin Immunol Pract. 2021;9(6):2195–2208.
  44. Church MK, Kolkhir P, Metz M, Maurer M. The role and relevance of mast cells in urticaria. Immunological Reviews. 2018;282(1):232–247.
  45. Ferrer M. Immunological events in chronic spontaneous urticaria. Clinical and Translational Allergy. 2015;5(1). doi:10.1186/s13601-015-0074-7.
  46. Chang TW, Chen C, Lin CJ, Metz M, Church MK, Maurer M. The potential pharmacologic mechanisms of omalizumab in patients with chronic spontaneous urticaria. Journal of Allergy and Clinical Immunology. 2015;135(2):337-342.e2.
  47. Guillén-Aguinaga S, Jáuregui Presa I, Aguinaga-Ontoso E, Guillén-Grima F, Ferrer M. Updosing nonsedating antihistamines in patients with chronic spontaneous urticaria: a systematic review and meta-analysis. British Journal of Dermatology. 2016;175(6):1153–1165.
  48. Elias J, Boss E, Kaplan AP. Studies of the cellular infiltrate of chronic idiopathic urticaria: Prominence of T-lymphocytes, monocytes, and mast cells. J Allergy Clin Immunol. 1986;78(5 PART 1):914–918.
  49. Natbony SF, Phillips ME, Elias JM, Godfrey HP, Kaplan AP. Histologic studies of chronic idiopathic urticaria. J Allergy Clin Immunol. 1983;71(2):177–183.
  50. Sabroe RA, Poon E, Orchard GE, Lane D, Francis DM, Barr RM, et al. Cutaneous inflammatory cell infiltrate in chronic idiopathic urticaria: Comparison of patients with and without anti-FcεRI or anti-lgE autoantibodies. J Allergy Clin Immunol. 1999;103(3 II):484–493.
  51. Ying S, Kikuchi Y, Meng Q, Kay AB, Kaplan AP. TH1/TH2 cytokines and inflammatory cells in skin biopsy specimens from patients with chronic idiopathic urticaria: Comparison with the allergen-induced late-phase cutaneous reaction. J Allergy Clin Immunol. 2002;109(4):694–700.
  52. Ito Y, Satoh T, Takayama K, Miyagishi C, Walls AF, Yokozeki H. Basophil recruitment and activation in inflammatory skin diseases. Allergy Eur J Allergy Clin Immunol. 2011;66(8):1107–1113.
  53. Sterba PM, Hamilton RG, Saini SS. Suppression of basophil FcεRI activation by serum from active chronic idiopathic/spontaneous urticaria (CIU/CSU) subjects. Journal of Investigative Dermatology. 2015;135(5):1454–1456.
  54. Metzger H, Alcaraz G, Hohman R, Kinet JP, Pribluda V, Quarto R. The receptor with high affinity for immunoglobulin E. Annual review of immunology. 1986;4:419–470.
  55. Ishizaka T, Conrad DH, Schulman ES, Sterk AR, Ishizaka K. Biochemical analysis of initial triggering events of IgE-mediated histamine release from human lung mast cells. J Immunol. 1983;130(5):2357–23562.
  56. Dehlink E, Fiebiger E. The Role of the High-Affinity IgE Receptor, FcϵRI, in Eosinophilic Gastrointestinal Diseases. Immunol Allergy Clin N Am. 2009;29(1):159–170.
  57. Rabe KF, Calhoun WJ, Smith N, Jimenez P. Can anti-IgE therapy prevent airway remodeling in allergic asthma? Allergy. 2011;66(9):1142–1151.
  58. Vonakis BM, Saini SS. New concepts in chronic urticaria. Current Opinion in Immunology. 2008;20(6):709–716.
  59. Stone KD, Prussin C, Metcalfe DD. IgE, mast cells, basophils, and eosinophils. J Allergy Clin Immunol. 2010;125(2 SUPPL. 2):S73.
  60. Wernersson S, Pejler G. Mast cell secretory granules: Armed for battle. Nature Reviews Immunology. 2014;14(7):478–494.
  61. Kaplan AP, Greaves M. Pathogenesis of chronic urticaria. Clinical and Experimental Allergy. 2009;39(6):777–787.
  62. Metz M, Maurer M. Omalizumab in chronic urticaria. Current Opinion in Allergy and Clinical Immunology. 2012;12(4):406–411.
  63. Greaves M. Chronic urticaria. J Allergy Clin Immunol. 2000;105(4):664–672.
  64. Altrichter S, Peter HJ, Pisarevskaja D, Metz M, Martus P, Maurer M. Ige mediated autoallergy against thyroid peroxidase - a novel pathomechanism of chronic spontaneous urticaria? PLoS One. 2011;6(4):e14794.
  65. Staubach P, Vonend A, Burow G, Metz M, Magerl M, Maurer M. Patients with chronic urticaria exhibit increased rates of sensitisation to Candida albicans, but not to common moulds. Mycoses. 2009;52(4):334–338.
  66. Goh CL, Tan KT. Chronic autoimmune urticaria : WWhere we stand. In: Indian Journal of Dermatology. 2009. Wolters Kluwer Medknow Publications: 269–274.
  67. Jain S. Pathogenesis of chronic urticaria: An overview. Dermatology Research and Practice. 2014;2014. doi:10.1155/2014/674709.
  68. Siebenhaar F, Melde A, Magerl M, Zuberbier T, Church MK, Maurer M. Histamine intolerance in patients with chronic spontaneous urticaria. J Eur Acad Dermatology Venereol. 2016;30(10):1774–1777.
  69. O’Donnell B, Lawlor F, Simpson J, Morgan M, Greaves M. The impact of chronic urticaria on the quality of life. Br J Dermatol. 1997;136(2):197–201.
  70. Barbosa F, Freitas J, Barbosa A. Chronic idiopathic urticaria and anxiety symptoms. J Health Psychol. 2011;16(7):1038–1047.
  71. Grattan C. The urticarias: Pathophysiology and management. Clin Med J R Coll Physicians London. 2012;12(2):164–167.
  72. Kulthanan K, Jiamton S, Boochangkool K, Jongjarearnprasert K. Angioedema: Clinical and etiological aspects. Clin Dev Immunol. 2007;2007:26438.
  73. Weller K, Maurer M, Grattan C, Nakonechna A, Abuzakouk M, Bérard F, et al. ASSURE-CSU: A real-world study of burden of disease in patients with symptomatic chronic spontaneous urticaria. Clin Transl Allergy. 2015;5(1). doi:10.1186/s13601-015-0072-9.
  74. Stull DE, McBride D, Houghton K, Finlay AY, Gnanasakthy A, Balp MM. Assessing Changes in Chronic Spontaneous/Idiopathic Urticaria: Comparisons of Patient-Reported Outcomes Using Latent Growth Modeling. Adv Ther. 2016;33(2):214–224.
