Current Medical Research & Opinion 0300-7995 doi:10.1185/03007995.2013.879441
Vol. 30, No. 5, 2014, 923–930
Article ST-0309.R1/879441 All rights reserved: reproduction in whole or part not permitted
py Un t rig au fo t ht di hor r S sp ize a la d le © y, u s 20 vi e o ew p r 14 r C o an h d p ibi om In rin ted m fo rm t a . Au e si th rc aU ng or i le is al K co ed D py us is Lim fo ers tr ite rp c i b a er n d so d ut na ow io l u nl n se oa d,
Katherine A. Altman
Touro University College of Osteopathic Medicine, Vallejo, CA, USA
David R. Naimi
Northwest Asthma and Allergy Center and University of Washington, Seattle, WA, USA Address for correspondence: David R. Naimi DO, Northwest Asthma and Allergy Center 9725 3rd Ave NE, Suite 500, Seattle, WA 98115, USA. Tel.: +1 425 385 2802; Fax: +1 425 337 7967; [email protected]
Keywords: Bradykinin – C1 esterase inhibitor – C1 inhibitor – Hereditary angioedema – Prophylaxis – Recombinant C1-inhibitor – Treatment Accepted: 23 December 2013; published online: 24 January 2014 Citation: Curr Med Res Opin 2014; 30:923–30
Abstract
Background: Angioedema is a serious medical condition characterized by recurrent non-pitting tissue edema. Hereditary (HAE) forms of this disorder are potentially fatal. Methods: PubMED, Up to Date and Cochrane Library databases were used to identify scholarly peer reviewed original research or review articles on angioedema. Search terms used were: angioedema, HAE, ACE inhibitor induced angioedema, acquired angioedema, type III HAE (now termed HAE with normal C1-INH), diagnosis of HAE, and treatment of HAE. Inclusive dates of the search were 1946 through 2013. Articles on urticaria were excluded. Results: The pathophysiology, clinical manifestations, differential diagnosis and treatments of angioedema are presented. Three variants of HAE are discussed and differentiated from acquired, ACE induced and allergic types of angioedema. Emphasis is placed on understanding that HAE is mediated by bradykinin, not histamine, and is therefore unresponsive to antihistamines, corticosteroids and epinephrine. In contrast, newer therapies that replace C1-INH or block bradykinin production or action are the appropriate treatments for prophylaxis and acute treatment of HAE. Conclusion: Recognition of HAE by primary care providers and distinguishing it from allergic histamine mediated angioedema is essential in preventing recurrent attacks and avoiding inappropriate therapy, and may be life-saving.
No
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Brief review Hereditary angioedema: a brief review of new developments
Introduction
Hereditary angioedema (HAE) is a rare, but potentially fatal genetic disease. It is estimated to have a prevalence between 1 in 35 to 50,0001–3. The inheritance is autosomal dominant so there is equal gender expression. Since the gene mutation is dominant, any child of an affected parent has a 50% chance of acquiring the disorder, and the disease does not skip generations4. The abnormal gene is on chromosome 11, and over 200 different mutations have been found which present with the same clinical phenotype5–11. About 25% of patients have no family history and are believed to have developed a de novo gene mutation8–13. Patients with HAE have recurrent attacks of non-pitting swelling of the face, lips, tongue, throat, extremities and genitals. They rarely have hives. Patients can frequently experience abdominal pain and vomiting lasting 1 to 3 days caused by swelling of the bowel wall. Emotional stress or physical trauma to ! 2014 Informa UK Ltd www.cmrojournal.com
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ALLERGIC IgEreceptor
May 2014
KININ
CLOTTING
Factor XII
Factor XII
COMPLEMENT C1qrs
MAST CELL/ BASOPHIL
XIIa
Prekallikrein C1
XIIa
kallikrein
MASP 1,2 XI
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Kininogen Histamine Prostaglandins Leukotrienes
XIa
BRADYKININ
Classical Alternative Complement Complement Pathway Pathway
Clotting Vasodilation/edema Smooth muscle relaxation
Inhibited by C1-INH Inhibited by Icatibant Inhibited by Ecallantide
Figure 1. Pathways involved in hereditary angioedema.
an area, such as dental procedures, can trigger an attack, but episodes can also occur spontaneously4,14–16. The pathogenesis of the two most common types of this condition is the lack of or abnormal function of C1 esterase inhibitor (C1-INH)17. There are three variants of HAE: types I and II, and HAE with normal C1-INH (formerly type III)7. Type I causes about 85% of cases and patients have low absolute levels of C1-INH. Type II constitutes about 15% of cases. These patients have normal or elevated levels of nonfunctional C1-INH. HAE with normal C1-INH is a newly described variant where all measurements of C1-INH are normal but attacks of angioedema are similar to those in types I and II. The mechanism of this condition is not fully understood18–22.
Pathophysiology In most cases HAE is the result of reduced or defective C1-INH, which is the inhibitor of the first step of the complement system. It normally blocks C1r and C1s and mannose-binding lectin-associated serine proteases (MASP 1 and 2) of the complement system, factors XIa and XIIa of the coagulation system, and kallikrein of the contact system23. The absence or defective function of this inhibitor allows for activation of these different cascade systems and generation of vasoactive substances. Bradykinin, developed in the contact system cascade, has been identified as the major substance mediating vascular 924
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permeability in this disease24–27. Bradykinin binds to and activates the B2 receptor. This results in vasodilation, vascular permeability, and smooth muscle contraction. All of these events cause swelling characteristic of HAE. Because bradykinin is the main culprit, patients with HAE do not respond to antihistamines and do not have itching4. Figure 1 is an overview of the pathways involved. Although bradykinin is the mediator of swelling in HAE, the diagnosis of types I and II of this condition is confirmed by measuring the serum levels of complement proteins. Since C4 is the immediate substrate for activated C1, low C4 values are characteristic of this disease and measuring this complement component is the most useful test to confirm the diagnosis28. In addition, measuring both the absolute level and functional activity of C1-INH is important to distinguish between HAE types I and II2,28,29. In type I HAE most patients have protein (antigenic) and functional levels of C1-INH which range from undetectable to 30% of normal. In type II HAE functional levels of C1-INH are low but the protein level is normal or may be high due to increased plasma half-life. The inheritance of types I and II HAE is autosomal dominant and most patients have one abnormal allele and are therefore heterozygotes. However, individuals carrying an abnormal gene can be asymptomatic in about 10% of cases. In contrast, in HAE with normal C1-INH, the C4 and C1-INH values are normal. Although this type of HAE does not involve absent or functionally abnormal C1-INH it nonetheless presents with similar clinical manifestations. HAE with normal C1-INH is also known as www.cmrojournal.com ! 2014 Informa UK Ltd
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estrogen-dependent/associated angioedema since most cases were originally seen in women and attacks were linked to high levels of estrogen either endogenous (pregnancy) or from administered estrogen19,20,22,30. More recently, male subjects have been described where high estrogen levels were not implicated31. Onset of symptoms in adulthood and facial and tongue swelling appear to be more common in HAE with normal C1-INH compared to types I and II32. In a subset of patients with HAE with normal C1-INH an amino acid substitution in the gene coding for coagulation factor XII has been found. The change is either arginine or lysine substituted for threonine at position 309 or 328. These substitutions might activate factor XII because the substituted amino acids are positively charged while the normal threonine is neutral. The positive charge might cause factor XII to be activated by negatively charged tissue surfaces leading to activation of prekallikrein and subsequent generation of bradykinin33–39.
have a serpiginous erythematous prodromal rash called erythema marginatum40–43. Swelling is most common in arms and legs. Over 90% of attacks involve these extremities. The face is often involved with genital and trunk swelling being less common. Abdominal swelling is the second most common presentation and can cause severe pain, nausea and vomiting9,44. These attacks can be confused with an acute abdominal emergency and lead to unnecessary surgery if the diagnosis of HAE is not known. These patients may also be hypotensive due to vascular fluid loss into the wall or lumen of the small or large bowel or the peritoneal space. Abdominal CT or ultrasound can reveal this tissue edema or free fluid to support the proper diagnosis. Facial swelling is usually very pronounced with distortion of facial features and a risk of laryngeal edema. Progression of facial edema to involve the airway can occur in minutes so this presentation must be treated as an emergency. Mortality has been reported as high as 40% in attacks of laryngeal angioedema45.
