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Successful treatment of idiopathic angioedema with ecallantide
Clinical Communications Successful treatment of idiopathic angioedema with ecallantide Alalia Berry, MDa, and Rafael Firszt, MDb Clinical Implications
Nonhistaminergic angioedema is often refractory to antihistamines, corticosteroids, and epinephrine. Ecallantide is a treatment option for refractory idiopathic angioedema. Further studies are needed to define patients with idiopathic angioedema and their response to bradykinin inhibitors.
TO THE EDITOR: We present the case of a 16-year-old girl with recurrent episodes of facial angioedema and severe abdominal pain. The patient developed recurrent swelling of her eyelids, tongue, and face without associated urticaria. She had severe abdominal pain and diarrhea during these attacks. On average, these episodes occurred once or twice a month and lasted for 72 hours without treatment. She had no history of allergies. She did not use nonsteroidal anti-inflammatory drugs, oral contraceptive pills, or angiotensin-converting enzyme inhibitors. She had no family history of angioedema. The patient underwent a diagnostic evaluation to exclude hereditary angioedema (HAE), acquired angioedema, or other causes of her facial swelling. Her physical examination was pertinent for absence of lymphadenopathy, enlarged salivary glands, urticarial lesions, or urticaria pigmentosa. Her laboratory values consisted of normal leukocyte and eosinophil counts, normal thyroid-stimulating hormone, and negative antinuclear antibody. She had normal IgE levels. On the basis of skin and in vitro allergy testing, she had no sensitivity to indoor or outdoor allergens. Tryptase levels at baseline and during an acute attack were normal. She had normal results of a urinalysis collected during an acute attack. Because of the primary involvement of her head and neck, a computed tomographic chest scan was obtained to rule out superior vena cava syndrome. Results of the imaging study were normal. The patient was also evaluated for HAE, characterized by abnormalities in the level or function of C1-inhibitor protein (C1-INH). She had no evidence of HAE type I, with a C1-INH level of 37 mg/dL at baseline and 39 mg/dL during an acute attack. In addition, she did not have HAE type II, with a C1-INH functional percentage of 118% at baseline and 127% during an attack. Her C4 level was 33 mg/dL at baseline and 38 mg/dL during an attack (Table I). Gene testing for factor XII mutation was negative. To prevent attacks, the patient tried high-dose antihistamines, including fexofenadine 180 mg daily, hydroxyzine 100 mg daily, diphenhydramine 50 mg 4 times a day, and cetirizine 10 mg daily. Despite antihistamine therapy, she continued to have frequent attacks, suggesting she had nonhistaminergic angioedema. In an attempt to prevent attacks, she tried danazol 200 mg
TABLE I. Patent’s complement and antigen levels Test
Value
Reference range
C1 inhibitor (mg/dL), baseline/during attack C1 inhibitor function (%), baseline/during attack C4 (mg/dL), baseline/during attack Angiotensin-converting enzyme (U/L) Tryptase (mg/L), baseline/during attack IgG (mg/dL) IgM (mg/dL) IgA (mg/dL) IgE (IU/mL)
37/39
21-39
118/127
>68 ¼ normal
33/38 49 8.1/7.6 821 88 103 13
14-41 18-101 2.2-13.2 549-1584 23-259 61-348 0-100
twice daily for 4 weeks, and Depo-Provera injections, without benefit. Because of the severity of her attacks, she required frequent hospitalization and received numerous courses of epinephrine, steroids, and diphenhydramine. None of these therapies were effective in resolving or shortening the duration of her symptoms. During an attack, she presented to our emergency department with acute facial swelling and severe abdominal pain. Because of her previous lack of response to other medications, we elected to treat her with ecallantide (total dose of 30 mg). Interestingly, her symptoms began to improve within 30 minutes and completely resolved within 4 hours. The patient was discharged from the emergency department later that evening. She has since received 9 ecallantide treatments for subsequent acute angioedema attacks. She continues to have symptom relief within 30 minutes of receiving