A novel mutation in exon 8 of C1 inhibitor (C1INH) gene leads to abolish its physiological stop codon in a large Chinese family with hereditary angioedema type I

C1 inhibitor (C1INH) plays an important role in the classical pathway of the complement system. Mutations in C1INH gene cause quantitative or qualitative deficiencies in C1INH, which can lead to hereditary angioedema (HAE) type I or II. Here, we identified a novel frame‐shift mutation c.1391‐1445del55 (p.v464fsx556) in exon 8 in a large Chinese family with HAE type I. This 55 base pairs deletion abolishes the original stop codon and introduces a new stop codon 220 bp downstream of the original one, and leads to mutated C1INH protein prolonged from 500 to 556 amino acids. The levels of C4 and C1INH as well as C1INH activity in serum were significantly reduced in affected individuals. This is the first report of a novel mutation abolishing the physiological stop codon of C1INH gene in a large Chinese family with HAE type I.     

Self‐administration of icatibant in acute attacks of Type I hereditary angioedema: A case report and review of hereditary angioedema

Hereditary angioedema (HAE) is a rare group of genetic disease characterized by non‐itchy swelling of subcutaneous and submucosal tissues of the extremities, genitalia, gastrointestinal tract, and upper airways, which can be life threatening. Moreover, unpredictability and recurrence of HAE attacks significantly affect patients' quality of life. Short‐ and long‐term prophylaxis is used to decrease the severity and frequency of attacks, but during severe or potentially severe acute episodes, treatment with C1‐INH replacement or icatibant is mandatory. Icatibant is a selective bradykinin B2 receptor antagonist that has been licensed for self‐administration at home, resulting in earlier treatment of the attack and quicker recovery, less emergency admittance with a significant improvement of patients' quality of life, and decrease of health care costs. The authors present a case of a young woman, affected by Type I HAE, who has been successfully treated with icatibant on demand at home, resulting in reduction of emergency admissions and improvement of quality of life. The authors also review the different types HAE, their clinical aspects, diagnosis, and management.     

Long‐term prophylaxis of hereditary angioedema with androgen derivates: a critical appraisal and potential alternatives

Androgen derivatives are regarded as standard in the long‐term prophylaxis of swelling attacks in patients with hereditary angioedema (HAE). Because of their relatively slow onset of action, they are not suitable for acute therapy. Long‐term prophylaxis with androgen derivatives must be regarded critically, especially on account of their androgenic and anabolic effects, some of which are severe. The risk of adverse events increases with the daily dose and the duration of treatment. Thus, treatment always calls for close monitoring of patients with regard to potential adverse events. In addition, androgens are subject to numerous contraindications and they show interactions with a large number of other drugs. Off‐label use, doping issues, clarification of reimbursement and the need to import the androgen derivatives, which are no longer marketed in Germany, result in additional effort for the treating physician in terms of logistics and time involved. In symptomatic treatment of acute attacks the intravenous substitution of C1‐INH and – since 2008 – subcutaneous administration of icatibant are available. The two substances are well tolerated and their effect occurs rapidly and, when the diagnosis has been confirmed, reliably. In the light of these two treatment options for controlling acute attacks, prophylactic treatment of HAE patients with androgen derivatives such as danazol should be reassessed. Patients might benefit from a dose reduction or the withdrawal of androgen prophylaxis and attacks can be controlled with demand‐oriented acute treatment using C1‐INH or icatibant.     

Successful treatment of hereditary angioedema with bradykinin B2‐receptor antagonist icatibant

The bradykinin B2 receptor antagonist icatibant has recently become available for treating hereditary angioedema. Our observations demonstrate icatibant to be effective and safe for the treatment of both, abdominal and cutaneous attacks in a practice setting beyond clinical studies.     

