Zsuzsanna Zotter

Short-term prophylaxis in hereditary angioedema due to deficiency of the C1-inhibitor – a long-term survey

Hereditary angioedema is a potentially life‐threatening disorder, because edema occurring in the mucosa of the upper airways can lead to suffocation. The management of HAE consists of avoiding the triggering factors, prophylaxis, and the acute treatment of edematous episodes. Medical procedures can also provoke edematous attacks, and therefore, short‐term prophylaxis (STP) is recommended before such interventions. Our aim was to evaluate the efficacy and safety of STP administered before medical procedures.

The influence of trigger factors on hereditary angioedema due to C1-inhibitor deficiency

BackgroundHereditary 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.MethodsIn 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.ResultsDuring 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%.ConclusionThis 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.

Treatment of attacks with plasma-derived C1-inhibitor concentrate in pediatric hereditary angioedema patients

reported that myeloperoxidase-positive neutrophils are easily detectable in the lesional skin of patients with SJS/TEN and suggested that neutrophils might contribute to the tissue damage through release of reactive oxygen species and lysosomal enzymes. TH17 cells might be involved in inflammation and tissue damage in patients with SJS/TEN through regulation of the recruitment of neutrophils and other inflammatory leukocytes. Pennino et al recently demonstrated that the IL-17 infiltrating skin lesions of patients with allergic contact dermatitis strongly enhance the display of adhesion molecules, such as intercellular adhesion molecule 1, on keratinocytes, thereby promoting T cell–keratinocyte adhesion and T cell–mediated cytotoxicity and resulting in keratinocyte apoptosis. Similarly, TH17 cells might contribute to the immune responses of patients with SJS/ TEN as enhancers. Thus, TH17 cells appear to be involved in the inflammation of SJS/TEN, as well as in psoriasis and bullous pemphigoid. Both SJS/TEN and EMM are characterized by cutaneous eruptions, such as typical or atypical target lesions, with mucosal involvement; however, the 2 diseases are now considered distinct entities on the basis of clinical, histopathologic, and etiologic differences. Our results suggest that SJS/TEN is different from EEM in terms of cellular cytokine pattern. In conclusion, TH17 cells might play a role in the pathogenesis of SJS/TEN.Our results provide new insight into the pathogenesis and possible treatment of this serious disease. Yuichi Teraki, MD Misaki Kawabe, MD Seiichi Izaki, MD

Lack of increased prevalence of immunoregulatory disorders in hereditary angioedema due to C1-inhibitor deficiency

Hereditary angioedema due to deficiency of C1-INH (HAE-C1-INH) is associated with enhanced consumption of the early complement components, which may predispose for autoimmune disease. We assessed the prevalence of such disorders among HAE- C1-INH patients and their impact on the natural course of HAE-C1-INH. Clinical data and immunoserological parameters of 130 HAE-C1-INH and 174 non-C1-INH-deficient patients with angioedema were analyzed. In our study, the incidence of immunoregulatory disorders was 11.5% in the population of HAE-C1-INH patients and 5.2% among non-C1-INH-deficient controls with angioedema. Immunoserology screening revealed a greater prevalence of anticardiolipin IgM (p=0.0118) among HAE-C1-INH patients, than in those with non-C1-INH-deficient angioedema. We did not find higher prevalence of immunoregulatory disorders among our HAE-C1-INH patients. However, in patients with confirmed immunoregulatory disorders, the latter influenced both the severity of HAE-C1-INH and the effectiveness of its long-term management. Appropriate management of the immunoregulatory disease thus identified improves the symptoms of HAE-C1-INH.

Comprehensive study into the activation of the plasma enzyme systems during attacks of hereditary angioedema due to C1-inhibitor deficiency

BackgroundThe 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.MethodsEleven 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.ResultsCompared 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.ConclusionsComparing 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.

Neutrophil activation during attacks in patients with hereditary angioedema due to C1-inhibitor deficiency.

BackgroundEarlier 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.MethodsWe 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.ResultsNGC 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.ConclusionIncreased 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.

Risk of thromboembolism in patients with hereditary angioedema treated with plasma-derived C1-inhibitor.