Clinical features HAE is characterized by nonpitting, nonpruritic tissue swelling which very rarely is accompanied by hives. This is an essential clinical finding which distinguishes HAE from allergic or idiopathic angioedema. A prodrome of tingling or burning may precede the swelling. In addition, approximately 25% of patients will
Treatment Treatment of HAE consists of management of acute attacks as well as long-term prophylaxis and transient prophylaxis. Table 1 lists current available and pending drugs for the treatment of HAE.
Table 1. Drugs for treatment of hereditary angioedema. Drug
Mechanism
Approved Use
Dosage
Clinical Studies vs Placebo
Danazol–Stanazolol
Stimulate hepatic synthesis of C1-INH
Prophylaxis
Variable 50 mg qd to 200 mg tid for danazol
Attacks significantly fewer 2.2 vs 93.6% of treatment courses
Cinryze
Human C1-INH inhibits kallikrein and suppresses bradykinin formation
Prophylaxis (Intravenous. Home infusion)
1000 units IV q 3–4 days
Reduced attack rate 6.26 vs 12.73 per 12 week period
Berinert
Human C1-INH, inhibits kallikrein and suppresses bradykinin formation
Treatment of acute abdominal, facial, or laryngeal attacks. (Intravenous. On-demand self-administration)
20 units/kg IV
More rapid symptom resolution 2 hrs vs 4 hrs
Ecalantide–Kalbitor
Kallikrein inhibitor
Treatment of acute attacks. Subcutaneous. Patients 16 yo
10 mg/ml SC, at three different sites
Improved treatment score at 4 hrs and faster time to significant improvement 165 min vs 240 min
Icatibant–Firazyr
Bradykinin receptor antagonist
Treatment of acute attacks. Subcutaneous. Selfadministration. Patients 18 yo
30 mg SC
More rapid symptom resolution 2.5 hrs vs 4.6 hrs
Ruconest–Rhucin
Recombinant C1-INH
Treatment of acute attacks
(Available in Europe – awaiting approval in the USA)
qd, once a day; tid, three times a day; IV, intravenous; q, every; SC, subcutaneous.
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Management of acute attacks The angioedema occurring in HAE does not respond to antihistamines, corticosteroids, or epinephrine. Epinephrine may have a small transient impact on swelling; however, it does not alter the course of an attack46,47. The main cause of death in HAE is laryngeoedema. Intubation and emergency tracheostomy must be performed if a patient’s airway is compromised. As part of acute management, intravenous fluid replacement is important, as some patients develop hypotension due to sequestration of fluid in the extravascular space. Pain management is also essential particularly in patients with abdominal attacks46,47. Prior therapy for acute HAE included fresh frozen plasma (FFP). Its use however is controversial as FFP might cause worsening angioedema by providing plasma proteins to generate bradykinin as well as replacing C1-INH46,48. FFP, like other blood products, could also carry a potential risk of infectious disease transmission. The current treatments of choice in acute attacks are replacement of C1-INH with a plasma derived concentrate of the missing or nonfunctional protein (Berinert*), use of a kallikrein inhibitor, ecallantide (Kalbitory), or injection of a bradykinin receptor antagonist, icatibant (Firazyrz)2,9,49,50. All three of these products are currently approved by the FDA to treat acute HAE attacks. The efficacy of these drugs is highest when used early in an HAE attack before it is possible to predict the ultimate severity of the episode. Ruconest (Rhucinx) is a recombinant C1-INH in contrast to Berinert which is a concentrate from human plasma. Ruconest is intended for the treatment of acute HAE attacks and may be approved in the US in the future. It is currently available in Europe51. Another product available in the United States is Cinryzeô. Cinryze and Berinert are different brands of C1-INH. The FDA approved both Berinert and Cinryze despite the fact that they are the same product, but specified that they be used for different indications. Cinryze was approved for prophylaxis to prevent attacks of angioedema and will be discussed in more detail later. C1-INH concentrate (Berinert) is given intravenous (IV) as emergency treatment. It can be administered for treatment of acute facial, laryngeal, or abdominal attacks and patients can be trained in self-administration. The largest study to establish the efficacy of C1-INH infusion for acute attacks was a placebo controlled study which compared 35 actively treated patients with 33 placebo treated subjects52. In the acute treatment group the median time of onset of symptom relief was 2 hours compared to *Berinert is a registered trade name of CSL Behring, King of Prussia, PA, USA yKalbitor is a registered trade name of Dyax Corp, Burlington, MA, USA zFirazyr is a registered trade name of Shire, Lexington, MA, USA xRhucin is a registered trade name of Pharming, The Netherlands ôCinryze is a registered trade name of ViroPharma, Exton, PA, USA
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4 hours in the placebo group. The median time to complete resolution was 12.3 hours in the C1-INH treated group and 25.0 hours in the placebo group. The differences were statistically significant. Other studies have reached similar conclusions53–56. Ecallantide (Kalbitor) is a first-line therapy approved for the treatment of acute HAE attacks by subcutaneous injection in patients 16 years of age and older. It is a recombinant protein kallikrein inhibitor. Kallikrein is the enzyme that activates high molecular weight kininogen (H-MWK) to form bradykinin. Because bradykinin is the mediator of swelling in HAE, blocking its formation is an alternative method of treating this disease. The safety and efficacy of ecallantide were evaluated in 168 patients with HAE in two randomized, double-blind, placebo-controlled trials57,58. The first study was performed with 72 subjects who were randomly divided 1:1 to receive subcutaneous ecallantide or placebo. They were scored on treatment outcome ranging from þ100 (significant improvement in symptoms) to 100 (worsening of symptoms) and by change from baseline in mean symptom scores ranging from þ2 (change from mild at baseline to severe) to 3 (change from severe at baseline to no symptoms). Those who received ecallantide had a median treatment outcome score of þ50 and a mean symptom score of 1 compared to 0 and 0.5 for the placebo group, respectively. Thus, ecallantide provided better efficacy than placebo and there were no adverse reactions. The other study was a randomized, double-blind, placebo-controlled trial in 96 patients where individuals were randomized 1:1 to receive ecallantide 30 mg subcutaneous or placebo for acute attacks of HAE. Patients treated with ecallantide demonstrated a greater decrease from baseline in the mean symptom complex severity and a greater treatment outcome score than patients treated with placebo. At 24 hours, patients treated with ecallantide also demonstrated a greater decrease from baseline in the mean symptom complex severity than placebo. The results were statistically significant. Another study evaluated ecallantide treatment for laryngeal angioedema attacks59. This paper combined the results of four clinical trials in 98 patients receiving 30 mg of subcutaneous ecallantide and used the mean symptom complex severity and treatment outcome response scores to measure outcomes. The patients experienced a total of 220 laryngeal attacks and only one required intubation. Ecallantide produced sustained improvement of laryngeal edema in 80% of the patients and complete or near complete symptom resolution in 63% of subjects within 4 hours. The improvement persisted for 24 hours after the one treatment. Two patients in the study had serious adverse reactions consistent with anaphylaxis and one required epinephrine treatment. This is the main safety concern with ecallantide60. www.cmrojournal.com ! 2014 Informa UK Ltd
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The newest drug for treatment of acute attacks in the US is icatibant (Firazyr), a bradykinin B2 receptor antagonist. This drug was approved for use in Europe in 2008 and in the United States in 2011. It is intended for the treatment of acute attacks by subcutaneous self-administration in patients 18 years of age of older. There have been two double-blind studies26,61. In the first, 56 patients received either icatibant or placebo and in the second 74 patients received icatibant or tranexamic acid, an older, rarely used treatment. The primary end point was time to relief of symptoms. In the first study, symptoms diminished in 2.5 hours with icatibant versus 4.6 hours with placebo. In the second study, the end point was 2 hours with icatibant and 12 hours with tranexamic acid. No serious adverse reactions were observed in either study. Thus relief of symptoms was achieved much more quickly with icatibant than with either placebo or tranexamic acid.
