Ibolya Czaller

The natural history of hereditary angioedema and the impact of treatment with human C1-inhibitor concentrate during pregnancy: a long-term survey

OBJECTIVE The course of hereditary angioedema (HAE) and the efficacy and safety of human C1-INH concentrate were appraised during pregnancy and the postpartum period, in patients with HAE. STUDY DESIGN Retrospective analysis of clinical data on 118 pregnancies (82 full-term and 36 abortions) in 41 female patients, extracted from the National HAE Registry, medical charts and patient diaries. RESULTS HAE attack frequency increases in 48% of pregnancies, whereas 33% of pregnancies were associated with mitigation of clinical signs and 19% of the pregnancies had no influence on the course of HAE, as compared to disease severity seen during the 2-year period preceding the pregnancy. During 46 full-term pregnancies, 26 patients reported attacks; 52% of these occurred in the third trimester. Abdominal attacks are the most common presentation of HAE during pregnancy. Attack number was significantly higher in patients who had sustained their initial attack before 8 years of age. Attack number increased during the third trimester if the fetus was afflicted by HAE. During the postpartum period, attacks occurred in 6/82 pregnancies. Patients received 91 vials of C1-INH concentrate altogether for the relief of acute attacks and for short- or long-term prophylaxis during pregnancy. This therapy was effective in all instances; no adverse effects were observed. CONCLUSIONS Pregnancy can either aggravate or mitigate edematous attacks, or alternatively, it may have no influence on the severity of the disease. According to our experience, C1-INH concentrate is an effective and safe therapeutic option during pregnancy.

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.

The effect of long-term danazol prophylaxis on liver function in hereditary angioedema?a longitudinal study

BackgroundDanazol is a drug most widely used for the prophylaxis of hereditary angioedema resulting from the deficiency of the C1-inhibitor. Potential hepatotoxic or liver tumor-inducing side effects of long-term danazol prophylaxis have been investigated during the follow-up of hereditary angioedema patients.MethodsCharacteristic parameters of liver function (including bilirubin, GOT, GPT, γGT, total protein, ALP, LDH), as well as findings of viral serology screens and abdominal ultrasonography—determined during years 0 and 5 of follow-up of patient groups taking/not taking danazol—have been reviewed and analyzed comparatively.ResultsFrom a population of 126 hereditary angioedema patients, 46 subjects taking danazol and another 46 not taking danazol fulfilled the inclusion criteria. Longitudinal follow-up did not reveal any clinically relevant difference between the liver function parameters determined in years 0 and 5 in the two groups. Abdominal ultrasound did not detect neoplastic or other potentially treatment-related alterations of the liver parenchyma. There were no discontinuations of treatment during the study.ConclusionsOur results clearly suggest that, administered at the lowest effective dose, danazol does not induce liver injury in hereditary angioedema patients.

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.

Association of celiac disease and hereditary angioedema due to C1-inhibitor deficiency. Screening patients with hereditary angioedema for celiac disease: is it worth the effort?

Objective Hereditary angioedema due to C1-inhibitor deficiency is a life-threatening condition, which manifests as edematous attacks involving subcutaneous tissues and/or the upper airway/gastrointestinal mucosa. Celiac disease is a gluten-sensitive small intestinal disorder that can lead to severe villous atrophy, malabsorption, and malignancy. Both hereditary angioedema and celiac disease may present with abdominal symptoms. Our aim was to study the occurrence of celiac disease in the hereditary angioedema population, as well as to analyze the clinical course of cases with both diseases. Methods One hundred and twenty-eight patients with hereditary angioedema were screened for celiac disease, using serological methods [antiendomysial antibodies-immunoglobulin A (IgA), antiendomysial antibodies-IgG and tissue transglutaminase-IgA, tissue transglutaminase-IgG]. Clinical data of a child with hereditary angioedema and celiac disease diagnosed earlier were added to the dataset to be analyzed. Thus, the total number of patients was 129, comprising 107 adults and 22 pediatric patients. In patients with celiac disease, molecular genetics analysis (human leukocyte antigen-DQA1, human leukocyte antigen-DQB1) was carried out along with the introduction of a gluten-free diet and regular follow-up. Results Four out of the 22 children were diagnosed with celiac disease in our hereditary angioedema population. The prevalence of celiac disease among our pediatric patients with hereditary angioedema (22 children) was higher than in the general population (18.1 vs. 1.2%). Switching from the wheat starch-containing tranexamic acid product to danazol and introducing a gluten-free diet mitigated abdominal symptoms of hereditary angioedema. Conclusion Similarities between the symptoms of hereditary angioedema and celiac disease may cause difficulties in differential diagnosis, as well as in choosing the appropriate therapy. In our opinion, screening hereditary angioedema patients for celiac disease is warranted if abdominal attacks or neurological symptoms persist despite adequate management. Complement testing is recommended whenever abdominal symptoms persist despite the histological and serological remission of gluten-sensitive enteropathy after the introduction of a gluten-free diet.

