Chronic urticaria: tools to aid the diagnosis and assessment of disease status in daily practice

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1 DOI: /jdv JEADV SECTION 6 Chronic urticaria: tools to aid the diagnosis and assessment of disease status in daily practice K. Weller, T. Zuberbier, M. Maurer* Department of Dermatology and Allergy, Allergie-Centrum-Charite, Charite Universit atsmedizin Berlin, Berlin, Germany *Correspondence: M. Maurer. marcus.maurer@charite.de Received: 27 March 2015; Accepted: 14 April 2015 Abstract This article focuses on practical considerations for the optimal management of chronic urticaria (CU) with regard to the tools and instruments that are currently available to assist in the diagnosis and assessment of this condition before and during treatment. Conflicts of interest Karsten Weller is, or was recently, a speaker, investigator and/or advisor for Novartis, Uriach, FAES, UCB, MSD, Shire, Viropharma and Moxie. Torsten Zuberbier has acted as a consultant for AnseIl, Bayer Schering, DST, FAES, Fujisawa, HAL, Henkel, Kryolan, Leti, Menarini, Merck, MSD, Novartis, Procter and Gamble, Ranbaxy, Sanofi-Aventis, Schering- Plough, Stallergenes, Takeda and UCB. Marcus Maurer is, or was recently, a speaker and/or advisor for FAES, Almirall Hermal, Genentech, GSK, Merckle Recordati, Novartis, Sanofi Aventis, Schering-Plough, MSD, Merck, Moxie, Takeda, UCB and Uriach. Funding source This supplement was funded by Novartis Pharma AG. It is a publication of the Novartis supported medical education meeting that took place in Prague in November The publication presents views of the authors and not Novartis. Diagnostic work up and initial assessment of CU in the clinic Urticaria can be classified based on the duration of symptoms and presence or absence of identifiable triggers. 1 In CU, hives (wheals) and/or angioedema usually occur daily or almost daily and always for 6 weeks or more. 1 Depending on whether a specific trigger can be identified or not, CU is either inducible (CINDU) or spontaneous (CSU) (also called chronic idiopathic urticaria [CIU]). 1 The signs and symptoms of CINDUs are most frequently due to physical triggers, e.g. temperature, friction, pressure, vibration or solar radiation, but may also be induced by sweating (cholinergic urticaria) or hive/angioedema eliciting factors (contact urticaria). 2 International guidelines for the diagnosis and management of urticaria provide recommendations for how to distinguish between CSU, CINDU or other differential diagnoses and how to measure disease activity and impact. 1 Patient history An important first step when a patient presents with suspected CU is to take a detailed patient history, including questions that take into consideration the duration and appearance of hives and/or angioedema, aggravating factors, duration of disease, impact on everyday life and any previous diagnostic tests or therapy (Fig. 1). Information from the patient regarding the duration of individual hives can be very helpful when distinguishing between specific types of CU. All inducible urticarias are characterized by hives that appear very rapidly and, except for delayed pressure urticaria (DPU), these usually resolve within an hour. In DPU, painful skin swellings appear usually 4 to 8 h after pressure has been applied and take over 24 h to resolve. Contact urticaria only occurs after skin or mucosal contact with the eliciting agent and the hives fade quickly (after approximately 2 h), even in allergic contact urticaria (such as latex contact). The hives of spontaneous urticaria usually fade within a day but those of urticarial vasculitis typically last for longer, often 2 3 days, and may leave bruising (Fig. 2). 3 Routine diagnostic tests for CSU A small number of routine diagnostic tests are recommended for patients with suspected CSU, to exclude potential differential diagnoses, including a differential blood count or measurement of erythrocyte sedimentation rate (ESR) or C- reactive protein (CRP) levels. 1 The result of a differential blood count is usually normal in urticaria; in the case of