Hereditary angioedema: an update on available therapeutic options

There is no cure for hereditary angioedema (HAE). Therapeutic approaches consist of symptomatic therapy for acute attacks, short‐term prophylaxis before surgery, and long‐term prophylaxis for those with frequent and severe attacks. In Germany, C1‐INH concentrate and icatibant are licensed for acute therapy. C1‐INH concentrate, which is obtained from human plasma, is administered intravenously to restore the deficient C1‐INH activity. This therapy, which has been available for decades, is effective and well‐tolerated. Batch documentation is required by German law. The synthetic decapeptide icatibant is administered subcutaneously. It competes with bradykinin, the responsible inducer of edema formation, for binding to the bradykinin B2 receptor. Icatibant is also effective and well‐tolerated, even on repeated administration. An additional human C1‐inhibitor, a recombinant human C1‐inhibitor and the recombinant inhibitor of kallikrein ecallantide are currently under development. There are no licensed treatment options available in Germany for long‐ and short‐term prophylaxis. Androgen derivatives are established in long‐term prophylaxis. However, they are associated with many adverse effects, some of which are severe. Many drug interactions also limit their use. They are contraindicated in pregnancy, lactation, for children and in cases of prostate cancer. Antifibrinolytics have fewer adverse effects but are also less effective than androgens. They are contraindicated in thromboembolic disease and impaired vision. If androgen therapy has too negative an effect on quality of life, it may be worth reducing the dose or discontinuing therapy entirely and treating attacks with acute therapy.     

Misdiagnosis of hereditary angio-oedema type 1 and type 2

BACKGROUND: Hereditary angio-oedema is a rare, life-threatening, autosomal dominant condition caused by deficiency (type 1) or dysfunction (type 2) of complement C1 inhibitor. Serological assays to measure C1 inhibitor concentration and function are widely available. However, expert interpretation may not be. OBJECTIVE: To review all cases within three NHS Trusts with a putative diagnosis of hereditary angio-oedema. METHOD: Review of laboratory results and clinical notes of 44 cases of presumed hereditary angio-oedema. RESULTS: Audit revealed that 11 of 42 (26%) cases had been incorrectly considered to have a diagnosis of hereditary angio-oedema. Two of 44 had insufficient data to assess. All 11 had low functional C1 inhibitor recorded at presentation. RESULTS: available in these 11 cases at the time of diagnosis showed a normal or borderline C4 level (>or= 50% of mean normal, in contrast to hereditary angio-oedema, where C4 was less than 40% of mean normal) indicating that the low C1 inhibitor levels were a result of sample decay. Cases incorrectly diagnosed were predominantly female and had a mean age at presentation of 40 years (compared with 22 years for type 1 hereditary angio-oedema). Six of the 11 cases were offered C1 inhibitor concentrate (pooled plasma product) as treatment. CONCLUSION: We recommend that all suspected cases of hereditary angio-oedema are reviewed, that specialist advice is sought before making the diagnosis and that the diagnosis is only made after initial abnormal serology is confirmed on a second sample.     

遗传性血管性水肿的治疗进展

遗传性血管性水肿是一种少见的常染色体显性遗传病,因血浆中功能性C1酯酶抑制剂缺乏引起皮下及黏膜水肿.喉水肿诱发呼吸道阻塞可危及生命.该病早期无特效药,曾将治疗荨麻疹的抗组胺药和糖皮质激素等用于急性水肿发作的患者,收效甚微,死亡率高达30%.随着对该病发病机制的深入研究,不断涌现出新的药物,为临床医生及患者提供更多选择.概述其发病机制、临床表现,着重围绕其治疗进展.

Abstract：

Hereditary angioedema is a rare autosomal dominantly inherited disease characterized by recurrent episodes of subcutaneous and mucosal edema due to the deficiency of plasma functional C1 esterase inhibitor.Acute attacks of laryngeal swelling are often associated with a substantial risk of death.In the past,hereditary angioedema was treated with anti-histamine drugs and glucocorticoids,but the outcome was unsatisfactory,and mortality was reported as high as 30%.With further insights into the pathogenesis of hereditary angioedema,new drugs have emerged and provided clinicians and patients with more choices.The authors summarize the pathogenesis and clinical manifestations of the entity with focus on the progress in its treatment.     

