Chiara Suffritti

Presentation, diagnosis and treatment of angioedema without wheals: a retrospective analysis of a cohort of 1058 patients

The first classification of angioedema without wheals was recently reported and comprises different forms of the disease distinguished by aetiology, mediator of oedema and inheritance.

High‐molecular‐weight kininogen cleavage correlates with disease states in the bradykinin‐mediated angioedema due to hereditary C1‐inhibitor deficiency

The inherited deficiency of C1‐inhibitor (C1‐INH), which can be quantitative (type I) or qualitative (type II), is characterized by recurrent attacks of oedema, and it is known as hereditary angioedema due to C1‐INH deficiency (HAE‐C1‐INH). The frequency of symptoms varies widely among patients and in the same patient during life.

Pharmacokinetics of plasma-derived C1-esterase inhibitor after subcutaneous versus intravenous administration in subjects with mild or moderate hereditary angioedema: the PASSION study

Hereditary angioedema (HAE) is a rare disease caused by C1‐esterase inhibitor (C1‐INH) deficiency, characterized by periodic attacks of acute edema affecting subcutaneous (SC) tissues and mucous membranes. Human C1‐INH concentrate given intravenously (IV) is effective and safe, but venous access may be difficult. We compared SC and IV administration of human pasteurized C1‐INH concentrate with respect to pharmacokinetics, pharmacodynamics, and safety.

Ongoing Contact Activation in Patients with Hereditary Angioedema

Hereditary angioedema (HAE) is predominantly caused by a deficiency in C1 esterase inhibitor (C1INH) (HAE-C1INH). C1INH inhibits activated factor XII (FXIIa), activated factor XI (FXIa), and kallikrein. In HAE-C1INH patients the thrombotic risk is not increased even though activation of the contact system is poorly regulated. Therefore, we hypothesized that contact activation preferentially leads to kallikrein formation and less to activation of the coagulation cascade in HAE-C1INH patients. We measured the levels of C1INH in complex with activated contact factors in plasma samples of HAE-C1INH patients (N=30, 17 during remission and 13 during acute attack) and healthy controls (N=10). We did not detect differences in enzyme-inhibitor complexes between samples of controls, patients during remission and patients during an acute attack. Reconstitution with C1INH did not change this result. Next, we determined the potential to form enzyme-inhibitory complexes after complete in vitro activation of the plasma samples with a FXII trigger. In all samples, enzyme-C1INH levels increased after activation even in patients during an acute attack. However, the levels of FXIIa-C1INH, FXIa-C1INH and kallikrein-C1INH were at least 52% lower in samples taken during remission and 70% lower in samples taken during attack compared to samples from controls (p<0.05). Addition of C1INH after activation led to an increase in levels of FXIIa-C1INH and FXIa-C1INH (p<0.05), which were still lower than in controls (p<0.05), while the levels of kallikrein-C1INH did not change. These results are consistent with constitutive activation and attenuated depletion of the contact system and show that the ongoing activation of the contact system, which is present in HAE-C1INH patients both during remission and during acute attacks, is not associated with preferential generation of kallikrein over FXIa.

High prevalence of splenic marginal zone lymphoma among patients with acquired C1 inhibtor deficiency.

Marginal zone lymphoma represents about 10% of all non‐Hodgkin lymphomas (NHLs). 33% of patients with acquired angioedema (AAE) due to acquired C1‐inhibitor (C1‐INH) deficiency (C1‐INH‐AAE) have or will develop NHLs. C1‐INH‐AAE is a rare condition. We report the follow‐up of 72 C1‐INH‐AAE patients, followed for a median of 15 years (range 1–24). Median age was 71 (range 64–79) years; median age at onset of angioedema symptoms was 57·5 (range 50–66) years and it was 63 [range 45–80) years at diagnosis]. Twenty patients were diagnosed with low‐grade non‐follicular B‐cell lymphomas (75% were splenic MZL), one with follicular and three with high‐grade lymphomas (two diffuse large B‐cell lymphomas and one mantle cell lymphoma). Fifteen NHLs were diagnosed at onset of AAE or thereafter (3 months to 7 years), eight had already been diagnosed at onset of angioedema. Two of 24 patients remain on watchful wait. Thirthen of 24 received chemotherapy, two received rituximab. Three underwent splenectomy. All 18 patients receiving therapy for NHL experienced post‐treatment reduction in AAE symptoms. Our study suggests that clonal B‐cell proliferation is the pathology underlying AAE leading to production of C1‐INH‐neutralizing autoantibodies and to NHLs. The post‐germinal centre origin of NHL suggests that immune stimulation may contribute to lymphomagenesis.

Elevated plasma levels of vascular permeability factors in C1 inhibitor‐deficient hereditary angioedema

Hereditary angioedema with C1 inhibitor deficiency (C1‐INH‐HAE) is a rare inherited genetic disease characterized by recurrent swelling episodes of the skin, gastrointestinal tract, and upper airways. Angioedema attacks result from increased vascular permeability due to the release of bradykinin from high molecular weight kininogen. Currently, there are no biomarkers predicting the frequency of angioedema attacks. Vascular permeability is modulated by several factors, including vascular endothelial growth factors (VEGFs) and angiopoietins (Angs). As increased circulating levels of VEGFs and Angs have been observed in diseases associated with higher vascular permeability (e.g., systemic capillary leak syndrome and sepsis), we sought to analyze plasma concentrations of VEGFs and Angs in patients with C1‐INH‐HAE.