2 Diagnosis and assessment tools 39 Figure 1 Considerations when taking a patient history in a case of suspected chronic urticaria. 1 NSAIDs, Non-steroidal anti-inflammatory drugs. CINDU provocation testing All patients with a history suggestive of CINDU should be offered provocation testing, which generally provides results within minutes. 2 A variety of provocation tests are available to help confirm the eliciting triggers and to establish, where possible, a trigger threshold (Fig. 3). Furthermore, a variety of tools have been developed to help simplify provocation testing, as well as to improve the accuracy of the trigger threshold determination (Fig. 4). Individual provocation tests have been described in more detail in Section 2 of this supplement: Diagnosis and assessment of chronic urticaria. Figure 2 Typical duration of individual hives in chronic urticaria. DPU, delayed pressure urticaria; H, hour. increased levels of certain blood cell types, e.g. eosinophils, further investigation for an atopic disorder may be required. 1,4 ESR or CRP test results are also usually normal in urticaria; raised levels may be indicative of urticarial vasculitis or an autoinflammatory condition. It is also important to exclude the possibility of drug-induced urticaria, e.g. by NSA- IDs. Use of extended diagnostic tests to identify underlying causes and to exclude other diagnoses is recommended only in patients with long-standing and/or severe disease and the diagnostic workup should be performed based on clues provided by the patient history. Tools to assess disease activity, disease control and health-related QoL in CU Patient-reported outcomes (PRO) are important for assessing disease status and the impact of symptoms on patients lives. 5,6 The episodic and unpredictable nature of urticaria means that information recorded by the patient is very useful. Some signs and symptoms of disease activity (e.g. pain or itch) are only obtainable from the patient and PROs allow this information to be collected directly. Tools available to assess disease activity, disease control and impact have been described in Section 2 of this supplement. Here, we provide further important practical considerations around the usefulness and implementation of each tool in clinical practice. The recommended tools have been validated and translated in a variety of countries and languages around the world (Table 1). Disease activity International guidelines recommend the use of the Urticaria Activity Score (UAS) to measure disease activity and monitor

3 40 Weller et al. Figure 3 Provocation and threshold tests for inducible urticaria (provided by urticaria network e.v.). (a) (b) (c) (d) (e) Figure 4 Equipment available for provocation and threshold testing of CINDUs include the TempTest â (Courage + Khazaka electronic GmbH) (a); dermographometer (HTZ) (b); FricTest â (Moxie GmbH) (c); UV/visible light projector (Saalmann) (d); delayed pressure test (Allergie-Centrum-Charite, Berlin) (e).

4 Diagnosis and assessment tools 41 Table 1 Global availability of the recommended patient-reported outcome (PRO) tools. Measurement Tool Symptoms assessed Disease activity Countries (languages) available UAS Itch and hives Globally N/A AAS Angioedema Arabia (Arabic); Azerbaijan (Azeri); Canada (French and English); Denmark (Danish); France (French); Greece (Greek); Hungary (Hungarian); Italy (Italian); Japan (Japanese); Mexico (Mexican-Spanish); Portugal (Portuguese); Poland (Polish); Romania (Romanian); Russia (Russian); Spain (Spanish); Sweden (Swedish); The Netherlands (Dutch); USA (American-English) QoL CU-Q2oL Itch, hives and angioedema Disease control Brazil (Brazilian-Portuguese); Bulgaria (Bulgarian); Germany (German); Greece (Greek); Italy (Italian); Persia (Persian); Poland (Polish); Spain (Spanish); Turkey (Turkish) AE-QoL Angioedema Arabia (Arabic); Azerbaijan (Azeri); Canada (French and English); Denmark (Danish); France (French); Greece (Greek); Hungary (Hungarian); Italy (Italian); Japan (Japanese); Mexico (Mexican-Spanish); Poland (Polish); Portugal (Portuguese); Romania (Romanian); Russia (Russian); Spain (Spanish); Sweden (Swedish); The Netherlands (Dutch); USA (American-English); UCT Itch, hives and angioedema Brazil (Brazilian-Portuguese); Canada (Canadian-English); Denmark (Danish); Finland (Finnish); France (French); Greece (Greek); Italy (Italian); Mexico (Mexican- Spanish); Norway (Norwegian); Russia (Russian); Spain (Spanish); Thailand (Thai); The Netherlands (Dutch); USA (American-English) Countries (languages) in development Australia (Australian-English); Brazil (Brazilian-Portuguese); Bulgaria (Bulgarian); China (Chinese); India (Indian); Macedonia (Macedonian); Slovenia (Slovenian); Turkey (Turkish); UK (British-English) China (Chinese); France (French); Portugal (Portuguese); Russia (Russian); Serbia (Serbian); Thailand (Thai) Australia (Australian-English); Brazil (Brazilian-Portuguese); Bulgaria (Bulgarian); China (Chinese); India (Indian); Macedonia (Macedonian); Slovenia (Slovenian); Turkey (Turkish); UK (British-English) Australia (Australian-English); Azerbaijan (Azeri); Bulgaria (Bulgarian); China (Chinese); Hungary (Hungarian); India; Korea (Korean); Poland (Polish); Portugal (Portuguese); Serbia (Serbian); Sweden (Swedish); Turkey (Turkish) AAS, Angioedema Activity Score; AE-QoL, Angioedema-Quality of Life questionnaire; CU-Q2oL, Chronic Urticaria-Quality of Life questionnaire; QoL, quality of life; UAS, Urticaria Activity Score; UCT, Urticaria Control Test. Available from: Available from: Table 2 Urticaria Activity Score (UAS). 1 Reproduced from Zuberbier et al. Allergy 2014;69(7): Copyright Ó 2015 Wiley, with permission. 1 Score* Hives (wheals) Score* Itch Severity Score (ISS) 0 None 0 None 1 Mild (<20 hives/24 h) 1 Mild (present, but not annoying or troublesome) 2 Moderate (20 50 hives/24 h 2 Moderate (troublesome, but does not interfere with normal daily activity or sleep) 3 Intense (50 hives/24 h or large confluent areas of hives) 3 Intense (severe itch, which is sufficiently troublesome to interfere with normal daily activity or sleep) *Since CSU symptoms may vary considerably from day to day, it is recommended to document disease activity with the Urticaria Activity Score over 7 days (UAS7). The sum of score is 0 6 for each day, and 0 42 for the UAS7, respectively. response to treatment. 1 For patients with recurrent angioedema, the Angioedema Activity Score (AAS) is available. 7 Since CSU symptoms may vary considerably from day to day, it is recommended to document disease activity with the UAS over a number of consecutive days. The UAS7 is a simple, validated, scoring system 8 based on the once-daily assessment of itch intensity/severity and number of hives over a period of 7 days. The UAS7 should be completed by the patient between clinic visits and can subsequently be evaluated by both patient and physician (Table 2). 1,7,8 The intensity of itch and the number of hives are each scored from 0 to 3 once-daily, higher scores indicating worse symptoms. Daily itch and hives scores are summed to create a daily UAS score (from 0 to 6) which is in turn summed over a week to create the weekly UAS (UAS7) with a score ranging from 0 to a maximum of 42. 1,8 UAS7 scores may be categorized into ranges describing CSU health states, to give a better

