SUPPLEMENT
`
`Hereditary Angioedema Caused By C1-Esterase Inhibitor
`Deficiency: A Literature-Based Analysis and Clinical
`Commentary on Prophylaxis Treatment Strategies
`
`Richard G. Gower, MD, FACAAI, FAAAAI, FACP,1 Paula J. Busse, MD,2
`Emel Aygo¨ren-Pu¨rsu¨n, MD, PhD,3 Amin J. Barakat, MD, FAAP,4 Teresa Caballero, MD, PhD,5
`Mark Davis-Lorton, MD, FAAAAI, FACAAI,6 Henriette Farkas, MD, PhD, DSci,7
`David S. Hurewitz, MD, FAAAAI, FACAAI, FACP,8 Joshua S. Jacobs, MD,9
`Douglas T. Johnston, DO, FAAAAI, FACAAI,10 William Lumry, MD, FAAAAI, FACAAI, FACP,11
`and Marcus Maurer, MD12
`
`Abstract: Hereditary angioedema (HAE) caused by C1-esterase inhib-
`itor deficiency is an autosomal-dominant disease resulting from a
`mutation in the C1-inhibitor gene. HAE is characterized by recurrent
`attacks of intense, massive, localized subcutaneous edema involving the
`extremities, genitalia, face, or trunk, or submucosal edema of upper
`airway or bowels. These symptoms may be disabling, have a dramatic
`impact on quality of life, and can be life-threatening when affecting the
`upper airways. Because the manifestations and severity of HAE are
`highly variable and unpredictable, patients need individualized care to
`reduce the burden of HAE on daily life. Although effective therapy for
`the treatment of HAE attacks has been available in many countries for
`more than 30 years, until recently, there were no agents approved in the
`United States to treat HAE acutely. Therefore, prophylactic therapy is
`an integral part of HAE treatment in the United States and for selected
`patients worldwide. Routine long-term prophylaxis with either attenu-
`ated androgens or C1-esterase inhibitor has been shown to reduce the
`
`From the 1Clinical Associate Professor of Medicine, University of Washington,
`Marycliff Allergy Specialists, PS, Spokane, WA; 2Assistant Professor,
`Department of Medicine - Allergy & Immunology, The Mount Sinai
`Medical Center, New York, NY; 3Klinikum der Johann Wolfgang
`Goethe-Universität, Frankfurt, Germany; 4Clinical Professor of Pediat-
`rics, Georgetown University Medical Center, Washington, DC; 5Hospital
`La Paz Health Research Institute (IdiPAZ), Allergy Service, Madrid,
`Spain; 6Winthrop Rheumatology, Allergy and Immunology, Mineola,
`NY; 7Associate Professor of 3rd Department of Internal Medicine,
`Semmelweis University, Budapest, Hungary; 8Clinical Professor of Med-
`icine, Allergy Clinic of Tulsa, Tulsa, OK; 9Allergy & Asthma Medical
`Group, Walnut Creek, CA; 10Allergy Partners, PA, Greenville, SC;
`11Clinical Professor Internal Medicine/Allergy Division, University of
`Texas Southwestern Medical School, Asthma and Allergy Research Associates,
`Dallas, TX; 12Professor of Dermatology and Allergy, Allergie-Centrum-
`Charité/ECARF, Charité-Universitätsmedizin Berlin, Berlin, Germany.
`This supplement was developed from a scientific panel of international
`experts in hereditary angioedema, held on August 13-14, 2010,
`in
`Philadelphia, PA, USA. Funding to the authors and for the meeting and
`supplement was provided by ViroPharma Inc.
`Correspondence to: Richard G. Gower, MD, Marycliff Allergy Specialists,
`PS, 823 W 7th Ave, Spokane, WA 99204.
`Telephone: 509-838-3655. Fax: 509-838-1952. E-mail: rgower@marycliffallergy.
`com.
`Copyright © 2011 by World Allergy Organization
`
`WAO Journal ● February 2011, Supplement
`
`frequency and severity of HAE attacks. Therapy with attenuated an-
`drogens, a mainstay of treatment in the past, has been marked by
`concern about potential adverse effects. C1-esterase inhibitor works
`directly on the complement and contact plasma cascades to reduce
`bradykinin release, which is the primary pathologic mechanism in
`HAE. Different approaches to long-term prophylactic therapy can be
`used to successfully manage HAE when tailored to meet the needs of
`the individual patient.
