Dorottya Csuka

Complement activation in thrombotic thrombocytopenic purpura

Summary.  Background:  Ultra‐large von Willebrand factor and deficiency of its cleaving protease are important factors in the events leading to thrombotic microangiopathy; however, the mechanisms involved are only partly understood. Whereas pathological activation of the alternative complement pathway is linked to atypical hemolytic uremic syndrome, the role of complement activation in thrombotic thrombocytopenic purpura (TTP) is unknown. The aim of this study was to investigate whether signs of complement activation are characteristic of TTP.

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.

Long-term efficacy of danazol treatment in hereditary angioedema

Eur J Clin Invest 2011; 41 (3): 256–262

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.

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.

Baseline level of functional C1-inhibitor correlates with disease severity scores in hereditary angioedema

The diagnosis of hereditary angioedema (HAE) is based on complement tests. We studied for the first time the possible association between complement parameters measured at the time of diagnosis and disease severity in 115 patients with HAE. Serum levels of functional C1-inhibitor (C1-INH(f)), antigenic C1-inhibitor (C1-INH(a)), C4 and hemolytic activity of the classical pathway (CH50) were determined at the time of diagnosis. We found a significant correlation between severity scores and baseline C1-INH(f) levels, as determined by ELISA assay (p=0.0003). On the other hand, there was no correlation between severity scores and other complement parameters (C1-INH(a), C4, and CH50). We consider the correlation between severity scores and baseline C1-INH(f) levels an important pathophysiological observation. Our findings underlie the potential significance of monitoring functional C1-INH levels in relation to clinical disease course.

High anti-EBNA-1 IgG levels are associated with early-onset myasthenia gravis

Background:  Myasthenia gravis (MG) is an autoimmune disorder mediated by antibodies against the acethylcholine receptor (AchR) of the neuromuscular junction in the majority of 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

Functional analysis of the mannose-binding lectin complement pathway in normal pregnancy and preeclampsia

Preeclampsia is a severe complication of pregnancy characterized by hypertension and proteinuria developing after midgestation. Previous studies have shown increased complement activation in normal and preeclamptic pregnancies. We aimed to investigate the role of the mannose-binding lectin pathway in the initiation of pathological complement activation observed in patients with preeclampsia. The study included 60 preeclamptic patients, 60 healthy pregnant women and 56 healthy non-pregnant women. Functional activity of the complex of mannose-binding lectin and mannose-binding lectin-associated serine protease 2 (MBL-MASP2 complex) was determined by ELISA. Circulating levels of complement components and C-reactive protein (CRP) were also measured. MBL-MASP2 activity was significantly higher in healthy pregnant than non-pregnant women. However, increased activity of the MBL-MASP2 complex in preeclamptic patients was not observed, compared to healthy pregnant women. MBL-MASP2 activity showed no relationship with either the levels of complement parameters, or with the clinical data and level of CRP in patients with preeclampsia. In conclusion, the complement system is activated with increased terminal complex formation in the third trimester of normal human pregnancy, and is further activated in preeclampsia as shown by the elevated amounts of activation markers. The activity of MBL-MASP2 is also increased in normal pregnancy, to the same level seen in preeclampsia. In our study, no relationship between MBL-MASP2 activity and extent of complement activation was observed in preeclampsia. We tentatively conclude, albeit without an evaluation of local placental concentrations, that the mannose-binding lectin pathway may play only a minor role in pathological complement activation during preeclampsia.