Transient prophylaxis Prophylaxis for surgical procedures, most commonly dental work, is necessary in HAE patients. Medications and equipment for acute treatment also need to be available on-site to treat HAE exacerbations. Prior to the advent of C1-INH therapy, daily high dose androgen therapy was recommended for at least 4 days prior to surgery and 2–4 days afterward. Fresh frozen plasma can also be used to prevent attacks. If given in asymptomatic patients prior to procedures (day of or day before), it does not carry the potential risk of exacerbating symptoms mentioned earlier for the treatment of an acute attack2. Now that C1-INH is available, it can be given 24 hours before the procedure or just prior to it66,67.
Differential diagnosis of angioedema Long-term prophylaxis The traditional and still utilized form of treatment is daily use of 17 a-alkylated androgens. The two widely used drugs are stanazolol and danazol, both synthetic androgens. The presumed mechanism of action of these drugs is stimulation of hepatic synthesis of C1-INH. In a placebo controlled study, patients suffered attacks in 44 of 47 (93.6%) placebo treatment periods and only one of 46 (2.2%) of the danazol treatment rounds62. This historic paper established attenuated androgens as the mainstay form of treatment until very recently with the release of newer forms of treatment63. Unfortunately, attenuated androgens have side effects, especially virilization in women and virilization and premature closure of epiphyseal plates and hence short stature in children. Hepatic toxicity is also a concern and patients taking these drugs need serial measurements of liver function tests. Of the four relatively new products on the market in the United States for the treatment of HAE only C1-INH concentrate (Cinryze) is approved for prophylaxis to prevent attacks of angioedema. It is given IV every 3–4 days. One treatment of Cinryze costs approximately $5000, so two treatments a week for a year costs more than $500,000. Due to the high expense of these newly developed drugs, when possible physicians may still choose to treat patients by the more traditional method with daily androgens. The primary study which established the efficacy of C1INH as prophylactic treatment enrolled 22 patients in a crossover design giving infusions of either active drug or placebo twice weekly for 12 weeks52. The active treatment period had an attack rate of 6.26 versus 12.73 for the placebo treatment, a highly significant difference. Other studies support the same conclusion64,65. ! 2014 Informa UK Ltd www.cmrojournal.com
Angioedema is a complex condition with the three types of HAE being quite uncommon compared to angiotensinconverting enzyme (ACE) inhibitor induced angioedema, and especially allergic and idiopathic types which constitute the majority of cases. Because the three types of HAE are described earlier, the section below will describe other types of angioedema and contrast them with HAE. Table 2 is a summary of all forms of angioedema. Acquired angioedema (AAE) has a similar clinical presentation to HAE types I, II or III. There are two subtypes of AAE. In AAE type I, the symptoms are usually associated with an underlying B-cell lymphoproliferative disorder68. The episodes of angioedema typically appear in the fourth decade of life or later. There is no genetic defect or associated family history in AAE type I. Laboratory evaluation typically demonstrates low levels of C1-INH, C4, and C1q69. AAE II is similar to AAE I in clinical presentation and laboratory values; however, autoantibodies to C1-INH are generally the underlying etiology in AAE type II70. AAE is very uncommon with estimates suggesting a prevalence of one twelfth that of HAE71. Low values of C1q distinguish AAE type I and II from forms of HAE. ACE inhibitors are the most common cause of druginduced angioedema in the United States, implicated in up to 20–40% of all angioedema cases presenting to emergency departments72. The overall incidence of angioedema related to ACE inhibitors has been estimated between 0.1 and 2.2% of patients receiving these drugs73,74. Inhibiting ACE results in the accumulation of bradykinin, which is the mediator of the angioedema; thus, this is not a histamine mediated reaction. The angioedema caused by this class of medications can begin anywhere from a few hours to even several years after starting the drug. The use of ACE inhibitors is contraindicated in patients with HAE. Review of hereditary angioedema Altman & Naimi
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Table 2. Differential diagnosis of angioedema.
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Type
Description
Clinical Presentation
Laboratory Findings
HAE type I
80 to 85% of HAE cases. Usually a family hx of angioedema (autosomal dominant), but 20–25% due to spontaneous gene mutation. Usually appears by age 13. Possible increased severity postpuberty. Episodes may be spontaneous or triggered by physical trauma or emotional stress.
Edema can occur in extremities, respiratory tract, GI tract or other organs. Laryngeal edema can be life threatening. Abdominal edema often presents with pain, vomiting and diarrhea. Urticaria is rare.
# C1-INH # C1-INH function # C4 Normal C1q
HAE type II
15 to 20% of HAE cases. Similar description to Type I.
Similar to HAE type I.
"/Normal C1-INH # C1-INH function # C4 Normal C1q
HAE with normal C1-INH or familial estrogen exacerbated angioedema
Usually occurs in females, Often experienced by 41 family member. Not caused by deficiency of C1-inhibitor. Episodes may correlate with pregnancy or oral contraceptive use. Possible correlation w/gene mutation of Factor XII.
Similar to HAE type I.
Normal
AAE type I
Usually associated with underlying B-cell lymphoproliferative disorder. Symptoms appear in fourth decade of life or later. No genetic defect or associated family history.
Similar to HAE.
# C1-INH # C4 # C1q
AAE type II
Autoantibodies to C1-inhibitor. Symptoms appear in fourth decade of life or later. No genetic defect or associated family history.
Similar to HAE.
# C1-INH # C4 # C1q
ACE inhibitor induced AE
Caused by ACE inhibitors. Edema can begin anytime (few hours to years after starting the medication).
Similar to HAE.
Normal
Allergic AE
Most common form. Triggers: food, medication, stinging insect, physical stimuli
Edema often on face, lips, mouth/tongue (less likely laryngeal), or upper airway. Often associated with urticaria. If symptoms 46 weeks then classified as chronic idiopathic.
Normal
Chronic idiopathic AE
Cause unknown. Symptoms 46 weeks. No family history. Can occur at any age.
Same as allergic HAE.
Normal
HAE, hereditary angioedema; hx, history; AAE, acquired angioedema; ACE, angiotensin converting enzyme; AE, angioedema.
Allergic angioedema is the most common form of angioedema. The causes can include: drugs, food, stinging insect allergy, and physical stimuli such as cold and pressure. These are histamine mediated reactions, usually accompanied by urticaria and pruritis and respond well to treatment with antihistamines, oral corticosteroids, and/or epinephrine. These clinical features and response to treatment differentiate allergic angioedema from HAE, AAE, and ACE inhibitor angioedema. If the symptoms of angioedema (often accompanied by urticaria) persist beyond 6 weeks with no known etiology, patients are given the diagnosis of chronic idiopathic angioedema75. There is no known genetic association and it can occur at any age.
