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ARTICLE IN PRESSNCH-1713; No. of Pages 10

Critical Reviews in Oncology/Hematology xxx (2013) xxx–xxx

Acquired C1-inhibitor deficiency 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, Italyc Dipartimento di Scienze Cliniche Luigi Sacco, Università degli Studi di Milano, Milano, Italy

Accepted 14 February 2013

ontents

. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

. Historical background and pathophysiology of acquired c1-inhibitor deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

. Clinical characteristics of acquired C1-inhibitor deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003.1. Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003.2. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003.3. Course . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003.4. Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

. Link between acquired angioedema and lymphoproliferative disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00Reviewer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

bstract

Angioedema due to the acquired deficiency of C1-inhibitor is a rare disease known as acquired angioedema (AAE), which was first describedn a patient with high-grade lymphoma and is frequently associated with lymphoproliferative diseases, including expansion of B cell clonesroducing anti-C1-INH autoantibodies, monoclonal gammopathy of uncertain significance (MGUS) and non-Hodgkin lymphoma (NHL).AE is clinically similar to hereditary angioedema (HAE), and is characterized by recurrent episodes of sub-cutaneous and sub-mucosal

dema. It may affect the face, tongue, extremities, trunk and genitals. The involvement of the gastrointestinal tract causes bowel sub-occlusionith severe pain, vomiting and diarrhea, whereas laryngeal edema can be life-threatening. Unlike those with HAE, AAE patients usually have

ate-onset symptoms, do not have a family history of angioedema and present variable response to treatment due to the hyper-catabolism of1-inhibitor. Reduced C1-inhibitor function leads to activation of the classic complement pathway with its consumption and activation of theontact 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. Experi-ental data indicate that neoplastic tissue and/or anti-C1-inhibitor antibodies induce C1-inhibitor consumption, and this is further supported by

he observation that cytotoxic treatment of the lymphoproliferative diseases associated with AAE variably reverses the complement impairment

nd leads to a clinical improvement in angioedema symptoms.

Please cite this article in press as: Castelli R, et al. Acquired C1-inhibitor dCrit Rev Oncol/Hematol (2013), http://dx.doi.org/10.1016/j.critrevonc.2

2013 Elsevier Ireland Ltd. All rights reserved.

eywords: C1-inhibitor deficiency; Acquired angioedema; Lymphoproliferative di

∗ Corresponding author at: Department of Pathophysiology and Transplantation,

el.: +39 02 55035340; fax: +39 02 50320742.E-mail address: massimo.cugno@unimi.it (M. Cugno).

040-8428/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved.ttp://dx.doi.org/10.1016/j.critrevonc.2013.02.004

eficiency and lymphoproliferative disorders: A tight relationship.013.02.004

sease; Auto-antibodies; Complement

Section of Internal Medicine, Via Pace 9, 20122 Milan, Italy.

ARTICLE IN PRESSONCH-1713; No. of Pages 10

2 Oncol

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. Introduction

The clinical characteristics of acquired C1-inhibitor defi-iency or acquired angioedema (AAE) are similar to thosef hereditary C1-inhibitor deficiency known as hereditaryngioedema (HAE), except for the later onset of symptoms,he absence of a family history, and the potential associationith lymphoproliferative diseases and/or anti-C1-inhibitor

uto-antibodies [1,2]. Scattered reports describe acquired1-inhibitor deficiency associated with nonhematologic neo-lasm, infections or autoimmune diseases, whereas 14% ofatients with acquired C1-inhibitor deficiency have no otherisease [2]. The symptoms include recurrent, self-limitingocal swelling located in the subcutaneous tissues (which

ay be disfiguring), the upper airways (which may causeossibly fatal laryngeal edema), and the gastrointestinal tractwhich induces bowel obstruction and severe abdominal pain)2–4].

A deficiency in C1-inhibitor leads to the activation of thelassic complement pathway and consumption of C1, C2 and4 components; furthermore, the contact system becomesnstable and prone to generate kallikrein, which cleavesigh-molecular-weight kininogen (HK) and thus releasesradykinin, the mediator of the increased vascular perme-bility [5–10]. The release of bradykinin is facilitated by thelasmin [11] generated during edema attacks in patients with1-inhibitor deficiency [10,12]. The mechanisms responsible

or the consumption of C1-inhibitor and the massive activa-ion of the classic complement pathway have been extensivelynvestigated [1,13–15], and the initial experiments indicatedhat C1-inhibitor and/or the classic complement pathway areonsumed by neoplastic lymphatic tissues; moreover, C1-nhibitor can be cleaved/inactivated by its auto-antibody.

