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Urticaria and Prodromal Symptoms Including Erythema Marginatum in Danish Patients with Hereditary Angioedema University of Southern Denmark Urticaria and Prodromal Symptoms Including Erythema Marginatum in Danish Patients with Hereditary Angioedema Rasmussen, Eva R; Valente de Freitas, Priscila; Bygum, Anette Published in: Acta Dermatovenereologica DOI: 10.2340/00015555-2233 Publication date: 2016 Document version: Final published version Document license: CC BY Citation for pulished version (APA): Rasmussen, E. R., Valente de Freitas, P., & Bygum, A. (2016). Urticaria and Prodromal Symptoms Including Erythema Marginatum in Danish Patients with Hereditary Angioedema. Acta Dermatovenereologica, 96(3), 373- 376. https://doi.org/10.2340/00015555-2233 Go to publication entry in University of Southern Denmark's Research Portal Terms of use This work is brought to you by the University of Southern Denmark. Unless otherwise specified it has been shared according to the terms for self-archiving. If no other license is stated, these terms apply: • You may download this work for personal use only. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying this open access version If you believe that this document breaches copyright please contact us providing details and we will investigate your claim. Please direct all enquiries to [email protected] Download date: 07. Oct. 2021 Acta Derm Venereol 2016; 96: 373–376 CLINICAL REPORT Urticaria and Prodromal Symptoms Including Erythema Marginatum in Danish Patients with Hereditary Angioedema Eva Rye RASMUSSEN1, Priscila VALENTE DE FREITAS2 and Anette BYGUM2 1Department of Otorhinolaryngology – Head and Neck Surgery and Audiology, Køge and Slagelse Hospitals, Slagelse, and 2Department of Dermatology and Allergy Centre, Odense University Hospital, Odense, Denmark Erythema marginatum is a characteristic skin rash seen Among these, the most specific symptom is erythema in patients with hereditary angioedema (HAE); however, marginatum (EM), which has attracted special attention it can be confused with urticaria, leading to delay in cor- in the literature since the original report by Dinckelacker rect diagnosis. The aim of this study was to clarify how in 1882 (7). EM is a reticular and serpiginous, usually often erythema marginatum is misinterpreted as urtica- non-pruritic, erythema (Fig. 1), mostly located on the up- ria, potentially leading physicians to refrain from testing per trunk that might precede or accompany angioedema, for HAE. Few studies have been published on urticaria although it can also occur independently (8). This type of and prodromal symptoms in HAE, thus the incidence rash has also been observed in association with rheumatic of these parameters were also investigated. A total of 87 fever (9). EM is distinct from urticaria, which is pruritic, patients affiliated to the national HAE Centre were in- transient and more widespread, often consisting of smal- cluded. Retrospective and prospective data on skin erup- ler or larger elevated wheals. The exact pathomechanism tions and prodromal symptoms were collected. Fifty-six of EM is unclear, although it has been suggested that it percent of 87 patients had a positive history of erythema is bradykinin-mediated (10, 11). Traditional anti-allergic marginatum. Half of the patients had experienced ery- treatment regimens have proven ineffective in HAE- thema marginatum being misinterpreted as urticaria. related EM and angioedema. The most prevalent other prodromal symptoms were It has long been a clinical dogma, that patients with other skin symptoms, malaise, psychological changes, HAE do not have urticaria, which might cause some fatigue and gastrointestinal symptoms. HAE patients clinicians to pre-exclude this important diagnosis when with erythema marginatum have a longer diagnostic de- urticarial rash and angioedema occur together or the lay, presumably caused by misinterpretation of the rash patient reports urticaria in the disease history (11–14). as urticaria. Key words: hereditary angioedema; erythema Misdiagnosis of EM as urticaria might therefore con- marginatum; urticaria; prodromal symptoms. tribute to diagnostic confusion and significant delay in Accepted Sep 2, 2015; Epub ahead of print Sep 4, 2015 Acta Derm Venereol 2016; 96: 373–376. Eva Rye Rasmussen, Specialty Registrar, Department of Otorhinolaryngology – Head and Neck Surgery and Audiology, Køge and Slagelse Hospitals, Ingemannsvej 18, 3, DK-4200 Slagelse, Denmark. E-mail: Eva.rye. [email protected] Hereditary angioedema (HAE) is an autosomal dominant inherited disease with bradykinin-mediated skin swel- lings caused by a diminished level (type I) or function (type II) of complement C1 inhibitor (C1INH) due to mu- tations of the SERPING1 gene (1). A third type of HAE with normal C1INH exists, which is often oestrogen- sensitive and may be associated with mutations of the factor XII gene, F12 (2). HAE has been described in the medical literature since the 19th century, but only recently have effective treatment regimens been widely establish- ed (1, 3). Angioedema is the main symptom of HAE, but a wide