`
`Key Words: C1-esterase inhibitor, attenuated androgen,
`angioedema, HAE, prophylaxis
`
`(WAO Journal 2011; 4:S9 –S21)
`
`Hereditary angioedema (HAE) caused by C1-esterase in-
`
`hibitor deficiency is an autosomal-dominant disease re-
`sulting from a mutation in the C1-inhibitor gene.1,2 Although
`HAE is an inherited disorder, 25% of cases arise from
`spontaneous mutations.3 HAE is characterized by recurrent
`attacks of intense, massive, localized subcutaneous edema,
`without pruritus, involving the extremities, genitalia, face, or
`trunk, or submucosal edema of the upper airway or bowels.2,4
`There is a scarcity of epidemiologic studies on HAE preva-
`lence. Studies based on national HAE registries show a
`minimal prevalence ranging from 1.09 to 1.51 in 100,000
`inhabitants,5–7 with the actual prevalence expected to be
`higher. Estimates indicate that approximately 1 in 50,000
`people in the general population has HAE.8 No sex or race
`predominance has been described.3
`Mutations in the C1-inhibitor gene located on chromo-
`some 11 cause 2 major forms of HAE: type I and type II.9 In
`type I HAE, which accounts for approximately 85% of HAE
`cases, low C1-esterase inhibitor levels result from a deficiency in
`the amount of C1-esterase inhibitor produced. Both functional
`and antigenic C1-esterase inhibitor levels are reduced.10,11 Type
`II HAE accounts for 15% of cases and is characterized by
`normal or elevated antigenic C1-esterase inhibitor with low
`levels of functional C1-esterase inhibitor.2,12,13 The 2 types of
`
`S9
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`

`Gower et al
`
`WAO Journal • February 2011, Supplement
`
`HAE are alike in clinical presentation, but are caused by differ-
`ent mutations. According to the C1-inhibitor gene mutation
`database, more than 275 different mutations have been identi-
`fied.14 Most mutations are small deletions, insertions, or point
`mutations, however, larger rearrangements of the gene with
`partial duplications or deletions account for 15 to 20% of all
`mutations leading to HAE.13,15–17
`A rare third type of HAE does not exhibit a deficiency
`in C1-esterase inhibitor.18,19 HAE with normal C1-esterase
`inhibitor may be associated with mutations in the coagulation
`factor XII gene but there are patients who do not exhibit any
`genetic mutations.18,20 This communication restricts the dis-
`cussion to the type I and type II HAE caused by deficiency of
`functional C1-esterase inhibitor.
`To review the current status of prophylactic manage-
`ment of HAE, an international panel of experts was assem-
`bled in Philadelphia, PA, on August 13–14, 2010. Because of
`different approaches to management of HAE in various
`countries, these proceedings attempt to reflect the spectrum of
`prophylaxis treatment options with a focus on androgen and
`C1-esterase inhibitor therapy.
`
`CLINICAL PRESENTATION
`The symptoms of both type I and type II HAE are
`indistinguishable. Although the initial symptoms of HAE can
`occur at any age, symptoms usually first appear in childhood,
`worsen during puberty, and persist
`throughout
`life, with
`attack frequency and severity varying from patient to patient.
`HAE is not generally diagnosed at initial presentation, and
`the time of diagnosis has been shown to range from 8 to 22
`years from the first attack.6,21,22 Attacks often occur without
`a trigger; however, precipitating factors that have been
`shown to contribute to the frequency of attacks include stress,
`trauma, infection, menstruation, and pregnancy.3,4,9,21,23 Vari-
`ous medications, such as estrogen-containing agents and
`angiotensin-converting enzyme inhibitors, may also induce
`HAE attacks.3,4,9,21,23 Before attacks, many patients experi-
`ence prodromal symptoms that can include tingling sensa-
`tions or erythema marginatum, a nonpruritic and not raised
`rash (Fig. 1).4,21,24 The patient’s family history or frequency and
`severity of attacks do not predict the course of future attacks nor
`do they predict involvement of the airway during an attack.25
`The cardinal symptoms of HAE include episodic, local-
`ized, nonurticarial, nonpitting subcutaneous edema of the skin
`(hands, arms, legs, feet, trunk, face, genitalia) and submucosal
`edema of the bowels and upper airway.2– 4,9 Attacks may affect
`several sites of the body simultaneously or consecutively.