ecallantide and complete resolution of her symptoms at 4 hours. Angioedema is characterized by swelling of the dermis, subcutaneous tissue, and mucous membranes. The swelling is generally asymmetric, nondependent, and non-pitting. If the larynx is involved, swelling of the head and neck can be life threatening. Treatment strategies focus on inhibiting various mediators of angioedema. Histamine, released by IgE, direct mast cell stimulation, or possibly other mechanisms, mediates angioedema and is prevented by antihistamine therapy. This is classified as histaminergic forms of angioedema. However, nonhistaminergic forms of angioedema may be mediated by bradykinin and refractory to antihistamine therapy. Nonhistaminergic angioedema includes HAE, with C1-INH deficiency or dysfunction (type I or type II, respectively), HAE type III (family history of angioedema and normal C1-INH), angiotensin-converting enzyme inhibitoreassociated angioedema, acquired angioedema, and idiopathic angioedema (IAE). Nonhistaminergic IAE is associated with normal C1-INH levels and function, lack of improvement with antihistamine therapy, and absence of a family history of angioedema.1,2 Patients with nonhistaminergic forms of angioedema often require alternative treatment strategies. Recently, several new products were approved in the US market that specifically and effectively treat HAE types I and II and acquired angioedema due to C1-INH deficiency, leading to a totally new approach in managing these 297
298
CLINICAL COMMUNICATIONS
J ALLERGY CLIN IMMUNOL: IN PRACTICE MAY/JUNE 2013
Factor XII
Factor XIIa
High-molecular weight- kininogen Kallikrein
Bradykinin B2 Receptor
Bradykinin
Prekallikrein
: Blocked by Ecallantide : Blocked by C1 - Inhibitor
FIGURE 1. C1-inhibitor and ecallantide inhibition on bradykinin cascade. Adapted from Firszt and Frank.3
diseases.3 In this case, ecallantide, one of these newer therapies, was an effective treatment for a patient with IAE refractory to antihistamine therapy. Ecallantide (Kalbitor; Dyax Corp, Cambridge, Mass) is a genetically engineered inhibitor to plasma kallikrein, effectively blocking the production of bradykinin (Figure 1).4,5 Ecallantide is currently approved to treat acute attacks of HAE type I and II in patients 16 years and older.6-8 Ecallantide has also been reported as a possible effective treatment for acute attacks of HAE type III.9 A poster presentation at the recent American College of Allergy, Asthma and Immunology meeting, showed the efficacy of ecallantide in a person with IAE.10 To our knowledge, no previous cases that used ecallantide in IAE are published. Icatibant, a selective antagonist of the bradykinin type 2 receptor, is another theoretical but unproven treatment option for IAE. In summary, we present a nonhistaminergic, nonfamilial case of angioedema with normal level and function of C1-INH. As a result of her clinical evolution and laboratory investigations, we diagnosed the patient’s condition as nonhistaminergic IAE, and her acute attacks have been successfully treated with ecallantide. Many treatments are ineffective or only partially effective for IAE, possibly reflecting the variation in this disease. When clinicians are presented with patients with IAE, refractory to antihistamines, corticosteroids, or epinephrine, ecallantide may be considered as a treatment option. The successful use of ecallantide in this patient suggests that her disease is mediated by bradykinin production. More studies are needed to investigate other pathway defects in IAE to better diagnose, categorize, and monitor response to treatment. Larger studies are needed to determine how effective ecallantide may be in treating patients with IAE. a
Department of Medicine, Division of Allergy and Immunology, University of Utah, Salt Lake City, Utah b Department of Pediatrics, Division of Allergy and Immunology, University of Utah, Salt Lake City, Utah
