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The condition of chronicity implies the need of a reorganization of one’s existence, both in the immediate and in the long term, due to the changes in personal resources and social roles and because of the constraints imposed by the disease. The Sense of Grip on Chronic Disease (SdiP-M) model intends to focus on the role of sensemaking processes in the psychological adjustment to illness, emphasizing the patient’s role and his skills in managing his health condition. In this study, the authors propose a mixed method research which implies the adaptation of the narrative interview on the Sense of Grip on chronic Disease. The interview was administered to 28 adults suffering from Hereditary Angioedema and has been analysed with a theory driven approach, aims at exploring the modalities of five narrative functions: temporal articulation, integration of the experience in everyday life, emotion regulation, social support and coping. Through a Multiple Corrispondence Analysis and a cluster analysis, the authors have identified three different Sense of Grip on Disease Profiles, representative of different degrees of flexibility, integration and adjustment to disease. Results suggest that Quality of Life is related to promotion of processes involved in Sense of Grip on Chronic Disease: these processes are relevant for supporting patient and healthcare system engagement.

The Icatibant Outcome Survey (IOS) is an observational study monitoring safety and effectiveness of icatibant in the real‐world setting. We analyzed safety data from 3025 icatibant‐treated attacks in 557 patients (enrolled between July 2009 and February 2015). Icatibant was generally well tolerated. Excluding off‐label use and pregnancy, 438 patients (78.6%) did not report adverse events (AEs). The remaining 119 (21.4%) patients reported 341 AEs, primarily gastrointestinal disorders (19.6%). Of these, 43 AEs in 17 patients (3.1%) were related to icatibant. Serious AEs (SAEs) occurred infrequently. A total of 143 SAEs occurred in 59 (10.6%) patients; only three events (drug inefficacy, gastritis, and reflux esophagitis) in two patients were considered related to icatibant. Notably, no SAEs related to icatibant occurred in patients with cardiovascular disease, nor in those using icatibant at a frequency above label guidelines. Additionally, no major differences were noted in AEs occurring in on‐label vs off‐label icatibant users.

The genetic alteration underlying the great majority of primary angioedema with normal C1 inhibitor (nl-C1-INH-HAE) cases remains unknown. To search for variants associated with nl-C1-INH-HAE, we genotyped 133 unrelated nl-C1-INH-HAE patients using a custom next-generation sequencing platform targeting 55 genes possibly involved in angioedema pathogenesis. Patients already diagnosed with F12 alterations as well as those with histaminergic acquired angioedema were excluded. A variant pathogenicity curation strategy was followed, including a comparison of the results with those of genotyping 169 patients with hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE), and only filtered-in variants were studied further. Among the examined nl-C1-INH-HAE patients, carriers of neither the ANGPT1 p.Ala119Ser nor the KNG1 p.Met379Lys variant were found, whereas the PLG p.Lys330Glu was detected in four (3%) unrelated probands (one homozygote). In total, 182 different variants were curated, 21 of which represented novel mutations. Although the frequency of variants per gene was comparable between nl-C1-INH-HAE and C1-INH-HAE, variants of the KNG1 and XPNPEP1 genes were detected only in nl-C1-INH-HAE patients (six and three, respectively). Twenty-seven filtered variants in 23 different genes were detected in nl-C1-INH-HAE more than once, whereas 69/133 nl-C1-INH-HAE patients had compound heterozygotes of filtered variants located in the same or different genes. Pedigree analysis was performed where feasible. Our results indicate the role that alterations in some genes, like KNG1, may play in disease pathogenesis, the complex trait that is possibly underlying in some cases, and the existence of hitherto unrecognized disease endotypes. © 2020 by the authors.

BACKGROUND: Patients with hereditary angioedema (HAE) due to C1-inhibitor deficiency (C1-INH-HAE) experience recurrent attacks of cutaneous or submucosal edema that may be frequent and severe; prophylactic treatments can be prescribed to prevent attacks. However, despite the use of long-term prophylaxis (LTP), breakthrough attacks are known to occur. We used data from the Icatibant Outcome Survey (IOS) to evaluate the characteristics of breakthrough attacks and the effectiveness of icatibant as a treatment option.METHODS: Data on LTP use, attacks, and treatments were recorded. Attack characteristics, treatment characteristics, and outcomes (time to treatment, time to resolution, and duration of attack) were compared for attacks that occurred with versus without LTP.RESULTS: Data on 3228 icatibant-treated attacks from 448 patients with C1-INH-HAE were analyzed; 30.1% of attacks occurred while patients were using LTP. Attack rate, attack severity, and the distribution of attack sites were similar across all types of LTP used, and were comparable to the results found in patients who did not receive LTP. Attacks were successfully treated with icatibant; 82.5% of all breakthrough attacks were treated with a single icatibant injection without C1-INH rescue medication. Treatment outcomes were comparable for breakthrough attacks across all LTP types, and for attacks without LTP.CONCLUSIONS: Patients who use LTP should be aware that breakthrough attacks can occur, and such attacks can be severe. Thus, patients with C1-INH-HAE using LTP should have emergency treatment readily available. Data from IOS show that icatibant is effective for the treatment of breakthrough attacks. Trial Registration NCT01034969.

