Table Of ContentCOBRA Combination Therapy in
Rheumatoid Arthritis
Implementation and Beyond
Printing of this thesis was financially supported by the Department of Epidemiology &
Biostatistics and the Department of Rheumatology of the VU University Medical Center
and by The Dutch Arthritis Association.
Cover design: Ghouse Samadh, www.3en3.nl
Printed by Ipskamp Drukkers, Enschede
Copyright © 2009 Lilian van Tuyl
www.cobratherapie.nl
ISBN nummer: 9789086593514
VRIJE UNIVERSITEIT
COBRA Combination Therapy in
Rheumatoid Arthritis
Implementation and Beyond
ACADEMISCH PROEFSCHRIFT
ter verkrijging van de graad Doctor aan
de Vrije Universiteit Amsterdam,
op gezag van de rector magnificus
prof.dr. L.M. Bouter,
in het openbaar te verdedigen
ten overstaan van de promotiecommissie
van de faculteit der Geneeskunde
op donderdag 1 oktober 2009 om 10.45 uur
in de aula van de universiteit,
De Boelelaan 1105
door
Huibertina Davida van Tuyl
geboren te Wageningen
promotoren: prof.dr. B.A.C. Dijkmans
prof.dr. M. Boers
copromotoren: prof.dr. W.F. Lems
dr. A.E. Voskuyl
Voor mijn ouders
en
voor Samadh
CONTENTS
Introduction 10
Section I COBRA implementation study
Chapter 1.1 Why are Dutch rheumatologists reluctant to use the COBRA 20
treatment strategy in early rheumatoid arthritis?
Chapter 1.2 Discordant perspectives of rheumatologists and patients on 28
COBRA combination therapy in rheumatoid arthritis
Chapter 1.3 Survival, comorbidities and joint damage 11 years after the 46
COBRA combination therapy trial in early rheumatoid arthritis
Chapter 1.4 Baseline RANKL:OPG ratio and markers of bone and 62
cartilage degradation predict annual radiological progression
over 11 years in rheumatoid arthritis
Chapter 1.5 Facilitating the use of COBRA combination therapy in early 76
rheumatoid arthritis: a pilot implementation study
Section II COBRA-CTX study
Chapter 2.1 Tight control and intensified COBRA combination therapy in 90
early rheumatoid arthritis: 90% remission in a pilot trial
Chapter 2.2 IgM-rheumatoid factor and anti-cyclic citrullinated peptide 104
decrease by 50% during intensive treatment in early
rheumatoid arthritis
Section III ACR/EULAR/OMERACT remission initiative
Chapter 3.1 Defining remission in rheumatoid arthritis: 112
results of an initial ACR / EULAR consensus conference
Chapter 3.2 Systematic review: evidence for predictive validity of 126
remission on long term outcome in rheumatoid arthritis
Discussion & Summary 142
Dutch Discussion & Summary / Discussie & Samenvatting 154
Curriculum Vitae 164
Publications / Publicaties 165
Acknowledgment / Dankwoord 166
INTRODUCTION
Introduction
CLINICAL FEATURES AND EVALUATION OF RHEUMATOID ARTHRITIS
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by symmetrical
inflammation of multiple joints. The prevalence of RA in the Western population is estimated
to be 1% and is three times more frequent in females than in males.
The burden of disease is high and patients typically present with pain, symmetrical swelling of
small joints, morning stiffness and a general feeling of despair and fatigue.
In the long term, the cartilage and bone of the affected joints are damaged. This development
of erosive disease is generally regarded as irreversible and greatly impairs the function of the
joints, leading to a loss of quality of life for the patient.
RA is a progressive disease, with periods of remission and periods of exacerbation.
Permanent remission occurs, but is rare once joint damage has started. Without treatment,
RA not only leads to severe joint deformations and loss of function, but ultimately to
premature death due to cardio vascular disease, infections, renal disease, respiratory disease
and RA itself1,2.
To reliably evaluate disease activity, numerous composite measures have been developed.
The most frequently used combined measure of disease activity in Europe and this thesis is
the disease activity score (DAS28). This composite measure includes a count of the number
of swollen and painful joints out of a selection of 28 joints in shoulders, elbows, wrists,
metacarpophalangeal joints, proximal interphalangeal joints and the knees; a measure of
global health from the patients’ perspective on a 100 mm visual analogue scale; and a
measure of the acute phase response (the erythrocyte sedimentation rate or C-reactive
protein3,4. The long term damage to the joints can be visualized by radiographs and quantified
by several scoring techniques5-8. The total damage score combines the severity of damage to
individual joints in hands and feet and is regarded as an important long term outcome
measure in RA. The patients’ physical disability is often assessed by the health assessment
questionnaire (HAQ) on which patients can fill out their impairments, resulting in a total
disability score9,10.
In recent decades the prognosis for patients with RA has improved considerably due to
greatly expanded treatment options.
TREATMENT HISTORY
Despite discovery of salicylates in the 19th century, therapy of RA was mostly non-
pharmacological and of very limited efficacy. Salicylates have analgesic and anti-inflammatory
properties similar to what we now call non-steroidal anti inflammatory drugs (NSAIDs) such as
ibuprofen and diclofenac, but with a less favorable safety profile11. In the early 20th century,
Jacques Forestier was the first to discover the effectiveness of gold compounds for the
treatment of RA12,13, which was the start of the discovery of the so called disease modifying
anti rheumatic drugs (DMARDs). Although the exact mode of action of these drugs is not yet
understood, research shows they can suppress the primary inflammation process and delay
radiographic progression14-16. While the first experiments with the DMARDs sulfasalazine
(SSZ) and hydroxychloroquine were performed17-19, Hench and his co-workers found that
glucocorticoids (GCs) dramatically improved the symptoms of patients with RA, which was
rewarded with the Nobel prize in 195020,21. These spectacular results led to the widespread
use of high doses of GCs, but changed drastically when the spectrum of unacceptable side
effects was disclosed. This shifted the focus of research once again towards development
and experiments with NSAIDs and DMARDs, leading to the introduction of indomethacine,
followed by many other NSAIDs, and also the currently most often used drug methotrexate
10
Description:Chapter 3.1 Defining remission in rheumatoid arthritis: results of an initial . Modified disease activity scores that include twenty- eight-joint counts.
