Lorenza C. Zingale

Angioedema without urticaria: a large clinical survey

Background: Angioedema without major urticarial flares (hives) is poorly understood. Its causes are diverse, and little is known about its pathogenic mechanisms. We report on our 11 years of experience with this condition and propose a classification of patients affected by angioedema unaccompanied by urticaria. Methods: From 1993 through 2003 at our outpatient clinic, 929 consecutive patients were examined for recurrent angioedema unaccompanied by urticaria. A detailed history was taken to identify known causes of angioedema, with special attention to external allergenic agents. Each patient underwent a complete physical examination, routine laboratory tests (blood cell count, protein electrophoresis, erythrosedimentation rate, examination of stool for ova and parasites, pharyngeal and urine cultures, sinus and dental radiography, and measurements of antitissue autoantibodies and rheumatoid factor in plasma), and complement parameters (C1 inhibitor, C4 and C1q). Further testing was done when pertinent, based on clinical findings. When all results were negative, response to H1-antihistamine was considered. Results: Angioedema could not be classified in 153 patients who were lost to follow-up (16.4%). Among the 776 cases with adequate data, these types of angioedema were identified: 124 (16%) related to external agents such as a drug, insect bite or foodstuff; 85 (11%) related to treatment with angiotensin-converting enzyme inhibitor; 55 (7%) associated with an autoimmune disease or infection; and 197 (25%) caused by C1 inhibitor deficiency. In the other 315 cases (41%), the etiology was undiscovered: 254 cases (33% of the study sample) were idiopathic histaminergic; 40 (5%) were idiopathic nonhistaminergic; and 21 (3%) had other causes of peripheral or generalyzed edema. Interpretation: Our data indicated that angioedema without urticaria could be classified according to specific clinical and pathogenic characteristics, and we have suggested a work-up for patients experiencing this condition.

Side effects of long-term prophylaxis with attenuated androgens in hereditary angioedema: Comparison of treated and untreated patients

Danazol and stanozolol, 17-a-alkylated attenuated androgens, prevent symptoms in hereditary angioedema (HAE), the inherited deficiency of Cl-inhibitor?, 2 Possible side effects can be due to: (1) residual hormonal activity (seborrhoea, acne, increased hair growth, weight gain, deepening of the voice, decreased breast size, vasomotor symptoms, irregular vaginal bleeding, decreased libido), (2) 17c~-alkylation (hepatotoxicity, ranging from signs of necrosis and cholestasis to the induction of hepatocellular and vascular neoplasm), (3) changes in the levels of lipoproteins (possible potentiation of atherogenesis)?. 4 The few reports on the safety of long-term treatment with androgens for prophylaxis of HAE have failed to show important drug-related side effects. 5, 6 However, none of these studies included a control group of untreated patients with HAE. The aim of this study was to compare clinical and biochemical parameters in patients with untreated HAE and in those who had been treated with attenuated androgens for long periods.

Angioedema due to angiotensin-converting enzyme inhibitors.

Angiotensin-converting enzyme (ACE) inhibitor associated angioedema was detected in 39 subjects (17%) of 231 consecutive patients examined in the last 5 years at our out-patient clinic for symptoms of angioedema without urticaria. In these patients, angioedema was most commonly localized to the face. The duration of ACE-inhibitor treatment at the onset of angioedema ranged from 1 day to 8 years with a median of 6 months. The time elapsed between onset of angioedema and withdrawal of ACE-inhibitor ranged from 1 day to 10 years with a median of 10 months. Delayed diagnosis is explained by the unusual characteristics of this adverse reaction: angioedema may start years after beginning the treatment and then it recurs irregularly. In fact, ACE-inhibitors seem to facilitate angioedema in predisposed subjects, rather than causing it with an allergic or idiosyncratic mechanism. Thus, while Cl-inhibitor levels are usually normal in subjects developing ACE-inhibitor-dependent angioedema, we found that ACE-inhibitors caused angioedema in Cl-inhibitor-deficient patients. Because the main inactivator of bradykinin is kininase II, which is identical with ACE, it is believed that bradykinin mediates ACE-inhibitor-dependent angioedema. We had the possibility to examine the plasma bradykinin levels in one ACE-inhibitor-treated patient during an angioedema attack and we found very high levels, but we did not find an increase of break-down products of high-molecular-weight-kininogen as observed during acute attacks in hereditary angioedema. Bradykinin fell to normal levels during remission after withdrawal of the drug. These observations indicate that in ACE-inhibitor-induced angioedema, contrary to hereditary angioedema, the reduction of bradykinin catabolic rate plays a predominant role.