  75. Goldstein S, Eftekhari S, Mitchell L, Winders TA, Kaufman L, Dudas D, et al. Perspectives on living with chronic spontaneous urticaria: From onset through diagnosis and disease management in the US. Acta Derm Venereol. 2019;99(12):1091–1098.
  76. Cappuccio A, Limonta T, Parodi A, Cristaudo A, Bugliaro F, Cannavò SP, et al. Living with chronic spontaneous urticaria in Italy: A narrative medicine project to improve the pathway of patient care. Acta Derm Venereol. 2017;97(1):81–85.
  77. Powell RJ, Leech SC, Till S, Huber PAJ, Nasser SM, Clark AT. BSACI guideline for the management of chronic urticaria and angioedema. Clin Exp Allergy. 2015;45(3):547–565.
  78. Magerl M, Altrichter S, Borzova E, Giménez-Arnau A, Grattan CEH, Lawlor F, et al. The definition, diagnostic testing, and management of chronic inducible urticarias - The EAACI/GA2LEN/EDF/UNEV consensus recommendations 2016 update and revision. Allergy Eur J Allergy Clin Immunol. 2016;71(6):780–802.
  79. Zuberbier T, Aberer W, Asero R, Bindslev-Jensen C, Brzoza Z, Canonica GW, et al. The EAACI/GA2LEN/EDF/WAO Guideline for the definition, classification, diagnosis, and management of urticaria: The 2013 revision and update. Allergy Eur J Allergy Clin Immunol. 2014;69(7):868–887.
  80. Bansal CJ, Bansal AS. Stress, pseudoallergens, autoimmunity, infection and inflammation in chronic spontaneous urticaria. Allergy, Asthma and Clinical Immunology. 2019;15(1):56.
  81. Kumaran M, Mangal S, Narang T, Parsad D. Autologous serum and plasma skin tests in chronic spontaneous urticaria: A reappraisal. Indian Dermatol Online J. 2017;8(2):94.
  82. Konstantinou GN, Asero R, Maurer M, Sabroe RA, Schmid-Grendelmeier P, Grattan CEH. EAACI/GA2LEN task force consensus report: The autologous serum skin test in urticaria. Allergy Eur J Allergy Clin Immunol. 2009;64(9):1256–1268.
  83. Weller K, Groffik A, Magerl M, Tohme N, Martus P, Krause K, et al. Development, validation, and initial results of the Angioedema Activity Score. Allergy Eur J Allergy Clin Immunol. 2013;68(9):1185–1192.
  84. Baiardini I, Pasquali M, Braido F, Fumagalli F, Guerra L, Compalati E, et al. A new tool to evaluate the impact of chronic urticaria on quality of life: Chronic urticaria quality of life questionnaire (CU-Q2oL). Allergy Eur J Allergy Clin Immunol. 2005;60(8):1073–1078.
  85. Weller K, Groffik A, Magerl M, Tohme N, Martus P, Krause K, et al. Development and construct validation of the angioedema quality of life questionnaire. Allergy Eur J Allergy Clin Immunol. 2012;67(10):1289–1298.
  86. Hollis K, Proctor C, McBride D, Balp MM, McLeod L, Hunter S, et al. Comparison of Urticaria Activity Score Over 7 Days (UAS7) Values Obtained from Once-Daily and Twice-Daily Versions: Results from the ASSURE-CSU Study. Am J Clin Dermatol. 2018;19(2):267–274.
  87. Stull D, McBride D, Tian H, Gimenez Arnau A, Maurer M, Marsland A, et al. Analysis of disease activity categories in chronic spontaneous/idiopathic urticaria. Br J Dermatol. 2017;177(4):1093–1101.
  88. Hawro T, Saluja R, Weller K, Altrichter S, Metz M, Maurer M. Interleukin-31 does not induce immediate itch in atopic dermatitis patients and healthy controls after skin challenge. Allergy. 2014;69(1):113–117.
  89. Baiardini I, Braido F, Bindslev-Jensen C, Bousquet PJ, Brzoza Z, Canonica GW, et al. Recommendations for assessing patient-reported outcomes and health-related quality of life in patients with urticaria: A GA2LEN taskforce position paper. Allergy Eur J Allergy Clin Immunol. 2011;66(7):840–844.
  90. Kocatürk E, Can PK, Akbas PE, Copur M, Degirmentepe EN, Kızıltac K, et al. Management of chronic inducible urticaria according to the guidelines: A prospective controlled study. J Dermatol Sci. 2017;87(1):60–69.
  91. Ring J. Chronic urticaria: New hope for an old disease. Journal of the European Academy of Dermatology and Venereology. 2016;30:3–4.
  92. Tat TS. Higher levels of depression and anxiety in patients with chronic urticaria. Med Sci Monit. 2019;25:115–120.
  93. Maurer M, Magerl M, Metz M, Zuberbier T. Revisions to the international guidelines on the diagnosis and therapy of chronic urticaria. JDDG - J Ger Soc Dermatology. 2013;11(10):971–978.
  94. Kolkhir P, Metz M, Altrichter S, Maurer M. Comorbidity of chronic spontaneous urticaria and autoimmune thyroid diseases: A systematic review. Allergy Eur J Allergy Clini Immunol. 2017;72(10):1440–1460.
  95. Kolkhir P, Borzova E, Grattan C, Asero R, Pogorelov D, Maurer M. Autoimmune comorbidity in chronic spontaneous urticaria: A systematic review. Autoimmun Rev. 2017;16(12):1196–1208.
  96. Confino-Cohen R, Chodick G, Shalev V, Leshno M, Kimhi O, Goldberg A. Chronic urticaria and autoimmunity: Associations found in a large population study. J Allergy Clin Immunol. 2012;129(5):1307–1313.
  97. Magen E, Chikovani T, Waitman DA, Kahan NR. Association of alopecia areata with atopic dermatitis and chronic spontaneous urticaria. Allergy Asthma Proc. 2018;39(2):96–102.
  98. Shalom G, Magen E, Dreiher J, Freud T, Bogen B, Comaneshter D, et al. Chronic urticaria and atopic disorders: a cross-sectional study of 11 271 patients. Br J Dermatol. 2017;177(4):e96–e97.
  99. Ban GY, Kim MY, Yoo HS, Nahm DH, Ye YM, Shin YS, et al. Clinical features of elderly chronic urticaria. Korean J Intern Med. 2014;29(6):800–806.
  100. Bewley A. WORKING PARTY REPORT ON MINIMUM STANDARDS FOR PSYCHODERMATOLOGY SERVICES 2012 Members of the Working Party Accessing Psychodermatology services. 2012 https://www.bad.org.uk/shared/get-file.ashx?itemtype=document&id=1622. Accessed 7 May 2021.