Conclusion Recognition of HAE by primary care providers can be important in preventing recurrent attacks and avoiding 928
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inappropriate therapy. Because this disease is poorly understood and generally confused with allergic angioedema, it is estimated that the time from first attack to diagnosis ranges from 10–22 years4. HAE is very rarely associated with pruritis or urticaria; therefore, its clinical presentation is usually distinct from allergic or idiopathic angioedema. Measurements of C4 and absolute and functional levels of C1-INH will identify most cases of HAE except for the variant of HAE with normal C1-INH. Accurate diagnosis is also important because therapeutic options have improved dramatically in the past few years. C1-INH concentrate is available either for prophylactic treatment or to control acute attacks. In addition, two drugs have been approved to treat acute attacks by blocking bradykinin which is the mediator of tissue swelling in HAE. One is ecallantide, which inhibits kallikrein, an enzyme required for bradykinin synthesis and the other is icatibant, a bradykinin receptor antagonist. www.cmrojournal.com ! 2014 Informa UK Ltd
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Further information is available in a recent review of English language peer reviewed articles on angioedema cited in PubMed, OVID and Google76.
Transparency
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Declaration of funding This study was not funded. Declaration of financial/other relationships K.A.A. and D.R.N. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article. CMRO peer reviewers may have received honoraria for their review work. The peer reviewers on this manuscript have disclosed that they have no relevant financial relationships.
References 1. Roche O, Blanch A, Caballero T, et al. Hereditary angioedema due to C1 inhibitor deficiency: patient registry and approach to the prevalence in Spain. Ann Allergy Asthma Immunol 2005;94:498-503 2. Bowen T, Cicardi M, Farkas H, et al. 2010 International consensus algorithm for the diagnosis, therapy and management of hereditary angioedema. Allergy Asthma Clin Immunol 2010;6:24 3. Lumry WR. Overview of epidemiology, pathophysiology, and disease progression in hereditary angioedema. Am J Manag Care 2013;19(7 Suppl):s103-10 4. Zuraw BL. Clinical practice. Hereditary angioedema. N Engl J Med 2008;359:1027-36 5. Bissler JJ, Cicardi M, Donaldson VH, et al. A cluster of mutations within a short triplet repeat in the C1 inhibitor gene. Proc Natl Acad Sci USA 1994;91:9622-5 6. Cicardi M, Agostoni A. Hereditary angioedema. N Engl J Med 1996;334: 1666-7 7. Bowen B, Hawk JJ, Sibunka S, et al. A review of the reported defects in the human C1 esterase inhibitor gene producing hereditary angioedema including four new mutations. Clin Immunol 2001;98:157-63 8. Pappalardo E, Cicardi M, Duponchel C, et al. Frequent de novo mutations and exon deletions in the C1inhibitor gene of patients with angioedema. J Allergy Clin Immunol 2000;106:1147-54 9. Gompels MM, Lock RJ, Abinun M, et al. C1 inhibitor deficiency: consensus document. Clin Exp Immunol 2005;139:379-94 10. Cicardi M, Igarashi T, Rosen FS, et al. Molecular basis for the deficiency of complement 1 inhibitor in type I hereditary angioneurotic edema. J Clin Invest 1987;79:698-702 11. Davis 3rd AE, Aulak K, Parad RB, et al. C1 inhibitor hinge region mutations produce dysfunction by different mechanisms. Nat Genet 1992;1:354-8 12. Banerji A. Hereditary angioedema: classification, pathogenesis, and diagnosis. Allergy Asthma Proc 2011;32:403-7 13. Tosi M. Molecular genetics of C1 inhibitor. Immunobiology 1998;199:358-65 14. Georgy MS, Pongracic JA. Hereditary and acquired angioedema. Allergy Asthma Proc 2012;33(Suppl 1):73-6 15. Bernstein JA. Update on angioedema: evaluation, diagnosis, and treatment. Allergy Asthma Proc 2011;32:408-12 16. Busse PJ. Angioedema: differential diagnosis and treatment. Allergy Asthma Proc 2011;32(Suppl 1):S3-11 17. Donaldson VH, Evans RR. A biochemical abnormality in hereditary angioneurotic edema: absence of serum inhibitor of C’ 1-esterase. Am J Med 1963;35:37-44 18. Bork K, Gul D, Hardt J, et al. Hereditary angioedema with normal C1 inhibitor: clinical symptoms and course. Am J Med 2007;120:987-92
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19. Bork K, Barnstedt SE, Koch P, et al. Hereditary angioedema with normal C1inhibitor activity in women. Lancet 2000;356:213-17 20. Binkley KE, Davis 3rd A. Clinical, biochemical, and genetic characterization of a novel estrogen-dependent inherited form of angioedema. J Allergy Clin Immunol 2000;106:546-50 21. Martin L, Degenne D, Toutain A, et al. Hereditary angioedema type III: an additional French pedigree with autosomal dominant transmission. J Allergy Clin Immunol 2001;107:747-8 22. Bork K, Fischer B, Dewald G. Recurrent episodes of skin angioedema and severe attacks of abdominal pain induced by oral contraceptives or hormone replacement therapy. Am J Med 2003;114:294-8 23. van Geffen M, Cugno M, Lap P, et al. Alterations of coagulation and fibrinolysis in patients with angioedema due to C1-inhibitor deficiency. Clin Exp Immunol 2012;167:472-8 24. Nussberger J, Cugno M, Cicardi M, et al. Local bradykinin generation in hereditary angioedema. J Allergy Clin Immunol 1999;104:1321-2 25. Cugno M, Nussberger J, Cicardi M, et al. Bradykinin and the pathophysiology of angioedema. Int Immunopharmacol 2003;3:311-17 26. Bork K, Frank J, Grundt B, et al. Treatment of acute edema attacks in hereditary angioedema with a bradykinin receptor-2 antagonist (Icatibant). J Allergy Clin Immunol 2007;119:1497-503 27. Bossi F, Fischetti F, Regoli D, et al. Novel pathogenic mechanism and therapeutic approaches to angioedema associated with C1 inhibitor deficiency. J Allergy Clin Immunol 2009;124:1303-10 e4 28. Wagenaar-Bos IG, Drouet C, Aygoren-Pursun E, et al. Functional C1-inhibitor diagnostics in hereditary angioedema: assay evaluation and recommendations. J Immunol Methods 2008;338:14-20 29. Agostoni A, Aygoren-Pursun E, Binkley KE, 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(3 Suppl):S51-131 30. Binkley KE, Davis 3rd AE. Estrogen-dependent inherited angioedema. Transfus Apher Sci 2003;29:215-19 31. Bork K, Gul D, Dewald G. Hereditary angio-oedema with normal C1 inhibitor in a family with affected women and men. Br J Dermatol 2006;154:542-5 32. Zuraw BL, Bork K, Binkley KE, et al. Hereditary angioedema with normal C1 inhibitor function: consensus of an international expert panel. Allergy Asthma Proc 2012;33:S145-56 33. Dewald G, Bork K. Missense mutations in the coagulation factor XII (Hageman factor) gene in hereditary angioedema with normal C1 inhibitor. Biochem Biophys Res Commun 2006;343:1286-9 34. Bork K, Wulff K, Meinke P, et al. A novel mutation in the coagulation factor 12 gene in subjects with hereditary angioedema and normal C1-inhibitor. Clin Immunol 2011;141:31-5 35. Cichon S, Martin L, Hennies HC, et al. Increased activity of coagulation factor XII (Hageman factor) causes hereditary angioedema type III. Am J Hum Genet 2006;79:1098-104 36. Bouillet L, Ponard D, Rousset H, et al. A case of hereditary angio-oedema type III presenting with C1-inhibitor cleavage and a missense mutation in the F12 gene. Br J Dermatol 2007;156:1063-5 37. Bell CG, Kwan E, Nolan RC, et al. First molecular confirmation of an Australian case of type III hereditary angioedema. Pathology 2008;40:82-3 38. Nagy N, Greaves MW, Tanaka A, et al. Recurrent European missense mutation in the F12 gene in a British family with type III hereditary angioedema. J Dermatol Sci 2009;56:62-4 39. Prieto A, Tornero P, Rubio M, et al. Missense mutation Thr309Lys in the coagulation factor XII gene in a Spanish family with hereditary angioedema type III. Allergy 2009;64:284-6 40. Farkas H, Harmat G, Fay A, et al. Erythema marginatum preceding an acute oedematous attack of hereditary angioneuroticoedema. Acta Derm Venereol 2001;81:376-7 41. Starr JC, Brasher GW. Erythema marginatum preceding hereditary angioedema. J Allergy Clin Immunol 1974;53:352-5 42. Williamson DM. Reticulate erythema – a prodrome in hereditary angiooedema. Br J Dermatol 1979;101:549-52
