Acquired C1-inhibitor deficiency and lymphoproliferative disorders: A tight relationship

https://doi.org/10.1016/j.critrevonc.2013.02.004Get rights and content

Abstract

Angioedema due to the acquired deficiency of C1-inhibitor is a rare disease known as acquired angioedema (AAE), which was first described in a patient with high-grade lymphoma and is frequently associated with lymphoproliferative diseases, including expansion of B cell clones producing anti-C1-INH autoantibodies, monoclonal gammopathy of uncertain significance (MGUS) and non-Hodgkin lymphoma (NHL). AAE is clinically similar to hereditary angioedema (HAE), and is characterized by recurrent episodes of sub-cutaneous and sub-mucosal edema. It may affect the face, tongue, extremities, trunk and genitals. The involvement of the gastrointestinal tract causes bowel sub-occlusion with severe pain, vomiting and diarrhea, whereas laryngeal edema can be life-threatening. Unlike those with HAE, AAE patients usually have late-onset symptoms, do not have a family history of angioedema and present variable response to treatment due to the hyper-catabolism of C1-inhibitor. Reduced C1-inhibitor function leads to activation of the classic complement pathway with its consumption and activation of the contact system leading to the generation of the vasoactive peptide bradykinin, which increases vascular permeability and induces angioedema.

Lymphoprolipherative diseases and AAE are tightly linked with either angioedema or limphoprolyferation being the first symptom. Experimental data indicate that neoplastic tissue and/or anti-C1-inhibitor antibodies induce C1-inhibitor consumption, and this is further supported by the observation that cytotoxic treatment of the lymphoproliferative diseases associated with AAE variably reverses the complement impairment and leads to a clinical improvement in angioedema symptoms.

Introduction

The clinical characteristics of acquired C1-inhibitor deficiency or acquired angioedema (AAE) are similar to those of hereditary C1-inhibitor deficiency known as hereditary angioedema (HAE), except for the later onset of symptoms, the absence of a family history, and the potential association with lymphoproliferative diseases and/or anti-C1-inhibitor auto-antibodies [1], [2]. Scattered reports describe acquired C1-inhibitor deficiency associated with nonhematologic neoplasm, infections or autoimmune diseases, whereas 14% of patients with acquired C1-inhibitor deficiency have no other disease [2]. The symptoms include recurrent, self-limiting local swelling located in the subcutaneous tissues (which may be disfiguring), the upper airways (which may cause possibly fatal laryngeal edema), and the gastrointestinal tract (which induces bowel obstruction and severe abdominal pain) [2], [3], [4].

A deficiency in C1-inhibitor leads to the activation of the classic complement pathway and consumption of C1, C2 and C4 components; furthermore, the contact system becomes unstable and prone to generate kallikrein, which cleaves high-molecular-weight kininogen (HK) and thus releases bradykinin, the mediator of the increased vascular permeability [5], [6], [7], [8], [9], [10]. The release of bradykinin is facilitated by the plasmin [11] generated during edema attacks in patients with C1-inhibitor deficiency [10], [12]. The mechanisms responsible for the consumption of C1-inhibitor and the massive activation of the classic complement pathway have been extensively investigated [1], [13], [14], [15], and the initial experiments indicated that C1-inhibitor and/or the classic complement pathway are consumed by neoplastic lymphatic tissues; moreover, C1-inhibitor can be cleaved/inactivated by its auto-antibody.

The majority of patients carry an underlying B cell disorder which is thought to cause C1-inhibitor consumption. These disorders range from the production of anti-C1-inhibitor auto-antibodies to monoclonal gammopathy of uncertain significance (MGUS) and non-Hodgkin lymphoma (NHL) [16], [17]. The relationship between pathological B cell clones and C1-inhibitor deficiency is easily identified when the clone produces auto-antibodies that cleave/inactivate C1-inhibitor, but it is not immediately obvious in the case of MGUS or NHL. Under these conditions, the presence of a cause-effect relationship between the pathological clone and C1-inhibitor consumption is supported by: (1) the prevalence of MGUS and NHL extraordinarily higher in AAE patients compared to the general population [16], [18]; (2) isolated reports showing various degrees of reversal of the biochemical and/or clinical abnormalities of AAE upon the therapeutically induced remission of NHL [18], [19], [20]; and (3) some experimental evidence suggesting that lymphatic tissues from AAE patients absorb or consume C1-inhibitor [1], [13], [14], [15].