遗传性血管性水肿1家系C1抑制物基因突变分析

目的对一个中国遗传性血管性水肿家系进行C1抑制物(C1INH)基因突变检测分析。方法采用聚合酶链反应(PCR)和直接测序法检测C1INH基因8个外显子及每个外显子与内含子的相邻序列,将检测结果与GenBank公布的C1INH基因正常序列进行比较。为除外基因多态性可能,在50名正常人群对照中对该突变进行分析。血清补体C4和C1INH浓度采用速率散射比浊法测定,血清C1INH功能水平通过酶联免疫吸附试验(ELISA)测定。结果 4例患者的第3外显子均检测到1个无义突变(c.400G>T),该突变导致编码第134位的谷氨酸变为终止密码子(p.E134X)。家系中4例正常对照和50例健康人群对照未检测到该突变。4例患者的血清C4浓度、C1INH浓度及功能水平均低于正常值下限。该家系中2例正常对照和2例健康人群对照血清C4浓度、C1INH浓度及功能水平均在正常范围内。结论在该家系中发现C1INH基因突变c.400G>T,该突变为此家系发病的分子基础。     

遗传性血管性水肿C1INH基因1440V变异及其对结构的影响

目的 通过基因测序了解遗传性血管性水肿(HAE)患者C1酯酶抑制剂(C1INH)基因第八外显子的变异情况.方法 从HAE患者外周血白细胞中提取基因组DNA,PCR扩增第八外显子片段后插入pUC19质粒载体冉转化入感受态大肠杆菌TG1菌株,培养扩增质粒DNA,提取纯化后进行基因测序.将患者血清进行SDS-PAGE及Westem印迹,以了解该变异对CIINH结构的可能影响.结果 在1例I型HAE患者的第八外显子中发现一个变异位点,16776A＞G,致440位的异亮氨酸突变成缬氨酸(1440V),SDS-PAGE及Westem印迹显示该患者血清中C1INH全部表现为96 000片段而非正常的105 000片段.结论 1440v是一个新的C1INH基因变异,位于C1INH反应中心环的P4位,变异可能导致C1INH分子构象发生改变.     

Icatibant use in Brazilian patients with hereditary angioedema (HAE) type 1 or 2 and HAE with normal C1-INH levels: findings from the Icatibant Outcome Survey Registry Study

BackgroundHereditary angioedema can be caused by C1-Inhibitor (C1-INH) deficiency and/or dysfunction (HAE-1/2) or can occur in patients with normal C1-INH (HAE nC1-INH).MethodsThe Icatibant Outcome Survey (IOS; NCT01034969) registry monitors the safety and effectiveness of icatibant for treating acute angioedema.ObjectivePresent findings from Brazilian patients with HAE-1/2 and HAE nC1-INH participating in IOS.Results42 patients were enrolled (HAE-1/2, n = 26; HAE nC1-INH, n = 16). Median age at symptom onset was significantly lower with HAE-1/2 vs. HAE nC1-INH (10.0 vs. 16.5y, respectively; p = 0.0105), whereas median age at diagnosis (31.1 vs. 40.9y; p = 0.1276) and the median time between symptom onset and diagnosis (15.0 vs. 23.8y; p = 0.6680) were numerically lower vs. HAE nC1-INH, respectively. One icatibant dose was used for > 95% of HAE attacks. Median (range) time-to-event outcomes were shorter for patients with HAE nC1-INH vs. HAE-1/2, including time to first administration (0.5 [0–96.0] vs. 1.0 [0–94.0]h, respectively), time from first administration to complete resolution (1.0 [0–88.0] vs. 5.5 [0–96.0]h, respectively), and total attack duration (7.0 [0.3–99.0] vs. 18.5 [0.1–100.0]h, respectively). Mean (SD) time from attack onset to resolution was significantly shorter for patients with HAE nC1-INH vs. HAE-1/2 (9.8 [18.7] vs. 19.6 [24.0]h, respectively; p = 0.0174). 83 adverse events (AEs) in 42 patients were reported; most were mild (66.3%) or moderate (13.3%) and non-serious (75.9%). The most common icatibant-related AE was injection site erythema (HAE-1/2, 34.6%; HAE nC1-INH, 18.8%).Study limitationsThis was an observational study without a treatment comparator and that relied on patient recall.ConclusionsFindings demonstrate effectiveness and tolerability of icatibant in Brazilian HAE patients.     

