What is the role of C1 (Complement 1) inhibitor in treating hereditary angioedema (HAE)?

Role of C1 Inhibitor in Treating Hereditary Angioedema (HAE)

Plasma-derived human C1 inhibitor concentrate (pdhC1INH) is the preferred treatment for acute attacks, short-term prophylaxis, and long-term prophylaxis in hereditary angioedema, offering rapid symptom relief within 15-60 minutes with an excellent safety profile. 1, 2

Types of Hereditary Angioedema

HAE can be classified into two main categories:

1. HAE with C1 Inhibitor Deficiency (HAE-C1INH):

   • Type I (85%): Characterized by low levels of C1-INH protein
   • Type II (15%): Normal or high C1-INH levels, but the protein is dysfunctional

2. HAE with Normal C1 Inhibitor (HAE-nC1INH):

   • Less common form first described in 2000
   • Normal quantity and function of C1-INH
   • May have genetic variants in other genes (e.g., Factor XII)

Treatment Approaches with C1 Inhibitor

Treatment of HAE can be divided into three main strategies:

1. Acute Attack Treatment (On-Demand)

• Plasma-derived human C1 inhibitor concentrate (pdhC1INH):

  • First-line therapy for acute attacks
  • Dosage: 20 U/kg or fixed dose of 500-1000 units
  • Onset of relief: 15-60 minutes
  • Highly effective for severe abdominal, subcutaneous, and laryngeal attacks 2
  • Can be self-administered
  • Safe for use in children and pregnant women

• Alternative options when C1-INH is unavailable:

  • Ecallantide (plasma kallikrein inhibitor)
  • Icatibant (bradykinin B2 receptor antagonist)
  • Fresh frozen plasma (less preferred)

2. Short-Term Prophylaxis

• Indications: Before medical procedures, dental work, surgeries
• pdhC1INH: Preferred option for short-term prophylaxis 1
• Alternative options:
  • Fresh frozen plasma
  • Short-term, high-dose anabolic androgens (with caution)

3. Long-Term Prophylaxis

• pdhC1INH: Safe and effective option for long-term prophylaxis 1, 3

  • Available in both intravenous and subcutaneous formulations
  • Subcutaneous administration facilitates self-administration at home

• Alternative options:

  • Attenuated androgens (danazol, stanozolol) - effective but with more side effects
  • Antifibrinolytic agents (tranexamic acid) - somewhat effective
  • Lanadelumab (monoclonal antibody)

Mechanism of Action

C1-INH functions as a critical regulator of multiple pathways:

• Regulates activation of the complement system
• Controls the contact system pathway (intrinsic coagulation)
• Acts as a major endogenous inhibitor of plasma kallikrein

In HAE, the deficiency or dysfunction of C1-INH leads to unregulated activity of plasma kallikrein, resulting in excessive bradykinin generation. Bradykinin is a vasodilator responsible for the characteristic HAE symptoms of localized swelling, inflammation, and pain 4.

Exogenous administration of C1-INH restores the concentration and functional activity of this protein, regulates bradykinin release, and prevents or attenuates angioedema attacks 3.

Special Considerations

Pregnancy

• Attenuated androgens are contraindicated
• pdhC1INH is the preferred treatment for acute attacks, short-term prophylaxis, and long-term prophylaxis during pregnancy 1
• No safety data available on icatibant, ecallantide, or recombinant human C1-INH during pregnancy

Children

• pdhC1INH has proven effective and safe in pediatric patients 2
• Dosing should be weight-based (20 U/kg)

Efficacy and Safety

• Studies show consistent relief of severe attacks with pdhC1INH
• No reports of viral infections or antibody formation against the purified protein 2
• No recurrent attacks within 72 hours after administration
• C1-INH requirements do not change after repeated use

HAE with Normal C1-INH

For patients with HAE-nC1INH, treatment options are similar to those for HAE-C1INH, although evidence is more limited:

• Drugs developed for HAE-C1INH (including C1-INH concentrates) have been reported to be effective in some patients with HAE-nC1INH 1
• Tranexamic acid may be more effective for HAE-nC1INH than for HAE-C1INH 1
• Some patients with HAE-nC1INH only have symptoms with high estrogen exposure, and discontinuing estrogen-containing medications may be effective 1

Acquired C1 Inhibitor Deficiency

It's important to distinguish hereditary from acquired C1 inhibitor deficiency:

• Acquired C1-INH deficiency presents later in life (middle-aged or older patients)
• Often associated with underlying conditions, particularly lymphoproliferative disorders 5
• Laboratory findings include reduced C1-INH function, low C4 levels, and low C1q levels (the latter distinguishes it from hereditary forms)
• Treatment approach differs slightly, with antifibrinolytics often being more effective than in hereditary forms 5
• Successful treatment of underlying conditions (e.g., lymphoma) can improve or resolve symptoms

In conclusion, C1 inhibitor replacement therapy remains the cornerstone of HAE management, providing effective and safe treatment for both acute attacks and prophylaxis.