Accessible Unlicensed Requires Authentication Published by De Gruyter June 12, 2015

The Janus faces of acquired angioedema: C1-inhibitor deficiency, lymphoproliferation and autoimmunity

Maddalena Alessandra Wu and Roberto Castelli

Abstract

Several clinical and biological features of lymphoproliferative diseases have been associated with an increased risk of developing autoimmune manifestations. Acquired deficiency of C1-inhibitor (C1-INH) (AAE) is a rare syndrome clinically similar to hereditary angioedema (HAE) characterized by local increase in vascular permeability (angioedema) of the skin and the gastrointestinal and oro-pharyngo-laryngeal mucosa. Bradykinin, a potent vasoactive peptide, released from high molecular weight kininogen when it is cleaved by plasma kallikrein (a serine protease controlled by C1-INH), is the mediator of symptoms. In total 46% of AAE patients carry an underlying hematological disorder including monoclonal gammopathy of uncertain significance (MGUS) or B cell malignancies. However, 74% of AAE patients have anti-C1-INH autoantibodies without hematological, clinical or instrumental evidence of lymphoproliferative disease. Unlike HAE patients, AAE patients usually have late-onset symptoms, do not have a family history of angioedema and present variable response to treatment due to the hypercatabolism of C1-INH. Experiments show that C1-INH and/or the classical complement pathway were consumed by the neoplastic lymphatic tissues and/or anti-C1-INH neutralizing autoantibodies. Therapy of AAE follows two directions: 1) prevention/reversal of the symptoms of angioedema; and 2) treatment of the associated disease. Different forms of B cell disorders coexist and/or evolve into each other in AAE and seem to be dominated by an altered control of B cell proliferation, thus AAE represents an example of the strict link between autoimmunity and lymphoproliferation.


Corresponding author: Roberto Castelli, MD, Department of Biomedical and Clinical Sciences Luigi Sacco, University of Milan, Luigi Sacco Hospital Milan, Milan, Italy, Phone: +39 2 50319830, Fax: +39 2 50319828, E-mail:

References

1. Hodgson K, Ferrer G, Montserrat E, Moreno C. Chronic lymphocytic leukemia and autoimmunity: a systematic review. Haematologica 2011;96:752–61.Search in Google Scholar

2. Chiorazzi N, Rai KR, Ferrarini M. Chronic lymphocytic leukemia. N Engl J Med 2005;352:804–15.Search in Google Scholar

3. Smedby KE, Askling J, Mariette X, Baecklund E. Autoimmune and inflammatory disorders and risk of malignant lymphomas – an update. J Intern Med 2008;264:514–27.Search in Google Scholar

4. Hodgson K, Ferrer G, Pereira A, Moreno C, Montserrat E. Autoimmune cytopenia in chronic lymphocytic leukaemia: diagnosis and treatment. Br J Haematol 2011;154:14–22.Search in Google Scholar

5. Tiede A, Rand JH, Budde U, Ganser A, Federici AB. How I treat the acquired von Willebrand syndrome. Blood 2011;117:6777–85.Search in Google Scholar

6. Cohen AJ, Kessler CM. Acquired inhibitors. Baillieres Clin Haematol 1996;9:331–54.Search in Google Scholar

7. Voisin S, Hamidou M, Lefrançois A, Sigaud M, Mahé B, Trossaërt M. Acquired von Willebrand syndrome associated with monoclonal gammopathy: a single-center study of 36 patients. Medicine (Baltimore) 2011;90:404–11.Search in Google Scholar

8. Castelli R, Vismara A, Pavia G, Dagani R, Porro T. Relapsing pure red cell aplasia associated with B-cell chronic lymphocytic leukemia successfully treated by intravenous immunoglobulin concentrate. Ann Ital Med Int 2002;17:47–50.Search in Google Scholar

9. Vlachaki E, Diamantidis MD, Klonizakis P, Haralambidou-Vranitsa S, Ioannidou-Papagiannaki E, Klonizakis I. Pure red cell aplasia and lymphoproliferative disorders: an infrequent association. Sci World J 2012;2012:475313.Search in Google Scholar

10. Zhang B, Zheng R, Wang J, Bu D, Zhu X. Epitopes in the linker subdomain region of envoplakin recognized by autoantibodies in paraneoplastic pemphigus patients. J Invest Dermatol 2006;126:832–40.Search in Google Scholar

11. Ramchandren S, Lisak RP. The immunopathogenesis of Guillain-Barré syndrome. Clin Adv Hematol Oncol 2010;8:203–6.Search in Google Scholar

