Cover Page
The following handle holds various files of this Leiden University dissertation:
http://hdl.handle.net/1887/67920
Author: Burgers, L.E.
The studies described in this thesis were performed at the Department of Rheumatology at the Leiden University Medical Centre, Leiden, the Netherlands
ISBN/EAN:978-94-9301-447-3
The printing of this thesis was financially supported by the Dutch Arthritis Foundation, UCB Pharma and Pfizer
Thesis layout and cover design: Leonie Burgers Picture on cover made by Petar Petkovski Printing: Gildeprint, Enschede, the Netherlands Copyright © 2019 by Leonie Burgers
TOWARDS PREVENTION OF RHEUMATOID ARTHRITIS
Proefschrift
ter verkrijging van
de graad van Doctor aan de Universiteit Leiden, op gezag van Rector Magnicius prof.mr. C.J.J.M. Stolker
volgens besluit van het College voor Promoties te verdedigen op donderdag 17 januari 2019
klokke 15.00
door
Leonie Elisabeth Burgers
Promotores
Prof. dr. A.H.M. van der Helm-van Mil Prof. dr. T.W.J. Huizinga
Leden promotiecommissie
TABLE OF CONTENTS
Chapter 1 Introduction 7
Part 1 DMARD-free sustained remission
Chapter 2 Long-term outcome of RA defined according to the 25 2010-classification criteria
Chapter 3 Does treatment strategy influence the ability to achieve 37 and sustain DMARD-free remission in patients with RA? -
results of an observational study comparing an intensified DAS-steered treatment strategy with treat-to-target in
routine care
Chapter 4 Large joint involvement at first presentation with RA, an 55 unfavourable feature: results of a large longitudinal study
with functioning and DMARD-free sustained remission as outcomes
Chapter 5 Does the presence of MRI-detected osteitis at diagnosis with 61 RA lower the risk for achieving DMARD-free sustained
remission? – results of a longitudinal study
Part 2 Symptoms preceding RA-development
Chapter 6 MRI-detected inflammation is associated with functional 79 disability in early arthritis – results of a cross-sectional study
Chapter 7 Is joint pain in patients with arthralgia suspicious for 97 progression to RA explained by subclinical inflammation?
- a cross-sectional MRI-study.
Chapter 8 Differences in the symptomatic phase preceding ACPA- 115 positive and ACPA-negative RA: a longitudinal study
in arthralgia during progression to clinical arthritis.
Part 3 Prevention of RA-development
Chapter 9 The window of opportunity in RA - definitions and 129 supporting evidence: from old to new perspectives
Chapter 10 Validation of the EULAR definition of arthralgia suspicious 149 for progression to RA
Chapter 11 Brief report: Clinical trials aiming to prevent RA cannot 161 detect prevention without adequate risk stratification: a trial of methotrexate versus placebo in undifferentiated arthritis as an example
Chapter 13 Nederlandse samenvatting 187
Appendices Curriculum Vitae 201
List of publications 202
CHAPTER 1
8 Chapter 1
RHEUMATOID ARTHRITIS
Rheumatoid arthritis (RA) is an autoimmune inflammatory disease that primarily affects small joints of the hand and feet and is characterized by persistent synovial inflammation
and consequent destruction of underlying cartilage and bone1. The term rheumatoid
stems from the Greek word ρεύμα, rheuma, meaning flowing current. RA was named
after this, as the disease seemed to spread, or flow, through a patient’s body2. RA is
the most common form of inflammatory arthritis. In the Netherlands, its prevalence is
estimated at 1.4% and more than 17.000 people get diagnosed each year3. RA is more
common in females and the incidence increases with age3.
Both the morbidity and economic burden of RA are considerable4. Uncontrolled,
it can result in significant joint damage, leading to disability, work loss, decreased quality
of life and increased mortality, which mostly stems from cardiovascular comorbidities1,5,6.
The economic burden of RA not only arises from medical care, which in 2011 in the
Netherlands was estimated at 568 million euros3, but even more so from indirect costs
such as RA-related work loss, which are estimated to exceed the costs of medical care by
approximately 4 times, thus accounting for ~80% of the total economic burden4,7,8.
To date, much still has to be elucidated about the pathophysiology of RA9.
Genetic risk factors are estimated to account for ~50% of the risk for RA-development1.
Many genetic risk factors have been identified10, of which the best known are several
HLA-DRB1 alleles, that are associated with seropositive disease1,12. Multiple environmental
risk factors have been proposed13, but only the association between smoking and
RA-development has been widely replicated13,14.