  101. Konstantinou GN, Konstantinou GN. Psychiatric comorbidity in chronic urticaria patients: A systematic review and meta-analysis. Clinical and Translational Allergy. 2019;9(1):1–12.
  102. Conrad R, Geiser F, Haidl G, Hutmacher M, Liedtke R, Wermter F. Relationship between anger and pruritus perception in patients with chronic idiopathic urticaria and psoriasis. J Eur Acad Dermatol Venereol. 2008;22(9):1062–1069.
  103. Chung MC, Symons C, Gilliam J, Kaminski ER. The relationship between posttraumatic stress disorder, psychiatric comorbidity, and personality traits among patients with chronic idiopathic urticaria. Compr Psychiatry. 2010;51(1):55–63.
  104. Gupta MA, Gupta AK. Chronic idiopathic urticaria and post-traumatic stress disorder (PTSD): An under-recognized comorbidity. Clinics in Dermatology. 2012;30(3):351–354.
  105. Gupta MA, Jarosz P, Gupta AK. Posttraumatic stress disorder (PTSD) and the dermatology patient. Clin Dermatol. 2017;35(3):260–266.
  106. Mendelson MH, Bernstein JA, Gabriel S, Balp MM, Tian H, Vietri J, et al. Patient-reported impact of chronic urticaria compared with psoriasis in theUnited States. J Dermatolog Treat. 2017;28(3):229–236.
  107. Eiber M, Maurer T, Souvatzoglou M, Beer AJ, Ruffani A, Haller B, et al. Evaluation of Hybrid 68Ga-PSMA Ligand PET/CT in 248 Patients with Biochemical Recurrence After Radical Prostatectomy. J Nucl Med. 2015;56(5):668–74.
  108. Maurer M, Church MK, Gonçalo M, Sussman G, Sánchez-Borges M. Management and treatment of chronic urticaria (CU). J Eur Acad Dermatology Venereol. 2015;29(S3):16–32.
  109. Zuberbier T, Asero R, Bindslev-Jensen C, Walter Canonica G, Church MK, Giménez-Arnau AM, et al. EAACI/GALEN/EDF/WAO guideline: Management of urticaria. Allergy Eur J Allergy Clin Immunol. 2009;64(10):1427–1443.
  110. Church MK, Maurer M, Simons FER, Bindslev-Jensen C, Van Cauwenberge P, Bousquet J, et al. Risk of first-generation H1-antihistamines: A GA2LEN position paper. Allergy. 2010;65(4):459–466.
  111. Simon FER, Simons KJ. H1 Antihistamines: Current Status and Future Directions. World Allergy Organ J. 2008;1(9):145–155.
  112. Phinyo P, Koompawichit P, Nochaiwong S, Tovanabutra N, Chiewchanvit S, Chuamanochan M. Comparative Efficacy and Acceptability of Licensed Dose Second-Generation Antihistamines in Chronic Spontaneous Urticaria: A Network Meta-Analysis. J Allergy Clin Immunol Pract. 2021;9(2):956-970.e57.
  113. Staevska M, Gugutkova M, Lazarova C, Kralimarkova T, Dimitrov V, Zuberbier T, et al. Night-time sedating H1-antihistamine increases daytime somnolence but not treatment efficacy in chronic spontaneous urticaria: A randomized controlled trial. Br J Dermatol. 2014;171(1):148–154.
  114. Zuberbier T, Oanta A, Bogacka E, Medina I, Wesel F, Uhl P, et al. Comparison of the efficacy and safety of bilastine 20 mg vs levocetirizine 5 mg for the treatment of chronic idiopathic urticaria: A multi-centre, double-blind, randomized, placebo-controlled study. Allergy Eur J Allergy Clin Immunol. 2010;65(4):516–528.
  115. Yagami A, Furue M, Togawa M, Saito A, Hide M. One-year safety and efficacy study of bilastine treatment in Japanese patients with chronic spontaneous urticaria or pruritus associated with skin diseases. J Dermatol. 2017;44(4):375–385.
  116. Juhlin L, Arendt C. Treatment of chronic urticaria with cetirizine dihydrochloride a non‐sedating antihistamine. Br J Dermatol. 1988;119(1):67–72.
  117. Kalivas J, Breneman D, Tharp M, Bruce S, Bigby M, nine other investigators. Urticaria: Clinical efficacy of cetirizine in comparison with hydroxyzine and placebo. J Allergy Clin Immunol. 1990;86(6 PART 2):1014–1018.
  118. Dakhale GN, Shinde AT, Mahatme MS, Hiware SK, Mishra DB, Mukhi JI, et al. Clinical effectiveness and safety of cetirizine versus rupatadine in chronic spontaneous urticaria: A randomized, double-blind, 6-week trial. Int J Dermatol. 2014;53(5):643–649.
  119. Ring J, Hein R, Gauger A, Bronsky E, Miller B. Once-daily desloratadine improves the signs and symptoms of chronic idiopathic urticaria: A randomized, double-blind, placebo-controlled study. Int J Dermatol. 2001;40(1):72–76.
  120. Monroe E, Finn A, Patel P, Guerrero R, Ratner P, Bernstein D, et al. Efficacy and safety of desloratadine 5 mg once daily in the treatment of chronic idiopathic urticaria: A double-blind, randomized, placebo-controlled trial. J Am Acad Dermatol. 2003;48(4):535–541.
  121. Ortonne JP, Grob JJ, Auquier P, Dreyfus I. Efficacy and safety of desloratadine in adults with chronic idiopathic urticaria: A randomized, double-blind, placebo-controlled, multicenter trial. Am J Clin Dermatol. 2007;8(1):37–42.
  122. Lachapelle JM, Decroix J, Henrijean A, Roquet-Gravy PP, De Swerdt A, Boonen H, et al. Desloratadine 5 mg once daily improves the quality of life of patients with chronic idiopathic urticaria. J Eur Acad Dermatology Venereol. 2006;20(3):288–292.
  123. Grob JJ, Auquier P, Dreyfus I, Ortonne JP. How to prescribe antihistamines for chronic idiopathic urticaria: Desloratadine daily vs PRN and quality of life. Allergy Eur J Allergy Clin Immunol. 2009;64(4):605–612.
  124. Weller K, Ardelean E, Scholz E, Martus P, Zuberbier T, Maurer M. Can on-demand non-sedating antihistamines improve Urticaria symptoms? A double-blind, randomized, single-dose study. Acta Derm Venereol. 2013;93(2):168–174.