12. Seffo F, Daw HA. Non-Hodgkin lymphoma and Guillain-Barré syndrome: a rare association. Clin Adv Hematol Oncol 2010;8:201–3.Search in Google Scholar

13. Nobile-Orazio E. Neuropathy and monoclonal gammopathy. Handb Clin Neurol 2013;115:443–59.Search in Google Scholar

14. Castelli R, Gritti G, Cannavò A, Moreo G, Conti G, Reda G, et al. Successful management with intravenous immunoglobulins in alemtuzumab-induced acute inflammatory demyelinating neuropathy: clinical report of three patients. Immunopharmacol Immunotoxicol 2012;34:717–20.Search in Google Scholar

15. Cicardi M, Zanichelli A. Acquired angioedema. Allergy Asthma Clin Immunol 2010;6:14.Search in Google Scholar

16. Cicardi M, Zanichelli A. The acquired deficiency of C1-inhibitor: lymphoproliferation and angioedema. Curr Mol Med 2010;10:354–60.Search in Google Scholar

17. Caldwell JR, Ruddy S, Schur PH, Austen KF. Acquired C1 inhibitor deficiency in lymphosarcoma. Clin. Immunol Immunopathol 1972;1:39–52.Search in Google Scholar

18. Jackson J, Sim RB, Whelan A, Feighery C. An IgG autoantibody which inactivates C1-inhibitor. Nature 1986;323:722–4.Search in Google Scholar

19. Alsenz J, Bork K, Loos M. Autoantibody-mediated acquired deficiency of C1 inhibitor. N Engl J Med 1987;316:1360–6.Search in Google Scholar

20. Hauptmann G, Petitjean F, Lang JM, Oberling F. Acquired C1 inhibitor deficiency in a case of lymphosarcoma of the spleen. Reversal of complement abnormalities after splenectomy. Clin Exp Immunol 1979;37:523–31.Search in Google Scholar

21. Schreiber AD, Zweiman B, Atkins P, Goldwein F, Pietra G, Atkinson B, et al. Acquired angioedema with lymphoproliferative disorder: association of C1 inhibitor deficiency with cellular abnormality. Blood 1976;48:567–80.Search in Google Scholar

22. Geha RS, Quinti I, Austen KF, Cicardi M, Sheffer A, Rosen FS. Acquired C1-inhibitor deficiency associated with antiidiotypic antibody to monoclonal immunoglobulins. N Engl J Med 1985;312:534–40.Search in Google Scholar

23. Cicardi M, Zingale LC, Pappalardo E, Folcioni A, Agostoni A. Autoantibodies and lymphoproliferative diseases in acquired C1-inhibitor deficiencies. Medicine (Baltimore) 2003;82:274–81.Search in Google Scholar

24. Cugno M, Bos I, Lubbers Y, Hack CE, Agostoni A. In vitro interaction of C1-inhibitor with thrombin. Blood Coagul Fibrinolysis 2001;4:253–60.Search in Google Scholar

25. Cugno M, Zanichelli A, Foieni F, Caccia S, Cicardi M. C1 inhibitor deficiency and angioedema: molecular mechanisms and clinical progress. Trends Mol Med 2009;15:69–78.Search in Google Scholar

26. Caccia S, Castelli R, Maiocchi D, Bergamaschini L, Cugno M. Interaction of C1-inhibitor with thrombin on the endothelial surface. Blood Coagul Fibrinolysis 2011;22:571–5.Search in Google Scholar

27. Castelli R, Deliliers DL, Zingale LC, Pogliani EM, Cicardi M. Lymphoproliferative disease and acquired C1-inhibitor deficiency. Haematologica 2007;92:716–8.Search in Google Scholar

28. Castelli R, Zanichelli A, Cicardi M, Cugno M. Acquired C1-inhibitor deficiency and lymphoproliferative disorders: a tight relationship. Crit Rev Oncol Hematol 2013;87:323–32.Search in Google Scholar

29. Cugno M, Castelli R, Cicardi M. Angioedema due to acquired C1-inhibitor deficiency: a bridging condition between autoimmunity and lymphoproliferation. Autoimmun Rev 2008;8:156–9.Search in Google Scholar

30. Monti G, Pioltelli P, Saccardo F, Campanini M, Candela M, Cavallero G, et al. Incidence and characteristics of non-Hodgkin lymphomas in a multicenter case file of patients with hepatitis C virus-related symptomatic mixed cryoglobulinemias. Arch Intern Med 2005;165:101–5.Search in Google Scholar