Conflicts of interest: R. Firszt has received research support from lecture fees from Dyax A. Berry declares no relevant conflicts of interest. Received for publication December 18, 2012; revised March 13, 2013; accepted for publication March 15, 2013. Cite this article as: Berry A, Firszt R. Successful treatment of idiopathic angioedema with ecallantide. J Allergy Clin Immunol: In Practice 2013;1:297-8. http://dx.doi .org/10.1016/j.jaip.2013.03.007. Corresponding author: Rafael Firszt, MD, Division of Allergy and Immunology, Department of Pediatrics, University of Utah, PO Box 581289, Salt Lake City, UT 84158. E-mail: rafael.fi[email protected]. 2213-2198/$36.00 Ó 2013 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaip.2013.03.007 REFERENCES 1. Bas M, Hoffman TK, Kojada G. Evaluation and management of angioedema of the head and neck. Curr Opinion Otolaryngol Head Neck Surg 2006;14:170-5. 2. Bas M, Adams V, Suvorava T, Niehues T, Hoffman TK, Kojada G. Nonallergic angioedema: role of bradykinin. Allergy 2007;62:842-56. 3. Firszt R, Frank MM. An overview of novel therapies for acute hereditary angioedema. Am J Clin Dermatol 2010;11:383-8. 4. Agostoni A, Aygören-Pürsün E, Binkley KE, Blanch A, Bork K, Bouillet L, et al. Hereditary and acquired angioedema: problems and progress: proceedings of the third C1 esterase inhibitor deficiency workshop and beyond. J Allergy Clin Immunol 2004;114:S51-131. 5. Schneider L, Lumry W, Vegh A, Williams AH, Schmalbach T. Critical role of kallikrein in hereditary angioedema pathogenesis: a clinical trial of ecallantide, a novel kallikrein inhibitor. J Allergy Clin Immunol 2007;120:416-22. 6. Kalbitor (ecallantide): US prescribing information [online]. Available from: http://www.kalbitor.com/pdf/KalbitorFullPrescribingInformation.pdf. Accessed December 15, 2012. 7. Cicardi M, Levy RJ, McNeil DL, Li HH, Sheffer AL, Campion M, et al. Ecallantide for the treatment of acute attacks in hereditary angioedema. N Engl J Med 2010;363:523-31. 8. Levy RJ, Lumry WR, McNeil DL, Li HH, Campion M, Horn PT, Pullman WE. EDEMA4: a phase 3, double-blind study of subcutaneous ecallantide treatment for acute attacks of hereditary angioedema. Ann Allergy Asthma Immunol 2010;104:523-9. 9. Cronin JA, Maples KM. Treatment of an acute attack of type III hereditary angioedema with ecallantide. Ann Allergy Asthma Immunol 2012;108:61-2. 10. McNeil DL. Clinical experience with ecallantide in idiopathic angioedema. Presented in poster form at American College of Allergy, Asthma and Immunology (ACAAI) Annual Meeting, November 2012, Anaheim, Calif.
Nonhistaminergic angioedema is often refractory to antihistamines, corticosteroids, and epinephrine. Ecallantide is a treatment option for refractory idiopathic angioedema. Further studies are needed to define patients with idiopathic angioedema and their response to bradykinin inhibitors.
TO THE EDITOR: We present the case of a 16-year-old girl with recurrent episodes of facial angioedema and severe abdominal pain. The patient developed recurrent swelling of her eyelids, tongue, and face without associated urticaria. She had severe abdominal pain and diarrhea during these attacks. On average, these episodes occurred once or twice a month and lasted for 72 hours without treatment. She had no history of allergies. She did not use nonsteroidal anti-inflammatory drugs, oral contraceptive pills, or angiotensin-converting enzyme inhibitors. She had no family history of angioedema. The patient underwent a diagnostic evaluation to exclude hereditary angioedema (HAE), acquired angioedema, or other causes of her facial swelling. Her physical examination was pertinent for absence of lymphadenopathy, enlarged salivary glands, urticarial lesions, or urticaria pigmentosa. Her laboratory values consisted of normal leukocyte and eosinophil counts, normal thyroid-stimulating hormone, and negative antinuclear antibody. She had normal IgE levels. On the basis of skin and in vitro allergy testing, she had no sensitivity to indoor or outdoor allergens. Tryptase levels at baseline and during an acute attack were normal. She had normal results of a urinalysis collected during an acute attack. Because of the primary involvement of her head and neck, a computed tomographic chest scan was obtained to rule out superior vena cava syndrome. Results of the imaging study were normal. The patient was also evaluated for HAE, characterized by abnormalities in the level or function of C1-inhibitor protein (C1-INH). She had no evidence of HAE type I, with a C1-INH level of 37 mg/dL at baseline and 39 