5 42 Weller et al. be summed to give 7-day scores (AAS7), 4-week scores (AAS28) and 12-week scores (AAS84). Experience suggests that scores should be documented for at least 4 weeks to obtain a good picture of the patient s angioedema activity. Quality of life The symptoms of CU have a substantial adverse impact on many aspects of patients daily lives. 5,6,10,11 The current international urticaria guidelines, as well as an international consensus document, recommend the use of PRO tools to measure the impact of disease on patients health-related QoL 1,12, including the Chronic Urticaria-Quality of Life questionnaire (CU-Q2oL) 13 and the Angioedema-Quality of Life questionnaire (AE-QoL). 14 The validated CU-Q2oL was specifically designed for the assessment of health-related quality of life impairment in patients with CU, including the physical, psychosocial and practical aspects of this condition. 13 A total of 23 questions were found to cover six key CU-specific domains: itch, swelling, impact on life activities, sleep problems, looks and limits. 13 CU-Q2oL is simple to administer, requiring approximately 5 minutes to complete. 13 A total score as well as six different domain scores may be computed, the latter providing insights into the individual pattern of QoL impairment. AE-QoL is the first angioedema-specific QoL questionnaire. 14 Its 17 questions cover 4 domains: functioning, fatigue/mood, fears/shame and food (Fig. 6). Again, a total score as well as four different domain scores may be computed. Figure 5 Angioedema Activity Score (AAS) (provided by Moxie GmbH, Berlin, Germany). understanding of impact on patients and response to treatment. 9 A UAS7 of 0 indicates that the patient is itch- and hive free. UAS7 scores of 6, 7 15, and have been suggested to reflect well-controlled, mild, moderate and severe disease respectively. 9 However, cut-off values for mild, moderate or severe disease have not been validated. In Phase III clinical trials of omalizumab in patients with refractory CSU a UAS7 score 16 was an inclusion criterion, based on the assumption that those patients may be regarded as having moderate-to-severe CSU. Limitations of the UAS7 are that it is not applicable to inducible urticarias, does not assess angioedema, and it can only provide a prospective assessment of the patient s disease (compliance of patients is critical). The AAS is a validated PRO to assess disease activity in patients with recurrent angioedema (Fig. 5). 1,7 The AAS, which is based on the daily prospective assessment of angioedema signs and symptoms, is completed by the patient and may subsequently be evaluated by both patient and physician. The AAS allows the patient to score each of five key factors relating to their angioedema (duration, physical discomfort caused, impact on daily activities, impact on appearance and overall severity) from 0 to 3 (giving a daily score of 0 15). Daily AAS scores can Disease control The Urticaria Control Test (UCT) is a validated instrument that was specifically designed to assess the level of disease control in CU patients and thereby aid, document and back treatment decisions. To this end, four simple questions assess control of signs and symptoms of the disease, QoL impairment, efficacy of treatment and overall disease control, over the prior 4 weeks. The UCT is completed by the patient and can be evaluated by both patient and physician (Fig. 7). 15 The answer to each question is rated from 0 to 4 and the total score is calculated by summing the four individual question scores. The lowest UCT score possible is 0 (no control) and the highest score possible is 16 (complete control). A score 12 indicates well-controlled urticaria, while a score of 11 points towards poor disease control. 15 The UCT may be used for ad hoc assessments, is simple and quick to complete and evaluate and is valid for all forms of CU (CSU and CINDU). Notably, UCT results have been found to correlate well with both UAS7 and CU-Q2oL scores. Summary A variety of tools and questionnaires are available to assist physicians in the diagnosis and assessment of patients with CU. Physicians should consider implementing these instruments into their clinical practice routine to optimize the management of this challenging disease.

