H1‐antihistamine‐refractory chronic spontaneous urticaria: it's worse than we thought – first results of the multicenter real‐life <scp>AWARE</scp> study

Maurer, Marcus; Staubach, Petra; Raap, Ulrike; Richter‐Huhn, Grit; Bauer, Andrea; Ruëff, Franziska; Jakob, Thilo; Yazdi, Amir S.; Mahler, Vera; Wagner, Nicola; Lippert, Undine; Hillen, Uwe; Schwinn, A.; Pawlak, Mario; Behnke, Norbert; Chaouche, Kamel; Chapman‐Rothe, Nadine

doi:10.1111/cea.12900

Cited by 115 publications

(134 citation statements)

References 39 publications

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“…The use of patient‐reported outcome measures such as the urticaria activity score (UAS), the angioedema activity score (AAS), the CU quality of life questionnaire (CU‐Q2oL), the angioedema quality of life questionnaire (AE‐QoL) and the urticaria control test (UCT) in studies and clinical practice has helped to better define the effects and impact of CU on patients . The available data indicate that urticaria markedly affects both objective functioning and subjective well‐being . Previously, O'Donnell et al showed that health status scores in CSU patients are comparable to those reported by patients with coronary artery disease .…”

Section: Definitionmentioning

confidence: 99%

The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria

Zuberbier

Aberer

Asero

et al. 2018

Allergy

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1,369

1,953

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This evidence- and consensus-based guideline was developed following the methods recommended by Cochrane and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group. The conference was held on 1 December 2016. It is a joint initiative of the Dermatology Section of the European Academy of Allergology and Clinical Immunology (EAACI), the EU-founded network of excellence, the Global Allergy and Asthma European Network (GA²LEN), the European Dermatology Forum (EDF) and the World Allergy Organization (WAO) with the participation of 48 delegates of 42 national and international societies. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS). Urticaria is a frequent, mast cell-driven disease, presenting with wheals, angioedema, or both. The lifetime prevalence for acute urticaria is approximately 20%. Chronic spontaneous urticaria and other chronic forms of urticaria are disabling, impair quality of life and affect performance at work and school. This guideline covers the definition and classification of urticaria, taking into account the recent progress in identifying its causes, eliciting factors and pathomechanisms. In addition, it outlines evidence-based diagnostic and therapeutic approaches for the different subtypes of urticaria.

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Section: Definitionmentioning

confidence: 99%

The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria

Zuberbier

Aberer

Asero

et al. 2018

Allergy

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1,369

1,953

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“…Angioedema is defined as rapid swelling at a deeper level under the skin than hives, occurring on the face, inside the mouth or elsewhere on the body . It is estimated that 33%‐67% of patients with CSU exhibit both hives and angioedema, 29%‐65% exhibit only hives and 1%‐13% exhibit only angioedema …”

Section: Introductionmentioning

confidence: 99%

“…Patients with CSU‐associated angioedema often experience concern over their health status, at times worrying that swelling episodes may cause problems with breathing or may be life‐threatening . A real‐world multicentre study in Germany has shown that in a 6‐month period, more than 40% of patients with inadequately controlled CSU experienced angioedema; among these patients, 78% rated their angioedema as severe or moderate in intensity, and a mean of 34 days with angioedema was reported during the 6‐month period . In addition to its considerable symptom burden, recurrent angioedema (in those with hereditary angioedema) can lead to absenteeism and can have a negative impact on work productivity …”

Section: Introductionmentioning

confidence: 99%

Angioedema in chronic spontaneous urticaria is underdiagnosed and has a substantial impact: Analyses from ASSURE‐CSU

Sussman

Abuzakouk

Berard

et al. 2018

Allergy

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Background ASSURE‐CSU revealed differences in physician and patient reporting of angioedema. This post hoc analysis was conducted to evaluate the actual rate of angioedema in the study population and explore differences between patients with and without angioedema.MethodsThis international observational study assessed 673 patients with inadequately controlled chronic spontaneous urticaria (CSU). Physicians abstracted angioedema data from medical records, which were compared with patient‐reported data. Patients in the Yes‐angioedema category had angioedema reported in the medical record and a patient‐reported source. For those in the No‐angioedema category, angioedema was reported in neither the medical record nor a patient‐reported source. Those in the Misaligned category had angioedema reported in only one source. Statistical comparisons between Yes‐angioedema and No‐angioedema categories were conducted for measures of CSU activity, health‐related quality of life (HRQoL), productivity and healthcare resource utilization (HCRU). Regression analyses explored the relationship between Dermatology Life Quality Index (DLQI) score and angioedema, adjusting for important covariates.ResultsAmong evaluable patients, 259 (40.3%), 173 (26.9%) and 211 (32.8%) were in the Yes‐angioedema, No‐angioedema and Misaligned category, respectively. CSU activity and impact on HRQoL, productivity, and HCRU was greater for Yes‐angioedema patients than No‐angioedema patients. After covariate adjustment, mean DLQI score was significantly higher (indicating worse HRQoL) for patients with angioedema versus no angioedema (9.88 vs 7.27, P < .001). The Misaligned category had similar results with Yes‐angioedema on all outcomes.ConclusionsAngioedema in CSU seems to be under‐reported but has significant negative impacts on HRQoL, daily activities, HCRU and work compared with no angioedema.

