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Please cite this article in press as: Castelli R, et al.
, et al. Acquired C1-inhibitor deciency and lymphoproliferative disorders: A tight relationship.

Crit Rev Oncol/Hematol (2013), http://dx.doi.org/10.1016/j.critrevonc.2013.02.004
ARTICLE IN PRESS
ONCH-1713; No. of Pages 10
Critical Reviews in Oncology/Hematology xxx (2013) xxxxxx
Acquired C1-inhibitor deciency and lymphoproliferative disorders:
A tight relationship
Roberto Castelli
a,b
, Andrea Zanichelli
c
, Marco Cicardi
c
, Massimo Cugno
a,b,
a
Department of Pathophysiology and Transplantation, Internal Medicine Section, University of Milan, Milan, Italy
b
Department of Medicine, Fondazione IRCCS Ca Granda, Ospedale Maggiore Policlinico, Milan, Italy
c
Dipartimento di Scienze Cliniche Luigi Sacco, Universit degli Studi di Milano, Milano, Italy
Accepted 14 February 2013
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2. Historical background and pathophysiology of acquired c1-inhibitor deciency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3. Clinical characteristics of acquired C1-inhibitor deciency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.1. Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.2. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.3. Course . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.4. Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4. Link between acquired angioedema and lymphoproliferative disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Conicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Reviewer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Abstract
Angioedema due to the acquired deciency of C1-inhibitor is a rare disease known as acquired angioedema (AAE), which was rst 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 signicance (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 rst symptom. Experi-
mental 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.
2013 Elsevier Ireland Ltd. All rights reserved.
Keywords: C1-inhibitor deciency; Acquired angioedema; Lymphoproliferative disease; Auto-antibodies; Complement
Corresponding author at: Department of Pathophysiology and Transplantation, Section of Internal Medicine, Via Pace 9, 20122 Milan, Italy.
Tel.: +39 02 55035340; fax: +39 02 50320742.
E-mail address: massimo.cugno@unimi.it (M. Cugno).
1040-8428/$ see front matter 2013 Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.critrevonc.2013.02.004
Please cite this article in press as: Castelli R, et al. Acquired C1-inhibitor deciency and lymphoproliferative disorders: A tight relationship.
ARTICLE IN PRESS
2 R. Castelli et al. / Critical Reviews in Oncology/Hematology xxx (2013) xxxxxx
1. Introduction
The clinical characteristics of acquired C1-inhibitor de-
ciency or acquired angioedema (AAE) are similar to those
of hereditary C1-inhibitor deciency 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 deciency associated with nonhematologic neo-
plasm, infections or autoimmune diseases, whereas 14% of
patients with acquired C1-inhibitor deciency have no other
disease [2]. The symptoms include recurrent, self-limiting
local swelling located in the subcutaneous tissues (which
may be disguring), the upper airways (which may cause
possibly fatal laryngeal edema), and the gastrointestinal tract
(whichinduces bowel obstruction and severe abdominal pain)
[24].
A deciency 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 perme-
ability [510]. The release of bradykinin is facilitated by the
plasmin [11] generated during edema attacks in patients with
C1-inhibitor deciency [10,12]. The mechanisms responsible
for the consumption of C1-inhibitor and the massive activa-
tionof the classic complement pathway have been extensively
investigated [1,1315], 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 dis-
order 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 signicance (MGUS) and non-Hodgkin lymphoma
(NHL) [16,17]. The relationship between pathological B cell
clones and C1-inhibitor deciency is easily identied 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 preva-
lence 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 [1820]; and (3)
some experimental evidence suggesting that lymphatic tis-
sues from AAE patients absorb or consume C1-inhibitor
[1,1315].
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 lym-
phoproliferative disease.
2. Historical background and pathophysiology of
acquired c1-inhibitor deciency
An acquired C1-inhibitor deciency resulting in
angioedema symptoms was rst 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 deciency. These and other ndings indicated
that the pathogenetic mechanism underlying acquired
C1-inhibitor deciency may be related to autoimmunity
[21,22].
