Prediction of response to therapy in rheumatoid arthritis

347 Pages·2017·8.94 MB·English

Prediction of response to therapy in rheumatoid arthritis
Lost in validation

Bart V.J. Cuppen
The studies presented in this thesis were conducted at the department of Rheumatology
& Clinical Immunology, University Medical Center Utrecht and participating centers of the
Society for Rheumatology Research Utrecht (SRU).

The research described in this thesis was financially supported by The Netherlands
Association for Health Research and Development (ZonMW, project “Efficiency Studies:
High cost medicines”), Foundation Friends of the UMCU, Pfizer, BMS, UCB, Roche, and
Schering-Plough.

Cover: Rick Wuisman
Lay-out: Marieke Vianen en Bart Cuppen
Printed by: Ipskamp Printing

ISBN: 978-90-393-6745-2

© 2017, B.V.J. Cuppen, the Netherlands. All rights reserved. No part of this thesis may be
reproduced or transmitted in any form or by any means, electronic or mechanical,
including photocopying, recording or any information storage and retrievel system,
without prior permission of the holder of the copyright.
Prediction of response to therapy in rheumatoid arthritis

Lost in validation

Predictie van respons op therapie in reumatoïde artritis: zoekgeraakt in validatie
(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 23 maart 2017
des ochtends te 10.30 uur

door

Bart Vincentius Joseph Cuppen
geboren op 17 juni 1988 te Nijmegen
PROMOTOREN:
Prof. dr. F.P.J.G. Lafeber
Prof. dr. J.W.J. Bijlsma

COPROMOTOREN:
Dr. R.D.E. Fritsch-Stork
Dr. A.C.A. Marijnissen
TABLE OF CONTENTS
1. General introduction 1

2. Personalized biological treatment for rheumatoid arthritis: a 13
systematic review with a focus on clinical applicability

3. Necessity of TNF-alpha inhibitor discontinuation in 43
rheumatoid arthritis is predicted by smoking and number of
previously used biological DMARDs

4. Can baseline serum microRNAs predict response to TNF-alpha 75
inhibitors in rheumatoid arthritis?

5. RNA-sequencing to predict response to TNF-α inhibitors 107
reveals possible mechanism for non-response in smokers

6. CD4+ T cell mRNA evaluation by microarray and sequencing 155
reveals no robust predictors of response to TNF-alpha
inhibitors

7. Proteomics to predict the response to TNF-alpha inhibitors in 185
rheumatoid arthritis using a supervised cluster-analysis based
protein score

8. Exploring the inflammatory metabolomic profile to predict 211
response to TNF-α inhibitors in rheumatoid arthritis

9. Differences between serum polar lipid profiles of male and 257
female rheumatoid arthritis patients in response to
glucocorticoid treatment

10. Polymorphisms in the multidrug-resistance 1 gene related to 279
glucocorticoid response in rheumatoid arthritis treatment

11. Summary of results and general discussion 293

12. Nederlandse samenvatting 318

Dankwoord 330

Curriculum vitae 336

List of publications 338

Chapter 1

General introduction

RHEUMATOID ARTHRITIS
Rheumatoid Arthritis (RA) is a multifactorial chronic autoimmune disorder affecting 0.5-
1.0% of the Western adult population [1-3]. In RA, overproduction of proinflammatory
cytokines drives persistent synovial tissue inflammation and via proteases destruction of
cartilage and subchondral bone [4]. Besides general complaints as fatigue, the more
characteristic features of high disease activity include swelling, pain, and function loss of
the affected joints with eventually structural damage [5]. The combination of a highly
prevalent chronic disease with a high morbidity, makes RA a notable health issue in 21st
century.
Although genetic and environmental risk factors for RA have been identified, the exact
etiology of RA remains incompletely known [6, 7]. Likewise, many important players of the
pathophysiological process have been identified, such as T-cells, B-cells,
monocytes/macrophages and fibroblasts which execute their function via many different
cytokines, yet these processes are very heterogeneous among patients [7, 8]. Still, the
evolving understanding of this complex and extensive network has enabled the search for
therapeutics with different targets, lowering disease activity by (partially) blocking diverse
inflammatory pathways. These anti-inflammatory treatments, the so called Disease-
modifying antirheumatic drugs (DMARDs), comprise a heterogeneous collection of agents
and form the basis of RA therapy. Basically, DMARDs can be divided into two categories:
the conventional synthetic DMARDs (csDMARDs) and the biological DMARDs (bDMARDs).
The csDMARDs are small active-substance molecules which have been used for decades in
the treatment of RA, and include drugs such as methotrexate (MTX), sulfasalazin (SSZ),
leflunomide (LEF) and hydroxychloroquine (HCQ) [9]. The newer bDMARDs or biologicals
are monoclonal antibodies that target and inhibit specific inflammatory pathways. From a
clinical, scientific, and commercial perspective biologicals are one of the biggest successes
of rational drug design, and have revolutionized the treatment options for RA patients
since the first trial in 1993 [10-12]. Among biologicals, there are five registered agents
inhibiting tumour necrosis factor alpha (TNF inhibitors (TNFi’s)), these are: adalimumab
(ADA), etanercept (ETN), infliximab (IFX), golimumab (GLM), and certolizumab pegol (CZP).
Other biological agents, also called non-TNFi’s, target IL-6 receptor (tocilizumab (TCZ)), T-
cell co-stimulation CD80/CD86 (abatacept (ABA)), B lymphocyte antigen CD20 (rituximab
General introduction | 3
(RTX)) or IL-1 receptor (anakinra (ANA)). The effective control of disease activity by
biologicals is clearly visible when the clinical response rates to MTX and the biologicals are
observed (see Figure 1)[13]. Of note, newer agents for RA have been introduced that
necessitated DMARD subdivision into more categories, such as targeted synthetic
DMARDs (e.g. tofacitinib; an inhibitor of JAK enzymes, interfering with transduction of
cellular pathways that are normally activated by proinflammatory cytokines) or biosimilar
DMARDs (e.g. bs-infliximab; sharing most but not all features of the parent compound)[9].
As current treatments only manage to suppress RA disease activity with variable success,
novel molecules are constantly under investigation.

Figure 1: Clinical responses to methotrexate (MTX) and several biologicals, as subdivided for MTX-
naïve (usually early RA), MTX-experienced and TNF-alpha inhibitor experienced (established RA). The
response to bDMARDs is superior to MTX, whereas the effectiveness of the bDMARDs (except for
anti-IL-1) is equal for patients with a comparable drug-experience. The American College for
Rheumatology (ACR) response criteria indicate an improvement of ≥20% and ≥70% for ACR20 and
ACR70, respectively. ND, not done; RA, rheumatoid arthritis; TNF = tumour necrosis factor. Figure by
Smolen et al. [13].
4 | Chapter 1