Background: Hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) is characterized by recurrent swelling in subcutaneous or submucosal tissues. Symptoms often begin by age 5-11 years and worsen during puberty, but attacks can occur at any age and recur throughout life. Disease course in elderly patients is rarely reported. Methods: The Icatibant Outcome Survey (IOS) is an observational study evaluating the safety, tolerability, and efficacy of icatibant. We conducted descriptive analyses in younger (age < 65 years) versus elderly patients (age >= 65 years). Here, we report patient characteristics and safety-related findings. Results: As of February 2018, 872 patients with C1-INH-HAE type I/II were enrolled, of whom 100 (11.5%) were >= 65 years old. Significant differences between elderly versus younger patients, respectively, were noted for median age at symptom onset (17.0 vs 12.0 years), age at diagnosis (41.0 vs 19.4 years), and delay between symptom onset and diagnosis (23.9 vs 4.8 years) (P

Summary Hereditary angioedema (HAE) is an autosomal dominant disease due to mutations in the C1 inhibitor gene (C1NH) that affects protein synthesis (HAE type I) or function (HAE type II). In 45 subjects affected by HAE diagnosed through clinical features and C1 inhibitor deficiency from the south of Italy (38 with type I and 7 with type II HAE), the whole C1NH coding region was screened for mutations by direct DNA sequencing. A severity score based on clinical manifestation, age at disease onset, and need for long-term prophylaxis was used to investigate possible genotype-phenotype correlations. A series of 22 different mutations was identified: nine missense (40.9%), five nonsense (22.7%), six frameshift (27.3), one small deletion (4.5%), and one splicing defect (4.5%). Nine C1NH mutations have not been previously described. No correlation was found between C1 inhibitor function level and severity score or age at first attack. Moreover, there was no correlation between different types of mutations and clinical phenotype. The number of different mutations identified highlights the heterogeneity of C1 inhibitor deficiency and supports the hypothesis that HAE clinical phenotype is not strictly related to the type of mutation but rather depends on unknown factors.

Background Hereditary angioedema (HAE) due to C1-inhibitor deficiency (C1-INH-HAE) is a rare, potentially fatal, bradykinin-mediated disease. Icatibant is a bradykinin B2 receptor antagonist originally approved in 2008 in the European Union and 2011 in the United States as an acute therapy option for HAE attacks in adults. Objective To compare demographics, disease characteristics and treatment outcomes of icatibant-treated HAE attacks in patients with C1-INH-HAE enrolled in the Icatibant Outcome Survey across six European countries: Austria, France, Germany, Italy, Spain and the UK. Methods The Icatibant Outcome Survey [IOS; Shire, Zug, Switzerland (NCT01034969)] is an international observational study monitoring the safety and effectiveness of icatibant. Descriptive, retrospective analyses compared IOS country data derived during July 2009–April 2015. Results Overall, 481 patients with C1-INH-HAE provided demographic data. A significant difference across countries in age at onset (P = 0.003) and baseline attack frequency (P < 0.001) was found although no significant differences were found with respect to gender (majority female; P = 0.109), age at diagnosis (P = 0.182) or delay in diagnosis (P = 0.059). Icatibant was used to treat 1893 attacks in 325 patients with majority self-administration in all countries. Overall, significant differences (all P < 0.001) were found across countries in time to treatment [median 1.8 h; median range: 0.0 (Germany–Austria) to 4.4 (France) h], time to resolution [median 6.5 h; median range: 3 (Germany–Austria) to 12 (France) h] and attack duration [median 10.5 h; median range: 3.1 (Germany–Austria) to 18.5 (France) h]. Conclusion These data form the first European cross-country comparison of disease characteristics and icatibant use in patients with C1-INH-HAE who are enrolled in IOS. International variation in icatibant practice and treatment outcomes across the six European countries assessed highlight the need to further investigate the range of country-specific parameters driving regional variations in icatibant use.

