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Acquired Angioedema Due to C1 Inhibitor Deficiency Medication

  • Author: Amanda T Moon, MD; Chief Editor: William D James, MD  more...
 
Updated: Mar 07, 2016
 

Medication Summary

The goals of pharmacotherapy for acquired angioedema are to reduce morbidity and to prevent complications. Medication may be used for acute or preventive treatment.

In Europe, purified C1 inhibitor (C1-INH) has been available for the treatment of acute attacks for decades, but it has not been available in the United States until recently. In October 2008, the US Food and Drug Administration (FDA) approved the use of C1-INH (Cinryze) at a dose of 1000 units IV 2-3 times/wk for prophylaxis to prevent attacks. In October 2009, the FDA approved C1-INH (Berinert) at a dose of 20 units/kg IV for the treatment of acute abdominal and facial angioedema attacks in adolescents and adults with HAE. Berinert was also approved for acute treatment of laryngeal attacks in January 2012.

In acquired angioedema, therapy for acute attacks may be aborted with C1-INH concentrates or, if those are unavailable, fresh-frozen plasma. However, rapid catabolism of C1-INH occurs in acquired angioedema, so higher doses of C1-INH plasma concentrate may be needed.

In December 2009, ecallantide (Kalbitor), a kallikrein inhibitor, at a dose of 30 mg SC was approved for the treatment of acute attacks.

In August 2011, icatibant (Firazyr), a selective bradykinin B2 receptor antagonist, was approved for treatment of acute attacks of HAE in adults at a dose of 30 mg SC in the abdominal area.

Androgens, such as danazol or stanozolol, may be beneficial in acquired angioedema type I but are of no value in acquired angioedema type II (AAE-II). Prostate cancer and pregnancy preclude the use of androgens.

Antifibrinolytics, such as epsilon-aminocaproic acid and tranexamic acid, have been found to be more effective for long-term prophylaxis in those with acquired angioedema.

Immunosuppressive therapy directed toward decreasing autoantibody production may be of value in patients with acquired angioedema type II, which may be accomplished by the use of plasmapheresis with cyclophosphamide.

In 2004 and 2006, two papers reported effective treatment of acquired angioedema cases with a series of 4 weekly injections with rituximab (a chimeric monoclonal antibody to CD20). In one study, rituximab treatment resulted in normalization of C1-INH and C4 levels and long-term remission of angioedema attacks in 3 patients with severe acquired angioedema.[12] In the second study, a patient with acquired angioedema type II refractory to standard treatment experienced a 6-month attack-free interval after treatment with rituximab.[13] Several more recent reports have supported the efficacy of rituximab in achieving remission of acquired angioedema in patients with either an underlying B-cell lymphoproliferative disorder or autoimmune disease. [14, 15, 16, 17]

Another immunosuppressant drug, etanercept, was reported to control angioedema in a 57-year old man with psoriatic arthritis. This man was treated with 25 mg of etanercept administered subcutaneously twice per week for recalcitrant psoriatic arthritis. The treatment also resulted in improvement of the patient's angioedema. The authors hypothesized that etanercept may have improved the angioedema by decreasing inflammation and vascular permeability.[18]

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Blood Products

Class Summary

These agents are used to improve the clinical aspects of the disease.[4]

Fresh Frozen Plasma

 

Infuse prior to airway manipulation (eg, dental extraction) to prevent angioedema. Administering 2 units of fresh frozen plasma (FFP) sustains complement control and prevents the development of angioedema. Improved screening programs greatly reduce risk of hepatitis. FFP is not recommended for treatment of acute attacks.

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Alkylating Agents

Class Summary

Some agents in this class have potent immunosuppressive activity.

Cyclophosphamide

 

Cyclophosphamide is chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.

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C1-Inhibitor Concentrates

Class Summary

These concentrates are used in the acute treatment of angioedema. They have recently been approved by the US FDA for routine prophylaxis against angioedema attacks and as treatment for acute attacks.

C1-inhibitor, human (Cinryze)

 

C1-INH is a normal constituent of human blood and is one of the serine proteinase inhibitors (serpins). It regulates activation of the pathway for complement and intrinsic coagulation, and it regulates the fibrinolytic system.

This agent is available as a sterile, lyophilized preparation derived from human plasma. Specific activity is 4-9 U/mg protein. One unit corresponds to the mean quantity of C1 inhibitor present in 1 mL of normal fresh plasma. It is indicated for routine prophylaxis against angioedema attacks in adolescents and adults with hereditary angioedema.