The majority of patients carry an underlying B cell dis-rder which is thought to cause C1-inhibitor consumption.hese disorders range from the production of anti-C1-

nhibitor auto-antibodies to monoclonal gammopathy ofncertain significance (MGUS) and non-Hodgkin lymphomaNHL) [16,17]. The relationship between pathological B celllones and C1-inhibitor deficiency is easily identified whenhe clone produces auto-antibodies that cleave/inactivate C1-nhibitor, but it is not immediately obvious in the case of

GUS or NHL. Under these conditions, the presence of cause-effect relationship between the pathological clonend C1-inhibitor consumption is supported by: (1) the preva-ence of MGUS and NHL extraordinarily higher in AAEatients compared to the general population [16,18]; (2)solated reports showing various degrees of reversal of theiochemical and/or clinical abnormalities of AAE upon theherapeutically induced remission of NHL [18–20]; and (3)ome experimental evidence suggesting that lymphatic tis-ues from AAE patients absorb or consume C1-inhibitor1,13–15].

Please cite this article in press as: Castelli R, et al. Acquired C1-inhibitor dCrit Rev Oncol/Hematol (2013), http://dx.doi.org/10.1016/j.critrevonc.2

We here review the pathophysiological mechanisms ofAE by concentrating on the relationship between it and

he associated B cell disorders, and underline the potential

wwe

ogy/Hematology xxx (2013) xxx–xxx

eversal of complement abnormalities after treating the lym-hoproliferative disease.

. Historical background and pathophysiology ofcquired c1-inhibitor deficiency

An acquired C1-inhibitor deficiency resulting inngioedema symptoms was first described in 1972 byaldwell et al. [1], who observed it in a patient with a

ymphoproliferative disorder. In 1986, Jackson et al. [13]iscovered an autoreactive immunoglobulin G against1-inhibitor in a patient with angioedema and acquired1-inhibitor deficiency. These and other findings indicated

hat the pathogenetic mechanism underlying acquired1-inhibitor deficiency may be related to autoimmunity

21,22].Initial experiments indicated that C1-inhibitor and/or

he classic complement pathway were consumed by neo-lastic lymphatic tissues. Schreiber et al. [14] described aatient with lymphoproliferative angioedema and acquired1-inhibitor deficiency whose complement profile revealedepletion of the first component of complement. It wasound that the patient’s peripheral blood mononuclear cellsnd a suspension of cells taken from pulmonary infiltrateere both capable of depleting the first component of

omplement and its inhibitor from homologous plasma. In979, Hauptmann et al. studied a patient with an extensiveymphosarcoma of the spleen (without the involvement ofther lymphoid organs) and hypogammaglobulinemia pre-enting the characteristic complement profile of acquired1-inhibitor deficiency [15]. Functional and immunochemi-al studies revealed extremely low C1-inhibitor levels, whichormalized after splenectomy together with the complementomponents. In vitro tests showed that lymphosarcoma tissueieces or cells were capable of interacting with complementnd reduced hemolytic activity. These findings showed thatumor cells were responsible for the abnormalities of theomplement system.

Geha et al. [23] found that some patients with acquired1-inhibitor deficiency and paraproteins had immunoglobu-

ins against the idiotypic determinants of the M components,nd these idiotype/anti-idiotype immune complexes mightx C1q and consume C1-inhibitor. However, these findingsere not subsequently confirmed. As auto-antibodies against1-inhibitor were first found in an otherwise healthy patient,cquired C1-inhibitor deficiency was divided into two sepa-ate forms (paraneoplastic type I, which is mainly associatedith lymphoproliferative disease, and auto-immune type

I caused by C1-inhibitor auto-antibodies), evidence thatutoimmunity and lymphoproliferation can co-exist in theame patients lead to abandon this distinction [24].