Analysis of Polymorphism C558T of MAL (TIRAP) in Mediterranean Spotted Fever M. Bova1, L. Scola1, C. Colomba1, L. Vaccarino1, P. Di Gangi1, G. Santini1, G. Giammanco1, C. R. Balistreri1, D. Lio1, L. Titone Lanza Di Scalea1 1University of Palermo, Palermo, Italy Background: In our previous studies, we have demonstrated that cytokine polymorphisms, such as IFNγ +874T/A or IL-17 SNP (7488T/C), might interfere with R. Conorii infection control. In addition, we have reported that +896A/G TLR4 SNP is a component of a genetic background that might influence the clinical outcome of Boutonneuse fever (Mediterranean spotted fever, MSF). The +869G allele, that attenuates receptor signaling, was actually significantly overrepresented in symptomatic patients. Rickettsial PAMPS recognised through TLR4 and TLR2, activates the MyD-88 signaling pathway, which is involved in the transcription activation of pro-inflammatory cytokine genes. In this pathway MAL (also known as TIRAP) plays a crucial role, therefore, TIRAP polymorphisms may influence the response to the pathogen. In particular, we analyzed C558T of TIRAP that seems to attenuate TLR signaling. Methods: A total of 70 Sicilian patients affected by MSF and 230 control subjects matched for age, gender, and geographic origin were typed for TIRAP SNP (C558T) according to our laboratory procedures. Results: No significant differences between the two groups were observed; therefore, the TIRAP C558T genotypes seem not to influence the susceptibility or protection against MSF. Conclusions: The results obtained suggest that the analyzed SNP on the gene coding for MAL does not seem relevant in determining increased susceptibility for the development of MSF. Nevertheless, it is appropriate to enlarge the casuistry and the number of SNPs involved in TLR signaling pathways to better define the genetic background that modulates the immune response against R. conorii infection and the consequential clinical outcome.

Background: Hereditary (HAE) is characterised by remarkable clini- cal variability and unpredictability of attacks. Previous studies suggested that stress and emotions can trigger HAE attacks. We carried out a study on 11 patients aged 4–17 years as well as their parents, to explore the connection between psychological factors and clinical symp- toms of HAE. Methods: We examined the psychopatho- logical risk of the patients, the connection between stress and illness and how the par- ents interpret the causes of the attacks. The Child Behaviour Check-List (CBCL) questionnaire was administered to 11 par- ents to evaluate the psychopathological risk. The young patients completed the Coddington Life Events Scale (CLES) to assess the level of perceived stressful events. Finally, semi-structured interviews were administered to the parents to explore their interpretations of the factors responsi- ble for the onset of the attacks. Results: On the CBCL scales more than one half of the patients achieved critical scores: five patients in the syndrome scale (3 of them in thought disorders); six patients in the scales dsm-oriented (anxiety and somatic complaints); six of them in the activity scale (competence scale). In the CLES 10 patients out of 11 were above the normal levels of stress, but frequency of attacks was not proportionally increased. The interviews show that 10 families out of 11 consider emotions to play a part in the expression of HAE, even if interpretation of them as symptoms, triggers or conse- quences of HAE differs between families. Conclusion: This pilot study confirms a connection between emotional and stressful factors and the onset of HAE attacks, evehough a larger study is needed. The per- ception of stress in patients with HAE is above the norm and the recognition of the role of emotions is constant. These dimen- sions do not correlate sistematically with the variablility of the symptoms. It is likely that processes of emotion regulation play a role in the onset of the attacks.

Background: Genes coding for the cytochrome P450 (CYP) enzyme system implied in antineoplastic drug metabolism pathways are highly polymorphic. This may influence both carcinogen metabolism and drug pharmacodynamics modifying their therapeutic efficacy and side effects. Methods: We investigated the influence of genetic polymorphisms of CYP enzymes: rs1799853 (CYP2C9), rs35742686 (CYP2D), rs5030655 (CYP2D6/3), rs2740574 (CYP3A4/1) rs776746 (CYP3A5) on the response of chemotherapy and clinical outcomes, in a group of 56 patients affected by sporadic CRC, treated with the standard protocols. A total of 44 patients were in complete remission after treatment, 12 had persistence of the disease. Polymorphisms were typed using a competitive allele specific PCR assay (KASPar), developed by KBioscience. Statistical were analyzed using the χ2 test with Yates correction and Fisher's Exact Test. Significance was defined as p values

