The enigma of uveitis in juvenile idiopathic arthritis

180 Pages·2017·15.03 MB·English

THE ENIGMA OF UVEITIS IN
THE ENIGMA OF UVEITIS IN
JJUUVVEENNIILLEE IIDDIIOOPPAATTHHIICC AARRTTHHRRIITTIISS

Genetic, immunologic and clinical aspects

Anne-Mieke Haasnoot
2018
THE ENIGMA OF UVEITIS IN

JUVENILE IDIOPATHIC ARTHRITIS

Genetic, immunologic and clinical aspects

Het raadsel van uveitis bij juveniele idiopathische artritis

Genetische, immunologische en klinische aspecten

(met een samenvatting in het Nederlands)

Proefschrift

ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de rector

magnificus, prof.dr. G.J. van der Zwaan, ingevolge het besluit van het college voor promoties

in het openbaar te verdedigen op donderdag 1 maart 2018 des middags te 2.30 uur

door

Colofon

© 2018 AAnnnnee--MMiieekkee HHaaaassnnoooott
ISBN: 997788--9944--66229955--881177--33
Printed by: PPrrooeeffsscchhrriiffttMmaakkeenn. nǀǀ l wǀǀw Uwit.gperoveerfisjc BhOrifXtPmraeksse n .nl Arenda Johanna Wilhelmina Haasnoot
Cover design: AAddaa HHaaaassnnoooott--tteerr MMaaaatt ((mmyy mmootthheerr))
Lay-out: AAnnnnee--MMiieekkee HHaaaassnnoooott && PPrrooeeffsscchhrriiffttmmaakkeenn..nnll geboren op 8 november 1988
te Rotterdam
THE ENIGMA OF UVEITIS IN
THE ENIGMA OF UVEITIS IN

JJUUVVEENNIILLEE IIDDIIOOPPAATTHHIICC AARRTTHHRRIITTIISS

Genetic, immunologic and clinical aspects

Het raadsel van uveitis bij juveniele idiopathische artritis

Genetische, immunologische en klinische aspecten

(met een samenvatting in het Nederlands)

Proefschrift

ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de rector

magnificus, prof.dr. G.J. van der Zwaan, ingevolge het besluit van het college voor promoties

in het openbaar te verdedigen op donderdag 1 maart 2018 des middags te 2.30 uur

door

Colofon

© 2018 Anne-Mieke Haasnoot
ISBN: 978-94-6295-817-3
Printed by: Proefschriftmaken.nl ǀǀ Uitgeverij BOXPress Arenda Johanna Wilhelmina Haasnoot
Cover design: Ada Haasnoot-ter Maat (my mother)
Lay-out: Anne-Mieke Haasnoot & Proefschriftmaken.nl geboren op 8 november 1988
te Rotterdam
Promotoren: Prof. dr. J.H. de Boer Commissie: Prof.dr. N.M. Wulffraat
Prof. dr. T.R.D.J. Radstake Prof.dr. S.M. Imhof
Dr. S. Nierkens
Copromotor: Dr. J.J.W. Kuiper Prof.dr. A. Rothova
Prof.dr. T.W. Kuijpers
The research in this thesis was supported by Dr. F.P. Fischer Stichting, ODAS Stichting,
Landelijke Stichting Voor Blinden en Slechtzienden, Stichting Nederlands Oogheelkundig
Onderzoek and chapter 3 partly by Research grant of the Federal Ministry of Education and
Research, Li Ka Shing Foundation.
Publication of this thesis was supported by Rotterdamse Stichting Blindenbelangen,
Stichting Blindenhulp, Stichting voor Ooglijders, Landelijke Stichting voor Blinden en
Slechtzienden, Ursapharm, Allergan, Tramedico, Bayer, Théa Pharma, Rockmed, Laméris
Ootech, ZEISS, Infection & Immunity Center Utrecht.
Promotoren: Prof. dr. J.H. de Boer Commissie: Prof.dr. N.M. Wulffraat
Prof. dr. T.R.D.J. Radstake Prof.dr. S.M. Imhof
Dr. S. Nierkens
Copromotor: Dr. J.J.W. Kuiper Prof.dr. A. Rothova
Prof.dr. T.W. Kuijpers

The research in this thesis was supported by Dr. F.P. Fischer Stichting, ODAS Stichting,
Landelijke Stichting Voor Blinden en Slechtzienden, Stichting Nederlands Oogheelkundig
Onderzoek and chapter 3 partly by Research grant of the Federal Ministry of Education and
Research, Li Ka Shing Foundation.