Auto-antibodies
RA is considered to have an autoimmune nature based on the association
of certain HLA-alleles and disease susceptibility12,15,16 as well as on the presence of
autoantibodies. Several RA-specific autoreactive antibodies have been identified that are associated with RA, of which rheumatoid factor (RF) and anticitrullinated protein
antibodies (ACPA) are best known. They are present in ~60% of all RA-patients17,18.
RF is the most classically known auto-antibody and has a sensitivity of 69%
and a specificity of 85% in the identification of RA19. However, it can also be present in
healthy elderly people and in other auto-immune diseases, such as Sjögren syndrome
or Wegener granulomatosis20. ACPA is more specific (95%) while retaining a similar
sensitivity (67%)19.
1
considered as two different disease entities, with differences in underlying risk-factors
and disease course21–23. Chapter 8 of this thesis will evaluate whether there are also
phenotypic differences in the phase preceding RA-development between the two subsets.
CLASSIFICATION OF RA
Typically, patients present with pain, stiffness and joint swelling, sometimes accompanied
by systemic systems such as fever24. The diagnosis of RA is made by rheumatologists
based on a combination of experience, clinical symptoms and findings of additional investigations, such as laboratory tests and imaging. Importantly, no diagnostic criteria for RA exist. Classification criteria for RA do exist and are mostly intended for clinical
research, in order to create homogeneous groups of patients25. Thus, classification criteria
should only be applied on patients with a clinical diagnosis of RA and therefore, not all patients with a clinical diagnosis of RA fulfil the classification criteria.
Currently, two sets of classification criteria for RA are widely used. The 1987 American College of Rheumatology (ACR) consists of seven criteria (Table 1) of which
4 have to be present in order to classify a patient as having RA26. The criteria include
the presence of rheumatic nodules and radiographic changes, which are generally not present in early RA, but are characteristic for established, long lasting disease. Thus, the 1987-criteria fail to classify patients with very early RA. To this end, new
ACR 1987 revised criteria 2010 ACR/EULAR criteria
1. Morning stiffness ≥ 1 hour 2. Arthritis in 3 or more joint areas 3. Arthritis of hand joints 4. Symmetric arthritis 5. Rheumatoid nodules 6. Presence of RF
7. Radiographic changes (erosions)
Joint involvement • 1 large (0) • 2-10 large joints (1)
• 1-3 small joints (with or without LJI) (2) • 4-10 small joints (with or withou LJI) (3) • >10, including at least 1 small joint (5) Serology
• ACPA and RF negative (0) • Low-positive ACPA or RF (2) • High-positive ACPA or RF (3) Acute-phase reactants
• Normal CRP and ESR (0) • Abnormal CRP or ESR (1) Duration of symptoms
• <6 weeks (0) • ≥6 weeks (1)
4/7 criteria must be present to fulfil criteria 6/10 criteria must be present to fulfil criteria
Table 1: Classification criteria for Rheumatoid Arthritis
10 Chapter 1
classification criteria were established in 2010 by the ACR and the European League
Against Rheumatism (EULAR) (Table 1)27. Indeed, studies have shown that these criteria
allow classification of patients with RA in an earlier disease phase28–30. A downside of the
2010-criteria is that seronegative patients require >10 involved joints in order to score 6/10 required points (Table 1). In Chapter 2 both criteria sets are compared with regards to long-term outcomes.
TREATMENT OF RA
Treatment of RA has changed dramatically over the last decades. Until the beginning of
the nineties remission and prevention of joint damage were not yet achievable goals32.
Initial treatment started with NSAIDs and only when this was ineffective in preventing disease progression rheumatologists could switch to a disease modifying antirheumatic drug (DMARD), such as gold or hydroxychloroquine. This approach, called the pyramid approach, was then increasingly questioned as it was recognized that it was
ineffective in controlling disease and preventing joint damage33,34. These observations led
to a change in treatment strategies. Treatment targets shifted from relief of symptoms towards remission and a disease activity score (DAS) was developed to improve disease
monitoring35,36. DMARD-therapy was started earlier in the disease course and several
trials revealed that initial aggressive combination therapy including corticosteroids in
early RA resulted in less joint destruction37,38. The latest advance in treating RA was
the introduction of biologicals, which have proven to be highly effective39. In short,
current treatment guidelines are aimed at sustained remission or low disease activity32.
Methotrexate is recommended as first-step treatment in combination with short-term glucocorticoids. If the treatment target is not achieved, other conventional DMARDs
should be started and if this is still not effective biologicals should be added32. The effect
of treatment strategy on achieving remission is investigated in Chapter 3 of this thesis.