Relationship of Circulating C5a and Complement Factor H Levels With Disease Control in Pregnant Women With Asthma

BACKGROUND: Asthma often complicates pregnancy and represents a risk of serious pregnancy complications. The complement system contributes to asthma pathogenesis and is up-regulated in healthy gestation as well. The anaphylatoxin C5a has a major pro-inflammatory role, and the complement factor H is a main soluble regulator protein both in asthma and during pregnancy; however, peripheral levels of these complement factors and their relationship to disease control have not yet been evaluated in pregnant subjects with asthma. METHODS: The present study aimed to investigate circulating C5a and complement factor H levels in asthma (non-pregnant subjects with asthma; n = 19) and in pregnancy with asthma (pregnant subjects with asthma; n = 22), compared with healthy non-pregnant (n = 21) and healthy pregnant women (n = 13) and to test their relationship to clinical parameters of asthma (lung function, airway inflammation, and symptoms). RESULTS: Circulating C5a levels were higher in the pregnant asthma subject group compared with the healthy non-pregnant, healthy pregnant, and non-pregnant asthma groups: median 2.629 (interquartile range [IQR] 2.257–3.052) ng/mL versus 1.84 (IQR 1.576–2.563), 1.783 (IQR 0.6064–2.786), and 2.024 (IQR 1.232–2.615) ng/mL, respectively (P = .02 in all cases). C5a correlated negatively with FEV1 (r = −0.44, P = .039) and FVC values (r = −0.64, P = .001) in the pregnant asthma group and positively with fraction of exhaled nitric oxide levels in the non-pregnant asthma group (n = 12, r = 0.78, P = .004). Complement factor H levels were elevated in both the healthy pregnant and pregnant asthma subject groups compared with the healthy non-pregnant group (median 1,082 [IQR 734.9–1,224] and 910.7 [IQR 614.5–1076] μg/mL vs 559.7 [IQR 388.7–783.1] μg/mL, P = .002 and P = .004, respectively) but not in the pregnant asthma group compared with the non-pregnant asthma group (median 687.4 [IQR 441.6–947.6] μg/mL, P = .10). CONCLUSIONS: Asthma during pregnancy increases the circulating level of pro-inflammatory C5a, which is accompanied by impaired lung function and partly counteracted by the gestation-specific elevation of regulatory complement factor H level (detected in pregnancy both in healthy and subjects with asthma).

Abdominal symptoms of hereditary angioedema and early weaning.

Hereditary angioedema (HAE), a condition caused by deficiency of C1 inhibitor that results in acute and painful swelling in locations that can include the face, neck, abdomen, extremities and genitals, is a potentially life-threatening disorder. Many factors may contribute to phenotype development. A case report prompted us to investigate the potential influence of early weaning on HAE gastrointestinal symptoms. Retrospective analysis was performed based on clinical data from 89 patients registered with our HAE center, including duration of breast-feeding, timing of cows milk introduction, age at symptom onset and localization of the attacks. We did not find any relationship between these factors. Although breastfeeding is known to confer protection against numerous diseases, it showed no efficacy against the manifestations of HAE in our patient population.

From genomes to diaries: a 3-year prospective, real-life study of ragweed-specific sublingual immunotherapy

During the last decades, the prevalence of allergy has dramatically increased. Allergen-specific immunotherapy is the only currently available medical intervention that has the potential to affect the natural course of the disease, but there are still many questions and unmet needs hindering its widespread use to fulfill its treatment potential and maximize its benefits for the society. To provide a comprehensive phenome-wide overview in sublingual immunotherapy, using ragweed allergy as a target, we planned and carried out a longitudinal, prospective, observational, open-label study (DesensIT). In this paper we present challenges of using deep and comprehensive phenotypes embracing biological, clinical and patient-reported outcomes in allergen-specific immunotherapy and show how we designed the DesensIT project to optimize data collection, processing and evaluation.