`Edema typically progresses slowly, peaks over the first 24 to 36
`hours, and usually resolves within 72 hours, but can persist for
`as long as 1 week. HAE attacks can be painful and disfiguring
`but are usually not life-threatening. Attacks affecting the upper
`airways, however, can lead to obstruction and suffocation, and
`the manifestations of gastrointestinal edema (ie, abdominal at-
`tacks) can include intractable abdominal pain, vomiting, nausea,
`diarrhea, and intestinal obstruction, and potentially can lead to
`hypovolemic shock.2– 4,9,26,27
`During an attack, the activation of the complement and
`contact cascades and the inadequate response by C1-esterase
`
`S10
`
`FIGURE 1.
`Erythema marginatum on the arm of a patient
`with hereditary angioedema. Note that lesions are neither
`raised nor pruritic. Photography courtesy of William R.
`Lumry, MD.
`
`inhibitor cause an overproduction of bradykinin (Fig. 2).2
`Increased bradykinin levels increase vascular permeability
`and extravasation, manifesting as edema (Fig. 2).1,28 –30 This
`is an important differentiating feature of HAE when com-
`pared with allergic reactions, which are primarily mediated
`by histamine. During an allergic reaction, IgE antibodies
`react with specific allergens, inducing histamine release from
`mast cells.9 This reaction leads to angioedema and/or urti-
`caria, which subside with use of epinephrine, antihistamines,
`or corticosteroids. In contrast, HAE manifestations do not
`respond to such therapies because symptoms and swelling are
`mediated by bradykinin.9
`
`CONSEQUENCES
`The consequences of HAE are considerable. HAE may
`account for 15,000 to 30,000 emergency department visits an-
`nually in the United States alone.31,32 Laryngeal edema presents
`the greatest risk to patients, and approximately 50% of patients
`with HAE have at least 1 laryngeal attack in their lifetime.9 In
`the past, fatality from asphyxiation during a laryngeal attack was
`reported in approximately 30% of patients with HAE.9 Fatal
`laryngeal attacks still may occur, particularly in the absence of a
`proper diagnosis or in patients who do not receive appropriate or
`timely treatment.2,33 Patients with HAE are often misdiagnosed,
`resulting in unnecessary medical and surgical
`interven-
`tions.22,31,34 Abdominal symptoms may mimic an acute appen-
`dicitis or other forms of acute abdomen and lead to unnecessary
`abdominal surgery.2,8,22 According to 1 estimate, 45% of pa-
`tients presenting to an emergency department with an HAE
`attack are subsequently hospitalized.35
`The symptoms of HAE may be disabling and have a
`dramatic impact on quality of life.36 Swelling in the hands
`and feet can be debilitating, abdominal attacks often cause
`extreme pain, and facial attacks are generally disfiguring and
`may extend to involve the larynx.21 HAE attacks typically
`
`© 2011 World Allergy Organization
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`

`WAO Journal • February 2011, Supplement
`
`Prophylaxis Treatment Strategies for HAE
`
`FIGURE 2. Pathways inhibited
`by C1-esterase inhibitor (C1INH)
`(reproduced from Zuraw,2 with
`permission).