eficiency and lymphoproliferative disorders: A tight relationship.013.02.004

A number of studies have investigated the mechanism byhich auto-antibodies consume C1-inhibitor. Experimentsith linearized peptides suggest that these antibodies bind

pitopes around the reactive center of C1-inhibitor [25]. This

ARTICLE IN PRESSONCH-1713; No. of Pages 10

Oncology/Hematology xxx (2013) xxx–xxx 3

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Fig. 1. Angioedema of the left foot in a patient with acquired C1-inhibitordeficiency and lymphoproliferative disease. This patient had high levelsof D-dimer as previously described in patients with such conditions [32].However, the presence of foot edema, lymphoproliferative disease and highlevels of D-dimer induced the physicians to rule out the diagnosis of deepvein thrombosis and pulmonary embolism by performing leg compressionu

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R. Castelli et al. / Critical Reviews in

inding could either create a steric impairement to the for-ation of C1-inhibitor-protease complexes and/or convert1-inhibitor into a substrate for proteases accounting for

arge amounts of a cleaved inactive form of C1-inhibitor thats detected in the serum of most patients with acquired C1-nhibitor deficiency [21,22]. Zuraw and Curd demonstratedn vitro that the cleavage mainly depends on the activation ofhe contact system and not on the complement system [22].owever, a preeminent role of plasmin in C1 inhibitor cleav-

ge has also been claimed based on the molecular weightf the cleaved form after incubation of plasma with plasmin21].

The low levels of C1-inhibitor due to its consumptiony pathological lymphatic tissue or its auto-antibody-ediated inactivation are associated with hyper-activation

f the complement or contact system, which may furtheronsume C1-inhibitor [26]. The contact and fibrinolyticystems are slightly activated during remission but greatlyyper-activated during acute attacks [10]. The incidentalver-activation of the contact system may initiate a cascadeeading to the generation of bradykinin, which mediates thencrease in vasopermeability that leads to angioedema. Thectivation of the contact system begins with the activationf factor XII, which activates pre-kallikrein to kallikrein.allikrein further activates factor XII and acts on high-olecular-weight kininogen releasing bradykinin, the mainediator of increased vascular permeability [27]. Moreover,1-inhibitor not only inhibits complement, the contact sys-

em and fibrinolysis, but also coagulation [28–31], whicheems to be activated in patients with C1-inhibitor deficiency7,32,33]. Experimental evidence showing that thrombinncreases vascular permeability [34–36] and can be inhibitedy C1-inhibitor [32], particularly at endothelial surface [33],urther supports the role of C1-inhibitor deficiency in edemaormation.

. Clinical characteristics of acquired C1-inhibitoreficiency

.1. Presentation

The typical symptom of both hereditary and acquired C1-nhibitor deficiency is angioedema, a recurrent, self-limiting,on-pitting, non-pruritic edema that completely resolves in–5 days [2,37–39]. Angioedema affects the subcutaneousissue, the gastrointestinal mucosa, and the mucosa of upperespiratory tract. Angioedema of the skin causes deformitieshat may involve the face, genitals, buttocks, and extremi-ies. Urticaria is usually absent, although transient and mildrticarial eruptions (erythema marginatum) may herald thevert swelling. Cutaneous angioedema creates discomfort

Please cite this article in press as: Castelli R, et al. Acquired C1-inhibitor dCrit Rev Oncol/Hematol (2013), http://dx.doi.org/10.1016/j.critrevonc.2

o patients, and can impair social life if it deforms theace (Fig. 1), or affects the function of hands and feet [2].bdominal attacks due to edema of the bowel wall are char-

cterized by vomiting, colicky abdominal pain and, more

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ltrasonography and spiral computed tomography of the chest.

arely, diarrhea [40]. These symptoms usually revert spon-aneously within two days if not treated. Dysphagia, voicehanges and respiratory stridor are signs of the involvementf the upper airways and may precede asphyxia due to laryn-eal edema. This condition is life-threatening and requiresmmediate emergency therapy [2].

.2. Diagnosis

Clinical suspicion should be confirmed by laboratory anal-ses [41]. Table 1 shows the clinical and laboratory criteriaor a diagnosis of C1-inhibitor deficiency.

