Search

Background: The generic 36-item Short-Form Health Survey (SF-36v2) has been used to assess health related quality of life in adult patients with hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE) even though it has not yet been validated for use in this specific disease.Objective: This study aims to validate the SF-36v2 for use in adult patients with C1-INH-HAE.Results: There was a very low item non-response rate (1-3.4%), with a high ceiling effect in 25/35 items and a low floor effect in 3/35 items. A moderate ceiling effect was observed in 5/8 dimensions of the SF-36v2, whereas no floor effect was noticed in any of the dimensions. Internal consistency was good to excellent with Cronbach's alpha coefficient ranging between 0.82 and 0.93 for the different dimensions. Construct validity was good: seven out of the 8 hypotheses defined on clinical criteria were confirmed, discriminant validity assessment showed significant differences among patients with different C1-INH-HAE severity, convergent validity showed a good correlation among the physical and mental component summaries of the SF-36v2 and the HAE-QoL total score (0.45 and 0.64 respectively, P < 0.001). Test-retest reliability was high with intraclass correlation coefficient varying from 0.758 to 0.962. The minimal clinically important difference was calculated by distribution methods and small differences in the domain scores and in the component summaries scores were shown to be meaningful.  CONCLUSIONS: The psychometric properties of the SF-36v2 show it can be a useful tool to assess HRQoL in adult patients with C1-INH-HAE, although with some content validity limitation.Methods: The psychometric properties of the SF-36v2 were evaluated in an international setting based on responses from 290 adult C1-INH-HAE patients in 11 countries. [ABSTRACT FROM AUTHOR]

Background: Acquired or genetic abnormalities of the complement alternative pathway are the primary cause of C3glomerulopathy(C3G) but may occur in immune-complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) as well. Less is known about the presence and role of C4nephritic factor(C4NeF) which may stabilize the classical pathway C3-convertase. Our aim was to examine the presence of C4NeF and its connection with clinical features and with other pathogenic factors., Results: One hunfe IC-MPGN/C3G patients were enrolled in the study. C4NeF activity was determined by hemolytic assay utilizing sensitized sheep erythrocytes. Seventeen patients were positive for C4NeF with lower prevalence of renal impairment and lower C4d level, and higher C3 nephritic factor (C3NeF) prevalence at time of diagnosis compared to C4NeF negative patients. Patients positive for both C3NeF and C4NeF had the lowest C3 levels and highest terminal pathway activation. End-stage renal disease did not develop in any of the C4NeF positive patients during follow-up period. Positivity to other complement autoantibodies (anti-C1q, anti-C3) was also linked to the presence of nephritic factors. Unsupervised, data-driven cluster analysis identified a group of patients with high prevalence of multiple complement autoantibodies, including C4NeF., Conclusions: In conclusion, C4NeF may be a possible cause of complement dysregulation in approximately 10-15% of IC-MPGN/C3G patients.

Background: Hereditary angioedema caused by C1-inhibitor deficiency (C1-INH-HAE) is a rare, autosomal dominant disorder. C1-INH-HAE is characterized by edema-formation, which may occur in response to stress. The individual's response to stress stimuli is partly genetically determined. Activation of the hypothalamic-pituitary-adrenal axis results in the release of cortisol. In turn, the secreted gluco- and mineralocorticoids affect the metabolism, as well as the cardiovascular and immune systems. We hypothesized that changes in serum cortisol level and polymorphisms of the glucocorticoid receptor (GR) modify the individual sensitivity to stressor stimuli of C1-INH-HAE patients., Results: We compared the response to stress with Rahe's Brief Stress and Coping Inventory of 43 C1-INH-HAE patients, 18 angioedema patients and 13 healthy controls. 139 C1-INH-HAE patients and 160 healthy controls were genotyped for glucocorticoid receptor polymorphisms BclI, N363S and A3669G. Serum cortisol levels were determined during attacks and during symptom-free periods in 36 C1-INH-HAE patients. The relationships between clinical, laboratory data and GR SNPs (Single Nucleotide Polymorphisms) were assessed using ANOVA. C1-INH-HAE patients have decreased coping capabilities compared to healthy controls. Cortisol levels were significantly higher during attacks than in symptom-free periods (p = 0.004). The magnitude of the elevation of cortisol levels did not show a significant correlation with any clinical or laboratory data. Among the C1-INH-HAE patients, the carriers of the A3669G allele had significantly lower cortisol levels, and increased body mass index compared with non-carriers., Conclusions: The higher cortisol level observed during attacks may reflect the effect of a stressful situation (such as of the attack itself), on the patients' neuroendocrine system. In A3669G carriers, the lower cortisol levels might reflect altered feedback to the hypothalamic-pituitary-adrenal axis, due to decreased sensitivity to glucocorticoids.