We here review the pathophysiological mechanisms of AAE by concentrating on the relationship between it and the associated B cell disorders, and underline the potential reversal of complement abnormalities after treating the lymphoproliferative disease.

Section snippets

Historical background and pathophysiology of acquired c1-inhibitor deficiency

An acquired C1-inhibitor deficiency resulting in angioedema symptoms was first described in 1972 by Caldwell et al. [1], who observed it in a patient with a lymphoproliferative disorder. In 1986, Jackson et al. [13] discovered an autoreactive immunoglobulin G against C1-inhibitor in a patient with angioedema and acquired C1-inhibitor deficiency. These and other findings indicated that the pathogenetic mechanism underlying acquired C1-inhibitor deficiency may be related to autoimmunity [21], [22]

Presentation

The typical symptom of both hereditary and acquired C1-inhibitor deficiency is angioedema, a recurrent, self-limiting, non-pitting, non-pruritic edema that completely resolves in 1–5 days [2], [37], [38], [39]. Angioedema affects the subcutaneous tissue, the gastrointestinal mucosa, and the mucosa of upper respiratory tract. Angioedema of the skin causes deformities that may involve the face, genitals, buttocks, and extremities. Urticaria is usually absent, although transient and mild

Link between acquired angioedema and lymphoproliferative disease

AAE is frequently associated with lymphoproliferative disorders of B cell lineage ranging from MGUS to NHL. Three studies by our group have previously demonstrated that patients with acquired C1-inhibitor deficiency are at higher risk of developing NHL than the general population [16], [17], [18]. A lymphoproliferative disease may be present at the onset of AAE symptoms, or may develop thereafter (in our experience, between three months and seven years after) [18]. The most frequent

Conclusions

Although the etiology of acquired C1-inhibitor deficiency is still partially unclear, the majority of patients present an underlying B cell disorder, which ranges from the simple production of C1-inhibitor auto-antibodies to MGUS and NHL. The most frequent histotypes are nodal and splenic marginal zone lymphomas and lymphoplasmocytic lymphomas/Waldeström disease. The association with such histotypes is similar to that of other autoimmune diseases and, as they develop during the post-antigen

Conflicts of interest

The authors have no conflicting interests to disclose.

Reviewer

Teresa Caballero, MD, PhD, Senior consultant, Hospital Universitario La Paz, Allergy Department, Paseo de la Castellana 261, ES-28046 Madrid, Spain.

Massimo Cugno MD, is an associate professor of Internal Medicine at the University of Milan. He is the chief of the Center for the study of complement at the Maggiore Hospital in Milan. He graduated “cum laude” from the University of Milan in 1982. He completed his post-graduated speciality in Hematology and Internal Medicine at the University of Milan. He is involved in research on prognostic, therapeutic and biological aspects of hematological disorders. The scientific work was conducted

References (74)

  • W.E. Van Nostrand et al.

    Functional and structural similarities between protease nexin I and C1-inhibitor

    Journal of Biological Chemistry

    (1988)
  • L.C. Zingale et al.

    Acquired C1-inhibitor deficiency: presentation, diagnosis, course and conventional management

    Immunology and Allergy Clinics of North America

    (2006)
  • M. Cicardi et al.

    Autoimmune C1-inhibitor deficiency: report of eight patients

    American Journal of Medicine

    (1993)
  • C. Drouet et al.

    Metallopeptidase activities in hereditary angioedema: effect of androgen prophylaxis on plasma aminopeptidase P

    Journal of Allergy and Clinical Immunology

    (2008)
  • K. Bork et al.

    Long-term prophylaxis with C1-inhibitor (C1 INH) concentrate in patients with recurrent angioedema caused by hereditary and acquired C1-inhibitor deficiency

    Journal of Allergy and Clinical Immunology

    (1989)
  • C. Healy et al.

    Acquired angioedema in non-Hodgkin's lymphoma

    Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology and Endodontics

    (2007)
  • M. Ramos-Casals et al.

    B-cell-depleting therapy in systemic lupus erythematosus

    American Journal of Medicine

    (2012)
  • C. Zwick et al.

    German High-Grade Non-Hodgkin Lymphoma Study Group. Rituximab in high-grade lymphoma

    Seminars in Hematology

    (2010)
  • T. Sousou et al.

