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

BMC Gastroenterology

Athos Bousvaros³  Chris Stevens²  Albert L Sheffer¹  Leslie E Stolz²  Eitan Rubinstein³ 

[1] Department of Allergy and Immunology, Brigham and Women’s Hospital, Boston, MA, USA;Dyax Corp, Burlington, MA, USA;Division of Gastroenterology, Hepatology and Nutrition, Boston Children’s Hospital, 300 Longwood Ave, Fegan 5th Floor, Boston, MA 02115, USA

关键词: Ecallantide;    Gastrointestinal angioedema;    Hereditary angioedema;   

Others  :  855634
DOI  :  10.1186/1471-230X-14-71

 received in 2014-01-11, accepted in 2014-03-28,  发布年份 2014

【 摘 要 】

Background

Hereditary angioedema (HAE) is characterized by unpredictable attacks of debilitating subcutaneous and mucosal edema. Gastrointestinal attacks are painful, of sudden onset and often mistaken for acute abdomen leading to unnecessary surgery. The purpose of this study was to analyze symptom presentation of gastrointestinal angioedema in pediatric and adult HAE patients.

Methods

Information collected during the clinical development of ecallantide for treatment of acute HAE attacks included affected anatomic location, accompanying symptoms, medical history, and pain assessments. Efficacy endpoints included Treatment Outcome Score (TOS, maximum score = 100; minimally important difference = 30), a point-in-time measure of treatment response, and time to treatment response.

Results

Forty-nine percent of 521 HAE attacks only involved abdominal symptoms. The most commonly reported abdominal symptoms were distension (77%), cramping (73%) and nausea (67%). The most common pain descriptors were tender, tiring-exhausting, aching, cramping and sickening. White blood cell counts were elevated (>10 × 10⁹/L) in 23% of attacks (mean ± SD: 15.1 ± 11.27 × 10⁹/L). A high proportion of patients reported a history of abdominal surgery, including appendectomy (23%), cholecystectomy (16.4%), and hysterectomy (8.2%). Mean TOS at 4 hours post ecallantide was 77±33 versus 29±65 for placebo. Median time to significant symptom resolution was 165 minutes (95% CI 136, 167) for ecallantide versus >4 hours (95% CI 161, >4 hours) for placebo. Anaphylactic reactions occurred in 6 of the 149 treated patients.

Conclusions

HAE should be considered in the differential diagnosis of patients with recurrent discrete episodes of severe, unexplained crampy abdominal pain associated with nausea.

Trials registration

The data used in the analysis were gathered across multiple clinical trials conducted during the clinical development program for ecallantide. All of the studies were conducted using Good Clinical Practices (GCP) and in accordance with the ethical principles that have their origins in the Declaration of Helsinki. Each site that participated in the clinical trials obtained the appropriate IRB or Ethics Committee approval prior to enrolling any patients. All patients provided written informed consent prior to undergoing any study-related procedures. Pediatric patients provided written assent and their parents or guardians gave written informed consent.

The following trials have been registered at http://www.clinicaltrials.gov webcite: EDEMA2 (identifier NCT01826916); EDEMA3 (identifier NCT00262080); EDEMA4 (identifier NCT00457015); and DX-88/19 (identifier NCT00456508).