Initial experiments indicated that C1-inhibitor and/or
the classic complement pathway were consumed by neo-
plastic lymphatic tissues. Schreiber et al. [14] described a
patient with lymphoproliferative angioedema and acquired
C1-inhibitor deciency whose complement prole revealed
depletion of the rst component of complement. It was
found that the patients peripheral blood mononuclear cells
and a suspension of cells taken from pulmonary inltrate
were both capable of depleting the rst component of
complement and its inhibitor from homologous plasma. In
1979, Hauptmann et al. studied a patient with an extensive
lymphosarcoma of the spleen (without the involvement of
other lymphoid organs) and hypogammaglobulinemia pre-
senting the characteristic complement prole of acquired
C1-inhibitor deciency [15]. Functional and immunochemi-
cal studies revealed extremely low C1-inhibitor levels, which
normalized after splenectomy together with the complement
components. In vitro tests showed that lymphosarcoma tissue
pieces or cells were capable of interacting with complement
and reduced hemolytic activity. These ndings showed that
tumor cells were responsible for the abnormalities of the
complement system.
Geha et al. [23] found that some patients with acquired
C1-inhibitor deciency and paraproteins had immunoglobu-
lins against the idiotypic determinants of the M components,
and these idiotype/anti-idiotype immune complexes might
x C1q and consume C1-inhibitor. However, these ndings
were not subsequently conrmed. As auto-antibodies against
C1-inhibitor were rst found in an otherwise healthy patient,
acquired C1-inhibitor deciency was divided into two sepa-
rate forms (paraneoplastic type I, which is mainly associated
with lymphoproliferative disease, and auto-immune type
II caused by C1-inhibitor auto-antibodies), evidence that
autoimmunity and lymphoproliferation can co-exist in the
same patients lead to abandon this distinction [24].
A number of studies have investigated the mechanism by
which auto-antibodies consume C1-inhibitor. Experiments
with linearized peptides suggest that these antibodies bind
epitopes around the reactive center of C1-inhibitor [25]. This
ARTICLE IN PRESS
R. Castelli et al. / Critical Reviews in Oncology/Hematology xxx (2013) xxxxxx 3
binding could either create a steric impairement to the for-
mation of C1-inhibitor-protease complexes and/or convert
C1-inhibitor into a substrate for proteases accounting for
large amounts of a cleaved inactive form of C1-inhibitor that
is detected in the serum of most patients with acquired C1-
inhibitor deciency [21,22]. Zuraw and Curd demonstrated
in vitro that the cleavage mainly depends on the activation of
the contact system and not on the complement system [22].
However, a preeminent role of plasmin in C1 inhibitor cleav-
age has also been claimed based on the molecular weight
of the cleaved form after incubation of plasma with plasmin
[21].
The low levels of C1-inhibitor due to its consumption
by pathological lymphatic tissue or its auto-antibody-
mediated inactivation are associated with hyper-activation
of the complement or contact system, which may further
consume C1-inhibitor [26]. The contact and brinolytic
systems are slightly activated during remission but greatly
hyper-activated during acute attacks [10]. The incidental
over-activation of the contact system may initiate a cascade
leading to the generation of bradykinin, which mediates the
increase in vasopermeability that leads to angioedema. The
activation of the contact system begins with the activation
of factor XII, which activates pre-kallikrein to kallikrein.
Kallikrein further activates factor XII and acts on high-
molecular-weight kininogen releasing bradykinin, the main
mediator of increased vascular permeability [27]. Moreover,
C1-inhibitor not only inhibits complement, the contact sys-
tem and brinolysis, but also coagulation [2831], which
seems to be activated in patients with C1-inhibitor deciency
[7,32,33]. Experimental evidence showing that thrombin
increases vascular permeability [3436] and can be inhibited
by C1-inhibitor [32], particularly at endothelial surface [33],
further supports the role of C1-inhibitor deciency in edema
formation.
3. Clinical characteristics of acquired C1-inhibitor
deciency
3.1. Presentation
The typical symptom of both hereditary and acquired C1-
inhibitor deciency is angioedema, a recurrent, self-limiting,
non-pitting, non-pruritic edema that completely resolves in
15 days [2,3739]. 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 extremi-
ties. Urticaria is usually absent, although transient and mild
urticarial eruptions (erythema marginatum) may herald the
overt swelling. Cutaneous angioedema creates discomfort
to patients, and can impair social life if it deforms the
face (Fig. 1), or affects the function of hands and feet [2].
Abdominal attacks due to edema of the bowel wall are char-
acterized by vomiting, colicky abdominal pain and, more
Fig. 1. Angioedema of the left foot in a patient with acquired C1-inhibitor
deciency and lymphoproliferative disease. This patient had high levels
of D-dimer as previously described in patients with such conditions [32].
