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C1-inhibitor (C1-INH) related hereditary angioedema (C1-INH-HAE) is a rare pathological condition caused by a deficiency or a functional alteration of serum protein C1-INH. Clinical manifestations are represented by recurrent, potentially life-threatening episodes of cutaneous or mucosal oedema. The present study analysed the effectiveness of a specific short-term prophylaxis protocol for the management of C1-INH-HAE patients requiring chronic periodontitis treatment.Ten consecutive C1-INH-HAE patients with mild to moderate chronic periodontitis were treated by non-surgical periodontal therapy with a full-mouth scaling approach (FMS) in two sessions 24 h apart. All patients underwent a short-term prophylaxis protocol of acute attacks based on the association of attenuated androgen (danazol), from 5 days before the first FMS session to 2 days after the second FMS session, and C1-INH concentrate given 1 h before the first FMS session. Patients were examined for periodontal changes over a 6-month period.None of patients developed complications or oedema up to 1 week postoperatively. Compared to baseline, scaling and root planing (SRP) treatment yielded, at 6 months, a statistically significant improvement in probing depth (PD) (baseline: 5.24 mm ± 0.85 mm vs 6 months: 2.96 ± 0.31 mm), clinical attachment level (CAL) (baseline: 5.46 ± 0.81 vs 6 months: 3.89 ± 0.38 mm), full-mouth bleeding score (FMBS) (baseline: 27.6 ± 2.2% vs 6 months: 18.5 ± 2.1%) and in full-mouth plaque score (FMPS) (baseline: 28.6 ± 2.4% vs 6 months: 21.66 ± 3.3%).This study showed the clinical effectiveness of the reported prophylaxis protocol in preventing acute attacks in HAE patients requiring non-surgical periodontal treatment, with no complications up to 1 week after FMS.

Maria Bova,1 Anna Valerieva,2 Maddalena Alessandra Wu,3 Riccardo Senter,4 Francesca Perego5 1Department of Translational Medical Sciences and Interdepartmental Center for Research in Basic and Clinical Immunology Sciences, University of Naples Federico II, Naples, Italy; 2Clinical Centre of Allergology, Medical University of Sofia, Sofia, Bulgaria; 3Department of Biomedical Science, University of Milan, Milan, Italy; 4Department of Medicine, University of Padova, Padova, Italy; 5Department of Cure Subacute, Istituti Clinici Scientifici Maugeri, IRCCS, Milan, ItalyCorrespondence: Francesca PeregoDepartment of Cure Subacute, Istituti Clinici Scientifici Maugeri, IRCCS, via Camaldoli 64, Milan 20138, ItalyTel +39 3489050440Email francesca.perego@icsmaugeri.itAbstract: Despite the efficacy of the on-demand treatment for the control of acute attacks of Hereditary Angioedema due to C1-Inhibitor Deficiency (C1-INH-HAE), the number and severity of attacks and the impairment in the quality of life of the affected patients have led to the development of a new monoclonal antibody, lanadelumab, directly addressed to the blockage of bradykinin, the principal mediator of vasodilation during angioedema attacks. It is indicated for the prophylactic treatment, it is easy to administer, highly effective and with known limited side effects. The current review summarizes the development of the drug, its clinical background and its perspectives.Keywords: C1-inhibitor hereditary angioedema, long-term prophylaxis, lanadelumab, monoclonal antibody, rare disease

Lo Scaffolding Psicologico alla Relazione Sanitaria è una proposta metodologica volta a favorire il riconoscimento dei ruoli assunti dai partecipanti alla visita medica. Nel contributo si presentano alcune esperienze cliniche quali esempio di applicazione in diversi contesti pediatrici.