`
`incapacitate patients for 20 to 100 days annually depending
`on attack severity, frequency, and duration.13 HAE signifi-
`cantly impacts the ability of a patient to work or go to school;
`these impairments are comparable to those experienced by
`patients with severe asthma or Crohn’s disease.36 Patients
`may develop narcotic dependence while trying to appropri-
`ately manage frequent and severe abdominal pain.37 Addi-
`tional care may be required to manage the psychologic impact
`of HAE disease.37 Patients with HAE are more likely to suffer
`symptoms of depression than the general population, with
`42.5% of patients showing at least mild symptoms of depres-
`sion.36 Data suggest that patients with more severe disease are
`more likely to experience depression than those with mild or
`infrequent attacks.36 Patients with HAE are nearly twice as
`likely to report taking psychotropic or antidepressant medi-
`cation compared with the general population.36
`
`DIAGNOSIS
`Identifying HAE may be difficult because of variability
`in clinical presentation. HAE should be suspected in patients
`presenting with any of the characteristic symptoms, espe-
`cially in the presence of a positive family history.25 Screening
`for genetic mutations is not generally performed for diagnos-
`tic reasons. Instead, laboratory testing is indicated for patients
`with suspected HAE. Biochemical markers used for the
`diagnosis of HAE are serum complement factor 4 (C4),
`C1-esterase inhibitor antigen, functional C1-esterase inhibi-
`tor, and C1q antigenic protein.25 The most cost-effective
`
`© 2011 World Allergy Organization
`
`method to screen for HAE is measurement of C4 levels.2 If
`C4 is normal, as can occur in some patients between attacks,
`the measurement should be repeated during an acute attack.25
`Whether to obtain C1-esterase inhibitor antigen and func-
`tional C1-esterase inhibitor studies at the time of C4 collec-
`tion or at a subsequent time can be based on the index of
`suspicion. Low levels of C4, C1-esterase inhibitor antigenic
`protein, and functional C1-esterase inhibitor are consistent
`with a type I HAE diagnosis but should be confirmed via a
`second measurement. Low levels of C4 and functional C1-
`esterase inhibitor with normal or elevated C1-esterase inhib-
`itor antigenic protein are indicative of type II HAE.25 C1q
`antigenic protein is normal in HAE.25 It should be noted that
`variability in symptoms is not related to the levels of biochem-
`ical markers and that patients with lower levels of the markers
`outlined here do not necessarily exhibit more severe HAE
`symptoms than those with higher levels.2 A recent study, how-
`ever, found a significant correlation between severity scores and
`baseline functional C1-esterase inhibitor levels, which suggests
`the potential significance of monitoring functional C1-esterase
`levels in relation to clinical disease course.38
`
`TREATMENT APPROACHES
`The goals of treatment for HAE are focused on life-saving
`efforts, slowing the progression and severity of attacks, and
`reducing the number of attacks and their impact on patient
`quality of life. Because of large variations in clinical presenta-
`
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`
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`

`Gower et al
`
`WAO Journal • February 2011, Supplement
`
`tion and severity of disease, HAE treatment is individualized and
`based on a close collaboration between physician and patient.
`The pharmacotherapy of HAE can be categorized into
`3 approaches: acute treatment, short-term prophylaxis, and
`long-term prophylaxis. Acute treatment options for HAE
`include C1-esterase inhibitor (human or recombinant) replace-
`ment therapy, icatibant, or ecallantide (Table 1)2,9,25,39 – 48; how-
`ever, it should be noted that not all agents are currently approved
`in all countries. Infusions of C1-esterase inhibitor concentrate
`have been shown to increase functional levels of C1-esterase
`inhibitor and C4 to near-normal levels.49 Icatibant is a bradyki-
`nin B2-receptor antagonist that reverses increased vascular per-
`meability and inhibits vasodilation and extravasation.40 Ecallan-
`tide is a human plasma kallikrein inhibitor that treats HAE
`symptoms by directly inhibiting plasma kallikrein and decreas-
`ing the conversion of high-molecular-weight kininogen to bra-
`dykinin.41 Fresh frozen plasma has been used, but its utility is
`limited because it contains additional kinins and complement
`factors, posing a potential threat of worsening HAE symp-
`toms.3,34 Nevertheless, successful use of fresh frozen plasma has
`been reported for both acute treatment and prophylaxis.50 –52
`HAE is mediated by bradykinin, therefore, it is noteworthy to