Efficacy of on-demand treatment in reducing morbidity in patients with hereditary angioedema due to C1 inhibitor deficiency.

Angioedema due to hereditary deficiency of C1 inhibitor causes temporarily disability. Guidelines recommend early on‐demand treatment of attacks to reduce morbidity. In this prospective observational study, we evaluated the efficacy of on‐demand approach.

C1 Inhibitor Autoantibodies

Abstract Autoantibodies to C1 inhibitor (C1-INH) bind to epitopes on the reactive center of the C1-INH molecule. As a consequence of this binding, C1-INH is converted into an inactive substrate that can be cleaved by proteases. C1-INH is a serine protease inhibitor that plays a role in the complement, contact, fibrinolytic, and coagulation cascades. Autoantibodies to C1-INH cause acquired C1-INH deficiency, activation of the classical complement pathway, and defective control of the contact-kinin system. This eventually leads to recurrent bradykinin release with increased vascular permeability and symptoms of angioedema involving subcutaneous tissue, gastrointestinal mucosa, and the upper respiratory tract. Autoantibodies inactivate C1-INH protein and may dramatically reduce efficacy of replacement therapy with plasma derived C1 inhibitor. Autoantibodies to C1-INH have also been described in absence of angioedema symptoms. They have been found in patients with systemic lupus erythematosus (SLE), with lupus-like syndrome and anticardiolipin antibodies and in a patient with primary antiphospholipid syndrome: their effect on C1-INH function in these conditions is only partially defined.

Intermittent C1-Inhibitor Deficiency Associated with Recessive Inheritance: Functional and Structural Insight

C1-inhibitor is a serine protease inhibitor (serpin) controlling complement and contact system activation. Gene mutations result in reduced C1-inhibitor functional plasma level causing hereditary angioedema, a life-threatening disorder. Despite a stable defect, the clinical expression of hereditary angioedema is unpredictable, and the molecular mechanism underlying this variability remains undisclosed. Here we report functional and structural studies on the Arg378Cys C1-inhibitor mutant found in a patient presenting reduced C1-inhibitor levels, episodically undergoing normalization. Expression studies resulted in a drop in mutant C1-innhibitor secretion compared to wild-type. Notwithstanding, the purified proteins had similar features. Thermal denaturation experiments showed a comparable denaturation profile, but the mutant thermal stability decays when tested in conditions reproducing intracellular crowding.Our findings suggest that once correctly folded, the Arg378Cys C1-inhibitor is secreted as an active, although quite unstable, monomer. However, it could bear a folding defect, occasionally promoting protein oligomerization and interfering with the secretion process, thus accounting for its plasma level variability. This defect is exacerbated by the nature of the mutation since the acquired cysteine leads to the formation of non-functional homodimers through inter-molecular disulphide bonding. All the proposed phenomena could be modulated by specific environmental conditions, rendering this mutant exceptionally vulnerable to mild stress.

Hereditary angioedema: Assessing the hypothesis for underlying autonomic dysfunction

Background Attacks of Hereditary Angioedema due to C1-inhibitor deficiency (C1-INH-HAE)are often triggered by stressful events/hormonal changes. Objective Our study evaluates the relationship between autonomic nervous system (ANS) and contact/complement system activation. Methods Twenty-three HAE patients (6 males, mean age 47.5±11.4 years) during remission and 24 healthy controls (8 males, mean age 45.3±10.6 years) were studied. ECG, beat-by-beat blood pressure, respiratory activity were continuously recorded during rest (10’) and 75-degrees-head-up tilt (10’). C1-INH, C4, cleaved high molecular weight kininogen (cHK) were assessed; in 16 patients and 11 controls plasma catecholamines were also evaluated. Spectral analysis of heart rate variability allowed extraction of low-(LF) and high-(HF) frequency components, markers of sympathetic and vagal modulation respectively. Results HAE patients showed higher mean systolic arterial pressure (SAP) than controls during both rest and tilt. Tilt induced a significant increase in SAP and its variability only in controls. Although sympathetic modulation (LFnu) increased significantly with tilt in both groups, LF/HF ratio, index of sympathovagal balance, increased significantly only in controls. At rest HAE patients showed higher noradrenaline values (301.4±132.9 pg/ml vs 210.5±89.6pg/ml, p = 0.05). Moreover, in patients tilt was associated with a significant increase in cHK, marker of contact system activation (49.5 ± 7.5% after T vs 47.1 ± 7.8% at R, p = 0.01). Conclusions Our data are consistent with altered ANS modulation in HAE patients, i.e. increased sympathetic activation at rest and blunted response to orthostatic challenge. Tilt test-induced increased HK cleavage suggests a link between stress and bradykinin production.