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43. Yucelten D, Kus S. Chicken-wire erythema, but not urticaria, as the presenting sign of hereditary angioedema. Eur J Dermatol 2006;16:197-8 44. Bork K, Meng G, Staubach P, et al. Hereditary angioedema: new findings concerning symptoms, affected organs, and course. Am J Med 2006;119:267-74 45. Gower R. HAE update: determining optimal patient specific therapy. Allergy Asthma Proc 2013;34:7-12 46. Zuraw BL. Diagnosis and management of hereditary angioedema: an American approach. Transfus Apher Sci 2003;29:239-45 47. Zuraw BL. Current and future therapy for hereditary angioedema. Clin Immunol 2005;114:10-16 48. Pekdemir M, Ersel M, Aksay E, et al. Effective treatment of hereditary angioedema with fresh frozen plasma in an emergency department. J Emerg Med 2007;33:137-9 49. Gower RG, Lumry WR, Davis-Lorton MA, et al. Current options for prophylactic treatment of hereditary angioedema in the United States: patient-based considerations. Allergy Asthma Proc 2012;33:235-40 50. Cicardi M, Bork K, Caballero T, et al; HAWK (Hereditary Angioedema International Working Group). Evidence-based recommendations for the therapeutic management of angioedema owing to hereditary C1 inhibitor deficiency: consensus report of an International Working Group. Allergy 2012;67:147-57 51. Zuraw B, Cicardi M, Levy RJ, et al. Recombinant human C1-inhibitor for the treatment of acute angioedema attacks in patients with hereditary angioedema. J Allergy Clin Immunol 2010;126:821-7 e14 52. Zuraw BL, Busse PJ, White M, et al. Nanofiltered C1 inhibitor concentrate for treatment of hereditary angioedema. N Engl J Med 2010;363:513-22 53. Craig TJ, Levy RJ, Wasserman RL, et al. Efficacy of human C1 esterase inhibitor concentrate compared with placebo in acute hereditary angioedema attacks. J Allergy Clin Immunol 2009;124:801-8 54. Bork K, Barnstedt SE. Treatment of 193 episodes of laryngeal edema with C1 inhibitor concentrate in patients with hereditary angioedema. Arch Intern Med 2001;161:714-18 55. Craig TJ, Wasserman RL, Levy RJ, et al. Prospective study of rapid relief provided by C1 esterase inhibitor in emergency treatment of acute laryngeal attacks in hereditary angioedema. J Clin Immunol 2010;30:823-9 56. Bork K, Steffensen I, Machnig T. Treatment with C1-esterase inhibitor concentrate in type I or II hereditary angioedema: a systematic literature review. Allergy Asthma Proc 2013;34:312-27 57. Cicardi M, Levy RJ, McNeil DL, et al. Ecallantide for the treatment of acute attacks in hereditary angioedema. N Engl J Med 2010;363:523-31 58. Levy RJ, Lumry WR, McNeil DL, et al. 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 59. Sheffer AL, Macginnitie AJ, Campion M, et al. Outcomes after ecallantide treatment of laryngeal hereditary angioedema attacks. Ann Allergy Asthma Immunol 2013;110:184-8
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60. MacGinnitie AJ, Campion M, Stolz LE, et al. Ecallantide for treatment of acute hereditary angioedema attacks: analysis of efficacy by patient characteristics. Allergy Asthma Proc 2012;33:178-85 61. Cicardi M, Banerji A, Bracho F, et al. Icatibant, a new bradykininreceptor antagonist, in hereditary angioedema. N Engl J Med 2010;363:532-41 62. Gelfand JA, Sherins RJ, Alling DW, et al. Treatment of hereditary angioedema with danazol. Reversal of clinical and biochemical abnormalities. N Engl J Med 1976;295:1444-8 63. Bork K, Bygum A, Hardt J. Benefits and risks of danazol in hereditary angioedema: a long-term survey of 118 patients. Ann Allergy Asthma Immunol 2008;100:153-61 64. Waytes AT, Rosen FS, Frank MM. Treatment of hereditary angioedema with a vapor-heated C1 inhibitor concentrate. N Engl J Med 1996;334:1630-4 65. Levi M, Choi G, Picavet C, et al. Self-administration of C1-inhibitor concentrate in patients with hereditary or acquired angioedema caused by C1-inhibitor deficiency. J Allergy Clin Immunol 2006;117:904-8 66. Grant JA, White MV, Li HH, et al. Preprocedural administration of nanofiltered C1 esterase inhibitor to prevent hereditary angioedema attacks. Allergy Asthma Proc 2012;33:348-53 67. Craig T, Pu¨rsu¨n EA, Bork K, et al. WAO guideline for the management of hereditary angioedema. World Allergy Organ J 2012;5:182-99 68. Agostoni A, Cicardi M. Hereditary and acquired C1-inhibitor deficiency: biological and clinical characteristics in 235 patients. Medicine (Baltimore) 1992;71:206-15 69. Gelfand JA, Boss GR, Conley CL, et al. Acquired C1 esterase inhibitor deficiency and angioedema: a review. Medicine (Baltimore) 1979;58:321-8 70. Cicardi M, Saini S, Feldweg AM. Acquired C1 inhibitor deficiency: clinical manifestations, epidemiology, pathogenesis, and diagnoses. UpToDate 2013 71. Alsenz J, Bork K, Loos M. Autoantibody-mediated acquired deficiency of C1 inhibitor. N Engl J Med 1987;316:1360-6 72. Banerji A, Clark S, Blanda M, et al. Multicenter study of patients with angiotensin-converting enzyme inhibitor-induced angioedema who present to the emergency department. Ann Allergy Asthma Immunol 2008;100:327-32 73. Miller DR, Oliveria SA, Berlowitz DR, et al. Angioedema incidence in US veterans initiating angiotensin-converting enzyme inhibitors. Hypertension 2008;51:1624-30 74. Makani H, Messerli FH, Romero J, et al. Meta-analysis of randomized trials of angioedema as an adverse event of renin-angiotensin system inhibitors. Am J Cardiol 2012;110:383-91 75. Maurer M, Weller K, Bindslev-Jensen C, et al. Unmet clinical needs in chronic spontaneous urticaria. A GA2LEN task force report. Allergy 2011;66:317-30 76. Xu YY, Buyantseva LV, Agarwal NS, et al. Update on treatment of hereditary angioedema. Clin Exp Allergy 2013;43:395-405
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Vol. 30, No. 5, 2014, 923–930
Article ST-0309.R1/879441 All rights reserved: reproduction in whole or part not permitted
py Un t rig au fo t ht di hor r S sp ize a la d le © y, u s 20 vi e o ew p r 14 r C o an h d p ibi om In rin ted m fo rm t a . Au e si th rc aU ng or i le is al K co ed D py us is Lim fo ers tr ite rp c i b a er n d so d ut na ow io l u nl n se oa d,
Katherine A. Altman
Touro University College of Osteopathic Medicine, Vallejo, CA, USA
David R. Naimi
Northwest Asthma and Allergy Center and University of Washington, Seattle, WA, USA Address for correspondence: David R. Naimi DO, Northwest Asthma and Allergy Center 9725 3rd Ave NE, Suite 500, Seattle, WA 98115, USA. Tel.: +1 425 385 2802; Fax: +1 425 337 7967; [email protected]
Keywords: Bradykinin – C1 esterase inhibitor – C1 inhibitor – Hereditary angioedema – Prophylaxis – Recombinant C1-inhibitor – Treatment Accepted: 23 December 2013; published online: 24 January 2014 Citation: Curr Med Res Opin 2014; 30:923–30
Abstract
Background: Angioedema is a serious medical condition characterized by recurrent non-pitting tissue edema. Hereditary (HAE) forms of this disorder are potentially fatal. Methods: PubMED, Up to Date and Cochrane Library databases were used to identify scholarly peer reviewed original research or review articles on angioedema. Search terms used were: angioedema, HAE, ACE inhibitor induced angioedema, acquired angioedema, type III HAE (now termed HAE with normal C1-INH), diagnosis of HAE, and treatment of HAE. Inclusive dates of the search were 1946 through 2013. Articles on urticaria were excluded. Results: The pathophysiology, clinical manifestations, differential diagnosis and treatments of angioedema are presented. Three variants of HAE are discussed and differentiated from acquired, ACE induced and allergic types of angioedema. Emphasis is placed on understanding that HAE is mediated by bradykinin, not histamine, and is therefore unresponsive to antihistamines, corticosteroids and epinephrine. In contrast, newer therapies that replace C1-INH or block bradykinin production or action are the appropriate treatments for prophylaxis and acute treatment of HAE. Conclusion: Recognition of HAE by primary care providers and distinguishing it from allergic histamine mediated angioedema is essential in preventing recurrent attacks and avoiding inappropriate therapy, and may be life-saving.