The typical biochemical picture of acquired C1-inhibitoreficiency is low plasma levels of C1-inhibitor function, C1-nhibitor antigen, C4 and C1q, with normal levels of C3. A

inority of patients have normal C1q levels. Antigen con-entrations of complement components (C1-inhibitor C4, C3nd C1q) are usually measured by means of radial immun-diffusion or nephelometry. C1-inhibitor functional activity

eficiency and lymphoproliferative disorders: A tight relationship.013.02.004

s measured by quantifying the capacity of plasma to inhibithe esterase activity of a fixed amount of C1s on a specifichromogenic substrate or by an immunoenzymatic assay [2].

ARTICLE IN PRESSONCH-1713; No. of Pages 10

4 R. Castelli et al. / Critical Reviews in Oncol

Table 1Clinical and laboratory markers for the diagnosis of acquired C1-inhibitordeficiencies.

Clinical markers-Self-limiting, non-inflammatory 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 edemaLaboratory 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 asimmunoglobulins preventing C1-inhibitor function or bindingC1-inhibitor.

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ny patient with acquired C1-inhibitor deficiency should beested for C1-inhibitor auto-antibodies [38], which may beresent in patients with AAE and induce C1-inhibitor hyper-atabolism [17,42–44]. C1-inhibitor auto-antibodies can beetected as immunoglobulins that prevent C1-inhibitor func-ion or bind C1-inhibitor. In the first assay, immunoglobulinssolated from serum block C1-inhibitor activity measured ashe inhibition of the conversion of synthetic substrates thatre specific for its target proteases [45]. In 1987, Alsenz et al.46] developed a solid-phase enzyme-linked immunosorbentssay (ELISA) for detecting immunoglobulins binding to C1-nhibitor coated on micro-titer plates, a simple and highlyensitive method that is still used with slight modifications42,43].

.3. Course

The course and prognosis of angioedema due to acquired1-inhibitor deficiency depends on the underlying diseasend the availability of appropriate therapy for life-threateningngioedema. Although angioedema attacks usually resolveithout treatment, patients are exposed to the risk of laryngeal

dema [38]. The frequency of attacks varies widely betweenubjects (from rare attacks to several events per year or evener month), and may also vary in the same subject at differentisease stages [2]. It has been reported that one patient experi-nced severe angioedema symptoms for five years that endedbruptly for no apparent reason [16]. Successful treatment ofhe underlying disease can resolve the angioedema symptomsnd biochemical abnormalities, but treatment responses varyidely [18,38].

.4. Therapy

Please cite this article in press as: Castelli R, et al. Acquired C1-inhibitor dCrit Rev Oncol/Hematol (2013), http://dx.doi.org/10.1016/j.critrevonc.2

The therapy of AAE follows two lines: (1) the pre-ention/reversal of the symptoms of angioedema; and (2)reatment of the associated disease [47–50].

ape

ogy/Hematology xxx (2013) xxx–xxx

Whatever the mechanism of C1-inhibitor consumptioncleavage by auto-antibodies or absorption by neoplasticymphatic tissue), the reduced C1-inhibitor levels in patientsith AAE induce the hyperactivation of the complement

nd contact systems, and this leads to further C1-inhibitoronsumption [26]. The hyper-consumption of C1-inhibitor44] explains why AAE patients are usually resistant tohe treatment normally used in cases of HAE [2]. For theong-term prevention of angioedema recurrences, patientsre currently treated with attenuated androgens (whichncrease C1-inhibitor synthesis and aminopeptidase Punction, an enzyme involved in bradykinin catabolism) andntifibrinolytic agents, which inhibit the enzyme plasminhat facilitates bradykinin production [10,43,50,51]. Patientsith acquired C1-inhibitor deficiency respond better to

ntifibrinolytic agents (which seem to be well tolerated) thano attenuated androgens [38,49]. Although antifibrinolyticgents are potentially prothrombotic, no increased throm-otic risk has ever been documented. Short- and long-termrophylaxis with C1-inhibitor concentrates has also beenuccessfully used in AEE patients, albeit at generally higheroses than those used to treat HAE [38,52].

Acute attacks are treated by the infusion of plasma-derived1-inhibitor despite the variable degree of resistance and

he need for high doses [2,37]. By overcoming the prob-em of accelerated C1-inhibitor catabolism, the bradykinin2 receptor antagonist icatibant is a promising alternative tolasma-derived C1-inhibitor for patients with acquired C1-nhibitor deficiencies. It is already an established treatmentor acute HAE attacks, and we have successfully used thisreatment in eight patients with AAE resistant to C1-inhibitorlasma concentrates [53].