【 授权许可】

   
2014 Rubinstein et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Zuraw BL: Clinical practice. Hereditary angioedema. N Engl J Med 2008, 359(10):1027-1036.
• [2]Roche O, Blanch A, Caballero T, Sastre N, Callejo D, Lopez-Trascasa M: Hereditary angioedema due to C1 inhibitor deficiency: patient registry and approach to the prevalence in Spain. Ann Allergy Asthma Immunol 2005, 94(4):498-503.
• [3]Pappalardo E, Cicardi M, Duponchel C, Carugati A, Choquet S, Agostoni A, Tosi M: Frequent de novo mutations and exon deletions in the C1inhibitor gene of patients with angioedema. J Allergy Clin Immunol 2000, 106(6):1147-1154.
• [4]Bork K, Staubach P, Eckardt AJ, Hardt J: Symptoms, course, and complications of abdominal attacks in hereditary angioedema due to C1 inhibitor deficiency. Am J Gastroenterol 2006, 101(3):619-627.
• [5]Bygum A: Hereditary angio-oedema in Denmark: a nationwide survey. Br J Dermatol 2009, 161(5):1153-1158.
• [6]Zuraw BL, Bork K, Binkley KE, Banerji A, Christiansen SC, Castaldo A, Kaplan A, Riedl M, Kirkpatrick C, Magerl M, Drouet C, Cicardi M: Hereditary angioedema with normal C1 inhibitor function: consensus of an international expert panel. Allergy Asthma Proc 2012, 33(6):145-156.
• [7]Kaplan AP, Joseph K: The bradykinin-forming cascade and its role in hereditary angioedema. Ann Allergy Asthma Immunol 2010, 104(3):193-204.
• [8]Nzeako UC, Longhurst HJ: Many faces of angioedema: focus on the diagnosis and management of abdominal manifestations of hereditary angioedema. Eur J Gastroenterol Hepatol 2012, 24(4):353-361.
• [9]Sheffer AL, Craig JM, Willms-Kretschmer K, Austen KF, Rosen FS: Histopathological and ultrastructural observations on tissues from patients with hereditary angioneurotic edema. J Allergy 1971, 47(5):292-297.
• [10]Melzack R: The short-form McGill pain questionnaire. Pain 1987, 30(2):191-197.
• [11]Vernon MK, Rentz AM, Wyrwich KW, White MV, Grienenberger A: Psychometric validation of two patient-reported outcome measures to assess symptom severity and changes in symptoms in hereditary angioedema. Qual Life Res 2009, 18(7):929-939.
• [12]MacGinnitie AJ, Campion M, Stolz LE, Pullman WE: Ecallantide for treatment of acute hereditary angioedema attacks: analysis of efficacy by patient characteristics. Allergy Asthma Proc 2012, 33(2):178-185.
• [13]Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, Brown SG, Camargo CA Jr, Cydulka R, Galli SJ, Gidudu J, Gruchalla RS, Harlor AD Jr, Hepner DL, Lewis LM, Lieberman PL, Metcalfe DD, O'Connor R, Muraro A, Rudman A, Schmitt C, Scherrer D, Simons FE, Thomas S, Wood JP, Decker WW: Second symposium on the definition and management of anaphylaxis: summary report--Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol 2006, 117(2):391-397.
• [14]Jalaj S, Scolapio JS: Gastrointestinal manifestations, diagnosis, and management of hereditary angioedema. J Clin Gastroenterol 2013, 47(10):817-823.
• [15]Feller EJ, Spiro HM, Katz LA: Hereditary angioneurotic oedema: an unusual cause of recurring abdominal pain. Gut 1970, 11(12):983-988.
• [16]Locascio EJ, Mahler SA, Arnold TC: Intestinal angioedema misdiagnosed as recurrent episodes of gastroenteritis. West J Emerg Med 2010, 11(4):391-394.
• [17]Jacobs J: Recurrent attacks of hereditary angioedema: a case of delayed diagnosis. Allergy Asthma Proc 2011, 32(Suppl 1):S23-S26.
