Recombinant human C1 esterase inhibitor for the treatment of hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE)

The lack of C1 inhibitor function that results in excessive production of bradykinin causing the angioedema seen in hereditary angioedema (HAE) is well established. Several drugs have been developed to treat and prevent attacks in patients suffering from HAE due to C1 inhibitor deficiency (C1-INH-HAE). Plasma-derived C1INH has been used to replace the deficiency of C1 inhibitor (C1INH) and has been approved for both treatment of attacks and for prophylactic therapy to prevent attacks. Plasma kallikrein inhibitor (ecallantide) and bradykinin receptor antagonist (icatibant) are both effective for treatment of acute attacks, but their short half-life limits the use for prophylaxis. Androgens, in particular danazol, are effective for long-term prophylaxis, but adverse event profile can limit its use. Recombinant C1 inhibitor derived from transgenic rabbits has recently been approved for use in treatment of C1-INH-HAE attacks and is effective and appears safe with minimal adverse event profile.     

Therapeutic management of hereditary angioedema due to C1 inhibitor deficiency

Hereditary angioedema (HAE) due to C1 inhibitor (C1-INH) deficiency is a rare genetic disease characterized by recurrent swellings of the subcutaneous and submucosal tissues that can manifest as cutaneous edema, abdominal pain and laryngeal edema with airway obstruction. These symptoms have a significant impact on patients’ quality of life. The reduction in C1-INH function leads to uncontrolled activation of the contact system and generation of bradykinin, the mediator of increased vascular permeability and edema formation. In the past, few treatment options were available; however, several new therapies with proven efficacy have recently become available to treat and prevent HAE attacks, such as plasma-derived and recombinant C1-INHs that replace the deficient protein, bradykinin receptor antagonist (icatibant) that blocks bradykinin activity and kallikrein inhibitor (ecallantide) that prevents bradykinin release. Such therapies can improve disease outcome. This article reviews the therapeutic management of HAE, which involves the treatment of acute attacks and prophylaxis.     

Normal C1 inhibitor mRNA expression level in type I hereditary angioedema patients: newly found C1 inhibitor gene mutations

BACKGROUND: C1 esterase inhibitor (C1INH) plays a key role in the classical pathway of the complement cascade. Mutations in this gene cause a decreased level of antigenic (type I hereditary angioedema, HAE) or functional (type II HAE) C1INH. OBJECTIVE: To find novel mutations in C1INH and evaluate the expression of C1INH gene in HAE patients. METHODS: Direct sequencing mutation analysis was performed for genomic DNA from three unrelated families (14 HAE patients and 18 family members). Genomic DNA from one family was also analyzed for larger genomic rearrangements, using Southern blotting analysis. We used real-time quantitative polymerase chain reaction (PCR) to evaluate C1INH mRNA expression level. RESULTS: Four mutations in exons (2,311 T-->C, 14,034 G-->A, 16,830 G-->A, and 16,979-16,980 G insertion) and four in introns (738 G-->A, 8,531 A-->G, 14,254 A-->G, and 14,337-14,378 TT deletion) were found. Interestingly, all of the nine patients in one family share the same mutation of Gly345Arg (14,034 G-->A) in the seventh exon. In another family, a single base mutation near the splice site (14,254 A-->G) was found in all of the three patients. In the last family, although a significant mutation was not found by direct sequencing, patients showed an abnormal 16 kb fragment in addition to the normal allele (21 kb Bcl I fragment). The C1INH mRNA expression of HAE patients in two families was not significantly different compared with that of normal controls. CONCLUSION: The two novel exonal mutations (G-->A and A-->G) and one large gene deletion were associated with the clinical phenotypes of HAE. Considering the normal C1INH mRNA levels but below normal protein levels in two families, their phenotypes would be associated with the post-translational defect.     

Detection of C1 inhibitor (SERPING1/C1NH) mutations in exon 8 in patients with hereditary angioedema: evidence for 10 novel mutations

Hereditary angioedema (HAE) is caused by mutations in the C1 inhibitor gene (SERPING1, C1NH) and the result is C1 inhibitor deficiency, either in levels or function. We have searched exon 8 for mutations by direct sequencing and analyzed the rest of the exons by SSCP in 87 Spanish families affected by HAE. Out of 87 screened families, we have detected exon 8 mutations in 26. Among these, 17 different mutations were identified: 14 point mutations and 3 frameshift. Seven of the point mutations and the three frameshift were not previously reported. Mutations were: S438P; R444P; V451G; W460X; V468D; G471E; X479R; S417fsX427; I440fsX450; E429fsX450. The rest of the families presented previously reported mutations, 5 missense and two nonsense. In none of the 26 families was an additional change identified in the rest of the exons by SSCP, and, in 20 out of the 22 families with point mutation, we verified that the mutation did not affect a healthy relative. Seven of these families had no history of the disease, and in five of them we were able to verify that the progenitors did not have the mutation. Therefore, they were de novo mutations.     