However, the presence of foot edema, lymphoproliferative disease and high
levels of D-dimer induced the physicians to rule out the diagnosis of deep
vein thrombosis and pulmonary embolism by performing leg compression
ultrasonography and spiral computed tomography of the chest.
rarely, diarrhea [40]. These symptoms usually revert spon-
taneously within two days if not treated. Dysphagia, voice
changes and respiratory stridor are signs of the involvement
of the upper airways and may precede asphyxia due to laryn-
geal edema. This condition is life-threatening and requires
immediate emergency therapy [2].
3.2. Diagnosis
Clinical suspicion should be conrmed by laboratory anal-
yses [41]. Table 1 shows the clinical and laboratory criteria
for a diagnosis of C1-inhibitor deciency.
The typical biochemical picture of acquired C1-inhibitor
deciency is low plasma levels of C1-inhibitor function, C1-
inhibitor antigen, C4 and C1q, with normal levels of C3. A
minority of patients have normal C1q levels. Antigen con-
centrations of complement components (C1-inhibitor C4, C3
and C1q) are usually measured by means of radial immun-
odiffusion or nephelometry. C1-inhibitor functional activity
is measured by quantifying the capacity of plasma to inhibit
the esterase activity of a xed amount of C1s on a specic
chromogenic substrate or by an immunoenzymatic assay [2].
ARTICLE IN PRESS
Table 1
Clinical and laboratory markers for the diagnosis of acquired C1-inhibitor
deciencies.
Clinical markers
-Self-limiting, non-inammatory subcutaneous angioedema without
hives, recurrent and lasting for more than 12 hours
-Self-remitting recurrent adominal pain without organic etiopathology
lasting for more than six hours
-Recurrent laryngeal edema
Laboratory markers
-C1-inhibitor antigen levels <50%of normal at two separate
measurements
-C1-inhibitor functional levels <50%of normal at two separate
measurements
-C1q levels <50%of normal at two separate measurements
*
-Auto-antibodies against C1-inhibitor can be detected as
immunoglobulins preventing C1-inhibitor function or binding
C1-inhibitor.
*
In some cases C1q levels can be normal.
Any patient with acquired C1-inhibitor deciency should be
tested for C1-inhibitor auto-antibodies [38], which may be
present in patients with AAE and induce C1-inhibitor hyper-
catabolism [17,4244]. C1-inhibitor auto-antibodies can be
detected as immunoglobulins that prevent C1-inhibitor func-
tion or bind C1-inhibitor. In the rst assay, immunoglobulins
isolated from serum block C1-inhibitor activity measured as
the inhibition of the conversion of synthetic substrates that
are specic for its target proteases [45]. In 1987, Alsenz et al.
[46] developed a solid-phase enzyme-linked immunosorbent
assay (ELISA) for detecting immunoglobulins binding to C1-
inhibitor coated on micro-titer plates, a simple and highly
sensitive method that is still used with slight modications
[42,43].
3.3. Course
The course and prognosis of angioedema due to acquired
C1-inhibitor deciency depends on the underlying disease
and the availability of appropriate therapy for life-threatening
angioedema. Although angioedema attacks usually resolve
without treatment, patients are exposed to the risk of laryngeal
edema [38]. The frequency of attacks varies widely between
subjects (from rare attacks to several events per year or even
per month), and may also vary in the same subject at different
disease stages [2]. It has been reported that one patient experi-
enced severe angioedema symptoms for ve years that ended
abruptly for no apparent reason [16]. Successful treatment of
the underlying disease can resolve the angioedema symptoms
and biochemical abnormalities, but treatment responses vary
widely [18,38].
3.4. Therapy
The therapy of AAE follows two lines: (1) the pre-
vention/reversal of the symptoms of angioedema; and (2)
treatment of the associated disease [4750].