The first descriptions of hereditary angioedema (HAE), in the early 1500’s, ascribed it to “neuroticism.” However, HAE is a rare autosomal dominant disease that causes swelling of the skin and mucosal tissues, but that varies greatly in terms of localization, frequency, and intensity both within and between individuals. Although the identification of a genetic origin dates to 1963, psychological stress is still one of the most reported triggers, often being cited in the conclusions of research and clinical reports. Despite this widespread assumption, the role of stress in HAE has never been analyzed in depth. In this chapter, the authors present their reflections on the results of the qualitative component of a broader mixed-method research on the interaction between stress and emotion regulation in the variability of clinical presentation of HAE. The role of psychology is discussed—as brought into play by the request of the medical team—in terms of research and intervention for HAE in medical contexts. They start with the results from a semantic and semiotic analysis of an ad-hoc semi-structured interview of the parents of young patients on the variability of the disease. This reliance on “lay experts” allows for a broader understanding of the phenotypic variability of HAE, as well as of the relational contexts of patients, including the relationship between the family, patient, and doctor. They conclude by highlighting the importance of shared meaning-making processes when seeking to influence strategies for the management of the disease.

Table S1. Binary Logistic Regression analysis: Coddington Life Event Scale (CLES) versus Total Severity Score and Alexithymia Questionnaire for Children (AQC). (DOCX 20 kb)

Objective To characterize the management and outcomes of life-threatening laryngeal attacks of hereditary angioedema (HAE) treated with icatibant in the observational Icatibant Outcome Survey (NCT01034969) registry. Methods This retrospective analysis was based on data from patients with HAE type I/II who received healthcare professional-administered or self-administered icatibant to treat laryngeal attacks between September 2008 and May 2013. Results Twenty centers in seven countries contributed data. Overall, 42 patients with HAE experienced 67 icatibant-treated laryngeal attacks. Icatibant was self-administered for 62.3% of attacks (healthcare professional-administered, 37.7%). One icatibant injection was used for 87.9% of attacks, with rescue or concomitant medication used for 9.0%. The median time to treatment was 2.0 h (n=31 attacks) and the median time to resolution was 6.0 h (n=35 attacks). Conclusions This analysis describes successful use of icatibant for the treatment of laryngeal HAE attacks in a real-world setting.

Background: Recent studies on adults report psychological stress among the trigger factors of Hereditary Angioedema(HAE) attacks (Fouche at al.,2013;Zotter et al.,2014). Objective:to explore the role of emotions and stress in the onset of symptoms in a group of paediatric patients with HAE and in two control groups. Methods: to date, 25 children with HAE, and 25 children from 2 control groups (diabetes and rheumatoid arthritis(RA)) together with their parents, have been administered: a structured interview on the illness experience and a self-reported scale on illness severity; 3 scales on stress, alexithymia and emotional awareness to children (CLES, Coddington,1999;AQC, Rieffe,2006;LEAS-C, Ciarocchi,2001). Results:From the interviews: 80% of parents of HAE children report the belief that psychological stress and intense emotions trigger the symptoms, 65% of parents of children with diabetes think that anger and anxiety are associated to hyper or hypo-glycaemia, only 30 % of parents of children with RA believe stress can exacerbate the illness. From the scale stress: children with HAE report higher levels of stress comparing with the other groups (75% HAE,60% diabetes, 50% RA). From the scale on alexithymia: all the groups report a high impairment in the ability to recognize and name one’s own emotions (78% HAE, 90% diabetes and 85% RA). From the scale on emotional awareness too, all the groups report a broad impairment, a bit higher for HAE children (80% of children with HAE, 75% of children with diabetes, 65% of children with RA). Conclusion: Paediatric patients with HAE show higher stress levels than the control groups. All the groups show a broad deficit in emotion regulation competencies. Stress is widely recognized to be a trigger both in HAE and in diabetes. The link between psychological stress and symptoms seems not to follow a causal relation. The links between HAE pathogenesis and neurochemical pathways of emotions need to be elucidated by further research.

L’Angioedema Ereditario da carenza di C1 Inibitore (C1-INH-HAE)(Cicardi et al., 2014) è una malattia rara che costringe i pazienti a confrontarsi con un’estrema variabilità interindividuale ed intraindividuale delle sue manifestazioni, e che compromette la qualità di vita delle persone che ne sono affette e delle loro famiglie (Banerji, 2013; Caballero et al., 2014). Nonostante i progressi della ricerca nell’individuazione dell’origine genetica, le cause dell’insorgenza dei sintomi restano ancora poco chiare. Recenti lavori scientifici annoverano lo stress psicologico tra i potenziali triggers degli attacchi di angioedema in base a dati auto-riferiti dai pazienti. La connessione tra stress psicologico ed attacchi tuttavia non è mai stata esplorata. (Fouche at al., 2013; Zotter at al., 2014). Obiettivo del contributo è approfondire il rapporto tra processi psicologici, stress e regolazione emotiva nelle manifestazioni di Angioedema Ereditario in età evolutiva. Inoltre, si intende osservare se tali aspetti assumano caratteristiche peculiari in questi pazienti oppure se riflettano condizioni comuni a giovani affetti da diverse patologie croniche.