IMIN11. Cytokine Polymorphism in Takotsubo Cardiomyopathy P. Di Gangi1, L. Scola1, S. Giambanco1, M. Bova1, G. Santini1, L. Vaccarino1, C. R. Balistreri1, D. Lio1, P. Assennato1, S. Novo1, G. Novo1 1University of Palermo, Palermo, Italy Background: Takotsubo (TT) cardiomyopathy is characterised by an acute left ventricular dysfunction triggered by emotional or physical stresses. Clinically, the syndrome is characterised by acute symptoms mimicking acute infarction without relevant electrocardiographic and biochemical markers of myocardial damage changes. Stressful events inducing an excess catecholamine release and myocardial β-adrenergic receptors (β-AR) seem to play a major role in TT. Accordingly, we have reported that the L41Q polymorphism of the G protein-coupled receptor kinase 5 (GRK5), which, leads to β-arrestin recruitment and mediates β- AR desensitisation might play a role in TT susceptibility. Extended sympathetic activation may influence the pro-inflammatory cytokine secretion triggering b-adrenergic receptors of the immuno system cells. In turn, IL-1, IL-6, TNF-α stimulating the synthesis and release of CRH and norepinephrine might magnify the activation of the sympathetic system. In this view, we have analyzed the role that polymorphisms of inflammatory cytokines might play in the pathogenesis of TT. Methods: We analysed ADRB-1 (rs1801253), IL–1A (rs1800587), IL-1B (rs16944), (rs1143634), IL-6 (rs1800795), TNF-α(rs1800629), TGF- β(rs1800471), IL-10 (rs1800872), (rs1800871), (rs1800896), MAL (rs8177374) and TLR-4 polymorphisms in 25 TT patients and 100 controls using KASPar SNP genotyping method. Statistical analysis of data was performed using dominant, codominant, and recessive models. Results: Analysis of the genotypic and allelic frequencies does not allow the detection of relevant differences in polymorphism frequencies in TT patients. Conclusions: Because of the low number of patients, further studies are necessary to understand the role of cytokine polymorphisms in Takotsubo cardiomyopathy. Work is in progress to recruit and analyse a larger group of patients.

BACKGROUND: The consensus documents published to date on hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) have focused on adult patients. Many of the previous recommendations have not been adapted to pediatric patients. We intended to produce consensus recommendations for the diagnosis and management of pediatric patients with C1-INH-HAE.METHODS: During an expert panel meeting that took place during the 9th C1 Inhibitor Deficiency Workshop in Budapest, 2015 (www.haenet.hu), pediatric data were presented and discussed and a consensus was developed by voting.RESULTS: The symptoms of C1-INH-HAE often present in childhood. Differential diagnosis can be difficult as abdominal pain is common in pediatric C1-INH-HAE, but also commonly occurs in the general pediatric population. The early onset of symptoms may predict a more severe subsequent course of the disease. Before the age of 1 year, C1-INH levels may be lower than in adults; therefore, it is advisable to confirm the diagnosis after the age of one year. All neonates/infants with an affected C1-INH-HAE family member should be screened for C1-INH deficiency. Pediatric patients should always carry a C1-INH-HAE information card and medicine for emergency use. The regulatory approval status of the drugs for prophylaxis and for acute treatment is different in each country. Plasma-derived C1-INH, recombinant C1-INH, and ecallantide are the only agents licensed for the acute treatment of pediatric patients. Clinical trials are underway with additional drugs. It is recommended to follow up patients in an HAE comprehensive care center.CONCLUSIONS: The pediatric-focused international consensus for the diagnosis and management of C1-INH-HAE patients was created.

Background: Genetic background implicated in cytokine network may have a key role in the susceptibility to colorectal cancer (CRC). The TGF-β pathway is involved in several biological processes, including cell proliferation, differentiation, migration and apoptosis. Methods: rs1800471 SNP polymorphism of TGF-ß1 rs334348 and rs334349 of TGF-βR1, rs900 of TGF-β2 and rs4522809 of TGF-β2R2 were typed in a group of 82 patients affected by sporadic CRC and in 237 age- and sex-matched healthy controls, using a competitive allele specific PCR assays (KASPar), developed by KBioscience (England). Results: No significant genetic contribution has been observed for 3 of the 5 SNPs tested. Indeed, a significant different allelic distribution between patients and controls has been observed for the polymorphism G→C (rs1800471) responsible for an arginine vs. proline missense change (R25P) in codon 25 of the TGF-β gene (P = 0.021). By this analysis, a weak protective role would emerge for the minor allele C in the susceptibility to the disease. Furthermore the analysis of genotype and allelic frequencies of rs4522809 showed a statistically significant difference (p =0,0016 and P = 0,0019 respectively) between patients and controls. Conclusions: All together these results, suggest that functional relevant SNPs of TGF-beta pathway might be involved in susceptibility to CRC, influencing the extension and severity of the disease.