Publication of this thesis was supported by Stichting Blindenhulp, Stichting voor Ooglijders,
Landelijke Stichting voor Blinden en Slechtzienden, Ursapharm, Allergan, Tramedico, Bayer,
Théa Pharma, Rockmed, Laméris Ootech, ZEISS, Infection & Immunity Center Utrecht.
Paranimfen: Fleurieke Verhagen CONTENTS
Kamil Laban

Chapter 1 Introduction and aims of the study 9

Chapter 2 Erythrocyte sedimentation rate as baseline predictor for the 25
development of uveitis in children with juvenile idiopathic arthritis.
Am J Ophthalmol. 2015 Feb;159(2):372-7

Chapter 3 An amino acid motif in HLA-DRβ1 distinguishes patients with 37
uveitis in juvenile idiopathic arthritis.
Submitted

Chapter 4 Ocular fluid analysis in children reveals interleukin-29/interferon-λ1 83
as a biomarker for juvenile idiopathic arthritis-associated uveitis.
Arthritis Rheumatol. 2016 Jul;68(7):1769-79

Chapter 5 Impact of uveitis on quality of life in adult patients with juvenile 113
idiopathic arthritis.
Arthritis Care Res (Hoboken). 2017 Dec;69(12):1895-1902

Chapter 6 Impact of juvenile idiopathic arthritis associated uveitis in early 133
adulthood.
PLoS One. 2016 Oct 10;11(10):e0164312

Chapter 7 Summary 151
Discussion and future perspectives

Chapter 8 Nederlandse samenvatting 167

Chapter 9 Dankwoord 173
Curriculum vitae
List of publications
Paranimfen: Fleurieke Verhagen CONTENTS
Kamil Laban

Chapter 1 Introduction and aims of the study 9

Chapter 2 Erythrocyte sedimentation rate as baseline predictor for the 2255
development of uveitis in children with juvenile idiopathic arthritis.
Am J Ophthalmol. 2015 Feb;159(2):372-7

Chapter 3 An amino acid motif in HLA-DRβ1 distinguishes patients with 3377
uveitis in juvenile idiopathic arthritis.
Submitted

Chapter 4 Ocular fluid analysis in children reveals interleukin-29/interferon-λ1 8833
as a biomarker for juvenile idiopathic arthritis-associated uveitis.
Arthritis Rheumatol. 2016 Jul;68(7):1769-79

Chapter 5 Impact of uveitis on quality of life in adult patients with juvenile 111133
idiopathic arthritis.
Arthritis Care Res (Hoboken). 2017 Dec;69(12):1895-1902

Chapter 6 Impact of juvenile idiopathic arthritis associated uveitis in early 113333
adulthood.
PLoS One. 2016 Oct 10;11(10):e0164312

Chapter 7 Summary 115511
Discussion and future perspectives

Chapter 8 Nederlandse samenvatting 116677

Chapter 9 Dankwoord 117733
Curriculum vitae
List of publications

Chapter 1
Introduction and aims of the study
Chapter 1
vision-related QoL assessment tool for eye diseases specifically (National Eye Institute Visual
Functioning Questionnaire).23 In children with JIA-associated uveitis the vision-related QoL
INTRODUCTION vision-related QoL assessment tool for eye diseases specifically (National Eye Institute Visual
was found to be worse in those with uveitis compared to those without uveitis, but both had
Functioning Questionnaire).23 In children with JIA-associated uveitis the vision-related QoL
similar general QoL scores.24 In adults, uveitis (not JIA-associated) was related to worse QoL
Epidemiology was found to be worse in those with uveitis compared to those without uveitis, but both had
outcomes compared to healthy people.25,26 In adult patients with a history of JIA QoL was also
Uveitis is a sight-threatening inflammation of the inner layers of the eye that affects about 29 similar general QoL scores.24 In adults, uveitis (not JIA-associated) was related to worse QoL
decreased compared to healthy people, however, no uveitis-related outcomes were
in every 100,000 children. Generally, uveitis is responsible for approximately 10% of all cases outcomes compared to healthy people.25,26 In adult patients with a history of JIA QoL was also
reported.27 A study investigating the QoL specifically in adults with JIA-associated uveitis is
of blindness in Western countries.1 The clinically heterogeneous cluster of conditions that fall decreased compared to healthy people, however, no uveitis-related outcomes were
currently lacking.
under the term ‘uveitis’ are commonly divided into two overarching groups; the ‘infectious reported.27 A study investigating the QoL specifically in adults with JIA-associated uveitis is