Icatibant was efficacious and generally well tolerated for type I or II hereditary angioedema (HAE) attacks in adults in the phase III, randomized, placebo-controlled For Angioedema Subcutaneous Treatment (FAST)-3 trial. The Icatibant Outcome Survey (IOS) is an international, observational study assessing icatibant treatment of HAE attacks. We conducted a posthoc analysis to compare for the first time the treatment of HAE type I or II attacks in patients prescribed icatibant in real-world (IOS) versus controlled trial settings (FAST-3). In FAST-3, patients received icatibant administered by health care professionals (HCPs). In IOS, patients self-administered icatibant or were treated by HCPs. Median time to treatment, time to resolution (almost complete resolution [FAST-3] or complete resolution [IOS]), and attack duration in patients who were treated by an HCP were compared between IOS and FAST-3. Descriptive statistical methods compared nonlaryngeal attacks treated less than 12 hours from attack onset. Analysis included 102 patients (376 attacks) from IOS and 43 patients (43 attacks) from FAST-3 (controlled phase). All endpoints were significantly longer for patients in FAST-3 (HCP administration) versus IOS (HCP administration) (p < .001; all comparisons). For FAST-3 (HCP administered) versus IOS (HCP administered), median time from attack onset to treatment was 6.5 versus 2.0 hours, median time to symptom resolution was 8.0 versus 3.5 hours, and median attack duration was 16.9 versus 7.3 hours, respectively. For combined HCP and self-administration in IOS, these endpoints were 1.6, 4.4, and 7.8 hours, respectively. This posthoc analysis showed for the first time that type I and II HAE attacks were treated earlier with icatibant in a real-world versus a phase III setting, with a shortened time to symptom resolution and attack duration. ClinicalTrials.gov NCT00912093 (FAST-3); NCT01034969 (IOS).

Hereditary Angiooedema (HAE) is characterized by a deficit or by a malfunctioning of C1- 1nh; its symptoms vary greatly from one individual to another. Some studies suggest that some of the attacks of HAE may be triggered or affected by stress and emotional states (Zotter et al.,2014), however this link has never been examined in depth. Moreover, recent research has highlighted the influence of the neurological correlatives of stress in theactivation of the compliment cascade, a system already compromised in those suffering from HAE [1] [2]. Aims With this pilot study we intend to explore the connection between stress, emotional states and the variability of the attacks, in a sample of 11 individuals aged between 4 and 17 with HAE, together with their parents. It is a preliminary study, which aims to explore whether emotions have a direct or indirect influence on the development of HAE. Methods We adopt a multi method approach, using widely -used, internationally recognized tests, listed below: - Semi-structured interviews with parents to explore their interpretation on the variability of the attacks; - CBCL to exclude cases of psychopathology; - CLES to evaluate the perceived level of stress; - AQC on alexithymia; - LEAS-C on emotional awareness; - TEMAS on the functions of personality; - A diary of symptoms, noting the frequency, intensity and the location of the attacks. Results Although 92% of parents believed that emotional states played an important role in the triggering of attacks, the young patients were unable or had difficulty articulating their emotional states, more in general with their processes of emotion regulation (De Steno et al., 2013). This may well be connected to the high levels of stress experienced by nearly all the patients seen in the CLES test. These high levels of stress, in 9 out of 11 cases, correlated with the frequency of the attacks. Finally, from the CBCL results no personality disorder emerged connected to HAE. Conclusions. We believe that by encouraging skills aimed at expressing emotions caused by stress, prove useful in the treatment and management of individuals suffering from HAE. The results of this pilot study highlighted the need for further research on the role of psychological factors connected to HAE.