Acquired Angioedema and Marginal Zone Lymphoma

Lam, David Chuen Chun; Levy, Norman B.; Nickerson, James M.; Gruenberg, David A.; Lansigan, Frederick

doi:10.1200/jco.2011.38.9957

Cited by 24 publications

(15 citation statements)

References 14 publications

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“…In a recent publication from the French National Reference Centre for Angioedema, 7 patients were described with a complete clinical efficacy in 3, partial in 2 and therapeutic failure in another 2 patients [12]. Levi et al [32] published 3 AAE patients who went into complete clinical remission, and single case reports can be found too [33,34,35]. One may assume that the treatment efficacy is dependent on the existence of anti-C1INH autoantibodies as a basic pathogenic factor, because RTX may disrupt the anti-C1INH antibody formation.…”

Section: Discussionmentioning

confidence: 99%

Acquired Angioedema - Occurrence, Clinical Features and Associated Disorders in a Danish Nationwide Patient Cohort

Bygum

Vestergaard

2013

Int Arch Allergy Immunol

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Background: The prevalence of acquired angioedema (AAE) is hitherto unknown and, to date, less than 200 patients have been reported worldwide. AAE is associated with lymphoproliferative conditions and autoantibodies against C1 inhibitor (C1INH). Rituximab (RTX) is increasingly used in the treatment of AAE patients. Methods: A nationwide study of AAE patients was performed in Denmark. Clinical features, associated disorders, treatments and outcomes were registered. Results: Eight AAE patients were identified. The diagnostic delay was on average 1 year and 8 months. Patients were treated with C1INH concentrate or icatibant on demand. Six patients were diagnosed with a clonal B-cell disorder during follow-up, on average 2.5 years after the first swelling. Two patients had monoclonal B-cell lymphocytosis (MBL). Two patients received RTX. Conclusions: AAE is a rare condition occurring in less than 10% of patients with C1INH deficiency in Denmark. AAE is highly associated with haematologic disorders, and we recommend yearly follow-up visits with clinical examination and blood tests including flow cytometry to diagnose B-cell conditions at an early stage. We report 2 patients with AAE and associated MBL, which is a benign expansion of clonal B lymphocytes. MBL can be the precursor of chronic lymphocytic leukaemia or is associated with non-Hodgkin's lymphoma. If angioedema is poorly controlled with standard treatment regimens, we suggest treatment of the associated haematologic disorder. Based on a review of the literature and our own data, we recommend therapy with RTX, especially in patients with anti-C1INH autoantibodies.

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Section: Discussionmentioning

confidence: 99%

Acquired Angioedema - Occurrence, Clinical Features and Associated Disorders in a Danish Nationwide Patient Cohort

Bygum

Vestergaard

2013

Int Arch Allergy Immunol

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“…Icatibant is a novel therapeutic option for AAE patients who inadequately respond to current therapies. Rituximab treatment has been used in small series of AAE patients and the results seem to be promising, (83,84) however controlled studies are lacking.…”

Section: Conventional Managementmentioning

confidence: 98%

Therapeutic options for patients with angioedema due to C1-inhibitor deficiencies: from pathophysiology to the clinic

Castelli¹,

Zanichelli²,

Cugno³

2012

Immunopharmacology and Immunotoxicology

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Deficiencies in the inhibitor of the first component of human complement (C1-INH) are clinically associated with both hereditary angioedema (HAE) and acquired angioedema (AAE). The reduction in C1-INH function leads to the activation of the classical complement pathway and consequent complement consumption, as well as to the activation of the contact system and the generation of bradykinin, the vasoactive peptide that increases vascular permeability and causes angioedema. The clinical features of C1-INH deficiencies are the same in both forms of angioedema, and include subcutaneous non-pruritic swelling, the involvement of the upper respiratory tract, and abdominal pain due to partial obstruction of the gastrointestinal tract; however, AAE patients have no family history of angioedema and are characterised by the late onset of symptoms. The aim of therapy is to prevent or reverse angioedema. Advances in our understanding of the complex effects of C1-INH deficiency at molecular level have led to new targeted approaches to the treatment of HAE and AAE. Three new treatments have recently become available: a kallikrein inhibitor that prevents bradykinin release, an antagonist of bradykinin receptors that blocks bradykinin action, and a recombinant human C1-INH molecule produced in transgenic rabbits that replaces the deficient protein. These new drugs have expanded the armamentarium of treatments for angioedema due to C1-INH deficiency, which was previously limited to attenuated androgen, antifibrinolytic drugs, and C1-INH plasma concentrate.

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“…However, the treatment of any lymphoproliferative or autoimmune disorder in AAE patients has usually proved successful in inducing partial or complete clinical and/or biochemical remission of AAE [44,45]. Recently published studies reported cases of eradication of life-threatening angioedema symptoms in patients suffering from AAE in the setting of low-grade B-cell lymphoma as well as effective clinical and biochemical angioedema remission in the setting of autoimmune disease, thanks to four standard infusions of rituximab (375 mg/m 2 ), inducing depletion of B lymphocytes and subsequent decreased titers of bound and free C1-INH protein auto-reactive immunoglobulins [36,45,46].…”

Section: Treatmentmentioning

confidence: 99%

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

Castelli

2016

Clinical Chemistry and Laboratory Medicine (CCLM)

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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.

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Acquired Angioedema and Marginal Zone Lymphoma

Cited by 24 publications

References 14 publications

Acquired Angioedema - Occurrence, Clinical Features and Associated Disorders in a Danish Nationwide Patient Cohort

Acquired Angioedema - Occurrence, Clinical Features and Associated Disorders in a Danish Nationwide Patient Cohort

Therapeutic options for patients with angioedema due to C1-inhibitor deficiencies: from pathophysiology to the clinic

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

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