C1-INH replaces some of the missing protein, but the half-life in the circulation is short. Approved use is 1000 units biweekly, with the possibility of a third dose of 1000 units/wk if needed. Although FDA approval is for prophylaxis only at this time, this agent has been available for the treatment of acute attacks in Europe for decades and has an excellent safety profile.

C1 esterase inhibitor, human (Berinert)

 

This agent is a serine proteinase inhibitor found in human blood that regulates activation of the kinin system, complement pathway, intrinsic coagulation system, and fibrinolytic system. It binds to and neutralizes substrates that activate these systems, thereby suppressing activity. It is available as a pasteurized, lyophilized preparation derived from purified human plasma. One unit corresponds to the mean quantity of C1 inhibitor present in 1 mL of normal fresh plasma. C1 esterase inhibitor is indicated for acute laryngeal, abdominal, and facial angioedema attacks in adolescents and adults with HAE.

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Kallikrein Inhibitors

Class Summary

These agents have specific kallikrein inhibitor activity, resulting in bradykinin reduction. They are useful for treating acute episodic attacks. The package insert carries a black box warning because a small subset of patients may have anaphylactic reactions to the drugs. They must be administered by medical personnel capable of treating anaphylaxis.

Ecallantide (Kalbitor)

 

A human plasma kallikrein inhibitor, ecallantide binds to plasma kallikrein and blocks its binding site. It reduces the conversion of kininogen to bradykinin. This agent is indicated for acute attacks of HAE. It is available as an injectable solution; 10 mg/mL per single-use vial.

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Bradykinin Receptor Antagonists

Class Summary

Bradykinin receptor antagonists such as icatibant inhibit bradykinin from binding the B2 receptor and thereby treat the clinical symptoms of an acute attack. Recommended dose of icatibant is 30 mg SC in the abdominal area. It is available as a single-use, prefilled syringe, which delivers a dose of 30 mg (10 mg/mL).

Icatibant (Firazyr)

 

Icatibant is a bradykinin B2 receptor antagonist indicated for acute attacks of hereditary angioedema (HAE).

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Androgens and Androgen Derivatives

Class Summary

These agents have immunosuppressive properties.

Danazol

 

Danazol increases levels of the C4 component of complement and prevents attacks associated with angioedema.

Stanozolol

 

A synthetic androgen with immunosuppressive properties, stanozolol increases levels of C1 esterase inhibitor and C4 component of the complement. It is no longer available in the United States.

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Antifibrinolytic Agents

Class Summary

Antifibrinolytic agents act through the inhibition of plasmin. They tend to be more effective than androgens for prophylaxis.[3]

Aminocaproic acid (Amicar)

 

Aminocaproic acid is a lysine analog that inhibits fibrinolysis via inhibition of plasminogen activator substances and, to a lesser degree, through antiplasmin activity.

This agent is widely distributed. Half-life is 1-2 h. Peak effect occurs within 2 h. Hepatic metabolism is minimal. It can be used PO or IV.

Tranexamic acid (Cyklokapron, Lysteda)

 

An alternative to aminocaproic acid, tranexamic acid inhibits fibrinolysis by displacing plasminogen from fibrin.

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Antineoplastics, Anti-CD20 Monoclonal Antibodies

Class Summary

The agents in this class target specific antigens in carcinoma cells and induce cytotoxicity.

Rituximab (Rituxan)

 

Rituximab is a humanized monoclonal antibody. It binds to the CD20 antigen, inducing complement- or antibody-mediated cytolysis. Variable treatment regimens have been used to treat acquired angioedema.

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Contributor Information and Disclosures
Author

Amanda T Moon, MD Resident Physician, Department of Dermatology, University of Rochester, Strong Memorial Hospital

Amanda T Moon, MD is a member of the following medical societies: American Academy of Dermatology, American Medical Association, American Medical Student Association/Foundation, Society for Pediatric Dermatology

Disclosure: Nothing to disclose.

Coauthor(s)

Warren R Heymann, MD Head, Division of Dermatology, Professor, Department of Internal Medicine, Rutgers New Jersey Medical School

Warren R Heymann, MD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Ru'aa Al Harithy, MBBS, FRCPC Clinical Fellow in Laser and Cosmetic Dermatology, Division of Dermatology, SunnyBrook Hospital, University of Toronto Faculty of Medicine, Canada

Ru'aa Al Harithy, MBBS, FRCPC is a member of the following medical societies: American Academy of Dermatology, Canadian Dermatology Association

Disclosure: Nothing to disclose.

Chief Editor

William D James, MD Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

William D James, MD is a member of the following medical societies: American Academy of Dermatology, Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Acknowledgements

Paul Krusinski, MD Director of Dermatology, Fletcher Allen Health Care; Professor, Department of Internal Medicine, University of Vermont College of Medicine

Paul Krusinski, MD is a member of the following medical societies: American Academy of Dermatology, American College of Physicians, and Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Kathleen M Rossy, MD Staff Physician, Department of Dermatology, New York Medical College, Metropolitan Hospital

Disclosure: Nothing to disclose.

