**5.1 Disease activity scores used in chronic urticaria**

CSU affects several domains of health-related quality of life, such as daily living, sleep, emotional and psychological well-being as well as work productivity [9, 18]. Several types of patient-reported-outcome (PRO) instruments have been used to assess quality of life and disease burden in CSU. They include:


The inclusion of PRO instruments in clinical practice is increasingly recommended by clinicians and commissioners as it allows patient input and view of their disease


#### **Table 6.**

*UAS7 = score for hives + score for itch = daily score; repeat daily assessments for 7 days and add up daily scores for UAS7 [2, 18].*

and response to therapy and can contribute to better informed treatment decisions and improve physician-patient communication.

The UAS (**Table 6**) is a diary-based PRO measure that assesses the key sign hives and the key symptom itch of CU. The international EAACI/GA<sup>2</sup> LEN/EDF/WAO guidelines for urticaria recommend the use of UAS in clinical practice to determine disease activity and response to treatment [9, 13, 18]. The UAS is calculated as the sum of the daily number of wheals and the pruritus severity score over a period of 7 days (UAS7). Currently two versions exist of the daily UAS7 – in the first version patients score themselves once per day (every 24 hours), in the second version the scoring happens twice daily (every 12 hours). No significant difference [18] has been identified between the two versions. It is recommended that the same version be used consistently in the same patient in order to be able to evaluate the results [16]. In current clinical practice most use the once daily scoring version, as it is less burdensome for patients. The Urticaria Control Test (UCT) is a retrospective tool consisting of four questions with a clear cut-off scoring for "well-controlled" vs. "poorly controlled" [6].

In regular clinical practice the PRO instruments commonly used to assess CU disease activity, disease control and effects on quality of life include the UAS7 and the DLQI [2].

#### **5.2 Burden of disease**

CU has significant negative impact on quality of life due to its debilitating symptoms [19, 20]. In addition to classic symptoms, like pruritus and wheals, other factors can be equally relevant to the patient, such as the unpredictability of flares, sleep disorders, fatigue, drug related side effects and physical appearance [21]. A major impairment is observed in patients with the highest disease activity and in patients with autoimmune urticaria [21]. Undertreated patients report high disease burden that leads to higher economic burden due to absence or presenteeism - reduced capacity while - at work and higher utilisation of health care resources [19, 20]. Itching and angioedema are the main reasons affecting capacity at work causing presenteeism [22].

Other reasons that contribute to high socio-economic burden include an often considerable delay in diagnosis and specialist referral [22], the inadequate knowledge about CSU in primary and secondary care, and high cost for unnecessary investigations and treatments due to poor adherence to guidelines and best practice [22].

### **6. Treatment of chronic urticaria**

The aim of CU therapy is symptom control as no cure is available to date. Often management of CSU and CINDU overlap. Approach to CU management [2, 10, 19] consists of:


Investigations to rule out any underlying inflammatory or infectious diseases should be initiated on a case-by-case basis. Plasmapheresis has been shown to provide temporary improvement in some autoantibody positive patients with refractory CSU [2] by reducing functional autoantibodies.

Two major professional bodies have published guidelines [1, 19] for the evaluation and management of urticaria. The US JTF Practice Parameter recommends a 4-step approach to management (**Table 7**), whereas the EAACI guidelines (**Table 8**) advocate a 3-step approach. Both guidelines concur in that first line therapy for acute and chronic urticaria should focus on the use of non-sedating 2nd generation H1 antihistamines (SGAs).

The European guidelines differ from the US guidelines in that treatment with sedating 1st generation H1 antihistamines (FGAs) and H2 antihistamines are not recommended. In addition, European guidelines regulate Leukotriene Modifying Agents (LTMAs) to the last Step 3 treatment, whereas US guidelines recommend these agents to be used earlier as adjunctive Step 2 [1].

Although both the US and the European urticaria guidelines recommend a step-by-step approach to CU therapy, patient specific parameters such as serologic, clinical or histological findings are not considered. To date no clinically effective treatment algorithm exists for CU that is based on patient specific parameters [19].