    Rituximab in indolent lymphomas

    Seminars in Hematology

    (2010)
  • B. Coiffier et al.

    Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: a multicenter phase II study

    Blood

    (1998)
  • M. Levi et al.

    Rituximab-induced elimination of acquired angioedema due to C1-inhibitoribitor deficiency

    American Journal of Medicine

    (2006)
  • V. Fremeaux-Bacchi et al.

    Prevalence of monoclonal gammopathy in patients presenting with acquired angioedema type 2

    American Journal of Medicine

    (2002)
  • A.P. Kaplan

    C1 inhibitor deficiency: hereditary and acquired forms

    Journal of Investigational Allergology and Clinical Immunology

    (2001)
  • M. Cugno et al.

    Plasma levels of C1-inhibitor complexes and cleaved C1-inhibitor in patients with hereditary angioneurotic edema

    Journal of Clinical Investigation

    (1990)
  • M. Schapira et al.

    Prekallikrein activation and high-molecular-weight kininogen consumption in hereditary angioedema

    New England Journal of Medicine

    (1983)
  • J. Nussberger et al.

    Bradykinin-mediated angioedema

    New England Journal of Medicine

    (2002)
  • J. Kleniewski et al.

    Mechanism of enhanced kinin release from high molecular weight kininogen by plasma kallikrein after its exposure to plasmin

    Journal of Laboratory and Clinical Medicine

    (1992)
  • M. Cugno et al.

    Generation of plasmin during acute attacks of hereditary angioedema

    Journal of Laboratory and Clinical Medicine

    (1993)
  • J. Jackson et al.

    An IgG autoantibody which inactivates C1-inhibitor

    Nature

    (1986)
  • G. Hauptmann et al.

    Acquired C1-inhibitor deficiency in a case of lymphosarcoma of the spleen. Reversal of complement abnormalities after splenectomy

    Clinical and Experimental Immunology

    (1979)
  • M. Cicardi et al.

    Autoantibodies and lymphoproliferative diseases in acquired C1-inhibitor deficiencies

    Medicine

    (2003)
  • M. Cicardi et al.

    Relevance of lymphoproliferative disorders and of anti-C1-inhibitor autoantibodies in acquired angio-oedema

    Clinical and Experimental Immunology

    (1996)
  • R. Castelli et al.

    Lymphoproliferative disease and acquired C1-inhibitor deficiency

    Haematologica

    (2007)
  • M. Guilarte et al.

    Acquired angioedema associated with hereditary angioedema due to C1-inhibitor deficiency

    Journal of Investigational Allergology and Clinical Immunology

    (2008)
  • J. Jackson et al.

    Autoantibody facilitated cleavage of C1-inhibitor in autoimmune angioedema

    Journal of Clinical Investigation

    (1989)
  • B.L. Zuraw et al.

    Demonstration of modified inactive first component of complement C1-inhibitor in the plasmas of C1-inhibitor-deficient patients

    Journal of Clinical Investigation

    (1986)
  • R.S. Geha et al.

    Acquired C1-inhibitor deficiency associated with antiidiotypic antibody to monoclonal immunoglobulins

    New England Journal of Medicine

    (1985)
  • Cited by (55)

    • Genetic Variants Leading to Urticaria and Angioedema and Associated Biomarkers

      2023, Journal of Allergy and Clinical Immunology: In Practice
    • Laryngeal angioedema caused by a rare disease—A case report

      2022, Current Problems in Cancer: Case Reports
    • Lanadelumab Efficacy, Safety, and Injection Interval Extension in HAE: A Real-Life Study

      2021, Journal of Allergy and Clinical Immunology: In Practice
    View all citing articles on Scopus

    Massimo Cugno MD, is an associate professor of Internal Medicine at the University of Milan. He is the chief of the Center for the study of complement at the Maggiore Hospital in Milan. He graduated “cum laude” from the University of Milan in 1982. He completed his post-graduated speciality in Hematology and Internal Medicine at the University of Milan. He is involved in research on prognostic, therapeutic and biological aspects of hematological disorders. The scientific work was conducted mainly in the field of proteasic systems, coagulation, fibrinolysis and complement. He has published around 150 original papers (130 in journals included in PubMed, some of excellence as New Engl J Med, Lancet, J Clin Invest, Am J Hum Genet, Circulation, and Blood).

    View full text