Abdominal attacks and treatment in hereditary angioedema with C1-inhibitor deficiency

Hereditary angioedema (HAE) is a rare and potentially life-threatening disease. It is characterized by non-pitting, non-pruritic swelling of subcutaneous or submucosal tissues of the skin, extremities, genitalia, respiratory and/or gastrointestinal tracts [1]. Because of the rarity of the disease and its self-resolving nature, many patients have historically faced a prolonged time to diagnosis (>10 years) [2]. The disease has an autosomal dominant pattern of inheritance and therefore patients typically present with a family history of angioedema. However, ~25% of cases are due to de novo mutations such that a family history is not always present [3]. Abdominal HAE attacks are very common, with up to 87% of patients rating abdominal attacks as excruciating or severely painful [4] often causing the patient to seek medical attention. Symptoms of abdominal HAE attacks often mimic other diseases such as appendicitis, small bowel obstruction, inflammatory bowel disease, gall bladder disease or diverticulitis. As a result, many patients report undergoing unnecessary abdominal surgery prior to diagnosis [5]. Thus, abdominal HAE attacks contribute significantly to the reduced quality of life and economic burden of HAE patients. Moreover, the accurate diagnosis of the disease, especially in patients who present only with recurrent abdominal symptoms, remains a challenge.

The primary cause of HAE is a deficiency in C1-inhibitor (HAE-C1INH), although HAE with normal C1-INH (HAEnC1) has been described [6]. C1-INH is a serine-protease inhibitor that regulates the activation of the coagulation, kallikrein-kinin and complement systems, with the kallikrein-kinin system playing a central role in the pathophysiology of HAE-C1INH [7]. During an HAE-C1INH attack, deficiency in C1-INH results in the unregulated activation of plasma kallikrein, a protease which cleaves high molecular weight kininogen to form the potent vasodilator bradykinin. As a result, excessive bradykinin is produced and activates the bradykinin B2 receptor on endothelial cells, causing the edema and inflammation characteristic of an HAE attack [7]. The precipitating events for an HAE attack are unknown but stress and minor trauma are thought to contribute.

The reported manifestations of intestinal angioedema in the literature include abdominal pain with or without nausea, vomiting and diarrhea, and abdominal distension from ascites [4, 8]. These symptoms are due to edema of the bowel wall which can lead to partial or complete small bowel obstruction often with associated ascites [8, 9]. Prior abdominal surgeries further complicate abdominal attacks due to the possibility of adhesions causing small bowel obstruction. To date, there have been limited prospective reports specifically detailing and quantitating the presenting symptoms of abdominal HAE attacks.

Herein, we provide prospectively collected data from adult and pediatric HAE-C1INH patients presenting with abdominal symptoms in the clinical program for ecallantide. Ecallantide is a subcutaneously administered plasma kallikrein inhibitor that was FDA approved in 2009 for the treatment of acute attacks of HAE in patients 16 years of age and older. These data provide information that should prove useful to the Gastroenterologist, Surgeon and ED Physician to consider HAE-C1INH when patients report with recurrent, unexplained abdominal distension, crampy abdominal pain with nausea.

Diagnosis of HAE-C1INH in patients with recurrent abdominal pain can be challenging, especially in the approximately 50% of cases that present only with abdominal symptoms. These patients are very likely to be referred to a Gastroenterologist at some point, particularly given that abdominal symptoms occur in approximately 80% of patients [14] and on average it takes 10 years from the time of onset of symptoms until a diagnosis is made [2]. It is commonplace for HAE-mediated abdominal pain to be mistaken for other causes of abdominal pain, such as appendicitis, cholecystitis and small bowel obstruction [15, 16]. As a consequence, many HAE patients report having undergone unnecessary surgeries for their HAE symptoms including exploratory laparotomy, cholecystectomy and hysterectomy [15, 17]. We observed a similar surgical history in patients enrolled in the clinical development program for ecallantide. These results highlight the difficulty in initially suspecting and then diagnosing HAE. Once a diagnosis of HAE is suspected, there are several published guidelines/consensus documents to aid the clinician in the diagnosis and management of HAE patients [18‐21].

Historical data suggests that up to 80% of HAE patients have recurrent abdominal pain [22]. This percentage is similar to that observed in the clinical development program of ecallantide in which 65% (149/230) of patients treated with SC ecallantide presented with HAE attacks with abdominal symptoms. The most commonly reported symptoms associated with abdominal attacks in this dataset were distension (77%), cramping (73%) and nausea (67%), which is in agreement with previous reports [4, 23]. These same symptoms were also commonly reported in pediatric patients with HAE.