Finally, both the US and European urticaria treatment guidelines should be used with caution and might require adaptation in children, pregnant/lactating women, and elderly patients with CU, as drug doses may have to be reduced or might be contraindicated [1, 2, 19].

#### **US urticaria guidelines to therapy approach**


#### **Step 1**


#### **Step 2**

One or more of the following can be used simultaneously:


#### **Step 3**

Advance dose of FGA (hydroxyzine or doxepin) as tolerated

#### **Step 4**

Alternative treatment can be added:


#### **Table 7.**

*Adapted from JTF practice parameters "The diagnosis and management of acute and chronic urticaria: 2014 update" [1].*

#### **Table 8.**

*Adapted from EAACI urticaria guideline for the definition, classification, diagnosis and management of urticaria: 2013 revision [1].*

#### **6.1 H1-antihistamines**

There is good evidence for the use of second-generation antihistamines (SGAs) as first line therapy in mild to moderate CU [1, 7, 19]. SGAs like cetirizine, levocetirizine, loratadine, desloratadine fexofenadine, azelastine, bilastine have a good safety, efficacy and tolerability profile. Over 50% of CU do not respond to the licenced dose of SGAs. For these patients 2–4 times higher than licenced dose is well tolerated and considered acceptable [1, 2, 10, 19]. First generation antihistamines (FGAs) are effective but due to their sedating effect and possible interference with daily activities they are not preferred choice. Side effects include excessive dryness, constipation (due to anticholinergic activity) and occasional Torsades de Pointe (especially linked to astemizole and terfenadine). About 30% of patients continue to experience CU symptoms despite maximal tolerated doses of SGAs [1, 2, 10, 19, 23] and are classified as non-responders [23].

#### **6.2 H2-antihistamines**

H2- Antihistamines can be added to H1-antihistamine monotherapy if they prove ineffective. Cimetidine has been shown to increase the half-life of H1-antihistamines [19]. Ranitidine was shown in a Cochrane review to be more *Chronic Spontaneous Urticaria – Diagnosis and Management DOI: http://dx.doi.org/10.5772/intechopen.97646*

effective in combination with diphenhydramine than diphenhydramine on its own [19]. The opinion about their use in combination with H1-antihistamines in the treatment of CU is however divided and is reflected in the difference of recommendation between the US and European urticaria guidelines (**Table 7** vs. **Table 8**). Doxepin a tricyclic antidepressant has combined H1 and H2 and muscarinic blocking activities. It has been shown to be effective in as high as 43% of patients who are recalcitrant to high dose antihistamines therapy [10, 23]. It can be given in doses of 25–50 mg at night or 10-25 mg 3–4 times per day.

### **6.3 Leukotriene modifier agents (LMAs)**

LMAs are leukotriene receptor antagonists and include montelukast and zafirlukast as well as the 5-lipoxygenase-inhibitor zileuton. Several RCTs on CU therapy showed mixed results and thus firm recommendations are not available. However, due the good safety profile of LMAs they might be considered an alternative addition in CU patients who are refractory to antihistamines therapy [17, 24] (**Table 7**). Predictors of good response to LMAs include urticaria triggered by Aspirin, NSAIDs, food additives or pseudoallergens and autoimmune urticaria with positive autologous serum skin prick test [1, 10, 19, 25]. Montelukast can be used in doses of 10 mg/day [10].

## **6.4 Oral corticosteroids (OCTs)**

Large control studies are not available on the use of OCTs in CU. However, OCTs show high efficacy in recalcitrant CU and are used for short term and at the lowest effective dose for severe flares. Long term use of OCTs in CU is not recommended due the multitude of known significant adverse effects [1, 2, 10, 23]. Tapering of OCTs dose is not needed if the patients take <40 mg daily dose and for a period of up to 3 weeks [19]. Oral mini pulses with methyl prednisolone 16 mg tablets twice weekly for 2 months and in combination with H1-antihistamines showed significant reduction in mean UAS7 in a small number of patients [10].