Monocyte activating factor originally found in sarcoidosis sera. I. Production of a similar factor by monocytes pretreated with interleukin 1

The culture medium for normal human monocytes pretreated with interleukin (IL)-1, either α and β, induced normal human monocytes to spread and to increase Fc (IgG) receptor sites, angiotensin converting enzyme production and glucose consumption of normal human monocytes, suggesting that this medium contains a monocyte activating factor(s). On TSK G3000SW gel filtration, the major monocyte activating factor in the culture medium and that in sarcoidosis serum were eluted at the same position (with a molecular weight of about 70,000). Thus, IL-1 may be able to induce normal human monocytes to produce a monocyte activating factor quite similar to that found in sarcoidosis serum.     

Safety of selective cyclooxygenase-2 inhibitors and a basic non-steroidal anti-inflammatory drug (NSAID) in Japanese patients with NSAID-induced urticaria and/or angioedema: Comparison of meloxicam, etodolac and tiaramide

The identification of a safe and reliable alternative for patients with non-steroidal anti-inflammatory drug (NSAID)-induced urticaria/angioedema is a frequent problem for dermatologists and other practitioners. Cyclooxygenase-2 (COX-2) inhibitors have been reported to be safe for NSAID-intolerant patients from the US and Europe but not all of them have yet been approved for use in Japan. It was our objective to investigate the clinical manifestations of oral NSAID challenges in Japanese patients with histories of urticaria and/or angioedema after the intake of NSAIDs and to find safe alternative drugs, including COX-2 inhibitors and a basic anti-inflammatory drug. Twenty subjects suspected NSAID-induced urticaria/angioedema from histories were included in a double-blind or single-blind, placebo-controlled oral challenge protocol using NSAIDs. Skin prick tests using NSAIDs, which were dissolved in saline, were conducted. The mean age of the patients was 37.3 years; 14 patients were female. The results of other challenge tests showed that the most frequently intolerated drugs was loxoprofen (100%), followed by acetyl salicylic (94.4%), etodolac (53.3%), dicrofenac (50%), acetaminophen (38.5%), meloxicam (33%), and tiaramide (21.4%). Urticaria and angioedema were induced after aspirin intake in 83.3% and 22.2% of patients, respectively, whereas an asthmatic response was seen in 5.6%. Skin prick tests with NSAIDs were 100% negative. This study showed that among the NSAIDs that are available in Japan and that were investigated in this study, tiaramide, which does not inhibit COX, is the relatively safe alternative drug for Japanese patients with NSAID-induced urtiacaria and/or angioedema. Furthermore, meloxicam seems to be better tolerated than etodolac between two selective COX-2 inhibitors.     

Increased activity of factor VIII coagulant associated with venous ulcer in a patient with Klinefelter''s syndrome

Klinefelter's syndrome is the most frequent major abnormality of sexual differentiation in men with two or more X chromosomes. Recurrent venous ulcers as a result of a post-thrombotic syndrome are a well known symptom in patients with Klinefelter's syndrome. Until now the underlying pathomechanisms are not completely understood. Platelet hyperaggregability, factor V Leiden mutation and abnormalities in fibrinolysis were implicated as possible contributing factors. Here we describe the detection of an increased activity of factor VIII coagulant (factor VIII:C). This is the first case report on increased factor VIII:C activity associated with venous ulcers in a patient with Klinefelter's syndrome. Elevated factor VIII plasma levels are gradually accepted to be associated with an increased risk for venous thromboembolism. Therefore, we discuss that the examination of factor VIII:C may help in clarifying individual thromboembolic risks, especially in patients with Klinefelter's syndrome.     