`mention that treatments used for other forms of angioedema,
`including antihistamines, epinephrine, and corticosteroids, are
`ineffective in treating HAE-related angioedema and should be
`avoided.4
`The goal of short-term, or procedural, prophylaxis is to
`prevent an HAE attack in patients that may be triggered by
`medical, surgical, or dental procedures.4,53 C1-esterase inhib-
`itor, attenuated androgens, antifibrinolytics, icatibant, and
`fresh frozen plasma have been used successfully for short-
`term prophylaxis.2,8,25,54 Consensus guidelines recommend
`that patients with HAE receive prophylactic treatment with
`500 to 1,500 U of C1-esterase inhibitor 1 to 6 hours before
`the procedure.25 If C1-esterase inhibitor is not available, the
`
`guidelines recommend treatment with an attenuated androgen
`for 5 days before the procedure and 2 to 5 days after, or
`administration of fresh frozen plasma 1 to 6 hours before the
`procedure.25
`Although effective therapy for the treatment of HAE
`attacks has been available in many countries for more than
`30 years, until recently, there were no agents approved in the
`United States to treat HAE acutely. Therefore, prophylactic
`therapy is an integral part of HAE treatment in the United
`States and for selected patients worldwide. Long-term, or rou-
`tine, prophylaxis is an important treatment option for patients
`with HAE. Patients who can be considered for prophylactic
`therapy are those who experience frequent or severe attacks,
`have had a previous laryngeal attack, have significant anxiety
`and poor quality of life as a result of HAE, have limited access
`to emergency medical care, or choose to receive prophylaxis.37
`In addition, long-term prophylaxis is indicated in patients for
`whom acute therapy is ineffective or unavailable.37 Attenuated
`(17-alpha alkylated) androgens have long been the gold standard
`for prophylaxis in numerous countries, with danazol, stanazolol,
`and oxandrolone being used more frequently than other andro-
`gens. Although the precise mechanism of action is not known,
`attenuated androgens are thought to increase endogenous C1-
`esterase inhibitor levels via hepatic synthesis and a subsequent
`increase in the expression of mRNA.55,56
`Another long-term prophylaxis treatment option, recently
`approved for use in the United States, is nanofiltered human
`C1-esterase inhibitor concentrate.43 The antifibrinolytic agents,
`␧-aminocaproic acid and tranexamic acid, are not approved in
`the United States but have been used extensively in some
`European countries for long-term prophylaxis, especially in
`children and pregnant women in whom androgen therapy is
`contraindicated because of significant risk of adverse ef-
`fects.4,8,37 Antifibrinolytics may also be useful in other patients
`in whom attenuated androgens or intravenous therapy is not
`
`TABLE 1. Drugs Commonly Used for Acute and Prophylactic Treatment of HAE2,9,25,45– 48
`Adult Dosage and Route of
`Administration
`
`Drug Class or Name
`
`Mechanism of Action
`
`Acute therapy
`C1-esterase inhibitor
`(human)
`Ecallantide
`
`Icatibant
`Prophylactic therapy
`17-alpha alkylated
`androgens
`Danazol
`Oxandrolone
`Stanozolol
`Antifibrinolytics
`Tranexamic acid
`␧-aminocaproic acid
`Nanofiltered C1-esterase
`inhibitor (human)
`
`20 U/kg IV
`
`Replaces missing or malfunctioning C1-esterase inhibitor
`
`30 mg SC split into 3 injections
`
`30 mg SC
`
`Potent, selective, reversible inhibitor of plasma kallikrein, which reduces the
`conversion of high–molecular-weight kininogen to bradykinin
`Selective competitive bradykinin type 2 receptor antagonist
`
`100 mg PO every 3 days to 600 mg QD
`2.5 mg PO every 3 days to 20 mg QD
`1 mg PO every 3 days to 6 mg QD
`
`20–50 mg/kg/d PO split BID or TID
`8 to 12 g PO daily in 4 divided doses
`1000 U IV every 3 to 4 days
`
`Exact mechanism not known. Thought to increase endogenous C1-esterase
`inhibitor levels via hepatic synthesis and a subsequent increase in the
`expression of mRNA
`
`Inhibit the formation and activity of plasmin and subsequently decrease
`plasmin-induced activation of C1
`
`Replaces missing or malfunctioning C1-esterase inhibitor
`
`BID, twice daily; HAE, hereditary angioedema; IV, intravenous; PO, by mouth; QD, once daily; SC, subcutaneous; TID, 3 times daily; U, units.
`
`S12
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`

`WAO Journal • February 2011, Supplement
`
`Prophylaxis Treatment Strategies for HAE
`
`TABLE 2. Common Adverse Events Associated With
`Attenuated Androgen Therapy*
`Prevalence
`Rate (%)
`
`Adverse Event
`
`Reference(s)
`
`FIGURE 3. Reduction rate of HAE attacks during long-term
`treatment with danazol in 118 patients (reproduced from
`Bork et al,59 with permission).