Table 2 summarizes the pharmacological approaches tohe prevention/treatment of AAE symptoms.

Treatment of the associated disease by means ofhemotherapy or other cytoreduction (radiotherapy, surgery,nd antibodies to specific cell populations) or immuno-uppressive treatment may not only control the underlyingisease, but also relieve the clinical symptoms ofngioedema and variably reverse the biochemical abnor-alities [18–20,54,55]. The therapeutic approaches to

ymphoproliferative diseases are the same in patients withr without C1-inhibitor deficiency. However, C1-inhibitoreficiency with frequent angioedema attacks that do notesponding to conventional AAE treatment should be con-idered a sign of active lymphoproliferative disease possiblyequiring cytoreductive therapy. In a previous study, webserved the reversal of complement abnormalities andhe remission of angioedema symptoms in two NHLatients treated with chemotherapy, and one patient witharginal splenic lymphoma undergoing splenectomy [8],

nd other groups have also reported a reduction in, or the

eficiency and lymphoproliferative disorders: A tight relationship.013.02.004

py, with an improvement in complement parameters inatients with AAE associated with lymphoproliferative dis-ase [15,19,20,54,55] (Table 3).

Please cite this article in press as: Castelli R, et al. Acquired C1-inhibitor dCrit Rev Oncol/Hematol (2013), http://dx.doi.org/10.1016/j.critrevonc.2

ARTICLE IN PRESSONCH-1713; No. of Pages 10

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gy/Hematology xxx (2013) xxx–xxx 5

Rituximab, a chimeric mouse/human monoclonal anti-D20 antibody, targets B cells and has been used successfully

n autoimmune disorders such as rheumatoid arthritis, sys-emic lupus erythematosus [56–58], and pemphigus [59,60].t has also been investigated in cases of aggressive and indo-ent NHL as a single agent or in combination with standardhemotherapy regimens [61–65]. Given the rarity of the dis-ase, no controlled clinical trials have systematically assessedhe efficacy and safety of rituximab in AAE patients but annalysis of the published data shows that 14 patients haveo far been treated with rituximab, which led to a clinicalmprovement in 12, and the reversal of complement abnor-

alities in 10 [66–71] (Table 4).Despite that absence of controlled clinical trials of rit-

ximab in patients with acquired C1-inhibitor deficiency,e believe it to be reasonable to use rituximab in the

ase of selected patients experiencing multiple episodesf angioedema who fail to respond to conventional treat-ents, and (in combination with chemotherapy) in patientsith high-grade lymphoproliferative disease or active lym-homas. In addition it seems reasonable to use rituximab inatients with severe and otherwise uncontrolled angioedemaymptoms associated with lymphoproliferative disease notequiring per se conventional chemotherapy treatments, suchs patients with MGUS or indolent lymphomas with no signsf active disease.

. Link between acquired angioedema andymphoproliferative disease

AAE is frequently associated with lymphoproliferativeisorders of B cell lineage ranging from MGUS to NHL.hree studies by our group have previously demonstrated

hat patients with acquired C1-inhibitor deficiency are atigher risk of developing NHL than the general popula-ion [16–18]. A lymphoproliferative disease may be presentt the onset of AAE symptoms, or may develop thereafterin our experience, between three months and seven yearsfter) [18]. The most frequent lymphoproliferative diseasessociated with acquired C1-inhibitor deficiency is indolentymphoma. According to the WHO classification, the mostrequent histotypes in patients with acquired C1-inhibitoreficiency are nodal and splenic marginal zone lymphomas,nd lymphoplasmocytic lymphomas/Waldeström’s disease.he association with these histotypes is similar to that of otherutoimmune diseases such as cryoglobulinemia, or rheuma-oid arthritis [72,73], these observations suggest that theisk of developing lymphoproliferative diseases in patientsith acquired C1-inhibitor deficiency is not generic but con-ned to specific histotypes. As these NHL subtypes developuring the post-antigen exposure stages of lymphocyte dif-

eficiency and lymphoproliferative disorders: A tight relationship.013.02.004

erentiation, it can be argued that the immunocomplexes of1-inhibitor and C1-inhibitor auto-antibodies may play a roles antigenic drivers in the genesis of autoimmunity-relatedymphomas [18,26].