mg/dL during an acute attack. In addition, she did not have HAE type II, with a C1-INH functional percentage of 118% at baseline and 127% during an attack. Her C4 level was 33 mg/dL at baseline and 38 mg/dL during an attack (Table I). Gene testing for factor XII mutation was negative. To prevent attacks, the patient tried high-dose antihistamines, including fexofenadine 180 mg daily, hydroxyzine 100 mg daily, diphenhydramine 50 mg 4 times a day, and cetirizine 10 mg daily. Despite antihistamine therapy, she continued to have frequent attacks, suggesting she had nonhistaminergic angioedema. In an attempt to prevent attacks, she tried danazol 200 mg
TABLE I. Patent’s complement and antigen levels Test
Value
Reference range
C1 inhibitor (mg/dL), baseline/during attack C1 inhibitor function (%), baseline/during attack C4 (mg/dL), baseline/during attack Angiotensin-converting enzyme (U/L) Tryptase (mg/L), baseline/during attack IgG (mg/dL) IgM (mg/dL) IgA (mg/dL) IgE (IU/mL)
37/39
21-39
118/127
>68 ¼ normal
33/38 49 8.1/7.6 821 88 103 13
14-41 18-101 2.2-13.2 549-1584 23-259 61-348 0-100
twice daily for 4 weeks, and Depo-Provera injections, without benefit. Because of the severity of her attacks, she required frequent hospitalization and received numerous courses of epinephrine, steroids, and diphenhydramine. None of these therapies were effective in resolving or shortening the duration of her symptoms. During an attack, she presented to our emergency department with acute facial swelling and severe abdominal pain. Because of her previous lack of response to other medications, we elected to treat her with ecallantide (total dose of 30 mg). Interestingly, her symptoms began to improve within 30 minutes and completely resolved within 4 hours. The patient was discharged from the emergency department later that evening. She has since received 9 ecallantide treatments for subsequent acute angioedema attacks. She continues to have symptom relief within 30 minutes of receiving ecallantide and complete resolution of her symptoms at 4 hours. Angioedema is characterized by swelling of the dermis, subcutaneous tissue, and mucous membranes. The swelling is generally asymmetric, nondependent, and non-pitting. If the larynx is involved, swelling of the head and neck can be life threatening. Treatment strategies focus on inhibiting various mediators of angioedema. Histamine, released by IgE, direct mast cell stimulation, or possibly other mechanisms, mediates angioedema and is prevented by antihistamine therapy. This is classified as histaminergic forms of angioedema. However, nonhistaminergic forms of angioedema may be mediated by bradykinin and refractory to antihistamine therapy. Nonhistaminergic angioedema includes HAE, with C1-INH deficiency or dysfunction (type I or type II, respectively), HAE type III (family history of angioedema and normal C1-INH), angiotensin-converting enzyme inhibitoreassociated angioedema, acquired angioedema, and idiopathic angioedema (IAE). Nonhistaminergic IAE is associated with normal C1-INH levels and function, lack of improvement with antihistamine therapy, and absence of a family history of angioedema.1,2 Patients with nonhistaminergic forms of angioedema often require alternative treatment strategies. Recently, several new products were approved in the US market that specifically and effectively treat HAE types I and II and acquired angioedema due to C1-INH deficiency, leading to a totally new approach in managing these 297
298
CLINICAL COMMUNICATIONS
J ALLERGY CLIN IMMUNOL: IN PRACTICE MAY/JUNE 2013
Factor XII
Factor XIIa
High-molecular weight- kininogen Kallikrein
Bradykinin B2 Receptor
Bradykinin
Prekallikrein
: Blocked by Ecallantide : Blocked by C1 - Inhibitor
FIGURE 1. C1-inhibitor and ecallantide inhibition on bradykinin cascade. Adapted from Firszt and Frank.3