`
`appropriate. However, because of relatively low efficacy and
`poor safety profile, including the potential to cause hypotension,
`cardiac arrhythmias, rhabdomyolysis, and thromboembolism,
`the use of antifibrinolytics is limited.2,9,41,57
`Attenuated androgens and C1-esterase inhibitor are at
`the forefront of long-term prophylaxis therapy options for
`HAE, and therefore the goal of this paper is to provide an
`overview of the literature and clinical experience with these
`agents and identify patients who are candidates for each type
`of treatment. A discussion of other therapies is beyond the
`scope of this paper.
`
`EXPERIENCE WITH ATTENUATED ANDROGEN
`THERAPY IN THE LONG-TERM PROPHYLAXIS
`OF HAE
`Attenuated androgen therapy is the most commonly
`prescribed prophylactic therapy and most extensively studied,
`largely because until recently,
`it was the only approved
`prophylaxis treatment option for HAE in the United States.58
`Danazol, stanozolol, and oxandrolone are the attenuated an-
`drogens typically used as prophylaxis for HAE.37 Data dem-
`onstrate that approximately 94 to 100% of patients respond to
`prophylactic therapy with danazol and report a decrease in
`frequency and severity of attacks; however, 5 to 8% of
`patients do not respond to danazol therapy (Fig. 3).59 – 62
`Although danazol is effective in reducing the number of
`attacks, the majority of patients treated with this agent are not
`symptom-free. In a large retrospective study, 24% of patients
`were symptom-free while taking danazol, whereas approxi-
`mately 14% who responded to danazol therapy had 11 or
`more attacks per year.59 Recent data suggest that long-term
`use of this agent may result in reduced efficacy over time.
`Reports indicate that in some patients the effect of danazol
`declines after 4 to 6 years of treatment.59,63– 65 Although
`attenuated androgens are not approved therapy for HAE in
`children, danazol has been shown to be effective prophylactic
`therapy in prepubescent children with severe recurrent HAE
`attacks.64,66 Stanozolol and oxandrolone are preferred by
`some clinicians for use in children partly because of their
`improved safety profiles.2,67,68 Therapy in children is compli-
`cated by the potential for androgens to affect growth and
`development, particularly premature closure of epiphyseal
`plates resulting in decreased growth.2,64 In all patients, atten-
`
`© 2011 World Allergy Organization
`
`Weight gain
`Acne
`Virilization†
`Menstrual irregularities
`Headache/migraine
`Psychological abnormalities‡
`Arterial hypertension
`Lipid abnormalities
`Hepatic disease/adenomas§
`Hematuria
`
`14.3–60.0
`4.8–22.0
`1.8–46.6
`14.4–80.0
`13.6–49.5
`9.4–16.0
`25.0–30.0
`27.0
`1.8–40.0
`13.0
`
`59, 60, 62, 70, 72, 74, 75
`59, 62, 70, 72, 75, 76
`59, 60, 62, 72, 75
`59–62, 70, 72, 75, 76
`59, 62, 74, 75
`59, 62, 72
`70, 74
`73, 75
`59, 60, 62, 75
`62
`
`*Includes data for danazol and stanozolol. Patients may have experienced more
`than 1 adverse event.
`†Includes voice changes, increased hair growth, decrease in breast size, clitoral
`hypertrophy, increase in muscle mass, laryngeal prominence.
`‡Includes depression, aggressiveness, fatigue, panic attacks, mood changes.
`§Includes increase in pathological laboratory findings, including hepatic enzymes.
`
`uated androgen dosing should be individualized and based on
`clinical response.2,25 Furthermore, caution should be exer-
`cised when switching agents because no dose-equivalency
`data currently exist.
`Attenuated androgens pose a significant risk for adverse
`events, leading some patients to refuse therapy. Side effects
`may include weight gain, acne, virilization, altered libido,
`menstrual irregularities, headaches, depression, fatigue, lipid
`abnormalities, hypertension, cholestasis,
`increased liver en-
`zymes, peliosis hepatitis, and hepatocellular adenomas.2,8,59,69 –73
`To review the published safety data on these agents, we per-
`formed a literature search and identified articles that included an
`evaluation of the safety of long-term attenuated androgen ther-
`apy in HAE (Table 2).59 – 62,70,72–76 We found that many patients
`experience adverse effects while taking attenuated andro-
`gens.59,62,72,77,78 These adverse effects can be controlled or min-
`imized by using the lowest effective dose, and some patients are
`capable of tolerating the adverse effects associated with attenu-
`ated androgen therapy. It should be noted, however, that many
`of the patients in these reports were treated with attenuated
`androgens at a time when there were very limited options for
`prophylactic therapy for HAE.