  125. Potter PC, Kapp A, Maurer M, Guillet G, Jian AM, Hauptmann P, et al. Comparison of the efficacy of levocetirizine 5 mg and desloratadine 5 mg in chronic idiopathic urticaria patients. Allergy Eur J Allergy Clin Immunol. 2009;64(4):596–604.
  126. Hong JB, Lee HC, Hu FC, Chu CY. A randomized, double-blind, active-controlled, parallel-group pilot study to compare the efficacy and sedative effects of desloratadine 5 mg with levocetirizine 5 mg in the treatment of chronic idiopathic urticaria. J Am Acad Dermatol. 2010;63(5):e100–e102.
  127. Kolasani BP, Mudium R, Reddy N. A comparative study of efficacy and safety of rupatadine versus desloratadine in patientswith chronic idiopathic urticaria. Asian J Biomed Pharm Sci. 2013;3(21):42–47.
  128. Goyal V, Gupta A, Gupta O, Lal D, Gill M. Comparative efficacy and safety of ebastine 20 mg, ebastine 10 mg and levocetirizine 5 mg in acute urticaria. J Clin Diagnostic Res. 2017;11(3):WC06–WC09.
  129. Kalis B. Double-blind multicentre comparative study of ebastine, terfenadine and placebo in the treatment of chronic idiopathic urticaria in adults. Drugs. 1996;52(SUPPL. 1):30–34.
  130. Josefson D. Hay fever drug to be banned by the FDA. BMJ. 1997;314(7076):248.
  131. Finn AF, Kaplan AP, Fretwell R, Qu R, Long J. A double-blind, placebo-controlled trial of fexofenadine HCl in the treatment of chronic idiopathic urticaria. J Allergy Clin Immunol. 1999;104(5):1071–1078.
  132. Nelson HS, Reynolds R, Mason J. Fexofenadine HCl is safe and effective for treatment of chronic idiopathic urticaria. Ann Allergy, Asthma Immunol. 2000;84(5):517–522.
  133. Kulthanan K, Sitakalin C, Korkij W, Janjumratsang P, Kuntiranont M, Gherunpong N, et al. Multicenter study of the efficacy and safety of fexofenadine 60 mg. Twice daily in 108 Thai patients with chronic idiopathic urticaria. J Med Assoc Thail. 2001;84(2):153–159.
  134. Thompson AK, Finn AF, Schoenwetter WF. Effect of 60 mg twice-daily fexofenadine HCL on quality of life, work and classroom productivity, and regular activity in patients with chronic idiopathic urticaria. J Am Acad Dermatol. 2000;43(1 I):24–30.
  135. Characteristics P. Fexofenadine hydrochloride 180mg film-coated Tablets. 2020;3–7.
  136. Kaplan AP, Spector SL, Meeves S, Liao Y, Varghese ST, Georges G. Once-daily fexofenadine treatment for chronic idiopathic urticaria: A multicenter, randomized, double-blind, placebo-controlled study. Ann Allergy, Asthma Immunol. 2005;94(6):662–669.
  137. Spector SL, Shikiar R, Harding G, Meeves S, Leahy MJ. The effect of fexofenadine hydrochloride on productivity and quality of life in patients with chronic idiopathic urticaria. Cutis. 2007;79(2):157–162.
  138. Handa S, Dogra S, Kumar B. Comparative efficacy of cetirizine and fexofenadine in the treatment of chronic idiopathic urticaria. J Dermatolog Treat. 2004;15(1):55–57.
  139. Dhar S, Varghese ST, Georges G. Assessing the therapeutic benefits of antihistamines for the treatment of chronic idiopathic urticaria - A requirement for well-designed comparative clinical studies. J Dermatol Treat. 2005;16(3):176–177.
  140. Nettis E, Colanardi MC, Barra L, Ferrannini A, Vacca A, Tursi A. Levocetirizine in the treatment of chronic idiopathic urticaria: A randomized, double-blind, placebo-controlled study. Br J Dermatol. 2006;154(3):533–538.
  141. Kapp A, Pichler WJ. Levocetirizine is an effective treatment in patients suffering from chronic idiopathic urticaria: A randomized, double-blind, placebo-controlled, parallel, multicenter study. Int J Dermatol. 2006;45(4):469–474.
  142. Garg G, Thami GP. Comparative efficacy of cetirizine and levocetirizine in chronic idiopathic urticaria. J Dermatolog Treat. 2007;18(1):23–24.
  143. Podder I, Das A, Ghosh S, Biswas D, Sengupta S, Chowdhury SN. Effectiveness, safety, and tolerability of bilastine 20 mg vs levocetirizine 5 mg for the treatment of chronic spontaneous urticaria: A double-blind, parallel group, randomized controlled trial. Dermatol Ther. 2020;33(6). doi:10.1111/dth.13946.
  144. Anuradha P, Maiti R, Jyothirmai J, Mujeebuddin O, Anuradha M. Loratadine versus levocetirizine in chronic idiopathic urticaria: A comparative study of efficacy and safety. Indian J Pharmacol. 2010;42(1):12–16.
  145. Maiti R, Rahman J, Jaida J, Allala U, Palani A. Rupatadine and levocetirizine for seasonal allergic rhinitis: A comparative study of efficacy and safety. Arch Otolaryngol - Head Neck Surg. 2010;136(8):796–800.
  146. Ventegodt S. World health organization model list of essential medicines. 2015 https://www.who.int/medicines/publications/essentialmedicines/en/. Accessed 6 March 2020.
  147. ABU SHAREEAH AM. Comparative Eficacy of Loratadine and Terfenadine in the Treatment of Chronic Idiopathic Urticaria. Int J Dermatol. 1992;31(5):355–356.
  148. Monroe EW, Bernstein DI, Fox RW, Grabiec S V., Honsinger RW, Kalivas JT, et al. Relative efficacy and safety of loratadine, hydroxyzine, and placebo in chronic idiopathic urticaria. Arzneimittel-Forschung/Drug Res. 1992;42(9):1119–1121.
  149. Metz M, Maurer M. Rupatadine for the treatment of allergic rhinitis and urticaria. Expert Rev Clin Immunol. 2011;7(1):15–20.
  150. Nettis E, Delle Donne P, Di Leo E, Calogiuri GF, Ferrannini A, Vacca A. Rupatadine for the treatment of urticaria. Expert Opin Pharmacother. 2013;14(13):1807–1813.
  151. Gimenez-Arnau A, Pujol RM, Ianosi S, Kaszuba A, Malbran A, Poop G, et al. Rupatadine in the treatment of chronic idiopathic urticaria: A double-blind, randomized, placebo-controlled multicentre study. Allergy Eur J Allergy Clin Immunol. 2007;62(5):539–546.
  152. González-Núñez V, Bachert C, Mullol J. Rupatadine: global safety evaluation in allergic rhinitis and urticaria. Expert Opin Drug Saf. 2016;15(10):1439–1448.
