Original Paper Int Arch Allergy Immunol 2014;164:326–332 DOI: 10.1159/000366276

Received: December 23, 2013 Accepted after revision: August 1, 2014 Published online: September 23, 2014

Hereditary Angioedema in Greece: The First Results of the Greek Hereditary Angioedema Registry Fotis Psarros a Nick Koutsostathis b Evangelia Farmaki c Matthaios G. Speletas b Anastasios E. Germenis b a

Allergy Department, Naval Hospital of Athens, Athens, b Department of Immunology and Histocompatibility, School of Medicine, University of Thessaly, Larissa, and c First Department of Pediatrics, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece

Abstract Background: No published data presently exist concerning hereditary angioedema (HAE) in Greece. The aim of this study was to present the results from patients recorded by the Greek Hereditary Angioedema Registry over the last 3 years (July 2010 to June 2013). Methods: A systematic recording of HAE cases was undertaken following a physician awareness campaign and confirmation of diagnosis. A questionnaire was also used for the assessment of key parameters of the patients’ disease-specific quality of life. Results: One hundred and sixteen patients from 41 non-related families were recorded. There were 33 (80.5%) families with type I HAE, 7 (17%) with type II HAE and 1 (2.5%) with non-C1 inhibitor (C1-INH), non-FXII HAE. Two further non-C1-INH, non-FXII HAE sporadic cases were recorded. An investigation of non-symptomatic family members revealed another 6 asymptomatic individuals with C1-INH deficiency. The average delay in diagnosis was 16.5 years and the incidence of death in the families of patients was 1 for every 2 families. The use of newer therapeutic agents seems to fall significantly short

© 2014 S. Karger AG, Basel 1018–2438/14/1644–0326$39.50/0 E-Mail [email protected] www.karger.com/iaa

of the existing needs. HAE was found to affect the quality of life slightly in 14%, greatly in 63% and significantly in 23% of the patients. Conclusion: Until recently, there has been a significant degree of underdiagnosis of HAE in Greece. Very low compliance with the provisions of the applicable international guidelines and consensus positions, with adverse consequences on the patients’ quality of life, was also observed. The centralized model we used to uncover the patients could be effective in other countries presenting with comparable disease characteristics. © 2014 S. Karger AG, Basel

Introduction

Hereditary angioedema (HAE) is a rare, potentially fatal genetic syndrome which is caused by functional deficiency of the C1 inhibitor (C1-INH) and is inherited in a dominant way. It manifests clinically by episodes of subcutaneous or submucosal edema affecting the limbs, torso, face, external genitalia, gut or throat; these usually begin to occur during childhood or adolescence [1–3]. Depending on the activity and concentration of C1-INH, we distinguish 2 types of HAE, which do not, however, present any differences in clinical expression. In type I HAE Prof. Anastasios E. Germenis Department of Immunology and Histocompatibility School of Medicine, University of Thessaly GR–41110 Biopolis, Larissa (Greece) E-Mail agermen @ med.uth.gr

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Key Words C1 inhibitor · Disease-specific quality of life · Greek Hereditary Angioedema Registry · Hereditary angioedema

Materials and Methods The GHAER was created in order to (1) collect and identify the epidemiological and clinical characteristics of HAE in Greece and, in particular, to accurately record the condition of patients (considering the significant underdiagnosis of the disease), (2) develop

HAE in Greece

a framework to study the quality life of patients, and (3) create the preconditions for further study of the disease (e.g. a genetic material biobank). The GHAER was developed in 3 phases. During the first phase (January 2009 to July 2010), a database was designed and a questionnaire was constructed which included which demographic, epidemiological and clinical data were to be collected from the patients. The questionnaire also included a series of 25 questions concerning the disease-specific quality of life. This was followed by a campaign to raise the awareness of physicians, who were requested to report to the GHAER any cases of HAE that they were treating. Initially, this campaign included a personal or telephone contact with all allergists and all allergy hospital departments in the country, distribution of relevant brochures and informative/scientific presentations of the subject at almost all allergy scientific events that took place between July 2010 and June 2011. Gradually, the campaign was extended and is still ongoing, addressing specialists in all fields involved in the diagnosis and treatment of the disease (e.g. pediatricians and ENT specialists). In July 2010, a team member began field visits to the patients recorded in the GHAER, with the purpose of completing the questionnaire and collecting a blood sample after obtaining written informed consent. Blood was also collected from the parents and one unaffected sibling of the patient, whenever possible. The collected blood was used for DNA isolation and for testing in order to confirm the diagnosis. All confirmatory diagnostic tests, in accordance with the 2010 international consensus algorithm [19], and storage of the DNA were at the Laboratory of Immunology and Histocompatibility, School of Medicine, University of Thessaly. We also performed molecular analysis of the SERPING1 and FXII genes for a more accurate determination of HAE type; these results are published in another paper [43]. The inclusion criteria for follow-up of patients by the GHAER team member were the clinical characteristics of the disease as indicated in the 2010 international consensus algorithm [19]. Patients with familial and hereditary chronic urticaria or urticaria-associated angioedema were excluded. Finally, patients were asked to complete the 25 questions of the disease-specific quality of life questionnaire and to indicate the level of their quality of life using a 10-point visual analogue scale.