Pasteurized C1 inhibitor concentrate in hereditary angioedema: pharmacology,safety, efficacy and future directions

Hereditary angioedema (HAE) is a relatively rare genetic disorder that is most commonly caused by a deficiency of C1 inhibitor. It is estimated that HAE affects at least one in 10,000 to one in 50,000 of the worldwide population, with relapsing swelling of the skin and abdominal pain attacks being the most common clinical symptoms. Most seriously, laryngeal edema associated with HAE may lead to death. Replacement therapy with intravenous pasteurized C1 inhibitor concentrate is the recommended treatment for acute attacks of HAE, resulting in a rapid resolution of symptoms. Pasteurized C1 inhibitor concentrates can also be used for prophylaxis of HAE, and are currently also being assessed for home therapy in this setting. Future advances may improve disease burden and mortality associated with HAE.     

C1 INH concentrate in the therapy of hereditary angioedema

Ten acute attacks were managed in nine patients with hereditary angioedema by means of the infusion of a C1 INH concentrate produced on large scale. No side effects were observed.     

C1 inhibitor deficiency: 2014 United Kingdom consensus document

C1 inhibitor deficiency is a rare disorder manifesting with recurrent attacks of disabling and potentially life-threatening angioedema. Here we present an updated 2014 United Kingdom consensus document for the management of C1 inhibitor-deficient patients, representing a joint venture between the United Kingdom Primary Immunodeficiency Network and Hereditary Angioedema UK. To develop the consensus, we assembled a multi-disciplinary steering group of clinicians, nurses and a patient representative. This steering group first met in 2012, developing a total of 48 recommendations across 11 themes. The statements were distributed to relevant clinicians and a representative group of patients to be scored for agreement on a Likert scale. All 48 statements achieved a high degree of consensus, indicating strong alignment of opinion. The recommendations have evolved significantly since the 2005 document, with particularly notable developments including an improved evidence base to guide dosing and indications for acute treatment, greater emphasis on home therapy for acute attacks and a strong focus on service organization.     

Evidence-based recommendations for the therapeutic management of angioedema owing to hereditary C1 inhibitor deficiency: consensus report of an International Working Group

Angioedema owing to hereditary deficiency of C1 inhibitor (HAE) is a rare, life-threatening, disabling disease. In the last 2 years, the results of well-designed and controlled trials with existing and new therapies for this condition have been published, and new treatments reached the market. Current guidelines for the treatment for HAE were released before the new trials and before the new treatments became available and were essentially based on observational studies and expert opinion. To provide evidence-based HAE treatment guidelines supported by the new studies, a conference was held in Gargnano del Garda, Italy, from September 26 to 29, 2010. The meeting hosted 58 experienced HAE expert physicians, representatives of pharmaceutical companies and representatives of HAE patients' associations. Here, we report the topics discussed during the meeting and evidence-based consensus about management approaches for HAE in adult/adolescent patients.     

Bacteriuria increases the risk of edematous attacks in hereditary angioedema with C1‐inhibitor deficiency

Urinary tract infections are considered among the most common infectious disorders in humans. Various infections may have a role in inducing HAE attacks. Our study intended to evaluate bacteriuria in the urinalysis of patients with C1‐INH‐HAE. Urine specimens contributed by 139 patients with C1‐INH‐HAE at the annual control visits were studied retrospectively for microorganisms. We analyzed the presence of bacteriuria in relation to the clinical symptoms. Taking into account three randomly selected urine specimens, we found that the cumulative number of edematous attacks was higher in patients with bacteriuria than in those without (P = 0.019, P = 0.022, P = 0.014). Considering the same patients, attack number was significantly higher (14.51 vs 8.63) in patients with bacteriuria than in those without (P < 0.0001). In patients with bacteriuria, we found a higher incidence of edema formation during the year before evaluation, which may suggest the triggering role of bacteriuria in the occurrence of edematous episodes.