Background: The 17-alpha-alkylated derivatives of testosterone are often used for the prevention of oedematous episodes in hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE). However, these agents can have many adverse effects, including erythrocytosis and polyglobulia. Our aim was to investigate occurrence of erythrocytosis and polyglobulia after long-term danazol prophylaxis in C1-INH-HAE., Methods: During the initial stage of our retrospective study, we explored whether C1-INH-HAE is associated with susceptibility to erythrocytosis and/or polyglobulia. In the second stage, we analyzed the haematological parameters of 39 C1-INH-HAE patients before, as well as after treatment with danazol for 1, 3, or 5 years. In the third stage, we studied the incidence of erythrocytosis and of polyglobulia after dosing with danazol for more than 5 years., Results: We did not find any significant difference between C1-INH-HAE patients not receiving danazol and healthy controls as regards the occurrence of erythrocytosis or polyglobulia. The haematological parameters did not change after treatment with danazol for 1, 3, or 5 years. Platelet count was an exception-it decreased significantly (p = 0.0115) versus baseline, but within the reference range. Treatment-related polyglobulia did not occur. We observed erythrocytosis in a single female patient after 1-year-and in three female patients after more than 5-year long-treatment with danazol. Erythrocytosis did not require intervention or the discontinuation of danazol therapy., Conclusions: We conclude that neither erythrocytosis, nor polyglobulia occurs more often in C1-INH-HAE patients than in healthy individuals; it can be observed only sporadically even after treatment with danazol.

Background: Earlier studies have shown that the absolute number of neutrophil granulocytes (NGs) may increase during attack of hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE). Whether NGs undergo activation during attack has not yet been investigated. However, as neutrophil elastase (NE) can cleave and inactivate C1-INH which may contribute to the dysregulation of the kallikrein-kinin system and hence, to edema formation. Our aim was to investigate the possible activation of NGs during attacks., Methods: We studied blood samples obtained from 26 patients with C1-INH-HAE during symptom-free periods and during attacks, along with samples from 26 healthy volunteers. NG count (NGC), NE, myeloperoxidase (MPO), pentraxin 3 (PTX3), CRP, C5a, factor H, IL-8, and TNF-α levels were measured., Results: NGC was higher during attacks than during symptom-free periods (p = 0.0132), and the same was observed for NE (p = 0.0026), MPO (p = 0.0008), and PTX3 levels (p = 0.0409). There was a strong positive correlation between NE and MPO levels during attacks (p < 0.0001, R = 0.709). Furthermore, IL-8 (p = 0.0061) and TNF-α (p = 0.0186) levels were also elevated during attacks, compared with symptom-free periods. By contrast, C5a and factor H levels were similar in samples obtained during attacks or in symptom-free periods., Conclusion: Increased NGC was associated with elevated NE and MPO levels - this suggests neutrophil activation during attacks. The strong positive correlation between NE and MPO levels, together with the elevated PTX3 concentration, may indicate the expression of neutrophil extracellular traps. All these processes may contribute to the activation of kallikrein-kinin system, which leads to the onset of an edematous episode.

