Full Length ArticleWhere we are with acquired angioedema due to C1 inhibitor deficiency: A systematic literature review
Introduction
Acquired angioedema due to C1 inhibitor deficiency (C1-INH-AAE) is a rare cause of adult-onset non-urticarial angioedema. Its symptoms include recurrent cutaneous, gastrointestinal, and life-threatening laryngeal edema, similar to those observed in patients with hereditary forms of C1-INH deficiency [1,2]. However, it almost always happens after the fourth decade of life with a negative family history and is commonly associated with lymphoproliferative disorders [3,4]. Plasma levels of C4 antigen, as well as C1-INH antigen and/or functional activity are characteristically low. Reduced C1INH function results in activation of the kallikrein-kinin system and accumulation of the vasoactive peptide bradykinin, which increases vascular permeability and induces angioedema [5]. Given its rarity, no controlled clinical treatment trials have been performed, and treatment options of angioedema are borrowed from hereditary forms of C1-INH deficiency [6,7]. In addition, targeting the associated diseases also showed various degrees of biochemical improvement of complement abnormalities and/or clinical remission of angioedema [8].
Our understanding of this rare disorder is still limited given the sparseness of data. Besides case reports and small series, most experiences were based on observations from a group of patients followed by Cicardi et al. in Milan since 1976 [[9], [10], [11]]. The last systematic review tabulated clinical features of such patients was published in 2006 [1]. Of note, multiple novel therapeutic options targeting kallikrein-kinin system have been introduced into clinical practice after that. Therefore, we aimed to summarize the clinical features, concurrent diseases, treatments, and outcomes of patients with C1-INH-AAE through a systematic review of cases described since 2006. Factors impacting angioedema remission were also explored.
Section snippets
Study design, search strategy and selection criteria
Following the PRISMA guidelines, we identified records by searching PubMed and Embase databases between January 2006 and February 2021 using the terms (“angioedema” OR “angio edema” OR “angioedemas” OR “angioneurotic edema” OR “angioneurotic oedema”) AND (“complement C1 inhibitor protein” OR “C1 inhibitor”). We chose 2006 as the initial year of searching because a previous systematic review tabulated clinical features of cases published between 1972 and 2006 [1]. Additional cases were further
Baseline clinical features and laboratory findings
A total of 121 patients from 54 records were included in the current systematic review [[13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56], [57], [58], [59], [60], [61], [62], [63], [64], [65], [66]] (Fig. 1). Patient characteristics are shown in Table 1, in comparison with two
Discussion
This systematic literature review presents the clinical features, treatments, and long-term outcomes of C1-INH-AAE by examining a large cohort of patients fulfilling the most updated diagnostic consensus. Our results not only confirm important observations from previous smaller cohorts but provide novel insights into its pathogenesis and management.
C1-INH-AAE is a very rare disorder with an estimated prevalence of 1:600,000 in general population [11]. Reduced C1-INH function causes
Funding sources
None.
Declaration of Competing Interest
None.
Acknowledgement
None.
References (73)
- et al.
Acquired deficiency of the inhibitor of the first complement component: presentation, diagnosis, course, and conventional management
Immunol. Allergy Clin. N. Am.
(2006) - et al.
Acquired C1 inhibitor deficiency
Immunol. Allergy Clin. N. Am.
(2017) - et al.
Acquired C1-inhibitor deficiency and lymphoproliferative disorders: a tight relationship
Crit. Rev. Oncol. Hematol.
(2013) - et al.
Diagnosis, course, and management of angioedema in patients with acquired C1-inhibitor deficiency
J Allergy Clin Immunol Pract
(2017) - et al.
Rituximab-induced elimination of acquired angioedema due to C1-inhibitor deficiency
Am. J. Med.
(2006) - et al.
Acquired angioedema in non-Hodgkin’s lymphoma
Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod.
(2007) - et al.
Acquired angioedema with raised serum tryptase
Ann. Allergy Asthma Immunol.
(2013) - et al.
Acquired C1 inhibitor deficiency: should we monitor for associated antibody deficiency?
Ann. Allergy Asthma Immunol.
(2014) - et al.
Short-term prophylaxis in a patient with acquired C1-INH deficiency
J. Allergy Clin. Immunol.
(2014) - et al.
Benefits of hydroxychloroquine in the treatment of a patient with angioedema due to acquired C1 inhibitor deficiency
Ann. Allergy Asthma Immunol.
(2015)
Lesson of the month 2: the limitations of steroid therapy in bradykinin-mediated angioedema attacks
Clin. Med.
Rituximab in a patient with splenic marginal zone lymphoma and acquired angioedema
Ann. Allergy Asthma Immunol.
Cases of acquired C1 inhibitor deficiency treated with rituximab
J Allergy Clin Immunol Pract
Clinical and biological response to rituximab treatment in 3 patients with acquired C1-inhibitor deficiency
Ann. Allergy Asthma Immunol.
The importance of complement testing in acquired angioedema related to angiotensin-converting enzyme inhibitors
J Allergy Clin Immunol Pract
Acquired angioedema with lymphoproliferative disorder: association of C1 inhibitor deficiency with cellular abnormality
Blood
Marginal zone lymphoma: associated autoimmunity and auto-immune disorders
Best Pract. Res. Clin. Haematol.
Monoclonal gammopathy of clinical significance: a novel concept with therapeutic implications
Blood
Lymphoproliferative disease and acquired C1 inhibitor deficiency
Haematologica
High prevalence of splenic marginal zone lymphoma among patients with acquired C1 inhibitor deficiency
Br. J. Haematol.
Hereditary and acquired C1-inhibitor-dependent angioedema: from pathophysiology to treatment
Ann. Med.
Classification, diagnosis, and approach to treatment for angioedema: consensus report from the hereditary angioedema international working group
Allergy
Current and emerging biologics for the treatment of hereditary angioedema
Expert. Opin. Biol. Ther.
Relevance of lymphoproliferative disorders and of anti-C1 inhibitor autoantibodies in acquired angio-oedema
Clin. Exp. Immunol.
Autoantibodies and lymphoproliferative diseases in acquired C1-inhibitor deficiencies
Medicine (Baltimore)
A nationwide study of acquired C1-inhibitor deficiency in France: characteristics and treatment responses in 92 patients
Medicine (Baltimore)
Deep venous thrombosis associated with acquired angioedema type II in a patient heterozygous for the mutation of factor V Leiden: effective treatment and follow-up for four years
Thromb. Haemost.
Falsely normal C4 in a case of acquired C1 esterase inhibitor deficiency
J. Clin. Pathol.
C1-esterase inhibitor autoantibodies in a patient with acute tongue swelling
Allergy Asthma. Proc.
Acute upper airway obstruction from acquired angioedema
Emerg. Med. Australas.
Angioedema, lymphoproliferative disorder and angiotensin-converting enzyme inhibitors: masking of diagnosis by corticosteroids
Intern. Med. J.
Acquired angioedema associated with primary antiphospholipid syndrome in a patient with antithrombin III deficiency
Int. Arch. Allergy Immunol.
Successful use of rituximab in acquired C1 inhibitor deficiency secondary to Sjögren’s syndrome
Lupus
Helicobacter Pylori Infection
Vanishing tumour of the colon ascendens due to acquired type II C1- inhibitor deficiency
Acta Clin. Belg.
Acquired angioedema: autoantibody associations and C1q utility as a diagnostic tool
Allergy Asthma. Proc.
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