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“…1 However, many patients with CSU do not show complete control of their disease with standard doses. 97 In these patients, updosing of up to fourfold higher than standard doses of their H 1 antihistamine is recommended by the current EAACI/GA 2 LEN/ EDF/WAO guideline for urticaria. 1 Several studies have confirmed that treatment of CSU by higher than standard doses of H 1 antihistamine, that is updosing of an sgAH, is more effective than treatment with the standard dose for most sgAHs.…”

Section: Con Clus Ionsmentioning

confidence: 99%

Cardiac safety of second‐generation H₁‐antihistamines when updosed in chronic spontaneous urticaria

Cataldi

Maurer

Taglialatela

et al. 2019

Clin Experimental Allergy

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The symptoms of chronic urticaria, be it chronic spontaneous urticaria (CSU) or chronic inducible urticaria (CindU), are mediated primarily by the actions of histamine on H1 receptors located on endothelial cells (the weal) and on sensory nerves (neurogenic flare and pruritus). Thus, second‐generation H1 antihistamines (sgAHs) are the primary treatment of these conditions. However, many patients are poorly responsive to licensed doses of antihistamines. In these patients, the current EAACI/GA2LEN/EDF/WAO guideline for urticaria suggests updosing of sgAHs up to fourfold. However, such updosing is off‐label and the responsibility resides with the prescribing physician. Therefore, the safety of the drug when used above its licensed dose is of paramount importance. An important aspect of safety is potential cardiotoxicity. This problem was initially identified some 20 years ago with cardiotoxic deaths occurring with astemizole and terfenadine, two early sgAHs. In this review, we discuss the mechanisms and assessments of potential cardiotoxicity of H1 antihistamines when updosed to four times their licensed dose. In particular, we have focused on the potential of H1 antihistamines to block hERG (human Ether‐a‐go‐go‐Related Gene) voltage‐gated K+ channels, also known as Kv11.1 channels according to the IUPHAR classification. Blockade of these channels causes QT prolongation leading to torsade de pointes that may possibly degenerate into ventricular fibrillation and sudden death. We considered in detail bilastine, cetirizine, levocetirizine, ebastine, fexofenadine, loratadine, desloratadine, mizolastine and rupatadine and concluded that all these drugs have an excellent safety profile with no evidence of cardiotoxicity even when updosed up to four times their standard licensed dose, provided that the prescribers carefully consider and rule out potential risk factors for cardiotoxicity, such as the presence of inherited long QT syndrome, older age, cardiovascular disorders, hypokalemia and hypomagnesemia, or the use of drugs that either have direct QT prolonging effects or inhibit sgAH metabolism.

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H1‐antihistamine‐refractory chronic spontaneous urticaria: it's worse than we thought – first results of the multicenter real‐life AWARE study

Abstract: This study reveals that German H1-antihistamine-refractory CSU patients have high rates of uncontrolled disease, angioedema, and comorbid CIndU, are undertreated, have impaired QoL, and rely heavily on healthcare resources.

Cited by 115 publications

References 39 publications

The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria

The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria

Angioedema in chronic spontaneous urticaria is underdiagnosed and has a substantial impact: Analyses from ASSURE‐CSU

Cardiac safety of second‐generation H₁‐antihistamines when updosed in chronic spontaneous urticaria

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H1‐antihistamine‐refractory chronic spontaneous urticaria: it's worse than we thought – first results of the multicenter real‐life AWARE study

Abstract: This study reveals that German H1-antihistamine-refractory CSU patients have high rates of uncontrolled disease, angioedema, and comorbid CIndU, are undertreated, have impaired QoL, and rely heavily on healthcare resources.

Cited by 115 publications

References 39 publications

The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria

The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria

Angioedema in chronic spontaneous urticaria is underdiagnosed and has a substantial impact: Analyses from ASSURE‐CSU

Cardiac safety of second‐generation H1‐antihistamines when updosed in chronic spontaneous urticaria

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Cardiac safety of second‐generation H₁‐antihistamines when updosed in chronic spontaneous urticaria