Autoantibodies and Lymphoproliferative Diseases in Acquired C1-inhibitor Deficiencies

Angioedema due to acquired C1-inhibitor (C1-INH) deficiency (also referred to as “acquired angioedema”) is a rare, life-threatening disease with poorly defined etiology, therapy, and prognosis. To define the profile of acquired C1-INH deficiency and to facilitate the clinical approach to these patients, we report on 23 patients with acquired C1-INH deficiency followed for up to 24 years (median, 8 yr), and review the literature.We measured C1-INH activity with chromogenic assay and detected autoantibodies to C1-INH by enzyme-linked immunosorbent assay (ELISA). Median age at onset of angioedema was 57 years (range, 39–75 yr). All patients had C1-INH function and C4 antigen below 50% of normal. C1q was reduced in 17 patients. Autoantibodies to C1-INH were present in 17 patients. Long-term prophylaxis of attacks with danazol was effective in 2 of 6 patients, and with tranexamic acid, in 12 of 13 patients. Therapy with C1-INH plasma concentrate was necessary in 12 patients: 9 had rapid positive response and 3 became progressively resistant. Associated diseases at the last follow-up were non-Hodgkin lymphomas (3 patients), chronic lymphocytic leukemia (1 patient), breast cancer (1 patient), monoclonal gammopathies of uncertain significance (13 patients). In 4 patients no pathologic condition could be demonstrated.Compared with the general population, patients with acquired C1-INH deficiency present higher risk for B-cell malignancies, but not for progression of monoclonal gammopathies of uncertain significance to malignancy. Antifibrinolytic agents are more effective than attenuated androgens in long-term prophylaxis. Patients with acquired C1-INH deficiency may be resistant to replacement therapy with C1-INH plasma concentrate.

Pathogenetic and Clinical Aspects of C1 Inhibitor Deficiency

People deficient in C1-INH present recurrent angioedema localized to subcutaneous or mucous tissues. The defect can be caused by impaired synthesis, due to a genetic defect (hereditary angioedema), or by increased catabolism (acquired angioedema). In our experience the majority of patients with acquired angioedema (16 of 18) have autoantibodies to C1-INH in their serum. These autoantibodies bind to C1-INH with different and generally low affinity. The vasopermeability mediator responsible for attacks is still undefined: bradykinin (derived from cleavage of high molecular weight kininogen) and a kinin-like peptide (derived from the second component of complement) still remain the two primary candidates. We examined the systems controlled by C1-INH (complement, contact system, fibrinolysis and coagulation) and found that all of them are activated during angioedema attacks. Activation of the coagulation leads to generation of thrombin whose vasoactive effect can thus influence edema formation. Treatment of severe angioedema attacks is satisfactorily performed with C1-INH plasma concentrate although patients with an acquired defect frequently need very high doses. Attenuated androgens effectively prevent attacks in hereditary angioedema, but their safety, on the very long-term, needs to be further assessed. Acquired angioedema generally fail to respond to these drugs, but can be treated prophylactically with antifibrinolytic agents.

Idiopathic nonhistaminergic angioedema.

PURPOSE We sought to describe the characteristics of a group of patients with idiopathic nonhistaminergic angioedema and their response to prophylactic treatment with tranexamic acid. METHODS We identified 25 patients (15 men and 10 women; age at diagnosis 16 to 77 years) who had idiopathic nonurticarial angioedema that was not prevented by histamine-1 (H1) blockers. Known causes of angioedema were excluded by clinical history, physical examination, and diagnostic tests. RESULTS The median age at the onset of symptoms was 35 years (range 8 to 66). The frequency of attacks was > 12 per year for 16 patients, six to 11 per year for 6 patients, and one to five per year for 3 patients. All patients had cutaneous attacks, 13 (52%) reported swellings of the pharynx or larynx, and 5 (20%) had symptoms consistent with bowel angioedema. Because of the similarities between these patients and patients who are deficient in C1 inhibitor, the 15 patients with severe and frequent attacks were started on prophylactic treatment with the antifibrinolytic agent tranexamic acid, 1 g three times a day orally for 3 months, tapered according to its effectiveness. The symptoms of 11 patients decreased to less than one attack per year, and the remaining 4 patients had partial remissions (less than 4 attacks per year). Fourteen patients are still being treated with tranexamic acid. CONCLUSION Patients with idiopathic nonhistaminergic angioedema appear to have similar clinical features and response to treatment with tranexamic acid as those who are deficient in C1 inhibitor. This suggests that those two forms of angioedema might have, at least in part, a similar pathogenesis.