Please cite

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astelli R

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cquired C

1-inhibitor deficiency

and lym

phoproliferative disorders:

A tight

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Table 3Clinical and complement parameters in acquired angioedema (AAE) patients with lymphoproliferative disease treated with chemotherapy or immunochemotherapy.

Author Patients Associatedhemopathy

Chemotherapy Pre-chemotherapyC1-INHAg/function/anti-C1-INH

Post-chemotherapyC1-INHAg/function/anti-C1-INH

Clinicalimprovement

Duration offollow-up

Jung M [19] 1 Chronic lymphocyticleukemia

Chlorambucil + danazol NA/83% (duringdanazol)/NA

NA/100%/NA Yes NA

2 Chronic lymphocyticleukemia

Fludarabine,CyC + rituximab

6.7 mg/dL/1%/NA NA/120%/NA Yes NA

3 Lymphocyticlymphoma

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 Waldestromlymphoplasmocyticlymphoma

R-CHOP 31%/<5%/IgM 500 U/mL 115%/116%/IgM60 U/mL

Yes 3 year

2 Follicular lymphoma CEOP/fludarabine/Cyc <1%/<1%/0 109%/90%/0 Yes 4 year3 Splenic marginal zone

lymphomaSplenectomy 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 monthsRossi D [55] 1 Anaplastic CD30+

large B celllymphoma

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.

Please cite

this article

in press

as: C

astelli R

, et

al. A

cquired C

1-inhibitor deficiency

and lym

phoproliferative disorders:

A tight

relationship.C

rit R

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atol (2013),

http://dx.doi.org/10.1016/j.critrevonc.2013.02.004

AR

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7

Table 4Clinical and complement parameters in acquired angioedema (AAE) patients treated with rituximab.

Author Patients Associated hemopathy orconcomitant disease

Frequency ofattacks

Pre-rituximab C1-inhibitorAg/function/anti-C1-inhibitor

Post-rituximabC1-inhibitorAg/function/anti C1inhibitor

Clinicalefficacy

Durationoffollow-up

Lam DH [67] 1 Marginal zone lymphoma;coronary artery disease

NR 2 mg/dL/20%/NA Normalization C1-INHAg

Yes 8 months

Branellec A [66]

1 N0 Twice monthly 139 mg/L/5 U/mL/IgM 2320 U 227 mg/L/16.1 U/mL/IgM760 U

Yes 6 months

2 Marginal zone lymphoma Every 8–10 days 96 mg/L/5.4 U/mL/IgM 271 U 202 mg/L/13.3 U/mL/IgM378 U

Yes NR

3 MGUS IgA � Monthly 170 mg/L/2.7 U/mL/IgA 339 U 103 mg/L/NA/NA Yes 6 months4 MGUS IgG 2 attacks/year 144 mg/L/4.9 U/mL/IgG

1000 U155 mg/L/4.1 U/mL/IgG1170 U

Yes 5 years

5 No Repeated 80 mg/L/NA/IgM 317 U 89 mg/L/3.7 U/mL/IgM696 U

Yes 6 months

6 MGUS IgG � Monthly 16 mg/L/<2/IgM positive 92 mg/L/<2/IgM positive No 3 years7 Marginal zone lymphoma NR 81 mg/L/ND/undetectable NA/NA/undetectable No 17 months

Sánchez-Cano D [70] 1 Sjögren’s syndrome 3/month 016 U/mL/32%/IgM 578 U NA – NA – IgM 346 U Yes 11 months

Levi M [68]1 None 3/month <0.5 U/mL/<0.25 U/mL/IgG

positiveNearnormal/>0.5 U/mL/NA

Yes 12 months

2 Follicular B cell lymphoma 3/month <0.5 U/mL/<0.25 U/mL/NA Nearnormal/>0.5 U/mL/NA

Yes 12 months

3 None 3/month <0.5 U/mL/<0.25 U/mL/NA Nearnormal/>0.5 U/mL/NA

Yes 12 months

Ziakas PD [69] 1 Monoclonal IgMnephrosclerosis

5–6/year Low/40%/Positive NA/NA/NA Yes NR

Hassan A [71]1 MGUS IgM k 6–8/month C4 (0.06 g/L, normal:

0.10–0.40 g/L)C1-INH functional levelsimproved to 3.1 U/mL

Yes 24 months

C1-INH antigen: 0.08 g/L(n.v.: 0.21–0.34 g/L); C1-INHfunctional levels: 2.0 U/mL(n.v.: 17.2–27.4 U/mL)

MGUS: monoclonal gammopathy of uncertain significance; Ag: antigen; NR: not reported; NA: not available.