  153. Hide M, Suzuki T, Tanaka A, Aoki H. Efficacy and safety of rupatadine in Japanese adult and adolescent patients with chronic spontaneous urticaria: A double-blind, randomized, multicenter, placebo-controlled clinical trial. Allergol Int. 2019;68(1):59–67.
  154. Metz M, Weller K, Neumeister C, Izquierdo I, Bödeker RH, Schwantes U, et al. Rupatadine in Established Treatment Schemes Improves Chronic Spontaneous Urticaria Symptoms and Patients’ Quality of Life: a Prospective, Non-interventional Trial. Dermatol Ther (Heidelb). 2015;5(4):217–230.
  155. Krause K, Spohr A, Zuberbier T, Church MK, Maurer M. Up-dosing with bilastine results in improved effectiveness in cold contact urticaria. Allergy Eur J Allergy Clin Immunol. 2013;68(7):921–928.
  156. Simons FER. Advances in H 1 -Antihistamines . N Engl J Med. 2004;351(21):2203–2217.
  157. Holgate ST, Canonica GW, F. Estelle R. Simons, Taglialatela M, Tharp M, Timmerman H, et al. Consensus group on new-generation antihistamines (CONGA): Present status and recommendations. Clin Exp Allergy. 2003;33(9):1305–1324.
  158. Hindmarch I, Johnson S, Meadows R, Kirkpatrick T, Shamsi Z. The acute and sub-chronic effects of levocetirizine, cetirizine, loratadine, promethazine and placebo on cognitive function, psychomotor performance, and weal and flare. Curr Med Res Opin. 2001;17(4):241–255.
  159. Shamsi Z, Hindmarch I. Sedation and antihistamines: A review of inter-drug differences using proportional impairment ratios. Human Psychopharmacol. 2000;15(SUPPL. 1):S3–S30.
  160. Casale TB, Blaiss MS, Gelfand E, Gilmore T, Harvey PD, Hindmarch I, et al. First do no harm: Managing antihistamine impairment in patients with allergic rhinitis. J Allergy Clin Immunol. 2003;111(5):S835–S842.
  161. Van den Elzen MT, Van Os-Medendorp H, Van den Brink I, Van den Hurk K, Kouznetsova OI, Lokin ASHJ, et al. Effectiveness and safety of antihistamines up to fourfold or higher in treatment of chronic spontaneous urticaria. Clin Transl Allergy. 2017;7(1):4.
  162. Weller K, Ziege C, Staubach P, Brockow K, Siebenhaar F, Krause K, et al. H 1-antihistamine up-dosing in chronic spontaneous urticaria: Patients’ perspective of effectiveness and side effects - a retrospective survey study. PLoS One. 2011;6(9):e23931.
  163. Sánchez-Borges M, Ansotegui I, Jimenez JM, Rojo MI, Serrano C, Yañez A. Comparative efficacy of non-sedating antihistamine updosing in patients with chronic urticaria. World Allergy Organ J. 2014;7(1):33.
  164. Iriarte Sotés P, Armisén M, Usero-Bárcena T, Rodriguez Fernández A, Otero Rivas MM, Gonzalez MT, et al. Efficacy and safety of up-dosing antihistamines in chronic spontaneous urticaria: A systematic review of the literature. J Investig Allergol Clin Immunol. 2021;31(4):282–291.
  165. Asero R. Chronic unremitting urticaria: Is the use of antihistamines above the licensed dose effective? A preliminary study of cetirizine at licensed and above-licensed doses. Clin Exp Dermatol. 2007;32(1):34–38.
  166. Kameyoshi Y, Tanaka T, Mihara S, Takahagi S, Niimi N, Hide M. Increasing the dose of cetirizine may lead to better control of chronic idiopathic urticaria: An open study of 21 patients [3]. Bri J Dermatol. 2007;157(4):803–804.
  167. Staevska M, Popov TA, Kralimarkova T, Lazarova C, Kraeva S, Popova D, et al. The effectiveness of levocetirizine and desloratadine in up to 4 times conventional doses in difficult-to-treat urticaria. J Allergy Clin Immunol. 2010;125(3):676–682.
  168. Dubertret L, Zalupca L, Cristodoulo T, Benea V, Medina I, Fantin S, et al. Once-daily rupatadine improves the symptoms of chronic idiopathic urticaria: A randomised, double-blind, placebo-controlled study. Eur J Dermatology. 2007;17(3):223–228.
  169. Giménez-Arnau A, Izquierdo I, Maurer M. The use of a responder analysis to identify clinically meaningful differences in chronic urticaria patients following placebo- controlled treatment with rupatadine 10 and 20 mg. J Eur Acad Dermatology Venereol. 2009;23(9):1088–1091.
  170. EMA. Xolair Summary of Opinion. 2014. https://www.ema.europa.eu/en/documents/smop/chmp-post-authorisation-summary-positive-opinion-xolair_en.pdf. Accessed 7 May 2021.
  171. FDA. Highlights of prescribing information. www.fda.gov/medwatch. Accessed 7 May 2021.
  172. Maurer M, Rosén K, Hsieh H-J, Saini S, Grattan C, Gimenéz-Arnau A, et al. Omalizumab for the Treatment of Chronic Idiopathic or Spontaneous Urticaria. N Engl J Med. 2013;368(10):924–935.
  173. Saini SS, Bindslev-Jensen C, Maurer M, Grob JJ, Bülbül Baskan E, Bradley MS, et al. Efficacy and safety of omalizumab in patients with chronic idiopathic/spontaneous urticaria who remain symptomatic on h 1 antihistamines: A randomized, placebo-controlled study. J Invest Dermatol. 2015;135(1):67–75.
  174. Kaplan A, Ledford D, Ashby M, Canvin J, Zazzali JL, Conner E, et al. Omalizumab in patients with symptomatic chronic idiopathic/spontaneous urticaria despite standard combination therapy. J Allergy Clin Immunol. 2013;132(1):101–109.
  175. Stull D, McBride D, Georgiou P, Zuberbier T, Grattan C BM-M. Measuring patient severity in CSU as categorical health states: efficient and informative? EAACI Congr. 2014;69(Suppl s99):317.
  176. Casale T, Maurer M, Saini SS, Bernstein J. Omalizumab reduced symptoms and improved health-related quality of life (HRQoL) in patients with refractory chronic spontaneous/idiopathic urticaria (CSU/CIU) in three randomized, doubleblind, placebo-controlled phase III trials: a post-hoc analysis of pe. In: Allergy. 2014: 573–619.