Whatever the mechanism of C1-inhibitor consumption
(cleavage by auto-antibodies or absorption by neoplastic
lymphatic tissue), the reduced C1-inhibitor levels in patients
with AAE induce the hyperactivation of the complement
and contact systems, and this leads to further C1-inhibitor
consumption [26]. The hyper-consumption of C1-inhibitor
[44] explains why AAE patients are usually resistant to
the treatment normally used in cases of HAE [2]. For the
long-term prevention of angioedema recurrences, patients
are currently treated with attenuated androgens (which
increase C1-inhibitor synthesis and aminopeptidase P
function, an enzyme involved in bradykinin catabolism) and
antibrinolytic agents, which inhibit the enzyme plasmin
that facilitates bradykinin production [10,43,50,51]. Patients
with acquired C1-inhibitor deciency respond better to
antibrinolytic agents (which seem to be well tolerated) than
to attenuated androgens [38,49]. Although antibrinolytic
agents are potentially prothrombotic, no increased throm-
botic risk has ever been documented. Short- and long-term
prophylaxis with C1-inhibitor concentrates has also been
successfully used in AEE patients, albeit at generally higher
doses than those used to treat HAE [38,52].
Acute attacks are treated by the infusion of plasma-derived
C1-inhibitor despite the variable degree of resistance and
the need for high doses [2,37]. By overcoming the prob-
lem of accelerated C1-inhibitor catabolism, the bradykinin
B2 receptor antagonist icatibant is a promising alternative to
plasma-derived C1-inhibitor for patients with acquired C1-
inhibitor deciencies. It is already an established treatment
for acute HAE attacks, and we have successfully used this
treatment in eight patients with AAE resistant to C1-inhibitor
plasma concentrates [53].
Table 2 summarizes the pharmacological approaches to
the prevention/treatment of AAE symptoms.
Treatment of the associated disease by means of
chemotherapy or other cytoreduction (radiotherapy, surgery,
and antibodies to specic cell populations) or immuno-
suppressive treatment may not only control the underlying
disease, but also relieve the clinical symptoms of
angioedema and variably reverse the biochemical abnor-
malities [1820,54,55]. The therapeutic approaches to
lymphoproliferative diseases are the same in patients with
or without C1-inhibitor deciency. However, C1-inhibitor
deciency with frequent angioedema attacks that do not
responding to conventional AAE treatment should be con-
sidered a sign of active lymphoproliferative disease possibly
requiring cytoreductive therapy. In a previous study, we
observed the reversal of complement abnormalities and
the remission of angioedema symptoms in two NHL
patients treated with chemotherapy, and one patient with
marginal splenic lymphoma undergoing splenectomy [8],
and other groups have also reported a reduction in, or the
disappearance of angioedema symptoms after chemother-
apy, with an improvement in complement parameters in
patients with AAE associated with lymphoproliferative dis-
ease [15,19,20,54,55] (Table 3).
ARTICLE IN PRESS
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Rituximab, a chimeric mouse/human monoclonal anti-
CD20 antibody, targets B cells and has been used successfully
in autoimmune disorders such as rheumatoid arthritis, sys-
temic lupus erythematosus [5658], and pemphigus [59,60].
It has also been investigated in cases of aggressive and indo-
lent NHL as a single agent or in combination with standard
chemotherapy regimens [6165]. Given the rarity of the dis-
ease, no controlled clinical trials have systematically assessed
the efcacy and safety of rituximab in AAE patients but an
analysis of the published data shows that 14 patients have
so far been treated with rituximab, which led to a clinical
improvement in 12, and the reversal of complement abnor-
malities in 10 [6671] (Table 4).
Despite that absence of controlled clinical trials of rit-
uximab in patients with acquired C1-inhibitor deciency,
we believe it to be reasonable to use rituximab in the
case of selected patients experiencing multiple episodes
of angioedema who fail to respond to conventional treat-
ments, and (in combination with chemotherapy) in patients
with high-grade lymphoproliferative disease or active lym-
phomas. In addition it seems reasonable to use rituximab in
patients with severe and otherwise uncontrolled angioedema
symptoms associated with lymphoproliferative disease not
requiring per se conventional chemotherapy treatments, such
as patients with MGUS or indolent lymphomas with no signs
of active disease.
4. 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 deciency are at
higher risk of developing NHL than the general popula-
tion [1618]. 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 lymphoproliferative disease
associated with acquired C1-inhibitor deciency is indolent
lymphoma. According to the WHO classication, the most
frequent histotypes in patients with acquired C1-inhibitor
deciency are nodal and splenic marginal zone lymphomas,
and lymphoplasmocytic lymphomas/Waldestrms disease.