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The prevalence of MGUS in patients with acquired C1-nhibitor deficiency is 35%, which is much higher than itspproximately 3% prevalence in the general population agedess than 70 years [74]. A study by our group has shown thatatients with MGUS and C1-inhibitor auto-antibodies fre-uently have the same heavy and light chain histotypes [18].GUS progresses to multiple myeloma as frequently in AAE

atients as in the general population [18]. Evidence that the Momponents detected in these patients frequently correspondo the C1-inhibitor auto-antibodies, and that patients withuto-antibodies may develop lymphoproliferative diseasesuggests that a single B cell clonal disorder with differentotential clinical evolutions underlies AAE. Furthermore, asymphoproliferative diseases may appear in AAE patients,atients with confirmed C1-inhibitor deficiency should belosely monitored for their development. For all patientsith angioedema due to acquired C1-inhibitor deficiency, we

uggest to perform annually a first level screening for lym-hoproliferative diseases based on complete blood cell countith differential leukocyte count, serum protein electrophore-

is, chest X ray and abdominal ultrasound, along with aomplete physical examination. Additional tests should beuided by clinical suspicion or abnormal laboratory find-ngs.

. Conclusions

Although the etiology of acquired C1-inhibitor deficiencys still partially unclear, the majority of patients presentn underlying B cell disorder, which ranges from the sim-le production of C1-inhibitor auto-antibodies to MGUSnd NHL. The most frequent histotypes are nodal andplenic marginal zone lymphomas and lymphoplasmocyticymphomas/Waldeström disease. The association with suchistotypes is similar to that of other autoimmune diseasesnd, as they develop during the post-antigen exposure stagesf lymphocyte differentiation, the immunocomplexes formedy auto-antibodies and C1-inhibitor may play a role inhe genesis of autoimmunity-related lymphomas. Lympho-roliferative disease may be present at the onset of AAEymptoms or may develop thereafter, thus AAE representsn example of the strict link between autoimmunity andymphoproliferation. Blocking autoreactive or neoplastic Bell proliferation is a pivotal step in the treatment of theisease. It has been shown that curing the associated dis-ase by means of chemotherapy and/or immunosuppressionan resolve angioedema symptoms and normalize the bio-hemical defects. However, AAE symptoms and pathologicalomplement parameters may reappear at the time of a recur-ence of the malignancy. In any case, patients with AAEhould be closely monitored because of its potential evolution

Please cite this article in press as: Castelli R, et al. Acquired C1-inhibitor dCrit Rev Oncol/Hematol (2013), http://dx.doi.org/10.1016/j.critrevonc.2

nto lymphoproliferative disease. It is still debated whetherhe exacerbation of angioedema symptoms in patients withndolent lymphoma is a sign of active disease requiringytoreductive treatment.

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ogy/Hematology xxx (2013) xxx–xxx

onflicts of interest

The authors have no conflicting interests to disclose.

eviewer

Teresa Caballero, MD, PhD, Senior consultant, Hospi-al Universitario La Paz, Allergy Department, Paseo de laastellana 261, ES-28046 Madrid, Spain.

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iography

Massimo Cugno MD, is an associate professor of Internaledicine at the University of Milan. He is the chief of theenter for the study of complement at the Maggiore Hospital

n Milan. He graduated “cum laude” from the University ofilan in 1982. He completed his post-graduated speciality

n Hematology and Internal Medicine at the University ofilan. He is involved in research on prognostic, therapeu-

ic and biological aspects of hematological disorders. Thecientific work was conducted mainly in the field of protea-ic systems, coagulation, fibrinolysis and complement. Heas published around 150 original papers (130 in journals

eficiency and lymphoproliferative disorders: A tight relationship.013.02.004

ncluded in PubMed, some of excellence as New Engl J Med,ancet, J Clin Invest, Am J Hum Genet, Circulation, andlood).