Psoriatic patients with arthropathy show significant expression of free HLA class I heavy chains on circulating monocytes: a potential role in the pathogenesis of psoriatic arthropathy

BACKGROUND: Surface free heavy chains on monocytes were recently implicated in playing a role in the pathogenesis of several forms of arthritis. OBJECTIVES: To determine the expression of surface free heavy chains (recognized by monoclonal antibody HC10) on peripheral blood mononuclear cells of psoriatic patients with or without arthropathy. METHODS: Twenty-eight psoriatic patients from the dermatology outpatient clinic were included in this study. Blood samples were collected during outpatient visits and clinical characteristics of the patients were documented. Quantitative analyses of circulating mononuclear cells were performed using flow cytometry. RESULTS: Circulating monocytes showed higher expression of HC10 compared with circulating lymphocytes (P < 0.05). Psoriatic patients with arthropathy showed elevated expression of HC10 on peripheral blood monocytes compared with those without arthropathy (P < 0.05). Among the arthropathic group, those without the human leucocyte antigen (HLA)-B27 allele showed even higher expression of HC10 on circulating monocytes compared with those possessing HLA-B27 (P < 0.05). The polyarthropathic subgroup showed the highest HC10 expression, but the level of expression was not high enough to be of statistical significance compared with other arthropathic subgroups. No correlation was found between psoriatic skin involvement and the expression of HC10 on circulating monocytes. CONCLUSIONS: The presence of free heavy chains on circulating monocytes is closely associated with psoriatic arthropathy, while the expression of free heavy chains on circulating monocytes has no significant influence on psoriatic skin lesions.     

积雪苷体外对瘢痕疙瘩成纤维细胞增殖及结缔组织生长因子表达的影响

目的 探讨积雪苷体外对瘢痕疙瘩成纤维细胞增殖和对结缔组织生长因子（CTGF）表达的影响。方法 取手术切除的瘢痕疙瘩组织作成纤维细胞的原代培养,加入不同浓度积雪苷,观察细胞的形态变化,MTT法检测细胞活性,免疫组化和Western印迹法检测积雪苷对瘢痕疙瘩成纤维细胞结缔组织生长因子表达的影响。结果 细胞形态学观察显示,经不同浓度积雪苷处理的成纤维细胞呈现明显的抑制及凋亡征象。积雪苷在1 ～ 100 mg/L范围内,在24、48、72 h时积雪苷浓度与细胞活性抑制率均呈正相关,r分别为0.95、0.90和0.92,P值均 ＜ 0.01;且各浓度不同时间段细胞活性抑制率间单因素方差分析,P值均 ＜ 0.01。瘢痕疙瘩成纤维细胞中CTGF呈强阳性表达,而经积雪苷处理瘢痕疙瘩成纤维细胞48 h后,CTGF表达有所减弱,每100个成纤维细胞中CTGF表达阳性细胞数均值未加药组为73个,1 mg/L积雪苷组为54个,10 mg/L积雪苷组为46个,未加药组与1 mg/L、10 mg/L积雪苷组比较,差异均有统计学意义（t值分别为4.34和6.26,P值均 ＜ 0.01）;1 mg/L积雪苷组与10 mg/L积雪苷组比较,差异亦有统计学意义（t = 1.95,P ＜ 0.05）。Western印迹显示,积雪苷作用48 h后,成纤维细胞中CTGF的表达量比未加药的细胞明显减弱,且表达量随药物剂量的加大有递减趋势。结论 积雪苷能有效抑制瘢痕疙瘩成纤维细胞的增殖和结缔组织生长因子的表达。     

Pseudoscleroderma associated with lung cancer: correlation of collagen type I and connective tissue growth factor gene expression

Pseudoscleroderma as a paraneoplastic syndrome is a rare disease. We report here a patient with lung cancer (undifferentiated squamous cell carcinoma), who developed acrosclerosis. Using in situ hybridization, marked expression of alpha1(I)-collagen and connective tissue growth factor (CTGF) mRNA was found in fibroblasts scattered throughout the dermis. However, transforming growth factor (TGF)-beta1 expression was not detected. The pattern of CTGF gene expression and collagen synthesis was similar to that in systemic scleroderma. The absence of TGF-beta1 mRNA could indicate that tumour-derived factors induce the expression of CTGF.