Elevated D-dimers in attacks of hereditary angioedema are not associated with increased thrombotic risk.

BACKGROUND: Recommended management of attacks of hereditary angioedema (HAE) due to C1 esterase inhibitor (C1-INH) deficiency (C1-INH-HAE) includes therapy with exogenous C1INH. Thrombotic/thromboembolic events (TEE) have been reported with plasma-derived C1INH, but so far none with recombinant human C1INH (rhC1INH). This phase III, randomized, placebo (saline)-controlled study evaluated the safety of rhC1INH 50 IU/kg for the treatment of acute attacks in 74 patients with C1-INH-HAE. METHODS: Monitoring for TEE and assessment of risk of deep vein thrombosis (DVT) by the Wells prediction rule were performed, and levels of fibrin degradation products (plasma D-dimers) were assessed before study drug administration (baseline), 2 h, and 7 days posttreatment. RESULTS: Plasma D-dimer levels were elevated in 80% of the patients (median [25th-75th percentiles]: 2149 [480-5105] µg/l; normal ≤250 µg/l) and were higher in patients with submucosal (abdominal, oropharyngeal-laryngeal) attacks (3095 [890-10000] µg/l; n = 29) compared with subcutaneous (peripheral, facial) attacks (960 [450-4060] µg/l; n = 35). Median plasma D-dimer levels were comparable across treatment groups at baseline (1874 [475-4568] µg/l rhC1INH; 2259 [586-7533] µg/l saline) and 2 h postinfusion (2389 [760-4974] µg/l rhC1INH; 2550 [310-8410] µg/l saline); median plasma D-dimer levels were decreased by Day 7 in both groups (425 [232-3240] µg/l rhC1INH; 418 [246-2318] µg/l saline). No increased risk of DVT was identified, nor any TEE reported in rhC1INH treated or controls. CONCLUSION: Elevated plasma D-dimer levels were associated with acute C1-INH-HAE attacks, particularly with submucosal involvement. However, rhC1INH therapy was not associated with thrombotic events.

C-reactive protein levels in hereditary angioedema.

Hereditary angioedema (HAE) patients experience recurrent episodes of angioedema attacks that can be painful, disfiguring and even life-threatening. The disorder results from a mutation in the gene that controls the synthesis of C1-inhibitor (C1INH). C1INH is a major regulator of activation of the contact system. It is often assumed that attacks results from uncontrolled local activation of the contact system with subsequent formation of bradykinin. To evaluate the involvement of inflammatory reactions in HAE, we analysed C-reactive protein (CRP) levels. HAE patients included in a clinical database of recombinant human C1-inhibitor (rhC1INH) studies were evaluated. For the current study we analysed CRP levels when patients were asymptomatic, during a clinical attack and in a follow-up period, and correlated these with the clinical manifestations of the attack. Data from 68 HAE patients were analysed and included CRP levels on 273 occasions. While asymptomatic, 20% of the patients analysed had increased CRP. At the onset of the attack (P = 0·049) and during the next 24 h CRP rose significantly (P = 0·002) in patients with an abdominal location, and post-attack levels were significantly higher in these patients than in patients with attacks at other locations (P = 0·034). In conclusion, CRP levels are elevated in a substantial proportion of asymptomatic HAE patients. Levels of CRP increase significantly during an abdominal attack. These data suggest low-grade systemic inflammatory reactions in HAE patients as well as a triggering event for attacks that starts prior to symptom onset.

Recombinant human C1 inhibitor for the prophylaxis of hereditary angioedema attacks: a pilot study.

BACKGROUND: Hereditary angioedema (HAE) is a disease characterized by recurrent tissue swelling affecting various body locations. Recent literature shows that patients with frequent attacks may benefit from long-term prophylaxis. This study evaluated the safety and prophylactic effect of weekly administrations of recombinant C1INH (rhC1INH). METHODS: Patients with a history of HAE attacks occurring ≥every 2 weeks received a once weekly administration of 50 U/kg rhC1INH. Hereditary angioedema attack history was collected at screening. Breakthrough attacks during the study were recorded at each visit. Following a 2-week run-in period, HAE patients received 8 weekly rhC1INH administrations and were followed-up for an additional 6 weeks. Efficacy was evaluated by comparing the HAE attack incidence during the treatment period to the historical attacks over the previous 2 years. Safety evaluation was based on clinical laboratory and adverse events (AEs) reports. RESULTS: The 25 participants reported a mean of 0.9 attacks/week over the past 2 years. The mean breakthrough attack rate during the treatment period was 0.4 attacks/week (95% CI 0.28-0.56). A total of 30 treatment-emergent-AEs were reported in 13 patients, all mild to moderate. One patient died from a laryngeal attack 25 days after last study drug administration. The only possible drug related AEs reported were dry mouth, dizziness and anxiety in one patient and hypotension in another. There were no allergic AEs and no neutralizing antibodies observed. CONCLUSIONS: Weekly administrations of 50 U/kg rhC1INH appeared to reduce the frequency of HAE attacks and were generally safe and well tolerated.