No
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Brief review Hereditary angioedema: a brief review of new developments
Introduction
Hereditary angioedema (HAE) is a rare, but potentially fatal genetic disease. It is estimated to have a prevalence between 1 in 35 to 50,0001–3. The inheritance is autosomal dominant so there is equal gender expression. Since the gene mutation is dominant, any child of an affected parent has a 50% chance of acquiring the disorder, and the disease does not skip generations4. The abnormal gene is on chromosome 11, and over 200 different mutations have been found which present with the same clinical phenotype5–11. About 25% of patients have no family history and are believed to have developed a de novo gene mutation8–13. Patients with HAE have recurrent attacks of non-pitting swelling of the face, lips, tongue, throat, extremities and genitals. They rarely have hives. Patients can frequently experience abdominal pain and vomiting lasting 1 to 3 days caused by swelling of the bowel wall. Emotional stress or physical trauma to ! 2014 Informa UK Ltd www.cmrojournal.com
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ALLERGIC IgEreceptor
May 2014
KININ
CLOTTING
Factor XII
Factor XII
COMPLEMENT C1qrs
MAST CELL/ BASOPHIL
XIIa
Prekallikrein C1
XIIa
kallikrein
MASP 1,2 XI
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Kininogen Histamine Prostaglandins Leukotrienes
XIa
BRADYKININ
Classical Alternative Complement Complement Pathway Pathway
Clotting Vasodilation/edema Smooth muscle relaxation
Inhibited by C1-INH Inhibited by Icatibant Inhibited by Ecallantide
Figure 1. Pathways involved in hereditary angioedema.
an area, such as dental procedures, can trigger an attack, but episodes can also occur spontaneously4,14–16. The pathogenesis of the two most common types of this condition is the lack of or abnormal function of C1 esterase inhibitor (C1-INH)17. There are three variants of HAE: types I and II, and HAE with normal C1-INH (formerly type III)7. Type I causes about 85% of cases and patients have low absolute levels of C1-INH. Type II constitutes about 15% of cases. These patients have normal or elevated levels of nonfunctional C1-INH. HAE with normal C1-INH is a newly described variant where all measurements of C1-INH are normal but attacks of angioedema are similar to those in types I and II. The mechanism of this condition is not fully understood18–22.
Pathophysiology In most cases HAE is the result of reduced or defective C1-INH, which is the inhibitor of the first step of the complement system. It normally blocks C1r and C1s and mannose-binding lectin-associated serine proteases (MASP 1 and 2) of the complement system, factors XIa and XIIa of the coagulation system, and kallikrein of the contact system23. The absence or defective function of this inhibitor allows for activation of these different cascade systems and generation of vasoactive substances. Bradykinin, developed in the contact system cascade, has been identified as the major substance mediating vascular 924
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permeability in this disease24–27. Bradykinin binds to and activates the B2 receptor. This results in vasodilation, vascular permeability, and smooth muscle contraction. All of these events cause swelling characteristic of HAE. Because bradykinin is the main culprit, patients with HAE do not respond to antihistamines and do not have itching4. Figure 1 is an overview of the pathways involved. Although bradykinin is the mediator of swelling in HAE, the diagnosis of types I and II of this condition is confirmed by measuring the serum levels of complement proteins. Since C4 is the immediate substrate for activated C1, low C4 values are characteristic of this disease and measuring this complement component is the most useful test to confirm the diagnosis28. In addition, measuring both the absolute level and functional activity of C1-INH is important to distinguish between HAE types I and II2,28,29. In type I HAE most patients have protein (antigenic) and functional levels of C1-INH which range from undetectable to 30% of normal. In type II HAE functional levels of C1-INH are low but the protein level is normal or may be high due to increased plasma half-life. The inheritance of types I and II HAE is autosomal dominant and most patients have one abnormal allele and are therefore heterozygotes. However, individuals carrying an abnormal gene can be asymptomatic in about 10% of cases. In contrast, in HAE with normal C1-INH, the C4 and C1-INH values are normal. Although this type of HAE does not involve absent or functionally abnormal C1-INH it nonetheless presents with similar clinical manifestations. HAE with normal C1-INH is also known as www.cmrojournal.com ! 2014 Informa UK Ltd
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estrogen-dependent/associated angioedema since most cases were originally seen in women and attacks were linked to high levels of estrogen either endogenous (pregnancy) or from administered estrogen19,20,22,30. More recently, male subjects have been described where high estrogen levels were not implicated31. Onset of symptoms in adulthood and facial and tongue swelling appear to be more common in HAE with normal C1-INH compared to types I and II32. In a subset of patients with HAE with normal C1-INH an amino acid substitution in the gene coding for coagulation factor XII has been found. The change is either arginine or lysine substituted for threonine at position 309 or 328. These substitutions might activate factor XII because the substituted amino acids are positively charged while the normal threonine is neutral. The positive charge might cause factor XII to be activated by negatively charged tissue surfaces leading to activation of prekallikrein and subsequent generation of bradykinin33–39.
have a serpiginous erythematous prodromal rash called erythema marginatum40–43. Swelling is most common in arms and legs. Over 90% of attacks involve these extremities. The face is often involved with genital and trunk swelling being less common. Abdominal swelling is the second most common presentation and can cause severe pain, nausea and vomiting9,44. These attacks can be confused with an acute abdominal emergency and lead to unnecessary surgery if the diagnosis of HAE is not known. These patients may also be hypotensive due to vascular fluid loss into the wall or lumen of the small or large bowel or the peritoneal space. Abdominal CT or ultrasound can reveal this tissue edema or free fluid to support the proper diagnosis. Facial swelling is usually very pronounced with distortion of facial features and a risk of laryngeal edema. Progression of facial edema to involve the airway can occur in minutes so this presentation must be treated as an emergency. Mortality has been reported as high as 40% in attacks of laryngeal angioedema45.
Clinical features HAE is characterized by nonpitting, nonpruritic tissue swelling which very rarely is accompanied by hives. This is an essential clinical finding which distinguishes HAE from allergic or idiopathic angioedema. A prodrome of tingling or burning may precede the swelling. In addition, approximately 25% of patients will
Treatment Treatment of HAE consists of management of acute attacks as well as long-term prophylaxis and transient prophylaxis. Table 1 lists current available and pending drugs for the treatment of HAE.