Results

Epidemiological Characteristics In total, 116 patients (62 men and 55 women) with a mean age at the time of recording of 43.4 years (median age 38 years, range 3–91 years), from 41 non-related families, were recorded by the GHAER in the past 3 years. Seven of the 75 patients (9.3%) had no family history of HAE, and genetic testing showed that their disease was due to de novo mutations. Patient distribution per geographic district is presented in table 1. Of the recorded families, there were 33 (80.5%) with type I HAE, 7 (17%) with type II HAE and 1 (2.5%) with non-C1-INH, nonInt Arch Allergy Immunol 2014;164:326–332 DOI: 10.1159/000366276

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(85% of patients), the antigenic concentration of C1-INH is 68%) (NV: 15 – 35) Type I HAE Type II HAE

7.34 (3 – 13) 5 (3 – 7.2)

8.4 (3 – 19) 51.6 (22 – 79)

44.3 (18 – 63) 50.5 (36.5 – 62)

Values in parentheses are ranges. NV = Normal values.

during menstruation and by 43% after taking contraceptive products. The GHAER also recorded 34 pregnancies in 28 of the affected women. Clinical improvement of the disease was observed in 85% of these cases, aggravation in 15% and no change in 3%. Laboratory Findings All diagnoses except those of the 3 patients with nonC1-INH, non-FXII HAE were confirmed by genetic analPsarros /Koutsostathis /Farmaki /Speletas / Germenis  

 

 

 

 

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328

graphic district

Factors Phobia concerning the availability of appropriate drugs at the next episode Phobia concerning insurance coverage Refusal of emergency room physicians to administer (particularly i.v.) the drugs that the patients had brought with them during the episodes (due to unfamiliarity with the disease or the drugs) Delayed administration of drugs in the emergency room and worsening anxiety Delay in performing appropriate dental procedures Dental procedures without the use of anesthetic Family problems due to anxiety, phobia, feelings of guilt and psychological stress Avoiding trips away from home Problems in social life Loss of employment due to frequent absences Change of employment due to frequent absences Fear of possible death at the next laryngeal episode Avoiding marriage because of phobias or feelings of guilt Children and adolescents Selecting sports habits with a reduced risk of injury Frequent absences from school Marginalization due to an inability to participate in certain school activities

Patients 53% 46%

31% 57% 26% 18% 33% 44% 47% 14% 6% 48% 50% 20% 39% 22%

ysis of the SERPING1 gene (and FXII gene, where appropriate). Episode frequency was not correlated with C4 concentration or with antigenic or functional levels of C1-INH in patient serum at the time of diagnosis (table 3). In the table and comparisons, we have not included patients who were on danazol treatment when we contacted them. Therapeutic Characteristics With regard to the 2 therapeutic agents available in Greece for the treatment of HAE episodes, 75% of patients had used C1-INH of human origin, i.e. plasma-derived C1-INH (pdC1-INH), 62% had used icatibant and 9% reported that they had not had access to these drugs. Of the patients who had used the drugs, 11 and 69% reported that they had been trained in the self-administration of pdC1-INH and icatibant, respectively, while 98% of them believed that the course of their disease would improve significantly if they were able to self-administer the drugs. Headache was reported in only 1 case after the administration of pdC1-INH, while redness and local reHAE in Greece