Efficacy and safety of recombinant human C1-inhibitor for the treatment of attacks of hereditary angioedema: European open-label extension study.

BACKGROUND: Hereditary angioedema (HAE) owing to C1 inhibitor deficiency is an autosomal dominant disorder, characterized by recurrent, potentially life-threatening, localized attacks of tissue swelling. Current treatment involves the infusion of C1 inhibitor protein (C1-INH) isolated from human plasma. OBJECTIVES: This open-label extension to a European, Israeli and Argentinean randomized study (NCT00262301) aimed to investigate the efficacy and safety of recombinant human C1 inhibitor (rhC1-INH) as a first-line treatment following an HAE attack, together with its effect on subsequent attacks. METHODS: An HAE-specific visual analogue scale (VAS) 0-100 mm was used by patients to assess the severity of attack at four anatomical locations. Patients were treated with one, single-vial, fixed-dose of rhC1-INH (2100 U), followed by up to two further vials at the investigators discretion. The primary end-point was the time from first rhC1-INH injection to first onset of relief of symptoms (≥ 20 mm decrease on VAS). Response to treatment was defined as the onset of relief within 4 h. RESULTS: A total of 57 patients were treated for 194 HAE attacks. Overall, sustained relief of symptoms was achieved in 87% of rhC1-INH-treated patients within 4 h of treatment, with 57% of attacks requiring only one vial of rhC1-INH. When categorized by successive attacks experienced by individual patients, the response rate to rhC1-INH treatment was 96%, 83%, 87%, 80% and 80% for attacks 1-5 respectively. Treatment with rhC1-INH was well tolerated, with no discontinuations owing to treatment-emergent adverse events and no adverse events relating to immunogenicity. CONCLUSIONS AND CLINICAL RELEVANCE: Treatment with rhC1-INH provides fast-onset relief for an HAE attack, with a high rate of therapeutic response maintained throughout subsequent attacks.

Target levels of functional C1-inhibitor in hereditary angioedema.

BACKGROUND: Hereditary angioedema (HAE) is a heterozygous deficiency of first component of complement-inhibitor (C1INH). Insufficient C1INH activity leads to uncontrolled activation of plasma cascade systems, which results in acute angioedema attacks in patients with HAE. Plasma-derived or recombinant C1INH products are approved for the treatment of such angioedema attacks. The target level of C1INH activity needed to achieve optimal efficacy, however, remains unknown. We determined the plasma level of C1INH associated with optimal clinical efficacy in the treatment of angioedema attacks. METHODS: Efficacy and pharmacokinetic data were reviewed from recently published placebo-controlled randomized trials in the treatment of HAE with either plasma-derived or recombinant C1INH products, tested at various doses. RESULTS: A dose-dependent effect was observed on time to the beginning of relief of symptoms, on time to resolution of symptoms, and on the response rate within 4 h. Optimal efficacy of C1INH therapy is achieved at doses ≥50 U/kg. This dose increases plasma C1INH activity in almost all patients to values ≥0.7 U/ml (70% of normal), the lower limit of the normal range. The differences in half-lives of the various C1INH products do not have an obvious effect on clinical efficacy. CONCLUSION: A review of the efficacy and pharmacokinetic data from recently published controlled studies in the treatment of HAE attacks suggests that efficacy of C1INH therapy is optimal when C1INH activity levels are restored to the normal range.

Relationship of the eye to the bony orbit, with clinical correlations.

PURPOSE: To examine normal anatomic relationship of the globe to the bony orbit, and relate variations in this relationship to clinical parameters. METHODS: Seventy-nine axial and sagittal magnetic resonance imaging (MRI) scans of the globe and orbit were studied. Any patients with pathology, as reported by the radiologists' findings, were excluded. Measurements were made on the images to determine the position of the globe relative to the bony orbit and to describe the configuration of the anterior face of the maxillary sinus. Clinical measurements were performed on photographs of 36 patients who underwent MRI scans. An independent observer rated these photographs for two clinical findings: inferior scleral show and tear trough deformity. RESULTS: Correlations were found in the following sets of variables. (i) Corneal projection from infraorbital rim and corneal projection from lateral rim; (ii) corneal projection from supraorbital rim and corneal projection from lateral rim; (iii) scleral show and corneal projection from lateral orbital rim; and (iv) tear trough deformity rating and angle of anterior face of maxillary sinus. There were no significant correlations found in the other data variables. CONCLUSIONS: The data show that abnormal relationships between the globe and the bony orbit can have clinical consequences. Inferior scleral show is shown to be related to relative globe prominence, measured from either the lateral or the inferior orbital rims. The tear trough deformity is correlated with a sloping maxillary face. The results provide a rational basis for surgeries designed to normalize these relationships.