• [18]Bowen T, Cicardi M, Farkas H, Bork K, Longhurst HJ, Zuraw B, Aygoeren-Pursun E, Craig T, Binkley K, Hebert J, Ritchie B, Bouillet L, Betschel S, Cogar D, Dean J, Devaraj R, Hamed A, Kamra P, Keith PK, Lacuesta G, Leith E, Lyons H, Mace S, Mako B, Neurath D, Poon MC, Rivard GE, Schellenberg R, Rowan D, Rowe A, et al.: International consensus algorithm for the diagnosis, therapy and management of hereditary angioedema. Allergy Asthma Clin Immunol 2010, 6(1):24. BioMed Central Full Text
• [19]Cicardi M, Bork K, Caballero T, Craig T, Li HH, Longhurst H, Reshef A, Zuraw B: 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(2):147-157.
• [20]Craig T, Pursun EA, Bork K, Bowen T, Boysen H, Farkas H, Grumach A, Katelaris CH, Lockey R, Longhurst H, Lumry W, Magerl M, Martinez-Saguer I, Ritchie B, Nast A, Pawankar R, Zuraw B, Maurer M: WAO Guideline for the Management of Hereditary Angioedema. World Allergy Organ J 2012, 5(12):182-199.
• [21]Zuraw BL, Banerji A, Bernstein JA, Busse PJ, Christiansen SC, Davis-Lorton M, Frank MM, Li HH, Lumry WR, Riedl M: US hereditary angioedema association medical advisory board 2013 recommendations for the management of hereditary angioedema due to C1 inhibitor deficiency. J Allergy Clin Immunol 2013, 1(5):458-467.
• [22]Nzeako UC: Diagnosis and management of angioedema with abdominal involvement: a gastroenterology perspective. World J Gastroenterol 2010, 16(39):4913-4921.
• [23]Bork K, Meng G, Staubach P, Hardt J: Treatment with C1 inhibitor concentrate in abdominal pain attacks of patients with hereditary angioedema. Transfusion 2005, 45:1774-1784.
• [24]Hara T, Shiotani A, Matsunaka H, Yamanishi T, Oka H, Ishiguchi T, Saika A, Itoh H, Nishioka S: Hereditary angioedema with gastrointestinal involvement: endoscopic appearance. Endoscopy 1999, 31(4):322-324.
• [25]Koruth JS, Eckardt AJ, Levey JM: Hereditary angioedema involving the colon: endoscopic appearance and review of GI manifestations. Gastrointest Endosc 2005, 61(7):907-911.
• [26]Ohsawa I, Nagamachi S, Suzuki H, Honda D, Sato N, Ohi H, Horikoshi S, Tomino Y: Leukocytosis and high hematocrit levels during abdominal attacks of hereditary angioedema. BMC Gastroenterol 2013, 13:123. BioMed Central Full Text
• [27]Zuraw BL, Bernstein JA, Lang DM, Craig T, Dreyfus D, Hsieh F, Khan D, Sheikh J, Weldon D, Bernstein DI, Blessing-Moore J, Cox L, Nicklas RA, Oppenheimer J, Portnoy JM, Randolph CR, Schuller DE, Spector SL, Tilles SA, Wallace D: A focused parameter update: Hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor-associated angioedema. J Allergy Clin Immunol 2013, 131(6):1491-1493. e1425
• [28]Zingale LC, Zanichelli A, Deliliers DL, Rondonotti E, De Franchis R, Cicardi M: Successful resolution of bowel obstruction in a patient with hereditary angioedema. Eur J Gastroenterol Hepatol 2008, 20(6):583-587.
• [29]Banerji A, Sloane DE, Sheffer AL: Hereditary angioedema: a current state-of-the-art review, V: attenuated androgens for the treatment of hereditary angioedema. Ann Allergy Asthma Immunol 2008, 100(1 Suppl 2):S19-S22.
• [30]DANOCRINE® [package insert] New York, NY: Sanofi-Synthelabo Inc; 2011.
• [31]CINRYZE® (C1 Esterase [Human]) package insert Exton, PA: ViroPharma Biologics, Inc; 2014.
• [32]Berinert® [C1 Esterase Inhibitor (Human)] package insert CSL Behring GmbH; 2014.
• [33]FIRAZYR® [package insert] Lexington, MA: Shire Orphan Therapies, Inc; 2013.
• [34]KALBITOR® (ecallantide)[package insert] Burlington, MA: Dyax Corp; 2012.
• [35]Gandhi PK, Gentry WM, Bottorff MB: Thrombotic events associated with C1 esterase inhibitor products in patients with hereditary angioedema: investigation from the United States Food and Drug Administration adverse event reporting system database. Pharmacotherapy 2012, 32(10):902-909.