Table 1. Drugs for treatment of hereditary angioedema. Drug
Mechanism
Approved Use
Dosage
Clinical Studies vs Placebo
Danazol–Stanazolol
Stimulate hepatic synthesis of C1-INH
Prophylaxis
Variable 50 mg qd to 200 mg tid for danazol
Attacks significantly fewer 2.2 vs 93.6% of treatment courses
Cinryze
Human C1-INH inhibits kallikrein and suppresses bradykinin formation
Prophylaxis (Intravenous. Home infusion)
1000 units IV q 3–4 days
Reduced attack rate 6.26 vs 12.73 per 12 week period
Berinert
Human C1-INH, inhibits kallikrein and suppresses bradykinin formation
Treatment of acute abdominal, facial, or laryngeal attacks. (Intravenous. On-demand self-administration)
20 units/kg IV
More rapid symptom resolution 2 hrs vs 4 hrs
Ecalantide–Kalbitor
Kallikrein inhibitor
Treatment of acute attacks. Subcutaneous. Patients 16 yo
10 mg/ml SC, at three different sites
Improved treatment score at 4 hrs and faster time to significant improvement 165 min vs 240 min
Icatibant–Firazyr
Bradykinin receptor antagonist
Treatment of acute attacks. Subcutaneous. Selfadministration. Patients 18 yo
30 mg SC
More rapid symptom resolution 2.5 hrs vs 4.6 hrs
Ruconest–Rhucin
Recombinant C1-INH
Treatment of acute attacks
(Available in Europe – awaiting approval in the USA)
qd, once a day; tid, three times a day; IV, intravenous; q, every; SC, subcutaneous.
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Management of acute attacks The angioedema occurring in HAE does not respond to antihistamines, corticosteroids, or epinephrine. Epinephrine may have a small transient impact on swelling; however, it does not alter the course of an attack46,47. The main cause of death in HAE is laryngeoedema. Intubation and emergency tracheostomy must be performed if a patient’s airway is compromised. As part of acute management, intravenous fluid replacement is important, as some patients develop hypotension due to sequestration of fluid in the extravascular space. Pain management is also essential particularly in patients with abdominal attacks46,47. Prior therapy for acute HAE included fresh frozen plasma (FFP). Its use however is controversial as FFP might cause worsening angioedema by providing plasma proteins to generate bradykinin as well as replacing C1-INH46,48. FFP, like other blood products, could also carry a potential risk of infectious disease transmission. The current treatments of choice in acute attacks are replacement of C1-INH with a plasma derived concentrate of the missing or nonfunctional protein (Berinert*), use of a kallikrein inhibitor, ecallantide (Kalbitory), or injection of a bradykinin receptor antagonist, icatibant (Firazyrz)2,9,49,50. All three of these products are currently approved by the FDA to treat acute HAE attacks. The efficacy of these drugs is highest when used early in an HAE attack before it is possible to predict the ultimate severity of the episode. Ruconest (Rhucinx) is a recombinant C1-INH in contrast to Berinert which is a concentrate from human plasma. Ruconest is intended for the treatment of acute HAE attacks and may be approved in the US in the future. It is currently available in Europe51. Another product available in the United States is Cinryzeô. Cinryze and Berinert are different brands of C1-INH. The FDA approved both Berinert and Cinryze despite the fact that they are the same product, but specified that they be used for different indications. Cinryze was approved for prophylaxis to prevent attacks of angioedema and will be discussed in more detail later. C1-INH concentrate (Berinert) is given intravenous (IV) as emergency treatment. It can be administered for treatment of acute facial, laryngeal, or abdominal attacks and patients can be trained in self-administration. The largest study to establish the efficacy of C1-INH infusion for acute attacks was a placebo controlled study which compared 35 actively treated patients with 33 placebo treated subjects52. In the acute treatment group the median time of onset of symptom relief was 2 hours compared to *Berinert is a registered trade name of CSL Behring, King of Prussia, PA, USA yKalbitor is a registered trade name of Dyax Corp, Burlington, MA, USA zFirazyr is a registered trade name of Shire, Lexington, MA, USA xRhucin is a registered trade name of Pharming, The Netherlands ôCinryze is a registered trade name of ViroPharma, Exton, PA, USA
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4 hours in the placebo group. The median time to complete resolution was 12.3 hours in the C1-INH treated group and 25.0 hours in the placebo group. The differences were statistically significant. Other studies have reached similar conclusions53–56. Ecallantide (Kalbitor) is a first-line therapy approved for the treatment of acute HAE attacks by subcutaneous injection in patients 16 years of age and older. It is a recombinant protein kallikrein inhibitor. Kallikrein is the enzyme that activates high molecular weight kininogen (H-MWK) to form bradykinin. Because bradykinin is the mediator of swelling in HAE, blocking its formation is an alternative method of treating this disease. The safety and efficacy of ecallantide were evaluated in 168 patients with HAE in two randomized, double-blind, placebo-controlled trials57,58. The first study was performed with 72 subjects who were randomly divided 1:1 to receive subcutaneous ecallantide or placebo. They were scored on treatment outcome ranging from þ100 (significant improvement in symptoms) to 100 (worsening of symptoms) and by change from baseline in mean symptom scores ranging from þ2 (change from mild at baseline to severe) to 3 (change from severe at baseline to no symptoms). Those who received ecallantide had a median treatment outcome score of þ50 and a mean symptom score of 1 compared to 0 and 0.5 for the placebo group, respectively. Thus, ecallantide provided better efficacy than placebo and there were no adverse reactions. The other study was a randomized, double-blind, placebo-controlled trial in 96 patients where individuals were randomized 1:1 to receive ecallantide 30 mg subcutaneous or placebo for acute attacks of HAE. Patients treated with ecallantide demonstrated a greater decrease from baseline in the mean symptom complex severity and a greater treatment outcome score than patients treated with placebo. At 24 hours, patients treated with ecallantide also demonstrated a greater decrease from baseline in the mean symptom complex severity than placebo. The results were statistically significant. Another study evaluated ecallantide treatment for laryngeal angioedema attacks59. This paper combined the results of four clinical trials in 98 patients receiving 30 mg of subcutaneous ecallantide and used the mean symptom complex severity and treatment outcome response scores to measure outcomes. The patients experienced a total of 220 laryngeal attacks and only one required intubation. Ecallantide produced sustained improvement of laryngeal edema in 80% of the patients and complete or near complete symptom resolution in 63% of subjects within 4 hours. The improvement persisted for 24 hours after the one treatment. Two patients in the study had serious adverse reactions consistent with anaphylaxis and one required epinephrine treatment. This is the main safety concern with ecallantide60. www.cmrojournal.com ! 2014 Informa UK Ltd
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The newest drug for treatment of acute attacks in the US is icatibant (Firazyr), a bradykinin B2 receptor antagonist. This drug was approved for use in Europe in 2008 and in the United States in 2011. It is intended for the treatment of acute attacks by subcutaneous self-administration in patients 18 years of age of older. There have been two double-blind studies26,61. In the first, 56 patients received either icatibant or placebo and in the second 74 patients received icatibant or tranexamic acid, an older, rarely used treatment. The primary end point was time to relief of symptoms. In the first study, symptoms diminished in 2.5 hours with icatibant versus 4.6 hours with placebo. In the second study, the end point was 2 hours with icatibant and 12 hours with tranexamic acid. No serious adverse reactions were observed in either study. Thus relief of symptoms was achieved much more quickly with icatibant than with either placebo or tranexamic acid.
Transient prophylaxis Prophylaxis for surgical procedures, most commonly dental work, is necessary in HAE patients. Medications and equipment for acute treatment also need to be available on-site to treat HAE exacerbations. Prior to the advent of C1-INH therapy, daily high dose androgen therapy was recommended for at least 4 days prior to surgery and 2–4 days afterward. Fresh frozen plasma can also be used to prevent attacks. If given in asymptomatic patients prior to procedures (day of or day before), it does not carry the potential risk of exacerbating symptoms mentioned earlier for the treatment of an acute attack2. Now that C1-INH is available, it can be given 24 hours before the procedure or just prior to it66,67.