The association with these histotypes is similar to that of other
autoimmune diseases such as cryoglobulinemia, or rheuma-
toid arthritis [72,73], these observations suggest that the
risk of developing lymphoproliferative diseases in patients
with acquired C1-inhibitor deciency is not generic but con-
ned to specic histotypes. As these NHL subtypes develop
during the post-antigen exposure stages of lymphocyte dif-
ferentiation, it can be argued that the immunocomplexes of
C1-inhibitor and C1-inhibitor auto-antibodies may play a role
as antigenic drivers in the genesis of autoimmunity-related
lymphomas [18,26].
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Table 3
Clinical and complement parameters in acquired angioedema (AAE) patients with lymphoproliferative disease treated with chemotherapy or immunochemotherapy.
Author Patients Associated
hemopathy
Chemotherapy Pre-chemotherapy
C1-INH
Ag/function/anti-C1-INH
Post-chemotherapy
C1-INH
Ag/function/anti-C1-INH
Clinical
improvement
Duration of
follow-up
Jung M[19] 1 Chronic lymphocytic
leukemia
Chlorambucil +danazol NA/83%(during
danazol)/NA
NA/100%/NA Yes NA
2 Chronic lymphocytic
leukemia
Fludarabine,
CyC+rituximab
6.7 mg/dL/1%/NA NA/120%/NA Yes NA
3 Lymphocytic
lymphoma
Cyc +danatrol NA/4%/NA NA/NA/NA Yes NA
Guilarte M[20] 1 Follicular lymphoma Chlorambucil
(0.2 mg/kg/d) and PDN
10 mg/dL/45%/NA 12 mg/dL/55%/NA Yes 8 months
Castelli R [18] 1 Waldestrom
lymphoplasmocytic
lymphoma
R-CHOP 31%/<5%/IgM500 U/mL 115%/116%/IgM
60 U/mL
Yes 3 year
2 Follicular lymphoma CEOP/udarabine/Cyc <1%/<1%/0 109%/90%/0 Yes 4 year
3 Splenic marginal zone
lymphoma
Splenectomy NA NA Yes 2 years
Healy C [54] 1 Follicular lymphoma CVP 2.54 mg/dL/NA/NA 3 mg/dL/NA/NA Yes 40 months
Rossi D [55] 1 Anaplastic CD30+
large B cell
lymphoma
Yes Reduced/NA/NA Normalized/NA/NA Yes NA
CYC: cyclophosphamide; R-CHOP: rituximab-cyclophosphamide-vincristine and prednisone; NA: not available; CVP: cyclophosphamide-vincristine and prednisone; CEOP: Cyclophosphamide-Etoposide-
Prednisolone-Vincristine.
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7
Table 4
Clinical and complement parameters in acquired angioedema (AAE) patients treated with rituximab.
Author Patients Associated hemopathy or
concomitant disease
Frequency of
attacks
Pre-rituximab C1-inhibitor
Ag/function/anti-C1-inhibitor
Post-rituximab
C1-inhibitor
Ag/function/anti C1
inhibitor
Clinical
efcacy
Duration
of
follow-up
Lam DH [67] 1 Marginal zone lymphoma;
coronary artery disease
NR 2 mg/dL/20%/NA Normalization C1-INH
Ag
Yes 8 months
Branellec A [66]
1 N0 Twice monthly 139 mg/L/5 U/mL/IgM2320 U 227 mg/L/16.1 U/mL/IgM
760 U
Yes 6 months
2 Marginal zone lymphoma Every 810 days 96 mg/L/5.4 U/mL/IgM271 U 202 mg/L/13.3 U/mL/IgM
378 U
Yes NR
3 MGUS IgA Monthly 170 mg/L/2.7 U/mL/IgA 339 U 103 mg/L/NA/NA Yes 6 months
4 MGUS IgG 2 attacks/year 144 mg/L/4.9 U/mL/IgG
1000 U
155 mg/L/4.1 U/mL/IgG
1170 U
Yes 5 years
5 No Repeated 80 mg/L/NA/IgM317 U 89 mg/L/3.7 U/mL/IgM
696 U
Yes 6 months
6 MGUS IgG Monthly 16 mg/L/<2/IgMpositive 92 mg/L/<2/IgMpositive No 3 years
7 Marginal zone lymphoma NR 81 mg/L/ND/undetectable NA/NA/undetectable No 17 months
Snchez-Cano D [70] 1 Sjgrens syndrome 3/month 016 U/mL/32%/IgM578 U NA NA IgM346 U Yes 11 months
Levi M[68]
1 None 3/month <0.5 U/mL/<0.25 U/mL/IgG
positive
Near
normal/>0.5 U/mL/NA
Yes 12 months
2 Follicular B cell lymphoma 3/month <0.5 U/mL/<0.25 U/mL/NA Near
normal/>0.5 U/mL/NA
Yes 12 months
3 None 3/month <0.5 U/mL/<0.25 U/mL/NA Near
normal/>0.5 U/mL/NA
Yes 12 months
Ziakas PD [69] 1 Monoclonal IgM
nephrosclerosis
56/year Low/40%/Positive NA/NA/NA Yes NR
Hassan A [71]
1 MGUS IgMk 68/month C4 (0.06 g/L, normal:
0.100.40 g/L)
C1-INH functional levels
improved to 3.1 U/mL
Yes 24 months
C1-INH antigen: 0.08 g/L
(n.v.: 0.210.34 g/L); C1-INH
functional levels: 2.0 U/mL
(n.v.: 17.227.4 U/mL)
MGUS: monoclonal gammopathy of uncertain signicance; Ag: antigen; NR: not reported; NA: not available.