uveitis’ - where the initiating factor is attributed to microbial infection, or ‘noninfectious currently lacking.
Risk factors and screening guideline
uveitis’ - where uveitis is considered to be driven by auto-inflammatory mechanisms. The
The majority of children with JIA-associated uveitis are diagnosed with JIA first (77-97%) and
latter concept is fairly based on the observation that in one third of the children uveitis arises Risk factors and screening guideline
develop uveitis afterwards, yet, to date we are unable to predict which JIA patients are
as part of a multi-organ inflammatory syndrome, of which junivele idiopathic arthritis (JIA) is The majority of children with JIA-associated uveitis are diagnosed with JIA first (77-97%) and
susceptible to developing uveitis.4,28 However, various risk factors had been identified and
by far the most frequent associated systemic condition.2 As a whole, JIA is the most common develop uveitis afterwards, yet, to date we are unable to predict which JIA patients are
patients with pauciarticular and polyarticular JIA* had the highest risk to develop uveitis.29
chronic rheumatic disease in childhood with an estimated prevalence of 16-150 in every susceptible to developing uveitis.4,28 However, various risk factors had been identified and
Also patients positive for antinuclear antibodies (ANA) and with arthritis onset below the age
100,000 individuals.3-6 There may be a molecular link between arthritis and uveitis, because patients with pauciarticular and polyarticular JIA* had the highest risk to develop uveitis.29
of 7 years were considered more susceptible to uveitis. According to these risk factors
also up to one third of JIA patients (depending on JIA subtype) are afflicted by a distinct form Also patients positive for antinuclear antibodies (ANA) and with arthritis onset below the age
ophthalmologic screening guidelines for JIA patients were first developed in 1993 (and
of noninfectious uveitis, making uveitis the most common extra-articular manifestation of of 7 years were considered more susceptible to uveitis. According to these risk factors
updated in 2006).29,30 According to these guidelines, high risk patients were screened by
JIA.7 ophthalmologic screening guidelines for JIA patients were first developed in 1993 (and
ophthalmologists every 3 to 4 months for at least 7 years to capture onset of uveitis and
updated in 2006).29,30 According to these guidelines, high risk patients were screened by
prevent severe eye inflammation. Nevertheless, the proportion of children with severe uveitis
Clinical course ophthalmologists every 3 to 4 months for at least 7 years to capture onset of uveitis and
at onset did not change, which strongly suggested the need for refinements in the screening
Uveitis associated with JIA (further referred as ‘JIA-associated uveitis’) typically manifests as prevent severe eye inflammation. Nevertheless, the proportion of children with severe uveitis
protocol.14
chronic noninfectious uveitis, which predominantly affects the anterior part of the eye. A at onset did not change, which strongly suggested the need for refinements in the screening

hallmark of JIA-associated uveitis is the typical asymptomatic onset and insidious disease Ipnr otthoec oflo.1l4l o wing years, new criteria for JIA were released by the International League of
course that conceal the occurrence of numerous complications ranging from posterior A ssociations for Rheumatology (ILAR).32 The new guidelines refined that those suffering from
In the following years, new criteria for JIA were released by the International League of
synechiae, band keratopathy, glaucoma, cataract, and cystoid macular edema, to refractory the most common (re-defined) categories of JIA - oligoarticular or polyarticular rheumatoid
hypotony or even phthisis bulbi.8-10 These complications usually become noticeable after Afascstoocri antieognast ifvoer RJIhAe u-m wateorleo gayt (pILaArRtic).u32l aTrh rei snke wfo rg udiedveelilnoepsin rge ficnherdo nthica ta nthteorsieo rs uufvfeeritinisg -f rothme
the most common (re-defined) categories of JIA - oligoarticular or polyarticular rheumatoid
irreversible or sight-threatening damage has occurred, which significantly hampers success of hallmark eye inflammation in JIA. In 2007 Heiligenhaus and associates improved the
factor negative JIA - were at particular risk for developing chronic anterior uveitis - the
clinical intervention to minimize visual loss. Consequently, recent studies describe that 6% of ophthalmologic screening guidelines using these new JIA criteria and by implementing their
hallmark eye inflammation in JIA. In 2007 Heiligenhaus and associates improved the
children with JIA-associated uveitis become unilaterally blind, whereas in the past observations that the highest risk to develop uveitis after JIA onset was within the first year
percentages of ~30% were reported.11,12 (o7p3h%th oalfm tohleo gpiac tsiecnretse)n.3i3n gIn g audiddeitliionnes, tuhseinyg o tuhtelisnee dn etwh aJtI At hceri tmeraiajo arintyd obfy pimatpielenmtse ndteinvegl otpheeidr
observations that the highest risk to develop uveitis after JIA onset was within the first year
Severe disease at onset has a poor visual prognosis, making early detection and prompt uveitis within a 4 year window after JIA onset (90%), which is in agreement with previous
treatment in these patients critical.8,12 Several other risk factors associated with a more severe (f7in3d%in gosf. 3t0h Ael tphaotuiegnht st)h.3e3 sIen gaudiddeitliionne,s tshigeny ifoicuatnlitnlye da idth atot sthineg lme aojourt itpya toief nptsa tpiernotnse dteov eulvoepiteisd,
uveitis within a 4 year window after JIA onset (90%), which is in agreement with previous
uveitis course include the male sex, a young age at uveitis onset, development of uveitis still there is a pressing need to further reduce the number of patients that present with
shortly after arthritis onset, or detection of uveitis before arthritis (JIA-suspected uveitis).12-14 sfienvdeirneg su.3v0e iAtilsth aotu fgirhs tt hviessite ign utihdee loinpehst hsiaglnmifoicloagntyl yc lainidic taon sdin cgolen voeurst eplya tmieinntism pizreo nsec rteoe nuivnegit iisn,
still there is a pressing need to further reduce the number of patients that present with
In contrast, prolonged periods of relative disease inactivity, and early and extended periods patients with a low risk profile for uveitis.
severe uveitis at first visit in the ophthalmology clinic and conversely minimize screening in
of immunomodulatory therapy substantially reduce the risk of uveitis relapse and vision
loss.8,15,16 pMaotlieecnutlsa wr mitha rak leorws trois gku pidroe fcillein fiocar lu mveaintias.g ement of JIA-associated uveitis