diseases.3 In this case, ecallantide, one of these newer therapies, was an effective treatment for a patient with IAE refractory to antihistamine therapy. Ecallantide (Kalbitor; Dyax Corp, Cambridge, Mass) is a genetically engineered inhibitor to plasma kallikrein, effectively blocking the production of bradykinin (Figure 1).4,5 Ecallantide is currently approved to treat acute attacks of HAE type I and II in patients 16 years and older.6-8 Ecallantide has also been reported as a possible effective treatment for acute attacks of HAE type III.9 A poster presentation at the recent American College of Allergy, Asthma and Immunology meeting, showed the efficacy of ecallantide in a person with IAE.10 To our knowledge, no previous cases that used ecallantide in IAE are published. Icatibant, a selective antagonist of the bradykinin type 2 receptor, is another theoretical but unproven treatment option for IAE. In summary, we present a nonhistaminergic, nonfamilial case of angioedema with normal level and function of C1-INH. As a result of her clinical evolution and laboratory investigations, we diagnosed the patient’s condition as nonhistaminergic IAE, and her acute attacks have been successfully treated with ecallantide. Many treatments are ineffective or only partially effective for IAE, possibly reflecting the variation in this disease. When clinicians are presented with patients with IAE, refractory to antihistamines, corticosteroids, or epinephrine, ecallantide may be considered as a treatment option. The successful use of ecallantide in this patient suggests that her disease is mediated by bradykinin production. More studies are needed to investigate other pathway defects in IAE to better diagnose, categorize, and monitor response to treatment. Larger studies are needed to determine how effective ecallantide may be in treating patients with IAE. a
Department of Medicine, Division of Allergy and Immunology, University of Utah, Salt Lake City, Utah b Department of Pediatrics, Division of Allergy and Immunology, University of Utah, Salt Lake City, Utah
Conflicts of interest: R. Firszt has received research support from lecture fees from Dyax A. Berry declares no relevant conflicts of interest. Received for publication December 18, 2012; revised March 13, 2013; accepted for publication March 15, 2013. Cite this article as: Berry A, Firszt R. Successful treatment of idiopathic angioedema with ecallantide. J Allergy Clin Immunol: In Practice 2013;1:297-8. http://dx.doi .org/10.1016/j.jaip.2013.03.007. Corresponding author: Rafael Firszt, MD, Division of Allergy and Immunology, Department of Pediatrics, University of Utah, PO Box 581289, Salt Lake City, UT 84158. E-mail: rafael.fi[email protected]. 2213-2198/$36.00 Ó 2013 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaip.2013.03.007 REFERENCES 1. Bas M, Hoffman TK, Kojada G. Evaluation and management of angioedema of the head and neck. Curr Opinion Otolaryngol Head Neck Surg 2006;14:170-5. 2. Bas M, Adams V, Suvorava T, Niehues T, Hoffman TK, Kojada G. Nonallergic angioedema: role of bradykinin. Allergy 2007;62:842-56. 3. Firszt R, Frank MM. An overview of novel therapies for acute hereditary angioedema. Am J Clin Dermatol 2010;11:383-8. 4. Agostoni A, Aygören-Pürsün E, Binkley KE, Blanch A, Bork K, Bouillet L, et al. Hereditary and acquired angioedema: problems and progress: proceedings of the third C1 esterase inhibitor deficiency workshop and beyond. J Allergy Clin Immunol 2004;114:S51-131. 5. Schneider L, Lumry W, Vegh A, Williams AH, Schmalbach T. Critical role of kallikrein in hereditary angioedema pathogenesis: a clinical trial of ecallantide, a novel kallikrein inhibitor. J Allergy Clin Immunol 2007;120:416-22. 6. Kalbitor (ecallantide): US prescribing information [online]. Available from: http://www.kalbitor.com/pdf/KalbitorFullPrescribingInformation.pdf. Accessed December 15, 2012. 7. Cicardi M, Levy RJ, McNeil DL, Li HH, Sheffer AL, Campion M, et al. Ecallantide for the treatment of acute attacks in hereditary angioedema. N Engl J Med 2010;363:523-31. 8. Levy RJ, Lumry WR, McNeil DL, Li HH, Campion M, Horn PT, Pullman WE. EDEMA4: a phase 3, double-blind study of subcutaneous ecallantide treatment for acute attacks of hereditary angioedema. Ann Allergy Asthma Immunol 2010;104:523-9. 9. Cronin JA, Maples KM. Treatment of an acute attack of type III hereditary angioedema with ecallantide. Ann Allergy Asthma Immunol 2012;108:61-2. 10. McNeil DL. Clinical experience with ecallantide in idiopathic angioedema. Presented in poster form at American College of Allergy, Asthma and Immunology (ACAAI) Annual Meeting, November 2012, Anaheim, Calif.