actions were the most common adverse events following the injection of icatibant. As long-term prophylaxis, 58% of all patients (68% of the men, 47% of the women and 37% of the women of childbearing-age) had received androgens (danazol) at an average daily dose of 100 mg for a period of 6 months to 32 years, and only 1 patient had received tranexamic acid for >6 months. At the time that our team member contacted the patients, only 3 were on long-term prophylaxis. The rest had discontinued this due to inefficacy, poor compliance or adverse effects. Dose-dependent adverse events from the use of danazol were reported by 72% of all patients (63.6% of the men and 84.6% of the women), while 30% indicated that use of the drug negatively and significantly affected their quality of life. The most common adverse events of danazol were myalgia (33%), followed by increased body weight, muscle cramps, headache, increased levels of liver enzymes and hypercholesterolemia. Furthermore, male patients reported hirsutism, decreased libido and erectile dysfunction, while women reported hirsutism, hoarseness of voice and menstruation disorders. Adverse events after taking tranexamic acid were reported by 1 patient (abdominal pain and nausea). Quality of Life Use of the 10-point visual analogue scale demonstrated that HAE affected the quality of life slightly (0–3) in 14%, greatly (4–7) in 63% and significantly (8–10) in 23% of patients. Table  4 lists the factors of disease-specific quality of life that were reported to be affected, through use of the relevant questionnaire.

Discussion

The first systematic attempt to record HAE in Greece succeeded in covering most of the country. By a rough extrapolation of the determined disease frequency to the entire population, its prevalence in Greece is estimated at approximately 1/90,000. However, there are still several areas, particularly in the northern and western parts of the country and on the islands, which have not yet been covered. This omission, along with a possibly general flaw in registration coverage, may be due to the fact that the awareness campaign focused mainly on allergists. The first and most frequent contact of HAE patients, however, usually involves an emergency room and specialists from other fields who frequently have difficulty identifying the disease. This highlights the necessity of better education Int Arch Allergy Immunol 2014;164:326–332 DOI: 10.1159/000366276

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Table 4. Factors influencing the disease-specific quality of life of HAE patients and the corresponding percentage of patients affected

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SERPING1 alterations [43]. In any case, this finding is worthy of further investigation. Regarding the use of newer therapeutic agents, our results indicate that this falls significantly short of the existing needs, since 9% of patients reported that they did not even have access to these drugs. Education on self-administration among those using these agents, however, seems to be satisfactory [30]. In addition, although the percentage of patients who needed long-term prophylactic treatment appeared to be quite large, only 1 patient had undergone such treatment, and then for 1 year only. It has been confirmed that long-term prophylaxis with these drugs has significant advantages, given the high frequency and severity of the adverse events of danazol (also recorded in our study) which have been shown to cause a deterioration in quality of life [31]. In general, and in conjunction with the relevant results of the disease-specific quality of life questionnaire, the treatment of HAE in our country does not seem to comply with the applicable international guidelines and consensus positions [32, 33]. This is an important problem, considering the high cost of newer therapeutic agents. In many countries, in order to address direct costs, efforts are undertaken to reduce the indirect costs of the disease, caused mainly by reduced productivity. It is estimated that each HAE episode results in the loss of 3.3 work days (range 0.5–180 days) [34], and the effect of the disease on the patients’ productivity overall is estimated to be similar to the effect of severe bronchial asthma and a little less than with Crohn’s disease [31]. Patient training in selfadministration of the drugs has been shown to significantly reduce the indirect costs. In addition to reducing hospital costs (because patients do not have to visit an emergency room when an episode occurs), it seems that this can even mean the discontinuation of prophylactic treatment for many patients [35]. As it is now generally accepted that all HAE patients can benefit from self-administration [36, 37], the percentage of patients in Greece who are currently given this opportunity cannot be considered satisfactory. As part of addressing the costs that HAE now imposes on the health care system, a portion of the support needs of patients in many countries is being covered by patient organizations as well as by the pharmaceutical companies involved [37]. This is also practiced in Greece for training patients to self-administer drugs (via patient support programs), and it could explain the differences noted between the two products marketed in our country (pdC1INH and icatibant).