Background: The activation of plasma enzyme systems contributes to hereditary angioedema attacks. We aimed to study the activation markers of the fibrinolytic, coagulation, and contact systems in a larger number of paired samples obtained from the same C1-INH-HAE patients in symptom-free periods and during attacks., Methods: Eleven parameters (Factors XI, XII, and C1-inhibitor activity; the concentrations of the D-dimer, prothrombin fragments 1 + 2, plasminogen, plasminogen activator inhibitor-1 [PAI-1], thrombin-anti-thrombin III [TAT] complex, fibrinogen) were measured along with prothrombin time and activated partial thromboplastin time (aPTT), using commercial kits. We compared these markers in samples obtained from the same 39 patients during attack-free periods and during 62 edematous episodes. Forty healthy subjects of matching sex and age served as controls., Results: Compared with the healthy controls, significantly higher FXI and FXII activity (p = 0.0007, p = 0.005), as well as D-dimer (p < 0.0001), prothrombin fragments 1 + 2 (p < 0.0001), and TAT (p = 0.0303) levels were ascertained in the patients during symptom-free periods. The evaluation of samples from symptom-free periods or obtained during attacks revealed the increase of FXII activity, as well as of the concentration of D-dimer, prothrombin fragments 1 + 2, and TAT during edematous episodes. PAI-1 level, prothrombin time, and aPTT decreased significantly during attacks, compared with symptom-free periods. D-dimer level was significantly higher during multiple- vs. single-site attacks., Conclusions: Comparing a large number of paired samples from symptom-free periods or from edematous episodes allowed accurate appraisal of the changes occurring during attacks. Moreover, our study pointed out that individual episodes may be characterized by different marker patterns.

Background: Danazol, a drug extensively used in the management of hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE), has various side effects. This study investigated the virilizing actions of this drug in 31 danazol-treated female patients with HAE-C1-INH. We compared our findings with those of healthy controls and with literature data., Methods: The patients were interviewed individually about the type and severity of the virilizing effects, as well as about their satisfaction with danazol therapy., Results: The average duration of danazol treatment was 10.31 years [2 to 23] and its mean daily dose was 131.7 mg [33 to 200]. The most common adverse effects were hirsutism (n=14), weight gain (n=13), and menstrual disturbances (n=8). The severity of danazol adverse effects did not differ by duration of treatment or by daily drug dose. The mean level of patient satisfaction with the treatment was high. The comparison of age-matched healthy controls and of HAE-C1-INH patients receiving danazol did not demonstrate a statistically higher incidence of any of the monitored symptoms in the danazol group., Conclusions: Our findings indicate that long-term danazol treatment - using the lowest effective dose - has only a mild virilizing effect.

Background: Hereditary angioedema (HAE) resulting from C1-inhibitor deficiency is characterized by attacks of subcutaneous and submucosal edema. Many factors have been presumed to induce edema. Our study analyzed these factors in a fairly large patient population., Methods: In the first stage of our study, we analyzed the data recorded by 92 subjects in their patient diaries over seven years. The second phase included 27 HAE patients, who had been completing the diary entry 'Trigger factors' every day for seven months whether or not they had experienced an attack., Results: During the initial stage, 91% of the subjects described some factor possibly related to the onset of an attack. They could identify a trigger factor - most commonly (21%) mental stress - in 30% of the 3176 attacks. We found a significant (p < 0.001) difference in the distribution of the trigger factors of the edematous attacks of different locations. The 27 participants of the second phase identified 882 potential trigger factors and recorded 365 attacks. Of these, 246 (67%) occurred on days when the patients identified a potential trigger factor. The likelihood of edema-formation associated with the latter was as follows: menstruation - 63%, infection - 38%, mental stress - 26%, physical exertion - 25%, meteorological changes - 21%, fatigue - 17%., Conclusion: This analysis of the trigger factors explored, for the first time, their potential role in inducing HAE attacks. Our findings might open new perspectives in extending the indications for edema-prophylaxis, and could contribute to a better understanding of the pathomechanism of HAE attacks.