  177. Bérard F, Ferrier Le Bouedec MC, Bouillet L, Reguiai Z, Barbaud A, Cambazard F, et al. Omalizumab in patients with chronic spontaneous urticaria nonresponsive to H1-antihistamine treatment: results of the phase IV open-label SUNRISE study. Br J Dermatol. 2019;180(1):56–66.
  178. Casale TB, Win PH, Bernstein JA, Rosén K, Holden M, Iqbal A, et al. Omalizumab response in patients with chronic idiopathic urticaria: Insights from the XTEND-CIU study. J Am Acad Dermatol. 2018;78(4):793–795.
  179. Agache I, Rocha C, Pereira A, Song Y, Alonso-Coello P, Solà I, et al. Efficacy and safety of treatment with omalizumab for chronic spontaneous urticaria: A systematic review for the EAACI Biologicals Guidelines. Allergy Eur J Allergy Clin Immunol. 2021;76(1):59–70.
  180. Deza G, Bertolín-Colilla M, Pujol RM, Curto-Barredo L, Soto D, García M, et al. Basophil Fc3 RI expression in chronic spontaneous urticaria: A potential immunological predictor of response to omalizumab therapy. Acta Derm Venereol. 2017;97(6):698–704.
  181. Jörg L, Pecaric-Petkovic T, Reichenbach S, Coslovsky M, Stalder O, Pichler W, et al. Double-blind placebo-controlled trial of the effect of omalizumab on basophils in chronic urticaria patients. Clin Exp Allergy. 2018;48(2):196–204.
  182. Marzano A V., Genovese G, Casazza G, Fierro MT, Dapavo P, Crimi N, et al. Predictors of response to omalizumab and relapse in chronic spontaneous urticaria: a study of 470 patients. J Eur Acad Dermatology Venereol. 2019;33(5):918–924.
  183. Magen E, Chikovani T, Waitman DA, Kahan NR. Factors related to omalizumab resistance in chronic spontaneous urticaria. Allergy Asthma Proc. 2019;40(4):273–278.
  184. Asero R, Tedeschi A, Cugno M. Treatment of refractory chronic urticaria: Current and future therapeutic options. American Journal of Clinical Dermatology. 2013;14(6):481–488.
  185. Kulthanan K, Subchookul C, Hunnangkul S, Chularojanamontri L, Tuchinda P. Factors predicting the response to cyclosporin treatment in patients with chronic spontaneous urticaria: A systematic review. Allergy, Asthma and Immunology Research. 2019;11(5):736–755.
  186. Savic S, Marsland A, McKay D, Ardern-Jones MR, Leslie T, Somenzi O, et al. Retrospective case note review of chronic spontaneous urticaria outcomes and adverse effects in patients treated with omalizumab or ciclosporin in UK secondary care. Allergy, Asthma Clin Immunol. 2015;11(1):21.
  187. Asero R, Tedesch A. Usefulness of a short course of oral prednisone in antihistamine-resistant chronic urticaria: A retrospective analysis. J Investig Allergol Clin Immunol. 2010;20(5):386–390.
  188. Weller K, Church MK, Hawro T, Altrichter S, Labeaga L, Magerl M, et al. Updosing of bilastine is effective in moderate to severe chronic spontaneous urticaria: A real-life study. Allergy. 2018;73(10):2073–2075.
  189. Augustin M, Ehrle S. Safety and efficacy of desloratadine in chronic idiopathic urticaria in clinical practice: An observational study of 9246 patients. J Eur Acad Dermatology Venereol. 2009;23(3):292–299.
  190. Bachert C, Maurer M. Safety and efficacy of desloratadine in subjects with seasonal allergic rhinitis or chronic urticaria: Results of four postmarketing surveillance studies. Clin Drug Investig. 2010;30(2):109–122.
  191. Yin OQP, Shi XJ, Tomlinson B, Chow MSS. Effect of CYP2D6*10 allele on the pharmacokinetics of loratadine in Chinese subjects. Drug Metab Dispos. 2005;33(9):1283–1287.
  192. Fang SY, Perng DW, Lee JYY, Lin DY, Huang CY. An open-label, multicentre study of levocetirizine for the treatment of allergic rhinitis and Urticaria in Taiwanese Patients. Chin J Physiol. 2010;53(4):199–207.
  193. Of H, Of H, Information P, Information P. Highlights of prescribing information. Metabolism Clinical And Experimental. 2008. https://www.gene.com/download/pdf/xolair_prescribing.pdf. Accessed 7 May 2021.
  194. Novartis Pharmaceuticals Australia Pty Ltd. Xolair (Omalizumab) [Bula]. 2014;1–31.
  195. Eghrari-Sabet J, Sher E, Kavati A, Pilon D, Zhdanava M, Balp MM, et al. Real-world use of omalizumab in patients with chronic Idiopathic/Spontaneous urticaria in the United States. Allergy Asthma Proc. 2018;39(3):191–200.
  196. Wang Z, Li M, Wang Y, Xu D, Wang Q, Zhang S, et al. Long-term mortality and morbidity of patients with systemic lupus erythematosus: a single-center cohort study in China. Lupus. 2018;27(5):864–869.
  197. Wang L, Ke X, Kavati A, Wertz D, Huang Q, Willey VJ, et al. Real-world treatment patterns and outcomes of omalizumab use in patients with chronic idiopathic urticaria. Curr Med Res Opin. 2018;34(1):35–39.
  198. Syrigos N, Grapsa D, Zande M, Tziotou M, Syrigou E. Treatment response to omalizumab in patients with refractory chronic spontaneous urticaria. Int J Dermatol. 2018;57(4):417–422.
  199. Tharp MD, Bernstein JA, Kavati A, Ortiz B, MacDonald K, Denhaerynck K, et al. Benefits and Harms of Omalizumab Treatment in Adolescent and Adult Patients with Chronic Idiopathic (Spontaneous) Urticaria: A Meta-analysis of ‘real-world’ Evidence. JAMA Dermatology. 2019;155(1):29–38.
  200. Metz M, Vadasz Z, Kocatürk E, Giménez-Arnau AM. Omalizumab Updosing in Chronic Spontaneous Urticaria: an Overview of Real-World Evidence. Clin Rev Allergy Immunol. 2020;59(1):38–45.
  201. Maurer M, Giménez-Arnau A, Ensina LF, Chu CY, Jaumont X, Tassinari P. Chronic urticaria treatment patterns and changes in quality of life: AWARE study 2-year results. World Allergy Organ J. 2020;13(9):100460.
  202. Bernstein JA, Lang DM, Khan DA, Craig T, Dreyfus D, Hsieh F, et al. The diagnosis and management of acute and chronic urticaria: 2014 update. J Allergy Clin Immunol. 2014;133(5):1270-1277.e66.
  203. Grattan CEH, Humphreys F. Guidelines for evaluation and management of urticaria in adults and children. Br J Dermatol. 2007;157(6):1116–1123.