Robert A Schwartz, MD, MPH Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, University of Medicine and Dentistry of New Jersey-New Jersey Medical School

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi

Disclosure: Nothing to disclose.

Michael J Wells, MD Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine

Michael J Wells, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, and Texas Medical Association

Disclosure: Nothing to disclose.

References
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  2. Caballero T, Baeza ML, Cabañas R, et al. Consensus statement on the diagnosis, management, and treatment of angioedema mediated by bradykinin. Part I. Classification, epidemiology, pathophysiology, genetics, clinical symptoms, and diagnosis. J Investig Allergol Clin Immunol. 2011. 21(5):333-47; quiz follow 347. [Medline].

  3. Cugno M, Zanichelli A, Foieni F, Caccia S, Cicardi M. C1-inhibitor deficiency and angioedema: molecular mechanisms and clinical progress. Trends Mol Med. 2009 Feb. 15(2):69-78. [Medline].

  4. Cugno M, Castelli R, Cicardi M. Angioedema due to acquired C1-inhibitor deficiency: a bridging condition between autoimmunity and lymphoproliferation. Autoimmun Rev. 2008 Dec. 8(2):156-9. [Medline].

  5. Castelli R, Wu MA, Arquati M, Zanichelli A, Suffritti C, Rossi D, et al. High prevalence of splenic marginal zone lymphoma among patients with acquired C1 inhibtor deficiency. Br J Haematol. 2016 Jan 5. [Medline].

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  7. Cicardi M, Zanichelli A. Acquired angioedema. Allergy Asthma Clin Immunol. 2010 Jul 28. 6(1):14. [Medline]. [Full Text].

  8. Bouillet-Claveyrolas L, Ponard D, Drouet C, Massot C. Clinical and biological distinctions between type I and type II acquired angioedema. Am J Med. 2003 Oct 1. 115(5):420-1. [Medline].

  9. Engel R, Rensink I, Roem D, Brouwer M, Kalei A, Perry D, et al. ELISA to measure neutralizing capacity of anti-C1-inhibitor antibodies in plasma of angioedema patients. J Immunol Methods. 2015 Aug 28. [Medline].

  10. Bork K. An evidence based therapeutic approach to hereditary and acquired angioedema. Curr Opin Allergy Clin Immunol. 2014 Aug. 14 (4):354-62. [Medline].

  11. Zegers IH, Aaldering KN, Nieuwhof CM, Schouten HC. Non-myeloablative allogeneic stem cell transplantation: a new treatment option for acquired angioedema?. Neth J Med. 2015 Oct. 73 (8):383-5. [Medline].

  12. Levi M, Hack CE, van Oers MH. Rituximab-induced elimination of acquired angioedema due to C1-inhibitor deficiency. Am J Med. 2006 Aug. 119(8):e3-5. [Medline].

  13. Ziakas PD, Giannouli S, Psimenou E, Evangelia K, Tzioufas AG, Voulgarelis M. Acquired angioedema: a new target for rituximab?. Haematologica. 2004 Aug. 89(8):ELT13. [Medline].

  14. Klossowski N, Braun SA, von Gruben V, Losem C, Plewe D, Homey B, et al. [Acquired angioedema with C1-INH deficiency and accompanying chronic spontaneous urticaria in a patient with chronic lymphatic B cell leukemia]. Hautarzt. 2015 Sep 3. [Medline].

  15. Desai HG, Shah SS. Recurrent intestinal obstruction with acquired angio-oedema, due to C1-esterase inhibitor deficiency. J Assoc Physicians India. 2014 Jun. 62 (6):524-5. [Medline].

  16. Kaur R, Williams AA, Swift CB, Caldwell JW. Rituximab therapy in a patient with low grade B-cell lymphoproliferative disease and concomitant acquired angioedema. J Asthma Allergy. 2014. 7:165-7. [Medline].

  17. Dreyfus DH, Na CR, Randolph CC, Kearney D, Price C, Podell D. Successful rituximab B lymphocyte depletion therapy for angioedema due to acquired C1 inhibitor protein deficiency: association with reduced C1 inhibitor protein autoantibody titers. Isr Med Assoc J. 2014 May. 16 (5):315-6. [Medline].

  18. Rottem M, Mader R. Successful use of etanercept in acquired angioedema in a patient with psoriatic arthritis. J Rheumatol. 2010 Jan. 37(1):209. [Medline].

 
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