The percentage of HAE attacks with symptoms of diarrhea (14%) and vomiting (21%) reported during the ecallantide development program were lower than those reported in previous studies. In two retrospective reports from Bork and colleagues, the percentage of attacks with vomiting were 83.3% and 73.3%, while 41.8% and 40.6% of attacks had symptoms of diarrhea [4, 23]. The reason for the discrepancies between these studies is unclear but may be due to differences in the severity of attacks included in the analyses, as well as how the severity of attacks was defined. Both reports from Bork et al. included a high percentage of severe attacks, 78.7% and 70.0% respectively. In contrast, in the ecallantide development program 37.9% of all attacks with abdominal symptoms were rated as severe. It may be that diarrhea occurs as the attack is resolving and the timing of the data collection in the EDEMA program (within 8 hours of symptom onset vs an average attack duration of 2 to 5 days) may not have detected this later symptom. In addition, retrospective analyses are subject to recall bias which may also contribute to the differences observed between studies.

White blood cell (WBC) count is often used in the differential diagnosis of acute abdominal pain and was collected in patients with primary abdominal attacks in the ecallantide development program. Interestingly, WBC count was elevated in ~25% of attacks and was more likely to be elevated in attacks rated as severe. This finding is in agreement with several published case reports of abdominal HAE attacks and therefore suggests that elevated WBC count is not a reliable measure to include or exclude HAE in the differential diagnosis of abdominal pain [24, 25]. Indeed, Ohsawa et al. recently reported significant leukocytosis with neutrophilia, as well as increased levels of hematocrit and low C-reactive protein (CRP) in HAE patients with severe abdominal pain, when compared with laboratory values when patients were not experiencing an attack [26].

To date, there is no reliable marker to define abdominal angioedema upon presentation of symptoms. Even in patients with a confirmed diagnosis of HAE, a diagnosis of an abdominal attack depends upon clinical judgment and the demonstrated efficacy of specific treatments. In undiagnosed patients, once HAE is suspected, blood tests can be used to confirm the diagnosis but these results will not be available for diagnosis and treatment in the initial emergency setting. The initial screening test is C4 blood levels, which will be low in HAE patients at baseline and even lower during an acute attack. However, a reduced C4 level during an attack does not identify the presence or absence of angioedema. The C4 test is inexpensive, common to most hospital laboratories, and typically has a high sensitivity and specificity, with at least 95% of HAE-C1INH patients showing a reduced C4 level during remission and virtually 100% showing reduced C4 during an attack [27]. If the C4 is low, an abnormal functional C1-INH test would confirm the diagnosis of HAE [27]. The endoscopic and computerized tomography (CT) appearance of abdominal angioedema has been previously reported and although nonspecific, in the right clinical setting of association with skin swelling and a family history, can suggest the diagnosis [16, 24, 25, 28]. Typical observations associated with abdominal angioedema include small bowel mucosal thickening, thumb printing of the bowel wall and ascites [16, 25].

There are now several therapeutic options available for the treatment of HAE. These include both long-term prophylaxis, as well as the treatment of acute attacks but studies of comparative effectiveness among treatments have not been conducted. Attenuated androgens have long been used for HAE prophylaxis but can have serious side-effects [29, 30]. CINRYZE® (ViroPharma, Exton, PA) is a nanofiltered, C1-INH (Human) replacement product also approved for prophylaxis [31]. Acute treatment options include: Berinert® (CSL Behring, Marburg, Germany), a nanofiltered C1-INH (Human) replacement product [32]; FIRAZYR® (icatibant, Shire, Lexington, MA), a bradykinin B2 receptor antagonist [33]; and KALBITOR® (ecallantide, Dyax Corp., Burlington, MA), a plasma kallikrein inhibitor [34].

Each of the HAE therapies have demonstrated efficacy in the management and treatment of HAE but also carry a risk of harm. As stated in the package inserts and reported in the literature, the use of C1 Esterase Inhibitor (Human) products is associated with serious arterial and venous thromboembolic events [31, 32, 35]. The use of icatibant is associated with injection site reactions, which occurred in almost all patients (97%) in clinical trials [33]. The major risk associated with use of ecallantide is hypersensitivity reactions [34]. Anaphylaxis has been reported after administration of ecallantide and because of this risk, should only be administered by a healthcare professional with appropriate medical support to manage anaphylaxis and HAE [34]. In the study presented here, ecallantide was shown to elicit a clinically meaningful treatment response for abdominal attacks within 1 hour post dosing, with significant symptom resolution occurring in 2 to 4 hours. Thus, in patients diagnosed with HAE-C1INH, a variety of effective treatment options are available to minimize the symptoms of HAE attacks and improve overall quality of life.

In summary, patients that present with attacks of recurrent abdominal pain that completely resolve in the absence of other symptoms are challenging to diagnose. The data from this study provide information that should aid the Gastroenterologist in suspecting the diagnosis of HAE in patients with such unexplained bouts of severe abdominal pain. Patients with HAE are likely to have intermittent exacerbations of moderate to severe, poorly localized pain, described as tender, tiring-or exhausting, aching cramping or sickening. Elevation of white blood cells frequently occurs during severe abdominal attacks and may lead to exploratory laparotomy for concern of other more common conditions. As Gastroenterologists increase their awareness of HAE, patients will be diagnosed earlier to receive both timely and effective treatment.