`Patient compliance with attenuated androgen therapy
`may be affected by considerable weight gain, the amount of
`which has been reported to be as high as 45 kg in 1 patient
`after receiving 1 year of therapy with danazol 800 mg daily.59
`Affecting women in particular, virilization symptoms such as
`voice changes, hirsutism, decrease in breast size, clitoral
`hypertrophy, increase in muscle mass, disturbances in libido,
`and laryngeal prominence have been reported with varying
`ranges of frequency and severity.58,59,72,74 Although some
`studies demonstrate a prevalence rate of approximately 2%,60
`symptoms of virilization have been reported to occur in as
`many as 1 in 3 patients72 and in up to 79% of female patients
`receiving attenuated androgens.74 Acne resulting from atten-
`uated androgen therapy also can be a significant source of
`anxiety among patients. Because of the risk of causing tera-
`
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`Gower et al
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`WAO Journal • February 2011, Supplement
`
`togenic effects in an unborn fetus, in particular masculiniza-
`tion, nonhormonal contraception or progestin-only birth con-
`trol pills are recommended in fertile female patients taking
`attenuated androgens.79 Many female patients also report
`menstrual irregularities such as menometrorrhagia or amen-
`orrhea while receiving attenuated androgen therapy.60,75 In
`male patients, loss of libido and gynecomastia have been
`known to occur with androgen use.58
`Other undesirable effects of androgens include headache,
`migraine, and alopecia.59,62,74,75 Psychologic abnormalities such
`as anxiety, depression, aggressiveness, fatigue, panic attacks,
`and mood changes have been reported to occur in as many as
`16% of patients receiving attenuated androgen therapy.59,62
`Additional serious adverse effects such as hypertension,
`lipid abnormalities, cystitis, hematuria, and liver disease, includ-
`ing adenomas and carcinoma, have also been associated with
`attenuated androgen therapy.59,60,62,70,73–75,80,81 In 1 study, pa-
`tients who received long-term prophylaxis for HAE with dana-
`zol were at a higher risk for developing abnormally low levels of
`high-density lipoprotein and high levels of low-density lipopro-
`tein when compared with patients not taking attenuated andro-
`gens and healthy control subjects.73 Liver disease, ranging from
`increased transaminases to adenomas and peliolosis hepatitis,
`has been reported with androgen use and warrants vigilant
`monitoring of liver function.59,60,62,75,82 According to the Inter-
`national Consensus Algorithm for the Diagnosis, Therapy, and
`Management of Hereditary Angioedema,25 patients receiving
`attenuated androgens should be monitored every 6 months for
`changes in liver function (ie, alanine aminotransferase [ALT]/
`aspartate aminotransferase [AST], alkaline phosphatase), lipid
`profile, complete blood cell count, and urinalysis. Patients re-
`ceiving more than 200 mg of danazol daily and patients who are
`of prepubescent age should undergo an ultrasound of the liver
`and spleen every 6 months and a yearly alpha fetoprotein level.