ARTICLE IN PRESS
The prevalence of MGUS in patients with acquired C1-
inhibitor deciency is 35%, which is much higher than its
approximately 3% prevalence in the general population aged
less than 70 years [74]. A study by our group has shown that
patients with MGUS and C1-inhibitor auto-antibodies fre-
quently have the same heavy and light chain histotypes [18].
MGUS progresses to multiple myeloma as frequently in AAE
patients as in the general population [18]. Evidence that the M
components detected in these patients frequently correspond
to the C1-inhibitor auto-antibodies, and that patients with
auto-antibodies may develop lymphoproliferative diseases
suggests that a single B cell clonal disorder with different
potential clinical evolutions underlies AAE. Furthermore, as
lymphoproliferative diseases may appear in AAE patients,
patients with conrmed C1-inhibitor deciency should be
closely monitored for their development. For all patients
with angioedema due to acquired C1-inhibitor deciency, we
suggest to perform annually a rst level screening for lym-
phoproliferative diseases based on complete blood cell count
withdifferential leukocyte count, serum protein electrophore-
sis, chest X ray and abdominal ultrasound, along with a
complete physical examination. Additional tests should be
guided by clinical suspicion or abnormal laboratory nd-
ings.
5. Conclusions
Although the etiology of acquired C1-inhibitor deciency
is still partially unclear, the majority of patients present
an underlying B cell disorder, which ranges from the sim-
ple production of C1-inhibitor auto-antibodies to MGUS
and NHL. The most frequent histotypes are nodal and
splenic marginal zone lymphomas and lymphoplasmocytic
lymphomas/Waldestrm disease. The association with such
histotypes is similar to that of other autoimmune diseases
and, as they develop during the post-antigen exposure stages
of lymphocyte differentiation, the immunocomplexes formed
by auto-antibodies and C1-inhibitor may play a role in
the genesis of autoimmunity-related lymphomas. Lympho-
proliferative disease may be present at the onset of AAE
symptoms or may develop thereafter, thus AAE represents
an example of the strict link between autoimmunity and
lymphoproliferation. Blocking autoreactive or neoplastic B
cell proliferation is a pivotal step in the treatment of the
disease. It has been shown that curing the associated dis-
ease by means of chemotherapy and/or immunosuppression
can resolve angioedema symptoms and normalize the bio-
chemical defects. However, AAE symptoms and pathological
complement parameters may reappear at the time of a recur-
rence of the malignancy. In any case, patients with AAE
should be closely monitored because of its potential evolution
into lymphoproliferative disease. It is still debated whether
the exacerbation of angioedema symptoms in patients with
indolent lymphoma is a sign of active disease requiring
cytoreductive treatment.
Conicts of interest
The authors have no conicting interests to disclose.
Reviewer
Teresa Caballero, MD, PhD, Senior consultant, Hospi-
tal Universitario La Paz, Allergy Department, Paseo de la
Castellana 261, ES-28046 Madrid, Spain.
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Biography
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, therapeu-
tic and biological aspects of hematological disorders. The
scientic work was conducted mainly in the eld of protea-
sic systems, coagulation, brinolysis 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).

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