JIA associated uveitis typically has its onset in childhood; however, patients continue to suffer Objective and accurate (bio)markers to determine whether a specific JIA patient will (or will
Molecular markers to guide clinical management of JIA-associated uveitis
from its complications into adulthood. In fact, persistence of uveitis activity has been not) develop uveitis are currently lacking. Side-by-side comparison of patients with and
Objective and accurate (bio)markers to determine whether a specific JIA patient will (or will
reported in 30-63% of adult patients with a history of JIA. Despite the alarming number of without uveitis can be performed using biological samples, including serum. As mentioned
not) develop uveitis are currently lacking. Side-by-side comparison of patients with and
adult patients with persisting uveitis activity, only little is known about this condition in above, serum levels of ANAs are associated with increased risk for uveitis in JIA.34 More
without uveitis can be performed using biological samples, including serum. As mentioned
adulthood and consequently study outcomes are conflicting, in part due to inconsistent specifically, anti-histone antibodies (AHA) and antibodies directed to iris/ciliary tissue are
follow-up.10,17-22 maboorvee ,f rseeqruuemn tllye voeblss eorfv eAdN iAns saerreu ma sosof cpiaatteiedn tws itwhi tihn cJrIeAa-saesdso rciisakt efdo ru vuevietiisti.s35 -i3n7 IJnIA a.3d4 dMitioorne,
specifically, anti-histone antibodies (AHA) and antibodies directed to iris/ciliary tissue are
The world health organization defines health as ‘a state of complete physical, mental, and various other serum markers have been linked to JIA-associated uveitis, such as increased
more frequently observed in serum of patients with JIA-associated uveitis.35-37 In addition,
social wellbeing not merely the absence of disease’. Meaning not only the above mentioned levels of soluble interleukin(IL)-2 receptor or the heterodimer calprotectin (S100A8/A9), and
various other serum markers have been linked to JIA-associated uveitis, such as increased
objective disease outcomes such as uveitis activity and extend of complications influence decreased amyloid A1.36,38 Despite the association of these blood markers with uveitis status,
levels of soluble interleukin(IL)-2 receptor or the heterodimer calprotectin (S100A8/A9), and
health, but also patients’ personal experiences. To determine patients’ subjective health
decreased amyloid A1.36,38 Despite the association of these blood markers with uveitis status,
experience, a variety of Quality of Life (QoL) assessment tools have been developed, with the
* previously known as ‘juvenile rheumatic arthritis, JRA’ according to the criteria of the American College of Rheumatology
(ACR) and as ‘juvenile chronic arthritis, JCA’ according to the criteria of the European League Against Rheumatism (EULAR),
*b optrhe vdieofuinselyd kinn othwen 1 a9s7 0‘jsu2v9,e31n ile rheumatic arthritis, JRA’ according to the criteria of the American College of Rheumatology
10 (ACR) and as ‘juvenile chronic arthritis, JCA’ according to the criteria of the European League Against Rheumatism (EULAR),
both defined in the 1970s29,31