Accepted Article

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Title: C-reactive protein levels in Hereditary Angioedema

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Short Title: C-reactive protein levels in Hereditary Angioedema

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Authors: Zonne Liza Michaëla Hofman1, Anurag Relan2, Cornelis Erik Hack1

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Affiliations:

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Centre Utrecht, Utrecht, the Netherlands. 2Pharming Technologies BV,

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Leiden, the Netherlands

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Correspondence: Z.L.M. Hofman, Laboratory for Translational

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Immunology, University Medical Center Utrecht, Lundlaan 6, P.O.Box

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85090, 3508 GA UTRECHT.

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Laboratory for Translational Immunology, University Medical

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Tel.: +31 (0)88 75 576 74

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Fax: +31 (0)88 75 543 05

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Keywords: C-reactive protein; Hereditary Angioedema; bradykinin

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receptor.

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Abbreviations:

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ACE

Angiotensin-converting-enzym

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B1R

Type 1 bradykinin receptor

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B2R

Type 2 bradykinin receptor

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BK

Bradykinin

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C1INH

C1-inhibitor

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CRP

C-reactive protein

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ESR

Erythrocyte sedimentation rate

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Factor XIIa

Activated factor XII

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HAE

Hereditary angioedema

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HK

High-molecular-weight kininogen

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IL

Interleukin

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RCT

Randomized controlled trial

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rhC1INH

Recombinant human C1-inhibitor

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/cei.12314 1 This article is protected by copyright. All rights reserved.

Accepted Article 28

TNF

Tumour necrosis factor

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VAS

Visual analog scale

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Abstract

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Background Hereditary Angioedema (HAE) patients experience recurrent

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episodes of angioedema attacks that can be painful, disfiguring and even

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life-threatening. The disorder results from a mutation in the gene that

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controls the synthesis of C1-inhibitor (C1INH). C1INH is a major regulator

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of activation of the contact system. It is often assumed that attacks results

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from uncontrolled, local activation of the contact system with subsequent

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formation of bradykinin.

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Objective To evaluate involvement of inflammatory reactions in HAE, we

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analyzed C-reactive protein (CRP) levels before, during, and after HAE

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attacks.

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Methods HAE patients included in a clinical database of recombinant

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human C1- inhibitor (rhC1INH) studies were evaluated. For the current

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study we analyzed CRP levels when patients were asymptomatic, during a

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clinical attack and in a follow up period, and correlated these with the

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clinical manifestations of the attack.

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Results Data from 68 HAE patients were analyzed and included CRP levels

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at 273 occasions. While asymptomatic, 20% of the patients analyzed had

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increased CRP. At the onset of the attack (p=0.049) and over the next 24

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hours CRP rose significantly (p=.002) in patients with an abdominal

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location, and post-attack levels were significantly higher in these patients

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than in patients with attacks at other locations (p=.034).

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Conclusion CRP levels are elevated in a substantial proportion of

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asymptomatic HAE patients. Levels of CRP significantly increase during an

(word count 248)

2 This article is protected by copyright. All rights reserved.

Accepted Article 54

abdominal attack. These data suggest low-grade systemic inflammatory

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reactions in HAE patients as well as a triggering event for attacks that

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starts prior to symptom onset.

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3 This article is protected by copyright. All rights reserved.

Accepted Article 91 92 93 94

Introduction

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for the plasma protein C1-inhibitor (C1INH). [1,2] HAE patients experience

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recurrent episodes of pain and edema that can be located at various sites in

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the body such as in the extremities and the uro-genital tract. Submucosal

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swelling in the upper airways can lead to life-threatening asphyxia, whereas

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abdominal attacks present as a functional bowel obstruction causing

(word count 2893)

Hereditary angioedema (HAE) results from a mutation in the gene coding

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extreme pain. [3,4]

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C1INH controls three intertwined cascade systems: the contact system, the

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classical and lectin complement pathways and the factor XII-dependent

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fibrinolytic cascade. Of these, the contact system is generally considered

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the most important for the pathogenesis of the angioedema attacks. [5,6]

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Activation of the contact system generates bradykinin (BK), which can bind

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to receptors on endothelial cells and mediate vasodilatation and increased

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permeability. BK is cleaved off from high-molecular-weight kininogen (HK)

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by kallikrein, which is generated from prekallikrein by activated factor XII

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(factor XIIa). C1INH regulates the activity of kallikrein as well as that of

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factor XIIa. [7-9] Hence a lack of C1INH, as occurs in HAE, results in

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enhanced BK formation, which presumably explains why C1INH deficiency

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leads to angioedema. [1-3,5,6]

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The effects of BK and its metabolites such as vasodilatation, increased

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vascular permeability, sensorial and sympathetic nerve stimulation and

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smooth muscle contraction are mediated by two types of G-protein coupled

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receptors, B1R and B2R. These receptors occur on vascular endothelium,

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primary sensory afferent neurons and vascular and non vascular smooth 4 This article is protected by copyright. All rights reserved.

Accepted Article 118

muscle cells. [7-9] B2R is constitutively expressed while B1R is absent in

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most tissues under physiological conditions. [7,8] B1R is upregulated by

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cells

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inflammation suggesting a role for B1R in pathophysiological processes.

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[10-12]

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pharmacological effects of B1R and B2R antagonists in inflammatory

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conditions. Early in inflammation plasma-extravasation reacts to a B2R

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antagonist whereas later when inflammation becomes

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antagonists are more efficacious. [13,14]

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In HAE B2R is considered to be the main BK receptor involved in

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vasopermeability changes with a minor, if any, role for B1R [7,15],

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implying BK, the main agonist for B2R, is the main mediator of

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angioedema. However, ex vivo studies by Bossi and co-workers showed

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that

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induced by HAE (C1INH-deficient) plasma required blocking of both B2R as

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well as B1R, suggesting involvement of both receptors in an acute

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angioedema attack in HAE. [16] Expression of B1R by endothelial cells,

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however, requires stimulation by cytokines such as tumour necrosis factor

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(TNF)α or interleukin-1 (IL1)β [7,11-13], which are not known to be

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involved in HAE.

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TNF and IL1 via induction of IL6 stimulate the synthesis of C-reactive

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protein (CRP) by the liver. [17-22] Hence, CRP levels reflect the release of

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these cytokines in vivo. In the present study we analyzed CRP levels in a

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cohort of HAE patients enrolled in randomized controlled trials with

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recombinant human C1INH. [23-26] As part of the clinical protocol CRP

upon

exposure

Differential

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bacterial

expression

endotoxins,

of

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tissue

receptors

trauma

explains

and

the

chronic, B1R

prevention of vascular leakage across cultured endothelial cells

5 This article is protected by copyright. All rights reserved.

Accepted Article 143

levels were collected from the patients at baseline and at various time

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points during and after an attack. [26] We evaluated CRP levels before,

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during, and after HAE attacks and analyzed how levels were related to

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clinical manifestations of the attack.

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6 This article is protected by copyright. All rights reserved.

Accepted Article 148

Patients, materials and methods

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Patients

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All patients included in this study were enrolled in two randomized, double-

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blind, placebo-controlled studies to evaluate recombinant human C1INH

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(rhC1INH) as a treatment for hereditary angioedema attacks. [24-26]

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Patients could participate when they were older than 12 years, had signed

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informed consent, and had a plasma level of functional C1INH

C-reactive protein levels in hereditary angioedema.

Hereditary angioedema (HAE) patients experience recurrent episodes of angioedema attacks that can be painful, disfiguring and even life-threatening. T...
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