BACKGROUND Plasma-derived C1-inhibitor (C1-INH) concentrates (pdC1-INH) have been used as safe and effective treatments for hereditary angioedema with C1-INH deficiency (C1-INH-HAE) for >30 years. Notwithstanding this, sporadic reports and a study into the high-dose therapy of neonates with C1-INH concentrate administered in an off-label indication raised concerns that this drug might increase the risk of thromboembolism. OBJECTIVE To investigate the incidence of thromboembolism and the background of the risk factors related to treatment with pdC1-INH. METHODS Our retrospective cohort study of 144 patients with C1-INH-HAE compared the incidence of thromboembolism and its risk factors in patients who received pdC1-INH with those who did not receive pdC1-INH as well as with those treated with danazol or with tranexamic acid. RESULTS During the observation period (29 years), 104 of the 144 subjects received pdC1-INH. The average dose per treatment was 573.59 IU. None of the patients used an indwelling central venous catheter. Multiple risk factors for thromboembolism were identified in 93 of the 104 patients treated with pdC1-INH. The incidence rate of thromboembolism was 0.0019/100 person-years in patients treated with pdC1-INH, whereas it was 0.0211/100 person-years in the not-treated group. CONCLUSION Our cohort study did not find any evidence for an increased risk of thromboembolism during treatment with pdC1-INH, despite the presence of multiple predisposing factors.

Home treatment of attacks with conestat alfa in hereditary angioedema due to C1-inhibitor deficiency.

Conestat alfa, a recombinant human C1 inhibitor (rhC1-INH) is a novel therapeutic option for the acute treatment of hereditary angioedema due to C1-INH (HAE-C1-INH) deficiency. Our aim was to investigate the efficacy and safety profile of conestat alfa in patients with HAE-C1-INH, under real-life conditions. We analyzed 65 edematous episodes requiring acute treatment and occurring in two female HAE-C1-INH patients. The patients were treated at home with rhC1-INH per occasion. They recorded the time of rhC1-INH administration, the time to the onset of improvement, and time to the complete resolution of symptoms, as well as the side effects. Symptom severity and patient satisfaction were measured with a visual analog scale (VAS). Thirty-three HAE attacks occurred in submucosal tissue, 17 in subcutaneous tissue, and 15 had mixed locations. After the administration of rhC1-INH, clinical symptoms improved within 0.50 (0.17-4.50 hours) hours and resolved completely within 9.00 (1.67-58.75 hours) hours. The time between the onset of the attack and the administration of rhC1-INH was correlated with the time when the symptoms stopped worsening (R = 0.3212; p = 0.0096) and the time to complete resolution of the symptoms (R = 0.4774; p < 0.0001). The time to response to the drug differed with attack location. The efficacy and safety of rhC1-INH persisted after repeated use. None of the patients experienced a recurrence of the HAE attack or drug-related systemic adverse events. The mean VAS score of patient satisfaction was 93.14. Home treatment with rhC1-INH was an effective and well-tolerated therapy for all types of HAE attacks.

Bacteriuria increases the risk of edematous attacks in hereditary angioedema with C1-inhibitor deficiency.

Urinary tract infections are considered among the most common infectious disorders in humans. Various infections may have a role in inducing HAE attacks. Our study intended to evaluate bacteriuria in the urinalysis of patients with C1‐INH‐HAE. Urine specimens contributed by 139 patients with C1‐INH‐HAE at the annual control visits were studied retrospectively for microorganisms. We analyzed the presence of bacteriuria in relation to the clinical symptoms. Taking into account three randomly selected urine specimens, we found that the cumulative number of edematous attacks was higher in patients with bacteriuria than in those without (P = 0.019, P = 0.022, P = 0.014). Considering the same patients, attack number was significantly higher (14.51 vs 8.63) in patients with bacteriuria than in those without (P < 0.0001). In patients with bacteriuria, we found a higher incidence of edema formation during the year before evaluation, which may suggest the triggering role of bacteriuria in the occurrence of edematous episodes.

Glucocorticoid receptor gene polymorphisms in hereditary angioedema with C1-inhibitor deficiency

BackgroundHereditary 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.ResultsWe 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.ConclusionsThe 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.