6 Diagnosis and assessment tools 43 Figure 6 Angioedema-Quality of life Questionnaire (AE-QoL) (provided by Moxie GmbH, Berlin, Germany). Figure 7 Urticaria Control Test (UCT) (provided by Moxie GmbH, Berlin, Germany). Acknowledgements We thank Dr. Ilaria Baiardini for providing information around the availability of the CU-Q2oL tool. Editorial assistance was provided by Brian Jepson, a professional medical writer contracted to CircleScience, an Ashfield Company, part of UDG Healthcare plc. Writing support was funded by Novartis Pharma AG. References 1 Zuberbier T, Aberer W, Asero R et al. The EAACI/GA²LEN/EDF/ WAO Guideline for the definition, classification, diagnosis and management of Urticaria. The 2013 revision and update. Allergy 2014; 69: Magerl M, Borzova E, Gimenez-Arnau A et al. The definition and diagnostic testing of physical and cholinergic urticarias EAACI/ GA2LEN/EDF/UNEV consensus panel recommendations. Allergy 2009; 64: Gimenez-Arnau A, Maurer M, De La CJ, Maibach H. Immediate contact skin reactions, an update of Contact Urticaria, Contact Urticaria Syndrome and Protein Contact Dermatitis - A Never Ending Story. Eur J Dermatol 2010; 20: Perera E, Sinclair R. Evaluation, diagnosis and management of chronic urticaria. Aust Fam Physician 2014; 43: 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: O Donnell BF, Lawlor F, Simpson J, Morgan M, Greaves MW. The impact of chronic urticaria on the quality of life. Br J Dermatol 1997; 136: Weller K, Groffik A, Magerl M et al. Development, validation, and initial results of the Angioedema Activity Score. Allergy 2013; 68: Mlynek A, Zalewska-Janowska A, Martus P, Staubach P, Zuberbier T, Maurer M. How to assess disease activity in patients with chronic urticaria? Allergy 2008; 63: Stull D, McBride D, Georgiou P, Zuberbier T, Grattan C, Balp M-M. Measuring patient severity in chronic spontaneous/idiopathic urticaria (CSU/CIU) as categorical health states: efficient and informative? Allergy 2014; 69(Suppl. 99): 317 (Abstract 826). 10 Mlynek A, Magerl M, Hanna M et al. The German version of the Chronic Urticaria Quality-of-Life Questionnaire: factor analysis, validation, and initial clinical findings. Allergy 2009; 64: Silvares MR, Fortes MR, Miot HA. Quality of life in chronic urticaria: a survey at a public university outpatient clinic, Botucatu (Brazil). Rev Assoc Med Bras 2011; 57:

7 44 Weller et al. 12 Baiardini I, Braido F, Bindslev-Jensen C et al. Recommendations for assessing patient-reported outcomes and health-related quality of life in patients with urticaria: a GA(2) LEN taskforce position paper. Allergy 2011; 66: Baiardini I, Pasquali M, Braido F et al. A new tool to evaluate the impact of chronic urticaria on quality of life: chronic urticaria quality of life questionnaire (CU-QoL). Allergy 2005; 60: Weller K, Groffik A, Magerl M et al. Development and construct validation of the angioedema quality of life questionnaire. Allergy 2012; 67: Weller K, Groffik A, Church MK et al. Development and validation of the Urticaria Control Test: a patient-reported outcome instrument for assessing urticaria control. J Allergy Clin Immunol 2014; 133: