Angioedema with acquired/sporadic C1 INH deficiency Andrea Zanichelli, Milan (Italy) Jonathan Bernstein, Cincinnati (USA)
Outline Definition Systematic Literature Search Prevalence Pathophysiology Case presentation Diagnosis Treatment Angioedema with acquired/sporadic C1 INH deficiency Questions to discuss
Definition: to be discussed Acquired Angioedema (AAK) Angioedema with acquired C1 INH deficiency Angioedema with sporadic C1 INH deficiency Non hereditary C1 INH deficiency angioedema Acquired C1 INH deficiency syndrome
1 Systematic Literature Search: Aquired Angioedema We searched in Pub Med for the following terms: angioedema or C1 inhibitor protein or C1 inhibitor. AND we matched these results with the following terms: acquired or sporadic or non hereditary. We found 397 results.
Literature Search Methods From 397 titles we excluded non-english papers and those not related to acquired C1 INH deficiency angioedema (i.e. urticaria, acquired angioedema due to allergy, hereditary angioedema, non angioedema symptoms) or full text not available. 117 papers were included in the review: - 24 reviews on angioedema including AAE - 78 case reports/case series - 14 observational studies - 1 clinical trial
Prevalence of AAE No epidemiologic study, prevalence unknown 180 pts with AAE reported in literature Prevalence of AE in the general Danish population (18-69) was 7.4% (Madsen Acta Derm Venereol 2012). Prevalence of HAE: Bygum A Br J Dermatol 2009: minimal prevalence of HAE in Denmark is 1,4:100.000 Usual estimated prevalence of HAE between 1:10,000 and 1:50,000 (Zuraw NEJM 2008) Milan population: 1 AAE patient for every 10 HAE patients (Cicardi and Zanichelli A Allergy, Asthma & Clinical Immunology 2010; Cicardi M Acta Haematol 2012)
Genetics Is AAE associated with mutations of C1 INH gene or impaired synthesis of functional C1 INH?
2 Systematic Literature Search: Genetics In Pub Med Advanced Search Builder, we entered the following search terms: angioedema AND genetics (MeSH Subheading) AND acquired or sporadic or non hereditary We found 89 results
2 Systematic Literature Search: Genetics None of the abstracts included research on the genetics of acquired angioedema
Pathophysiology. Mechanism of C1 INH deficiency The C1 INH deficiency is thought to be due to either/both: An underlying lymphoproliferative disease leading to hyperactivation of the classical complement pathway (i.e., lymphoma) Autoantibodies to C1INH resulting in depletion of C1INH Increased catabolism of C1 INH leads to hyperactivation of classic complement pathway and consumption of C1 (Zingale Immun Allergy Clin N Am 2006)
Associated lymphoproliferative diseases AAE was first reported in the presence of lymphoma in 1972. (Caldwell JR Clin Immunol Immunopathol 1972) We found 47 subsequent studies that confirmed this association and also reported association with MGUS Zingale Immun Allergy Clin N Am 2006 reported a prevalence of MGUS in 35% of AAE, higher than the 3% observed in general population Mechanism of C1 INH deficiency is thought to be due to massive lymphocytic activation of classical complement pathway or to direct action on C1 INH (Cugno Trends in Molecular Medicine 2009)
Autoantibodies to C1 INH On the basis of initial findings of autoantibodies to C1 INH in otherwise healthy patient (Jackson et al Nature 1986; Alsenz J et al NEJM 1987), AEE was divided in type I, associated with lymphoproliferative disease, and type II, caused by autoantibodies to C1INH. Because lymphoproliferation and autoimmunity coexist in most patients and may induce one another it is difficult to distinguish different types of AAE (Cicardi M Medicine 2003; D Incan M Dermatology 1999; Whaley K Clin Exp Immunol Dec 1996, Zingale LC et al. Immun Allergy Clin N Am 2006)
Associated diseases in 30 AAE pts SLE: 5 pts (Cacoub Arthriti Rheum2001, Ochonisky Dermatology 1993, Nettis Eur J Clin Invest 2005) Autoimmune Haemolytic Anemia: 1 pt (Hauptmann G Blut 1976) Cryoglobulinemia: 2 pts (Mandle J Immunol 1994; Casali P Acta Haematol 1978) Rheumatoid Arthritis: 1 pt (Fremeaux-Bacchi VAm J Med 2002) Sjogren s syndrome: 1 pt (Sanchez-Cano D Lupus 2008) Anticardiolipin antibodies: 2 pt (Di Leo E Int J Immunopathol pharmacol 2011; Szeplaki G Int Arch Allergy Immunol 2008) Neoplasms: 9 pts (Fremeaux-Bacchi Am J Med 2002; Cicardi Medicine 2003; Wasserfallen J Allergy Clin Immunol 1995; Cohen J Allergy Clin Immunol 1978; Alonso Acta Anaesthesiol Scand 2002; Van Spronsen Net J Med 1998; Spath Aech Intern Med 1989) Infectious disease: Echinococcus 2 pts, Helicobacter pylori 3 pts Thrombotic disorder 3 pts Leucocytoclastic vasculitis1 pt (Farkas Acta Derm Venereol 2001) No associated diseases: 20 pts out of 180