Differential diagnosis of angioedema Long-term prophylaxis The traditional and still utilized form of treatment is daily use of 17 a-alkylated androgens. The two widely used drugs are stanazolol and danazol, both synthetic androgens. The presumed mechanism of action of these drugs is stimulation of hepatic synthesis of C1-INH. In a placebo controlled study, patients suffered attacks in 44 of 47 (93.6%) placebo treatment periods and only one of 46 (2.2%) of the danazol treatment rounds62. This historic paper established attenuated androgens as the mainstay form of treatment until very recently with the release of newer forms of treatment63. Unfortunately, attenuated androgens have side effects, especially virilization in women and virilization and premature closure of epiphyseal plates and hence short stature in children. Hepatic toxicity is also a concern and patients taking these drugs need serial measurements of liver function tests. Of the four relatively new products on the market in the United States for the treatment of HAE only C1-INH concentrate (Cinryze) is approved for prophylaxis to prevent attacks of angioedema. It is given IV every 3–4 days. One treatment of Cinryze costs approximately $5000, so two treatments a week for a year costs more than $500,000. Due to the high expense of these newly developed drugs, when possible physicians may still choose to treat patients by the more traditional method with daily androgens. The primary study which established the efficacy of C1INH as prophylactic treatment enrolled 22 patients in a crossover design giving infusions of either active drug or placebo twice weekly for 12 weeks52. The active treatment period had an attack rate of 6.26 versus 12.73 for the placebo treatment, a highly significant difference. Other studies support the same conclusion64,65. ! 2014 Informa UK Ltd www.cmrojournal.com
Angioedema is a complex condition with the three types of HAE being quite uncommon compared to angiotensinconverting enzyme (ACE) inhibitor induced angioedema, and especially allergic and idiopathic types which constitute the majority of cases. Because the three types of HAE are described earlier, the section below will describe other types of angioedema and contrast them with HAE. Table 2 is a summary of all forms of angioedema. Acquired angioedema (AAE) has a similar clinical presentation to HAE types I, II or III. There are two subtypes of AAE. In AAE type I, the symptoms are usually associated with an underlying B-cell lymphoproliferative disorder68. The episodes of angioedema typically appear in the fourth decade of life or later. There is no genetic defect or associated family history in AAE type I. Laboratory evaluation typically demonstrates low levels of C1-INH, C4, and C1q69. AAE II is similar to AAE I in clinical presentation and laboratory values; however, autoantibodies to C1-INH are generally the underlying etiology in AAE type II70. AAE is very uncommon with estimates suggesting a prevalence of one twelfth that of HAE71. Low values of C1q distinguish AAE type I and II from forms of HAE. ACE inhibitors are the most common cause of druginduced angioedema in the United States, implicated in up to 20–40% of all angioedema cases presenting to emergency departments72. The overall incidence of angioedema related to ACE inhibitors has been estimated between 0.1 and 2.2% of patients receiving these drugs73,74. Inhibiting ACE results in the accumulation of bradykinin, which is the mediator of the angioedema; thus, this is not a histamine mediated reaction. The angioedema caused by this class of medications can begin anywhere from a few hours to even several years after starting the drug. The use of ACE inhibitors is contraindicated in patients with HAE. Review of hereditary angioedema Altman & Naimi
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Table 2. Differential diagnosis of angioedema.
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Type
Description
Clinical Presentation
Laboratory Findings
HAE type I
80 to 85% of HAE cases. Usually a family hx of angioedema (autosomal dominant), but 20–25% due to spontaneous gene mutation. Usually appears by age 13. Possible increased severity postpuberty. Episodes may be spontaneous or triggered by physical trauma or emotional stress.
Edema can occur in extremities, respiratory tract, GI tract or other organs. Laryngeal edema can be life threatening. Abdominal edema often presents with pain, vomiting and diarrhea. Urticaria is rare.
# C1-INH # C1-INH function # C4 Normal C1q
HAE type II
15 to 20% of HAE cases. Similar description to Type I.
Similar to HAE type I.
"/Normal C1-INH # C1-INH function # C4 Normal C1q
HAE with normal C1-INH or familial estrogen exacerbated angioedema
Usually occurs in females, Often experienced by 41 family member. Not caused by deficiency of C1-inhibitor. Episodes may correlate with pregnancy or oral contraceptive use. Possible correlation w/gene mutation of Factor XII.
Similar to HAE type I.
Normal
AAE type I
Usually associated with underlying B-cell lymphoproliferative disorder. Symptoms appear in fourth decade of life or later. No genetic defect or associated family history.
Similar to HAE.
# C1-INH # C4 # C1q
AAE type II
Autoantibodies to C1-inhibitor. Symptoms appear in fourth decade of life or later. No genetic defect or associated family history.
Similar to HAE.
# C1-INH # C4 # C1q
ACE inhibitor induced AE
Caused by ACE inhibitors. Edema can begin anytime (few hours to years after starting the medication).
Similar to HAE.
Normal
Allergic AE
Most common form. Triggers: food, medication, stinging insect, physical stimuli
Edema often on face, lips, mouth/tongue (less likely laryngeal), or upper airway. Often associated with urticaria. If symptoms 46 weeks then classified as chronic idiopathic.
Normal
Chronic idiopathic AE
Cause unknown. Symptoms 46 weeks. No family history. Can occur at any age.
Same as allergic HAE.
Normal
HAE, hereditary angioedema; hx, history; AAE, acquired angioedema; ACE, angiotensin converting enzyme; AE, angioedema.
Allergic angioedema is the most common form of angioedema. The causes can include: drugs, food, stinging insect allergy, and physical stimuli such as cold and pressure. These are histamine mediated reactions, usually accompanied by urticaria and pruritis and respond well to treatment with antihistamines, oral corticosteroids, and/or epinephrine. These clinical features and response to treatment differentiate allergic angioedema from HAE, AAE, and ACE inhibitor angioedema. If the symptoms of angioedema (often accompanied by urticaria) persist beyond 6 weeks with no known etiology, patients are given the diagnosis of chronic idiopathic angioedema75. There is no known genetic association and it can occur at any age.
Conclusion Recognition of HAE by primary care providers can be important in preventing recurrent attacks and avoiding 928
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inappropriate therapy. Because this disease is poorly understood and generally confused with allergic angioedema, it is estimated that the time from first attack to diagnosis ranges from 10–22 years4. HAE is very rarely associated with pruritis or urticaria; therefore, its clinical presentation is usually distinct from allergic or idiopathic angioedema. Measurements of C4 and absolute and functional levels of C1-INH will identify most cases of HAE except for the variant of HAE with normal C1-INH. Accurate diagnosis is also important because therapeutic options have improved dramatically in the past few years. C1-INH concentrate is available either for prophylactic treatment or to control acute attacks. In addition, two drugs have been approved to treat acute attacks by blocking bradykinin which is the mediator of tissue swelling in HAE. One is ecallantide, which inhibits kallikrein, an enzyme required for bradykinin synthesis and the other is icatibant, a bradykinin receptor antagonist. www.cmrojournal.com ! 2014 Informa UK Ltd
Current Medical Research & Opinion Volume 30, Number 5 May 2014
Further information is available in a recent review of English language peer reviewed articles on angioedema cited in PubMed, OVID and Google76.
Transparency
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Declaration of funding This study was not funded. Declaration of financial/other relationships K.A.A. and D.R.N. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article. CMRO peer reviewers may have received honoraria for their review work. The peer reviewers on this manuscript have disclosed that they have no relevant financial relationships.
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