#### **6.5 Immunosuppressive agents (IAs)**

IAs should be considered in the case of OCTs therapy being required for longer periods of time. Ciclosporin is the most studied medication and is recommended to be used either at a weight-based dose of 4 mg/kg/per day or at a daily dose of 200 mg for a period of 16 weeks [1, 2, 10, 19]. Improvement in UAS can be as early as 2 weeks of commencing treatment and complete remission occurs in 3 out of 4 patients [10] particularly in autoimmune associated CSU. Regular monitoring is required due to the risk of significant adverse effects and it is reserved in the treatment of severe refractory CSU. Other IAs include:


### **6.6 Alternative agents**

Alternative Agents have also been anecdotally used in refractory CSU and may be of value to individual patients and in certain clinical circumstances [1, 2, 5, 24]. These agents include:


#### **6.7 NB-UVB therapy**

NB-UVB Therapy has been shown in combination with levocetirizine to significantly reduce urticaria activity and to have a long-lasting positive effect on UAS7 [10, 19]. PUVA and BB-UVB have so far shown mixed to neutral results [19].

#### **6.8 Biologic agents**

Omalizumab is licenced for the treatment of CU in adults and adolescents that continue to be symptomatic despite the use H1 antihistamines therapy.

Omalizumab is a recombinant humanised IgG monoclonal antibody against the Fc portion of the IgE antibody. It prevents free IgE binding to the high affinity IgE receptor FcεRI and downregulates these receptors on MC and basophils [4, 19]. It has been shown to be effective and well tolerated in 3 phase III and 2 phase II studies at doses from 150 to 300 mg every 4 weeks independent of total serum IgE level or body weight [2, 19]. Omalizumab improves angioedema and quality of life, is suitable for long-term use, and treats relapse after discontinuation [2]. 35–40% of patients achieve complete relief and another 30% reported partial relief after 3 and 6 months [2, 4]. The recommended dose is 300 mg by subcutaneous injection every 4 weeks. Some patients may achieve symptom control with a dose of 150 mg subcutaneous injection every 4 weeks [2]. If no therapeutic response is seen within 6 months of treatment efficacy is unlikely to be achieved and omalizumab can be discontinued [19]. Patients with type I autoimmune CSU experience faster response to omalizumab than type IIb autoimmune CSU. A large real-world US study [26] showed majority of CSU patients started on 300 mg omalizumab dose, were continuously treated for >6 months and without up or down titration for an average of 9 months. 25% of patients that discontinued therapy restarted it. The use of other CU related treatments particularly OCTs was lower after omalizumab commencement [26].

#### **6.9 CSU therapy in special patient groups**

The management of CSU in pregnant/lactating women, children and the elderly is largely the same as for non-pregnant adults.

In **pregnant and lactating women** antihistamines should be used at the lowest effective dose [10, 19]. and for the shortest periods of time. SGAs are classified

pregnancy category B by US FDA [10]. All antihistamines are secreted in breast milk and use of FGAs is discouraged during lactation to avoid excessive sedation of the breastfed child [10].

A short course of OCTs may be considered during pregnancy, in case of severe exacerbation. Potential side effects include malformation, neonatal adrenal insufficiency, low birth weight. Although OCTs are secreted in breast milk they are generally considered safe during lactation [10].

Omalizumab is classified pregnancy category B by US FDA [10].

In **children** SGAs rather than FGAs should be used as first line therapy and adjusted for age and weight [10, 19].

OCTs should be avoided where possible and if required only used for 10–14 days because of growth related side effects [10, 19]. The use of omalizumab in adolescents is well supported by the current literature and recommended as step 3 and before the use of ciclosporin in the 2017 urticaria guidelines of EAACI/GA<sup>2</sup> LEN/ EDF/WAO [27].

Ciclosporin is recommended as step 4 and was reported effective in a single open label trial of 7 children aged 9–16 years, at the dose of 3 mg/kg/day in two divided doses for maximum of 8 weeks. Regular monitoring of blood pressure and renal function [10] is required.

There is limited data available regarding the up dosing of SGAs and omalizumab in children with CSU under 12 years of age, and the treatment with cyclosporine and LMAs in paediatric patients of all ages [27].

Therapy of CSU in the **elderly** needs to consider comorbidities, polypharmacotherapy and organ insufficiency and adjusted accordingly [19].