`Patients receiving less than 200 mg of danazol daily should
`undergo an ultrasound of the liver and spleen on a yearly
`basis.25,83
`The side effects associated with attenuated androgens
`may lead patients to discontinue therapy. In a large series of
`patients with HAE who were treated with prophylactic dana-
`zol from 2 months to 30 years, more than 25% discontinued
`danazol because of adverse effects and almost 10% discon-
`tinued because of a fear of adverse effects.59 One half of
`patients who discontinued danazol as a result of adverse
`effects did so within the first 2 years of therapy. Also, the
`average dose of danazol was higher in patients who discon-
`tinued because of adverse effects than in patients who reported
`side effects but continued therapy (254 mg/d vs 154 mg/d,
`respectively). The side effects associated with attenuated andro-
`gens seem to be dose dependent and increase with duration of
`therapy.58 This underscores the importance of titrating to the
`lowest dose that confers adequate prophylaxis to avoid or at least
`mitigate adverse effects.2,78
`
`EXPERIENCE WITH C1-ESTERASE INHIBITOR IN
`THE LONG-TERM PROPHYLAXIS OF HAE
`The first large-scale attempt to purify C1-esterase in-
`hibitor was documented in 1974.84 The development of im-
`
`S14
`
`proved manufacturing processes resulting in purified human
`plasma-derived C1-esterase inhibitor formulations has en-
`abled their use for the treatment of HAE attacks since the
`1980s.85 C1-esterase inhibitor is also highly effective in
`patients requiring short-term prophylaxis85– 88 and its utility
`has been confirmed in patients with frequent attacks who
`experience intolerance to or lack of efficacy with danazol
`therapy.89,90 However, experience with C1-esterase inhibitor
`in long-term prophylactic therapy is not as extensive as for
`acute treatment or short-term prophylaxis; long-term prophy-
`laxis was not explored until 1989 and efficacy in a controlled
`trial was not confirmed until 1996.49,91 Studies with earlier
`C1-esterase inhibitor formulations have shown a reduction in
`the frequency of attacks in patients with HAE.92 In 1 study,
`more than 75% of patients were almost asymptomatic while
`receiving bolus intravenous (IV) injections of C1-esterase
`inhibitor 2 to 3 times weekly.93 In a more recent study, 19
`patients with HAE underwent weekly long-term therapy with
`C1-esterase inhibitor for an average of 9 years.94 Disease
`severity was significantly improved by 1 or more injections of
`C1-esterase inhibitor per week; the percentage of severe
`attacks was 93.3% without and 3.8% with treatment.94 To
`achieve this reduction in severity, patients were willing to
`accept 1 or more weekly IV injections. Although the majority
`of patients had fewer attacks during the last 12 months of the
`study, approximately one third reported more attacks. Signs
`of increasing disease activity (eg, multilocular edema) were
`reported in several patients, but no causal link was demon-
`strated in this observational study.
`Efficacy data for the nanofiltered C1-esterase inhibitor
`approved for prophylactic therapy demonstrate an approxi-
`mate 50% reduction in average normalized attack rates com-
`pared with placebo when administered over two, 12-week
`crossover periods (6.26 vs 12.73 attacks for C1-esterase
`inhibitor and placebo, respectively; difference 6.47 [95%
`confidence interval 4.21, 8.73]; P ⬍ 0.001).43 In the same
`study, prophylaxis with C1-esterase inhibitor demonstrated
`significantly lower severity of attacks (1.3 ⫾ 0.85 vs 1.9 ⫾
`0.36, P ⬍ 0.001) and significantly shorter duration of attacks
`(2.1 ⫾ 1.13 vs 3.4 ⫾ 1.39 days, P ⫽ 0.002) when compared
`with placebo, respectively.43 Recent data from an open-label
`trial confirm this finding. Patients enrolled in the study had a
`decrease in the median number of HAE attacks from 3.0 per
`month to 0.2 per month, and 86% of patients had ⱕ1 attacks
`per month.95
`The selection of a C1-esterase inhibitor over other
`prophylactic therapy options is a choice made as a result of
`consultation between physician and patient; the focus is on
`treatment failure or intolerance to other regimens or the
`inability to receive other prophylactic treatment options be-
`cause of contraindications.37 Similar to all drug therapies,
`C1-esterase inhibitor products also have safety concerns. In a
`clinical trial evaluating the use of 1 C1-esterase inhibitor
`(Berinert, CSL-Behring, King of Prussia, PA) in HAE at-
`tacks, the following adverse events were observed: headache,
`abdominal pain, nausea, muscle spasms, pain, diarrhea, and
`vomiting.42 The safety results of a study evaluating the efficacy
`of nanofiltered human C1-esterase inhibitor (CINRYZE, Viro-
`
`© 2011 World Allergy Organization
`
`Page 6 of 13
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`

`WAO Journal • February 2011, Supplement
`
`Prophylaxis Treatment Strategies for HAE
`
`Pharma Inc, Exton, PA) in prophylactic therapy show the
`most common adverse events to be sinusitis, rash, headache,
`and up