Pathophysiology. Mediators In 4 AAE patients during remission plasma bradykinin concentration was higher compared to healthy volunteers and further increased during acute attacks (Nussberger J Lancet 1998) AAE is similar to HAE, where inappropriate activation of a C1INH-deficient contact-kinin system releases excess bradykinin, resulting in edema (Davis AE Annu Rev Immunol 2004, Cugno Trends in Molecul Medicine 2009)
Case Presentation A 59 yo WF with hx of angioedema presents with recurrent abdominal pain and two throat swelling episodes; no family history of AE Screening C4 level < 2 mg/dl Further testing revealed a C1INH function = 1%, C1INH quantitative=9 mg/dl (nl=21-39 mg/dl), C1q =50ug/ml (nl=109-242) C1INH Ab = 14,283.8 (245.3% of standard normal =.89-36) CBC with diff, SPEP, UIE normal Bone marrow biopsy normal Due to precedence (Donaldson VH, et.al. J Lab Clin Med 1992; 119:397-406) patient was started on plasmapheresis x 5 followed by cytoxan treatments x 6. Tolerated well without significant side effects 3 month follow-up no symptoms since last August. She has completed 5 plasmapheresis treatment and cytoxan x 6 without complications. C1INH Ab decreased to 15.2 after 3 months (normal range is <36) Six month follow up still asymptomatic; repeat C1INH Ab pending
Diagnosis. Clinical Characteristics Age of onset > 40 y.o. 94% of pts (Cicardi and Zanichelli Allergy Asthma Clin Immunol 2010) Facial, tongue, and uvular swelling prominent (Bouillet-Claveyrolas Am J Med 2003; Cicardi and Zanichelli Allergy Asthma Clin Immunol 2010) GI swelling less common than HAE less than 50% of pts (Cicardi and Zanichelli Allergy Asthma Clin Immunol 2010) 30% of pts (Bouillet-Claveyrolas Am J Med 2003, Cicardi and Zanichelli Allergy Asthma Clin Immunol 2010) Upper airway edema: 50% of AAE pts (Breitbart Allergy Asthma Proc 2010, Bouillet-Claveyrolas Am J Med 2003) No family history of AE
NL = Normal Complement levels in the differential diagnosis of Angioedema
Laboratory testing C1INH function and antigen and C4 below 50% of normal (Agostoni J allergy Clin Immunol 2004; Zingale Immunol Allergy Clin N Am 2006; Cicardi and Zanichelli Allergy Asthma Clin Immunol 2010) Temporary normalization of one of these parameters has been reported (Spath Arch Intern Med 1989). Low C1q 70% of pts (Cicardi Allergy Asthma Clin Immunol 2010) review of the 168 cases of AAE shows that the C1q value is normal in 10 cases and diminished in 94 cases (Breitbart Allergy Asth Proc 2010) Presence of anti-c1inh antibodies in 71 pts out of 136 (Zingale Immunol Allergy Clin N Am 2006). tested only in few specialized research lab!
Falsely normal C4 in a case of acquired C1 esterase inhibitor deficiency (McLean-Tooke A J Clin Pathol 2007) A 59-year-old lady presented with recurrent AE without urticaria. The clinical history and examination were consistent with an acquired C1 esterase deficiency secondary to lymphoproliferative disease (splenic marginal lymphoma). C4 level assayed by nephelometry on automated analyser was normal. Analysis using different nephelometric analysers revealed consistently low C4, despite consistent normal readings in the analyser used from the authors. Further investigation revealed an IgM-k paraprotein that seemed to interfere with both this and haematology coagulation assays. Conclusion: monoclonal paraproteins may interfere with nephelometric, turbidimetric and immunological assays in a non-antibody- specific manner and should be considered when there are unusual or unexpected results, particularly in a patient with lymphoproliferative disease.
Is C1q a reliable marker for AAE? Yamamoto T et.al. Am J Med Sci 2012;343(3):210 214.
HAE patients can develop low C1q: a case report 51 y/o female HAE patient with normal C1q since age 12 developed worsening symptoms C1q level was found to be very low CBC and bone marrow biopsy revealed follicular lymphoma Guilarte, M et.al. J Investig Allergol Clin Immunol 2008; 18:126-130. Bernstein has found a similar case of a 31 year old WM with HAE since childhood who developed CML coinciding with worsening attacks and a low C1q level
Unusual Cases of AAE AAE patients may not have low C1q level and/or anti-c1 inhibitor antibodies. Genetics can distinguish between AAE and de novo HAE Zuraw B, Bernstein JA, Lang D. A Focused Parameter Update: Hereditary Angioedema, Acquired C1 Inhibitor Deficiency, and ACE-Inhibitor Associated Angioedema 2012, JACI (in press).