31. Dias C, Isenberg DA. Susceptibility of patients with rheumatic diseases to B-cell non-Hodgkin lymphoma. Nat Rev Rheumatol 2011;7:360–8.Search in Google Scholar

32. Jung M, Rice L. Unusual autoimmune nonhematologic complications in chronic lymphocytic leukemia. Clin Lymphoma, Myeloma Leuk 2011;11(Suppl 1):S10–3.Search in Google Scholar

33. Guillarte M, Luengo O, Nogueiras C, Labrador-Horrillo M, Muñoz E, López A, et al. Acquired angioedema associated with hereditary angioedema due to C1-inhibitor deficiency. J Investig Allergol Clin Immunol 2008;18:126–30.Search in Google Scholar

34. Healy C, Abuzakouk M, Feighery C, Flint S. Acquired angioedema in non-Hodgkin’s lymphoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;103:e29–32.Search in Google Scholar

35. Rossi D, Gaidano G. Anaplastic large cell lymphoma and acquired angioedema: a novel association? Ann Ital Med Int 2002;17:143–5.Search in Google Scholar

36. Kaur R, Williams AA, Swift CB, Caldwell JW. Rituximab therapy in a patient with low grade B-cell lymphoproliferative disease and concomitant acquired angioedema. J Asthma Allergy 2014;7:165–7.Search in Google Scholar

37. Gunatilake SS, Wimalaratna H. Angioedema as the first presentation of B-cell non-Hodgkin lymphoma – an unusual case with normal C1 esterase inhibitor level: a case report. BMC Res Notes 2014;7:495.Search in Google Scholar

38. Agostoni A, Aygören-Pürsün E, Binkley KE, Blanch A, Bork K, Bouillet L, et al. Hereditary and acquired angioedema: problems and progress proceedings of the third C1 esterase inhibitor deficiency workshop and beyond. J Allergy Clin Immunol 2004;114(Suppl 3):S51–131.Search in Google Scholar

39. Spath PJ, Wuthrich B, Matter L, Loos M, Alsenz J. Acquired angioedema and anti-C1-inhibitor autoantibody. Arch Intern Med 1989;149:1213–6.Search in Google Scholar

40. Cicardi M, Bisiani G, Cugno M, Spath P, Agostoni A. Autoimmune C1-inhibitor deficiency: report of eight patients. Am J Med 1993;95:169–75.Search in Google Scholar

41. Cicardi M, Aberer W, Banerji A, Bas M, Bernstein JA, Bork K, et al.; HAWK under the patronage of EAACI (European Academy of Allergy and Clinical Immunology). Classification, diagnosis, and approach to treatment for angioedema: consensus report from the Hereditary Angioedema International Working Group. Allergy 2014;69:602–16.Search in Google Scholar

42. Zanichelli A, Bova M, Coerezza A, Petraroli A, Triggiani M, Cicardi M. Icatibant treatment for acquired C1-inhibitor deficiency: a real-world observational study. Allergy 2012;67:1074–7.Search in Google Scholar

43. Patel NS, Fung SM, Zanichelli A, Cicardi M, Cohn JR. Ecallantide for treatment of acute attacks of acquired C1 esterase inhibitor deficiency. Allergy Asthma Proc 2013;34:72–7.Search in Google Scholar

44. Lam DH, Levy NB, Nickerson JM, Gruenberg DA, Lansigan F. Acquired angioedema and marginal zone lymphoma. J Clin Oncol 2012;30:e151–3.Search in Google Scholar

45. Branellec A, Bouillet L, Javaud N, Mekinian A, Boccon-Gibod I, Blanchard-Delaunay C, et al; French National Reference Center for Angioedema (CREAK). Acquired C1-inhibitor deficiency: 7 patients treated with rituximab. J Clin Immunol 2012;32:936–41.Search in Google Scholar

46. Dreyfus DH, Na CR, Randolph CC, Kearney D, Price C, Podell D. Successful rituximab B lymphocyte depletion therapy for angioedema due to acquired C1 inhibitor protein deficiency: association with reduced C1 inhibitor protein autoantibody titers. Isr Med Assoc J 2014;16:315–6.Search in Google Scholar

47. Cugno M, Cicardi M, Agostoni A. Activation of the contact system and fibrinolysis in autoimmune acquired angioedema: a rationale for prophylactic use of tranexamic acid. J Allergy Clin Immunol 1994;93:870–6.Search in Google Scholar

Received: 2015-2-25
Accepted: 2015-5-7
Published Online: 2015-6-12
Published in Print: 2016-2-1

©2016 by De Gruyter