C1 inhibitor: molecular and clinical aspects

C1 inhibitor (C1-INH) is a serine protease inhibitor (serpins) that inactivates several different proteases in the complement, contact, coagulation, and fibrinolytic systems. By its C-terminal part (serpin domain), characterized by three β-sheets and an exposed mobile reactive loop, C1-INH binds, and blocks the activity of its target proteases. The N-terminal end (nonserpin domain) confers to C1-INH the capacity to bind lipopolysaccharides and E-selectin. Owing to this moiety, C1-INH intervenes in regulation of the inflammatory reaction. The heterozygous deficiency of C1-INH results in hereditary angioedema (HAE). The clinical picture of HAE is characterized by bouts of local increase in vascular permeability. Depending on the affected site, patients suffer from disfiguring subcutaneous edema, abdominal pain, vomiting and/or diarrhoea for edema of the gastrointestinal mucosa, dysphagia, and dysphonia up to asphyxia for edema of the pharynx and larynx. Apart from its genetic deficiency, there are several pathological conditions such as ischemia–reperfusion, septic shock, capillary leak syndrome, and pancreatitis, in which C1-INH has been reported to either play a pathogenic role or be a potential therapeutic tool. These potential applications were identified long ago, but controlled studies have not been performed to confirm pilot experiences. Recombinant C1-INH, produced in transgenic animals, has recently been produced for treatment of HAE, and clinical trials are in progress. We can expect that the introduction of this new product, along with the existing plasma derivative, will renew interest in exploiting C1-INH as a therapeutic agent.

Long-term follow-up of 111 patients with angiotensin-converting enzyme inhibitor-related angioedema.

Objective To investigate, for the first time, the frequency of recurrences of angiotensin-converting enzyme inhibitor (ACE-I)-related angioedema after the discontinuation of ACE-I. Methods This retrospective study was conducted in an outpatient tertiary-level centre for a total period of 173 months (about 14 years). Consecutive patients with recurrent angioedema symptoms, initiated during treatment with an ACE-I, who had been followed for at least 12 months after discontinuation of the drug were eligible. The primary study variable was the incidence of recurrences of angioedema after ACE-I discontinuation. Angioedema location, type of ACE-I and indication for this treatment and the drugs prescribed after the discontinuation of ACE-I were also evaluated. Results In total, 111 patients were followed; 54 of them (49%) were on enalapril. After discontinuation from ACE-I, 51 patients (46%) had further recurrences of angioedema; in 18 relapsers (16% of the total), the frequency of angioedema recurrences remained unchanged when compared with that reported during ACE-I treatment. The large majority of relapsers (88%) had the first recurrence of angioedema within the first month since ACE-I discontinuation. The switch to a different antihypertensive therapy did not seem associated with a reduction in the frequency of angioedema attacks. Conclusion Even with all the limitations on any observational analysis, this long-term study suggests for the first time that patients with angioedema started while on ACE-I treatment seem to have a condition predisposing to angioedema that is elicited by the treatment with these drugs. Further studies in this field appear advocated due to the potential severity of angioedema attacks.

How do we treat patients with hereditary angioedema

Hereditary angioedema (HAE) is due to the inherited deficiency of C1-Inhibitor (C1-Inh). When specific treatment was not available, the mortality rate for this disease was as high as 50% and the disability up to 100-150 days per year (Agostoni and Cicardi, Hereditary and acquired C1-inhibitor deficiency: biological and clinical characteristics in 235 patients). Such a worrying scenario dramatically improves upon appropriate treatment. Nevertheless, the disease still frequently goes undiagnosed or misdiagnosed as an allergic condition. Both circumstances prevent patients from receiving drugs that could save and/or improve the quality of their life. The interest of our group for patients with HAE goes back to the early seventies. Since that time, 441 such patients have been examined and treated at our department; 403 are still actively followed. Here we present our experience on the treatment of HAE.

Increased expression of C1-inhibitor mRNA in patients with hereditary angioedema treated with Danazol

The attenuated androgen Danazol can partially reverse the biochemical defect and prevent angioedema in patients with inherited C1-inhibitor (C1-INH) deficiency (hereditary angioedema, HAE). Though its clinical effectiveness is independent from significant increase of C1-INH plasma levels, its mechanism of action remains unknown. Since angioedema is a local phenomenon, it could be controlled by restoring tissue levels of C1-INH. We measured the expression of C1-INH mRNA in peripheral blood mononuclear cells (PBMCs) of 13 patients with HAE type 1 (seven untreated and asymptomatic, and six on Danazol at the minimal effective dose) and of eight normal controls. mRNA levels were quantitated by computerized optical densitometry of reverse transcriptase-PCR products, normalized for the amount of glyceraldehyde-3-phosphate-dehydrogenase and expressed as percent of normal pooled RNAs. Each determination represented the mean of three separate experiments. Measurement of C1-INH mRNA in two patients before and after 1 month of Danazol 400 mg per day demonstrated a post-treatment increase of 15 and 21%, respectively. When HAE patients and controls were analyzed as groups, C1-INH mRNA levels of patients untreated and asymptomatic (median 73%, range 65-78) were significantly lower (P=0.001) compared to controls (median 101%, range 87-121) and to patients on Danazol (median 91%, range 82-96); the difference among the last two groups was not statistically significant. Our data demonstrate that minimal effective doses of Danazol increase the expression of C1-INH mRNA in PBMC of HAE patients even in the absence of a significant increase of C1-INH plasma levels.