Additional clinical evaluation Complete blood count with differential Erythrocyte sed rate, C-reactive protein Serum protein electrophoresis Urine analysis for light chain proteins Bone marrow biopsy?
Rituximab. Review of 14 AAE pts with lymphoproliferative disease and /or ant-c1 INH autoantibodies Rituximab in 14 AAE pts with lymhoproliferative disease (lymphomas and MGUS) and/or anti-c1inh autoantibodies Branellec A J Clin Immunol 2012: 7 pts, follow up of 6-24 months 2 with no subsequent attacks,1 very rare attack 2 with partial response: 1pt less severe symptoms and 1 pt less frequent attack 2 with initial benefit with regression of symptoms after several months Lam J Clinical Oncology: 1 pt, 8 months follow up Clinical improvement, no subsequent attacks Hassan A Acta Derm Venereol 2011: 1 pt, follow up 2 y.o. Clinical improvement : less frequent and mild attacks Sanchez-Cano D Lupus 2008: 1 pt, follow up 11 months Initial clinical response, relapse after 3 months. Additional course of Rituximab with no subsequent attacks Levi M Am J Med 2006: 3 pts, follow up 8-10 months clinical improvement and no AE symptoms Ziakas PD Haematologica 2004: 1 pt, follow up 6 months Less severe and less frequent symptoms
Plasmapheresis and cyclophoshamide for treatment of AAE Donaldson (J Lab Clin Med, 1992) repoted 1 pt with anti-c1inh autoantibody treated with plasmapheresis and additional treatment with cyclophosphamide with sustained remission. Bernstein JA et.al. has recently treated 3 patients with this regimen without side effects and sustained remission (not published as of yet)
Treatment of Acute attacks On demand therapy Replacement therapy with pdc1inh (2000 UI) partially or completely non-responsive pts to pdc1inh treatment (Agostoni A J allergy Clin Immunol 2004; Zanichelli Allergy 2012) Icatibant 11 pts successfully treated with Icatibant (Zanichelli Allergy 2012; Zanichelli A Intern Emerg Med 2011; Bygum A Acta Derm Venereol 2011; Weller K J Eur Acad Dermatol Venereol 2011; Bright P Clin Exp Dermatol 2010) Ecallantide 2 pts successfully treated with Ecallantide (Cicardi and Zanichelli Allergy Asthma Clin Immunol 2010)
Prophylaxis Anti-fibrinolytics (tranexamic acid, epsilon aminocaproic acid) Better efficacy than in HAE first choice drug for prophylaxis (Cicardi and Zanichelli Allergy Asthma Clin Immunol 2010) Androgens less effective than in HAE (Agostoni A J allergy Clin Immunol 2004;Cicardi and Zanichelli Allergy Asthma Clin Immunol 2010) Pd C1 INH Prevention of attacks with pd C1 INH 1000UI every 5-7 days in 3 pts (Bork J Allergy Clin Immunol 1989, Levi J Allergy Clin Immunol 2006)
Discussion/Consensus (hopefully!)
Name of Angioedema Acquired Angioedema with C1 INH deficiency (AAE C1INH)
No family history of AE Clinical Diagnosis Late age of onset usually above 40 y/o Facial, tongue, and uvular swelling more common than HAE Frequently associated with B cell lymphoproliferative disease (including MGUS) and/or autoantibodies to C1INH
Laboratory Diagnosis Low C1INH function (below 50% of lower limits of normal using chromogenic assay) and low C4 Low C1q found in majority of patients Presence of anti-c1inh antibodies in majority of patients Genetic testing to exclude HAE when diagnosis is inconclusive Laboratory testing including CBC with differential, WSR, serum protein electropheresis Further work-up as appropriate to exclude other associated diseases Refer to a hematologist/oncologist Flow cytometry for lymphocyte populations Bone marrow biopsy
Therapeutic approach Burden of disease vs. Harm of treatment Treatment of underlying disease if appropriate Consult with hematologist/oncologist if evidence of underlying lymphoproliferative disease Treatment of angioedema as appropriate On-demand therapy (icatibant, ecallantide) for angioedema attacks Prophylaxis therapy for frequent angioedema attacks (tranexamic acid, attenuated androgens) Treatment with on-demand or prophylaxis C1INH may be not be effective in some cases because of potential risk of immunogenicity; long term risk vs. benefits is currently unknown Reconsider treating the underlying disease if angioedema poorly controlled