range of associated and prodromal symptoms Fig. 1. Erythema marginatum. Erythema marginatum in two separate have been systematically reported in recent studies (4–6). patients: back of a woman (top) and thorax of a young man (bottom). © 2016 The Authors. doi: 10.2340/00015555-2233 Acta Derm Venereol 96 Journal Compilation © 2016 Acta Dermato-Venereologica. ISSN 0001-5555 374 E. R. Rasmussen et al. the diagnosis of HAE, leading to ineffective and poten- Table I. Characterization of the Danish cohort of 87 patients with tially harmful treatment regimens with anti-histamines, hereditary angioedema (HAE) glucocorticoids and/or adrenaline. Characteristics In this study we report the incidence of urticaria and Patients, male/female, n 44/43 prodromal symptoms, including EM, in a cohort of Male:female ratio 1.02 Danish HAE patients with a focus on diagnostic chal- Age, years, median, (range) 41 (0–83) HAE type Ia, n (%) 81 (93) lenges of skin signs. HAE type IIb, n (%) 6 (7) Children <18 years old, n 17 Adults, n 70 MATERIALS AND METHODS Diagnostic delay, in patients without EM, years, mean 15.6 Inclusion criteria were HAE type I or II and attendance at the Diagnostic delay in patients with EM, years, mean 17.7 national HAE Centre in Denmark. Eighty-eight HAE patients Can predict an oncoming attack, patients, n (%) were included, but one patient had died at the time of follow-up Always before an attack 37 (43) and was excluded due to a lack of information, leaving 87 pa- Sometimes 27 (31) tients for data analysis. Adult patients provided written consent Never 12 (14) prior to participation in this study and parents provided written Patient unsure 2 (2) consent on behalf of their children. Although some patients had No verified attacks 4 (5) their initial HAE testing carried out at other health facilities, Missing data 5 (6) all patients had the diagnosis confirmed at the HAE Centre. a 81 individuals from 29 families; b 6 individuals from 2 families. The study comprised 3 separate parts: (i) baseline data col- EM: erythema marginatum. lection: at the first visit in the HAE Centre, patients completed purposely designed questionnaires with questions about skin eruptions, prodromal symptoms, treatment regimens and their ef- of all patients experiencing EM reported that EM has fectiveness. The patients were assisted by a trained dermatologist been misinterpreted as being urticaria by healthcare per- in the process of completing the questionnaires. Special emphasis sonnel primarily at the emergency department or by their was put on the difference between EM and urticarial eruptions. general practitioner. In support of this finding, the mean Family history was explored and pedigrees were drawn in order diagnostic delay was almost 2 years longer in patients to identify other possible HAE patients and assess the likelihood of hereditability or de novo mutation. Medical records from other with EM. A high percentage of patients had been treated hospitals were retrieved and reviewed when deemed relevant. (ii) with anti-allergic medications before they were correctly Prospective data collection: once the patient was enrolled at the diagnosed with HAE and these medications had little or HAE Centre medical records were kept updated regarding symp- no effect on EM or angioedema. However, patients who toms, prodromes, treatment regimens, effectiveness, well-being had both urticarial lesions and EM were, in most cases, and other relevant medical and social information. Furthermore, patients completed a HAE-specific diary, which was also used not able to distinguish between the efficacy of anti-allergic as an evaluation tool at each visit. (iii) Follow-up: in patients treatment on their urticaria vs. EM, as, in the past, many with a lack of information in their diaries (especially children), were not aware of the differences between the 2 entities. an e-mail was sent or a telephone call made at the end of 2013 Seventy-eight patients answered additional questions or beginning of 2014 to retrieve updated information. concerning prodromal symptoms (Table III). The most Microsoft Excel for Windows 8 and STATA version 13 were used for data analysis. This study was approved by the Danish Data Protection Table II. Urticarial eruptions and erythema marginatum (EM) Agency (number 2009-41-2987). In Denmark questionnaire in 83 symptomatic patients with hereditary angioedema studies are not required to be approved by an ethics commit- History of EM, n (%) tee. The study was conducted according to the principles of the Yes 49 (56) Declaration of Helsinki. No 37 (43) Patient unsure 1 (1) Lifetime prevalence of urticarial eruptions, n (%) RESULTS Yes 22 (25) Penicillin allergy 2 Eighty-seven patients were identified, with a male:female Cold urticaria 1 ratio of 1.02 (Table I). Four children were still asymp- Combined delayed pressure urticaria and dermatographism 1 tomatic. Sixty-four patients (74%) could always or so- Provoked by fresh frozen plasma infusion 1 metimes predict an upcoming attack, which meant that Chronic spontaneous urticaria 1 Unspecified 16 they had some kinds of prodromal symptoms.
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