  204. National Institute for Health and Care Excellence (NICE). Omalizumab for previously treated chronic spontaneous urticaria - NICE technology Guidance 339. 2015;1–56.
  205. Hide M, Hiragun T. Japanese guidelines for diagnosis and treatment of urticaria in comparison with other countries. Allergol Int. 2012;61(4):517–527.
  206. Tedeschi A, Girolomoni G, Asero R. AAITO position paper. Chronic urticaria: Diagnostic workup and treatment. Eur Ann Allergy Clin Immunol. 2007;39(7):225–231.
  207. Godse K, Rajagopalan M, Girdhar M, Kandhari S, Shah B, Chhajed P, et al. Position statement for the use of omalizumab in the management of chronic spontaneous urticaria in Indian patients. Indian Dermatol Online J. 2016;7(1):6.
  208. Société Française de Dermatologie. Consensus Conference Management of chronic urticaria Wednesday 8 January 2003 Institut Pasteur - Paris, France Recommendations. Eur J Dermatology. 2003;13(4):385–392.
  209. Chow SKW. Management of chronic urticaria in Asia: 2010 AADV consensus guidelines. Asia Pac Allergy. 2012;2(2):149.
  210. Godse K, Zawar V, Krupashankar D, Girdhar M, Kandhari S, Dhar S, et al. Consensus statement on the management of urticaria. Indian J Dermatol. 2011;56(5):485–489.
  211. Simons FER, Simons KJ. Histamine and H1-antihistamines: Celebrating a century of progress. Journal of Allergy and Clinical Immunology. 2011;128(6):1139–1150.
  212. Khakoo G, Sofianou-Katsoulis A, Perkin MR, Lack G. Clinical features and natural history of physical urticaria in children. Pediatr Allergy Immunol. 2008;19(4):363–366.
  213. Kjaer HF, Eller E, Høst A, Andersen KE, Bindslev-Jensen C. The prevalence of allergic diseases in an unselected group of 6-year-old children. The DARC birth cohort study. Pediatr Allergy Immunol. 2008;19(8):737–745.
  214. Brüske I, Standl M, Weidinger S, Klümper C, Hoffmann B, Schaaf B, et al. Epidemiology of urticaria in infants and young children in Germany - Results from the German LISAplus and GINIplus Birth Cohort Studies. Pediatr Allergy Immunol. 2014;25(1):36–42.
  215. Tuchinda M, Srimaruta N, Habanananda S, Vareenil J, Assatherawatts A. Urticaria in Thai children. Asian Pac J Allergy Immunol. 1986;4(1):41–45.
  216. Lee JY, Kang S, Park JS, Jo SJ. Prevalence of psoriasis in Korea: A population-based epidemiological study using the Korean national health insurance database. Ann Dermatol. 2017;29(6):761–767.
  217. Choi SH, Baek HS. Approaches to the diagnosis and management of chronic urticaria in children. Korean J Pediatr. 2015;58(5):159–164.
  218. Chansakulporn S, Pongpreuksa S, Sangacharoenkit P, Pacharn P, Visitsunthorn N, Vichyanond P, et al. The natural history of chronic urticaria in childhood: A prospective study. J Am Acad Dermatol. 2014;71(4):663–668.
  219. Lee XHM, Ong LX, Cheong JYV, Sultana R, Rao R, Lim HH, et al. A stepwise approach in the management of chronic spontaneous urticaria in children. Asia Pac Allergy. 2016;6(1):16–28.
  220. Netchiporouk E, Sasseville D, Moreau L, Habel Y, Rahme E, Ben-Shoshan M. Evaluating comorbidities, natural history, and predictors of early resolution in a cohort of children with Chronic Urticaria. JAMA Dermatol. 2017;153(12):1236–1242.
  221. Pite H, Wedi B, Borrego LM, Kapp A, Raap U. Management of childhood urticaria: Current knowledge and practical recommendations. Acta Dermato-Venereologica. 2013;93(5):500–508.
  222. Konstantinou GN, Papadopoulos NG, Tavladaki T, Tsekoura T, Tsilimigaki A, Grattan CEH. Childhood acute urticaria in northern and southern Europe shows a similar epidemiological pattern and significant meteorological influences. Pediatr Allergy Immunol. 2011;22(1 PART 1):36–42.
  223. Rebelo Gomes E, Fonseca J, Araujo L, Demoly P. Drug allergy claims in children: From self-reporting to confirmed diagnosis. Clin Exp Allergy. 2008;38(1):191–198.
  224. Seitz CS, Bröcker EB, Trautmann A. Diagnosis of drug hypersensitivity in children and adolescents: Discrepancy between physician-based assessment and results of testing. Pediatr Allergy Immunol. 2011;22(4):405–410.
  225. Sackesen C, Sekerel BE, Orhan F, Kocabas CN, Tuncer A, Adalioglu G. The Etiology of Different Forms of Urticarta in Childhood. Pediatr Dermatol. 2004;21(2):102–108.
  226. Ricci G, Giannetti A, Belotti T, Dondi A, Bendandi B, Cipriani F, et al. Allergy is not the main trigger of urticaria in children referred to the emergency room. J Eur Acad Dermatology Venereol. 2010;24(11):1347–1348.
  227. Marrouche N, Grattan C. Childhood urticaria. Curr Opin Allergy Clin Immunol. 2012;12(5):485–490.
  228. Church MK, Weller K, Stock P, Maurer M. Chronic spontaneous urticaria in children: Itching for insight. Pediatr Allergy Immunol. 2011;22(1 PART 1):1–8.
  229. Jirapongsananuruk O, Pongpreuksa S, Sangacharoenkit P, Visitsunthorn N, Vichyanond P. Identification of the etiologies of chronic urticaria in children: A prospective study of 94 patients. Pediatr Allergy Immunol. 2010;21(3):508–514.
  230. Brunetti L, Francavilla R, Miniello VL, Platzer MH, Rizzi D, Lospalluti ML, et al. High prevalence of autoimmune urticaria in children with chronic urticaria. J Allergy Clin Immunol. 2004;114(4):922–927.
  231. Alangari AA, Twarog FJ, Shih MC, Schneider LC. Clinical features and anaphylaxis in children with cold urticaria. Pediatrics. 2004;113(4):e313–e317.
  232. Volonakis M, Katsarou-Katsari A, Stratigos J. Etiologic factors in childhood chronic urticaria. Ann Allergy. 1992;69(1):61–65.
  233. Du Toit G, Prescott R, Lawrence P, Johar A, Brown G, Weinberg EG, et al. Autoantibodies to the high-affinity IgE receptor in children with chronic urticaria. Ann Allergy, Asthma Immunol. 2006;96(2):341–344.
