Tailoring Treatment in Juvenile Idiopathic Arthritis

374 Pages·2017·9.25 MB·English

Tailoring Treatment in
Juvenile Idiopathic Arthritis
Joost Frans Swart
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Tailoring Treatment in Juvenile Idiopathic Arthritis
ISBN: 978-90-393-6989-0
Author: Joost Frans Swart
Cover design: Ilse Spijker; www.studiospijker.nl
Lay out: Wendy Schoneveld, www.wenziD.nl
Printed by: Proefschriftmaken.nl
All rights reserved. No part of this thesis may be reproduced or transmitted in any
form by any means without permission in writing of the author. The copyright of articles
that have been published might have been transferred to the respective journals.
Publication of this thesis was kindly supported by the University Medical Center Utrecht
Copyright © 2018, Joost Frans Swart, Utrecht, The Netherlands
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Tailoring Treatment in Juvenile
Idiopathic Arthritis
Behandeling op Maat in Jeugdreuma
(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. H.R.B.M. Kummeling,
ingevolge het besluit van het college voor promoties
in het openbaar te verdedigen op
donderdag 28 juni 2018 des middags te 2.30 uur
door
Joost Frans Swart
geboren op 21 april 1973
te Groningen
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Promotor: Prof. dr. N.M. Wulffraat
Copromotoren: Dr. S. de Roock
Dr. J.J. Boelens
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“It is more important to know what sort of person has a disease
than to know what sort of disease a person has.”
“There are, in effect, two things, to know and to believe one knows;
to know is science; to believe one knows is ignorance.”
Hippocrates of Kos (circa 460 – 370 BC)
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TABLE OF CONTENTS
CHAPTER 1 General introduction 9
PART ONE | THERAPEUTIC STRATEGIES IN JIA
CHAPTER 2 Biomarkers guiding clinical strategies in JIA 21
CHAPTER 3 cJADAS in treat-to-target therapy in JIA 43
PART TWO | PHARMACOVIGILANCE IN JIA
CHAPTER 4 Immunological consequences of biologicals in JIA 75
CHAPTER 5 Pharmacovigilance in JIA 105
CHAPTER 6 Risk of infections in JIA 125
CHAPTER 7 Opportunistic infections in JIA 141
PART THREE | THE BURDEN OF COMORBID CONDITIONS
CHAPTER 8 Comorbidity burden in JIA 165
PART FOUR | CELLULAR THERAPIES FOR THERAPY-REFRACTORY ARTHRITIS
CHAPTER 9 Haematopoietic stem cell transplantation for autoimmune 193
diseases
CHAPTER 10 Mesenchymal stromal cell therapy in proteoglycan induced 223
arthritis
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CHAPTER 11 Mesenchymal stromal cells for treatment of arthritis 243
CHAPTER 12 Mesenchymal stromal cell infusion in therapy refractory JIA 271
patients
CHAPTER 13 General discussion 291
CHAPTER 14 Summary 325
List of Abbreviations 333
Nederlandse samenvatting 337
Dankwoord 349
Curriculum vitae 359
List of Publications 367
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CHAPTER 1
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General introduction
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CHAPTER 1
Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in
children with an incidence in Europe of about 16-150/100,000/yr and an important
cause of short-term and long-term disability.1 JIA is defined as arthritis with no apparent
cause lasting more than 6 weeks with disease onset prior to age 16.2 JIA is a complex
inflammatory disease with a multifactorial immune pathogenesis. Next to a certain
genetic predisposition, environmental factors play a role leading to a chronic
inflammatory response, which involves uncontrolled activation of both innate and
adaptive immunity.3 The resulting autoimmune assault targets primarily, synovial
tissue, leading to chronic arthritis. The classification of patients is still essentially based
on the same clinical features as twenty years ago. Thus, the counting of clinically active
joints is still the hallmark for the classification of JIA1 and for all clinically important
decisions, e.g. the choice of treatment to start the patient on,4 when to escalate therapy
or switch to another agent,4 and also when to taper or withdraw treatment. Based on
6 months of clinical symptoms and global prognostic factors, the following clinical
subtypes of JIA are recognized: oligoarthritis, Rheumatoid Factor (RF)-negative
polyarthritis, RF-positive polyarticular JIA, psoriatic JIA, enthesitis-related arthritis,
systemic-onset JIA and undifferentiated arthritis.1 The biologic basis of these clinical
subtypes is not very distinctive and indeed this classification is subject to new debate
since it seems unlikely that a simple joint count would be sufficient to identify patients
with different immune pathogenesis.5
Therapeutic strategies in JIA
In the last 10 years the implementation of an adequate legislation fostering controlled
clinical trials in children and the availability of new potent medications such as the
biologicals have led to a dramatic improvement in the treatment of JIA.6 In 2011 the
worldwide very much appreciated “American College of Rheumatology (ACR)
recommendations on the treatment of JIA” was published.4 However, these
recommendations scored very poorly in applicability (8%) because they did not clearly
state the costs and resources needed in order to implement them. Criteria for assessing
their impact were not provided either.7 The likely reason that these recommendations
are not fully implemented is that the criteria that recommend the next treatment step
are much too complicated to be literally applicable in clinical practice. Although the
order in the step up treatment schemes is roughly similarly used by most pediatric
rheumatologists in the developed world, it still leads to therapy-failures of at least 50%
in the first 12 months of treatment resulting in frustration, pain and probably even
damage to the treated tissue.8,9 In a Canadian cohort, almost one fourth of all patients
did not reach inactive disease, even within 2 years.9 It is unclear what the exact decisive
reasons are that physicians escalate therapy, but already the more straight forward
10
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