Background: We have recently reported that the susceptibility for Mediterranean spotted fever (MSF) caused by Rickettsia conorii, is influenced by the Th2 and Th1 cytokine genetic polymorphism profiles. Less it is known on the effect of gene polymorphisms of cytokine produced by the Th17. Methods: 70 Sicilian patients affected by MSF and 239 control subjects matched for age, gender, and geographic origin were typed for functionally relevant single nucleotide polymorphisms (SNPs) of IFN-γ (+874 T/A), IL-18 (-137 G/C and -607A/C ) and IL-17 (7488T/C) according to our laboratory procedures. Results: No significant differences in IL-18 -137 G/C, -607A/C and in IFN-γ +874 T /A genotype frequencies were observed. On the contrary a statistically significant (p value= 0.0126) increase of the IL-17 TT genotype frequency of in MSF was observed. Conclusions: Cytokines play a crucial role in modulation of the host defense and genetically determined differences in cytokine production seem to influence the extent and severity of a large number of infectious diseases. 7488T/C SNP impinge on IL-17 signaling and might play a crucial role in neutrophil recruitment, induction of IFN-γ and IL-12 production in macrophages and in the induction of T regulatory cells. Our results suggest that a genetically determined increase of IL-17 dependent activation pathways might interfere with R. Conorii infection control.

Background: It is well known that exercise has beneficial effects on health. Although intense exercise is experienced by the body as a condition of stress, a well designed training has long term beneficial effects on the organism of an athlete. Less is known about the effects that the genetic background might have on training adaptation and on the consequent modification of laboratory parameters. Methods: In our study we evaluated the blood chemistry parameters of a group of 41 athletes compared with a group of 45 amateur athletes, to assess whether the training has effects on their variation. In addition we typed our subjects for polymorphisms 308 A/G of the tumor necrosis factor-α (TNF-α) and 1082 A/G of Interleukin-10 (IL10). Results: After statistical analysis, performed with Mann-Whitney Test, we observed a statistically significant (p value< 0,05) increase of basophils, eosinophils, monocytes, and total bilirubin and decreased levels of neutrophils, glucose, electrolytes and AST in professionals compared to amateurs. These parameters were not modified by the genetic background. Actually the training modification observed were independent of the presence of pro-inflammatory (carrier allele A of 1082 A/G of IL10) or anti-inflammatory alleles (subjects A negative for 308 A/G of TNFα). Conclusions: The genetic polymorphisms analyzed do not influence changes in laboratory parameters values induced by professional training.

Hereditary angioedema (HAE) due to C1-inhibitor (C1-INH) deficiency (C1-INH-HAE) is a rare disease, with a reported prevalence of about 1 : 50 000. C1-INH-HAE causes disabling symptoms, which may be life-threatening if swelling affects upper airways. Diagnostic procedures are now well established and the role of bradykinin as the main mediator of plasma outflow eliciting angioedema formation has been clearly elucidated.Increased understanding of the pathogenesis of C1-INH-HAE allowed in recent years the development of new drugs targeted to inhibit bradykinin synthesis (Ecallantide) or activity (Icatibant). At the same time, a recombinant C1-INH concentrate (Ruconest) was produced from the milk of transgenic rabbits and two plasma-derived C1-INHs (Berinert, Cinryze) underwent controlled trials to obtain marketing authorization. In 2012, an Italian network for C1-INH-HAE (ITACA) was established by physicians of 17 HAE reference centres to collect data from Italian patients and to homogenize and improve the diagnostic and therapeutic approach to the disease.Although there is a widespread agreement on therapeutic goals and treatment of C1-INH-HAE acute attacks, different approaches to prophylaxis are still present among HAE experts. The clinical experience of ITACA on a large population of C1-INH-HAE patients followed for several years may help in identifying the most effective strategies for the management of the disease.

Angioedema owing to hereditary deficiency of C1 inhibitor (HAE) is a rare, life-threatening, disabling disease. In the last 2 years, the results of well-designed and controlled trials with existing and new therapies for this condition have been published, and new treatments reached the market. Current guidelines for the treatment for HAE were released before the new trials and before the new treatments became available and were essentially based on observational studies and expert opinion. To provide evidence-based HAE treatment guidelines supported by the new studies, a conference was held in Gargnano del Garda, Italy, from September 26 to 29, 2010. The meeting hosted 58 experienced HAE expert physicians, representatives of pharmaceutical companies and representatives of HAE patients' associations. Here, we report the topics discussed during the meeting and evidence-based consensus about management approaches for HAE in adult/adolescent patients.