  234. Beattie PE, Lewis-Jones MS. A comparative study of impairment of quality of life in children with skin disease and children with other chronic childhood diseases. Br J Dermatol. 2006;155(1):145–151.
  235. Olsen JR, Gallacher J, Finlay AY, Piguet V, Francis NA. Quality of life impact of childhood skin conditions measured using the Children’s Dermatology Life Quality Index (CDLQI): A meta-analysis. Br J Dermatol. 2016;174(4):853–861.
  236. Ferrer M. Epidemiology, healthcare, resources, use and clinical features of different types of urticaria. Alergológica 2005. J Investig Allergol Clin Immunol. 2009;19(SUPPL. 2):21–26.
  237. Potter P, Mitha E, Barkai L, Mezei G, Santamaría E, Izquierdo I, et al. Rupatadine is effective in the treatment of chronic spontaneous urticaria in children aged 2-11 years. Pediatr Allergy Immunol. 2016;27(1):55–61.
  238. European Medicines Agency (EMA), European Medicines Agency, Electronic Medicines Compendium (EMC), CHMP, Electronic Medicines Compendium (EMC), European Medicines Agency (EMA), et al. Summary of product characteristics. Pharmaceutical Medicine. 2014;87–89.
  239. Chlorpromazine Hydrochloride. Summary of Product Characteristics. 2015. https://www.medicines.org.uk/emc/medicine/29498. Accessed 11 May 2021.
  240. Xyzal (oral solution) Summary of Product Characteristics. 2019. https://www.medicines.org.uk/emc/product/348/smpc#gref. Accessed 6 July 2021.
  241. Desloratadine (tablet) Summary of Product Characteristics. 2021. https://www.medicines.org.uk/emc/product/12005/smpc. Accessed 11 May 2021.
  242. Desloratadine (oral solution) Summary of Product Characteristics (SmPC) - (emc). 2020. https://www.medicines.org.uk/emc/product/7287/smpc. Accessed 6 July 2021.
  243. EMC. Fexofenadine hydrochloride 180mg film-coated Tablets - Summary of Product Characteristics (SmPC) - (emc). 2013. https://www.medicines.org.uk/emc/product/3488/smpc. Accessed 11 May 2021.
  244. Levocetirizine dihydrochloride Summary of Product Characterisitics. 2017. https://www.medicines.org.uk/emc/product/8568/smpc#gref. Accessed 6 July 2021.
  245. Loratadine (syrup) Summary of Product Characteristics. 2016. https://www.medicines.org.uk/emc/product/4567/smpc#gref. Accessed 6 July 2021.
  246. Loratadine (tablet) Summary of Product Characteristics. 2020. https://www.medicines.org.uk/emc/product/8911/smpc. Accessed 11 May 2021.
  247. Rupatadine (tablet) Summary of Product Characteristics. 2020. https://www.medicines.org.uk/emc/product/2501/smpc#gref. Accessed 11 May 2021.
  248. Rupatadine (oral solution) Summary of Product Characteristics. 2020. https://www.medicines.org.uk/emc/product/9888/smpc#gref. Accessed 6 July 2021.
  249. FDA. ALLEGRA® Tablets and Suspension. https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/021963lbl.pdf. Accessed 23 July 2021.
  250. Belloni Fortina A, Fontana E. Update on Antihistamine Treatment for Chronic Urticaria in Children. Current Treatment Options in Allergy. 2014;1(3):287–298.
  251. Corsico AG, Leonardi S, Licari A, Marseglia G, Miraglia Del Giudice M, Peroni DG, et al. Focus on the cetirizine use in clinical practice: A reappraisal 30 years later. Multidiscip Respir Med. 2019;14(1):1–7.
  252. Simons FER. Prevention of acute urticaria in young children with atopic dermatitis. J Allergy Clin Immunol. 2001;107(4):703–706.
  253. Bloom M, Staudinger H, Herron J. Safety of desloratadine syrup in children. In: Current Medical Research and Opinion. 2004. Curr Med Res Opin: 1959–1965.
  254. Prenner B, Ballona R, Bueso A, Cardona R, Kim K, Larsen L, et al. Safety of desloratadine syrup in children 6 months to younger than 2 years of age: A randomized, double-blinded, placebo-controlled study. Pediatr Asthma, Allergy Immunol. 2006;19(2):91–99.
  255. Simons FER. Safety of levocetirizine treatment in young atopic children: An 18-month study. Pediatr Allergy Immunol. 2007;18(6):535–542.
  256. Salmun LM, Herron JM, Banfield C, Padhi D, Lorber R, Affrime MB. The pharmacokinetics, electrocardiographic effects, and tolerability of loratadine syrup in children aged 2 to 5 years. Clin Ther. 2000;22(5):613–621.
  257. Doshi DR, Weinberger MM. Experience with cyclosporine in children with chronic idiopathic urticaria. Pediatr Dermatol. 2009;26(4):409–413.
  258. Neverman L, Weinberger M. Treatment of chronic urticaria in children with antihistamines and cyclosporine. J Allergy Clin Immunol Pract. 2014;2(4):434–438.
  259. Sanada S, Tanaka T, Kameyoshi Y, Hide M. The effectiveness of montelukast for the treatment of anti-histamine- resistant chronic urticaria. Arch Dermatol Res. 2005;297(3):134–138.
  260. Sarkar T, Sil A, Pal S, Ghosh C, Das N. Effectiveness and safety of levocetirizine 10 mg versus a combination of levocetirizine 5 mg and montelukast 10 mg in chronic urticaria resistant to levocetirizine 5 mg: A double-blind, randomized, controlled trial. Indian J Dermatol Venereol Leprol. 2017;83(5):561–568.
  261. Novartis Pharmaceuticals UK Ltd. Xolair 150 mg solution for injection in pre-filled syringe. 2019. https://www.medicines.org.uk/emc/product/4725/smpc. Accessed 10 May 2021.
  262. Cornillier H, Giraudeau B, Munck S, Hacard F, Jonville-Bera AP, d’Acremont G, et al. Chronic spontaneous urticaria in children - a systematic review on interventions and comorbidities. Pediatr Allergy Immunol. 2018;29(3):303–310.
  263. Goldstein S, Gabriel S, Kianifard F, Ortiz B, Skoner DP. Clinical features of adolescents with chronic idiopathic or spontaneous urticaria: Review of omalizumab clinical trials. In: Annals of Allergy, Asthma and Immunology. 2017. American College of Allergy, Asthma and Immunology: 500–504.
  264. Lee SJ, Ha EK, Jee HM, Lee KS, Lee SW, Kim MA, et al. Prevalence and risk factors of urticaria with a focus on chronic urticaria in children. Allergy, Asthma Immunol Res. 2017;9(3):212–219.
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