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and awareness regarding HAE. This is supported by the fact that 30% of the patients recorded mentioned that they had encountered doctors who refused to administer the indicated medication – which the patients had brought with them for the treatment of HAE episodes – because they were admittedly unfamiliar with the disease or the drugs. Consequently, any further effort to discover and register the cases of HAE in our country should focus on informing all specialist physicians potentially involved in its diagnosis. The delay in diagnosing the disease, which was as long as 21 years in 1976 [20], has decreased significantly in recent years. For example, a recent multinational study showed that this figure has dropped to 8.3 years [21]. It is estimated to be approximately 7 years in the USA [22], 10 years in Spain [23] and 16 years in Denmark [24]. Consequently, the delay in HAE diagnosis found in Greece is one of the longest worldwide, which is not surprising since most of the patients were only diagnosed during the last 5 years. In terms of the clinical presentation of the disease, there are no significant differences in Greece compared to the phenotypic descriptions in the international literature [25, 26]. Interestingly, 24% of the patients recorded were older than 60 years (up to an age of 91 years) and 18.7% had developed the disease after the age of 20 (in the 57th year in 1 case). This confirms the fact that the disease first occurs, usually but not always, during childhood and adolescence (before the age of 15 in 75% of patients) [27] and that episodes may even occur at an advanced age. This is in contrast to earlier perceptions which held that the disease clinically disappears after the age of 60 years. On the other hand, our finding that 6 apparently healthy children from the families of the patients had serological and genetic findings of HAE without having yet developed the disease once again raises the issue of screening asymptomatic family members; however, there is no consensus on this yet in the international literature [8, 28]. Another remarkable finding is the emergence of viral infections as triggering factors for HAE episodes; there are no relevant references in the literature in which triggering factors in general have been well studied. The rate of HAE deterioration observed in Greek women taking contraceptive products or during menstruation is significantly lower than that reported in the literature [29]. This discrepancy might be attributed to a simultaneous effect exerted by other genetic or environmental factors on the disease phenotype. In favor of this, we have recently found that significant differences exist amongst European populations regarding the pathogenic

The fact that HAE adversely affects the quality of life of patients has been reported in the literature for many years [31, 38–40]. The very high rates of patients who responded affirmatively to the relevant study questions suggest that the management of the disease in our country is inadequate. It should be stressed, of course, that the objectives of our study did not include the systematic investigation of the disease-specific quality of life of the patients, but only the description of certain major problems that are necessarily associated with the unique basic features of the clinical picture and treatment of the disease. For this reason, we did not undertake to construct and validate a special questionnaire lege artis. Such a questionnaire, the HAE-HRQoL (Hereditary Angioedema Health-Related Quality of Life) questionnaire, was recently developed by a Spanish study group on bradykinin-induced angioedema [41] and has already been translated into several languages. The GHAER has completed the Greek translation of the HAE-HRQoL and intends to implement it in our country in order to perform a systematic study of the quality of life in HAE patients and draw internationally comparable conclusions. Detailed data about the disease-specific quality of life, such as those recently presented by the French National Reference Center for Hereditary Angioedema [42], will allow us to take targeted action towards improving the situation for the patients and, especially, to schedule a more rational management of the cost of the disease, as shaped by the use of highly effective but costly newer therapeutic agents. In conclusion, analysis of the data recorded so far by the GHAER shows that until recently there was a significant degree of underdiagnosis of HEA in Greece. This seems to have reversed dramatically in the last 3 years. The epidemiological and clinical characteristics of the disease in our country do not differ from those reported

worldwide. We found, however, very low compliance with the provisions of the applicable international guidelines and consensus positions amongst all involved parties. As a result, there is clear evidence that the quality of life of patients with HAE in Greece is significantly inferior, and that there is a need to promote practices to address the problem. Our achievement of uncovering, in 3 years, the vast majority of HAE patients in Greece represents a great contribution towards improving their situation. Their diagnosis would otherwise have been significantly delayed, with all that this entails. Our success can obviously be attributed to our centralized approach. We are therefore continuing our work and try to ameliorate the situation for patients. We think that such an approach could be used equally successfully in several other countries that present, like ours, extensive underdiagnosis of HAE.

Acknowledgments We thank the Hellenic Society of Allergology and Clinical Immunology for the adoption of our proposal and for their support in the development and operation of the GHAER. The study was partially funded by an unrestricted grant by Shire Hellas SA to the Research Committee of the University of Thessaly. The patient cases recorded to date in the GHAER were reported by the following colleagues, whom we thank warmly for their excellent cooperation: V. Vovolis, E. Kompoti and N. Mikos, General Hospital ‘Laiko’, Athens; C. Theodorou and G. Stoumbos, Vostanio Hospital, Lesbos; L. Kalogeros and I. Paraskevopoulos, 401 General Military Hospital of Athens, Athens; C. Koilia, Allergist, Athens; M. Manoussakis, Children’s Hospital ‘Aglaia Kyriakou’, Athens; G. Nottas, University General Hospital of Herakleion, Herakleion; E. Papadopoulou-Alataki, ‘Papageorgiou’ Hospital, Thessaloniki; C. Petalas, Air Force General Hospital, Athens; E. Stefanaki, Allergist, Ioannina; A. Hatziioannou, Allergist, Xanthi, and S. Chrisoulakis, Naval Hospital of Athens, Athens.

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Hereditary angioedema in Greece: the first results of the greek hereditary angioedema registry.

No published data presently exist concerning hereditary angioedema (HAE) in Greece. The aim of this study was to present the results from patients rec...
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