DMARD-free sustained remission
Traditionally, joint damage was the most important outcome in rheumatoid arthritis. However, with current treatment, damage can often be prevented. This has led to a shift in disease outcomes towards patient reported outcomes including fatigue, pain
and general wellbeing40,41. Furthermore, there is growing evidence that part of all
RA-patients can achieve DMARD-free remission42–46.
DMARD-free remission is an outcome that is of increasing interest. Not only is it an increasingly achievable outcome with improving treatment options and strategies, it
also corresponds with a patient perceived state of remission40,43. If DMARD-free remission
1
percentage of patients who achieves this outcome, suggests that RA no longer has to be a chronic disease. Part I of the current thesis focusses on DMARD-free sustained remission in order to learn more about mechanisms underlying chronicity of RA.
EARLY IDENTIFICATION AND TREATMENT OF RA Window of opportunity
Early treatment initiation is known to be associated with better long-term outcomes, such as less radiologic damage progression, less disability and an increased change on
achieving DMARD-free sustained remission17,42,47,48. Interestingly, recent evidence has
suggested that the relation between symptom duration and the chance for achieving DMARD-free sustained remission is not linear, but initially decreases steeply and stabilises afterwards, suggesting that there is a confined period of approximately 3
months after first symptoms, in which RA is more susceptible to treatment49. This implies
that early in the disease course, disease processes have not fully matured yet and are still modifiable. These findings have emphasized the importance of early identification of patients with RA and swift treatment initiation. An overview of all the available evidence for a window of opportunity is provided in Chapter 9.
Figure 1: Hypothesized association between timing of treatment initiation and RA resolution or even prevention
12 Chapter 1
Early identification of Rheumatoid Arthritis
Findings that auto-antibodies and inflammatory markers can precede the onset of RA by several years revealed that the onset of RA is preceded by a preclinical
phase50–52. This has led to a growing interest in this early phase as it is hypothesized that
treatment in this period falls within the window of opportunity and may even prevent
RA-development (Figure 1)53,54. To this end, a EULAR study group formulated 6 phases
in the development of RA: (A) genetic risk factors, (B) environmental risk factors, (C) systemic autoimmunity associated with RA, (D) symptoms without clinical arthritis, (E)
unclassified arthritis (UA) and (F) RA (Figure 2)55. Importantly, patients do not necessarily
go through all phases and an individual can be in two phases at the same time by for example having both genetic and environmental risk factors. More importantly, not all patients with risk factors for RA will develop RA. Therefore, the term ‘pre-RA’ can only be used in retrospect, as otherwise healthy persons with certain risk factors could be unjustly labelled as having a ‘pre’ disease.
Phase D, in which patients have symptoms without clinical arthritis, is of interest as this is usually the first point at which patients present themselves at a general practitioner (GP) or rheumatologist. However, identifying patients who will go on and develop RA is very challenging. The vast majority of patients presenting with musculoskeletal symptoms will never develop RA. For GPs, recognition of arthritis has proven to be difficult and the median delay to refer a patient to a rheumatologist is 8
weeks17,56. Therefore, GPs in the Netherlands are encouraged to refer patients early, even
in doubt57. Furthermore, early recognition clinics have been set up and have proven to
lead to earlier recognition of arthritis58.
THE ROLE OF MRI IN EARLY ARTHRITIS AND ARTHRALGIA Role of MRI in early arthritis
MRI is an imaging modality that is very sensitive in depicting inflammation. Well
1
validated scoring systems for MRI exists, making it possible to obtain MRI-scores in a
more objective way compared to for example ultrasound, which is more subjective59–62.
Compared to X-ray it is able to detect erosions at an earlier stage63 and furthermore,
periarticular structures such as the synovium and tendons can be visualised. The most unique feature that can be visualised by MRI is bone marrow edema (BME), or osteitis, within the bone. BME has repeatedly been shown to be a strong predictor for erosive
progression64–68, while tenosynovitis is predictive for progression from UA to RA69.
Role of MRI in arthralgia
In patients with arthralgia but without clinical arthritis, subclinical inflammation
can be depicted by MRI in a large proportion of patients, ranging from 68.8-93%70–72. Of
the different inflammatory features, synovitis was most prevalent72. However, while the
presence of subclinical inflammation was associated with arthritis development73, this
was not always the case70,73. Interestingly, it was observed that MRI-detected inflammation
was also present in the majority of healthy controls70,71,74. Therefore, when deciding
whether MRI-detected information is normal or abnormal, it is always important to keep in mind what kind of MRI-detected inflammation is present in healthy, age-matched
controls75. Chapter 6 and 7 of this thesis further study the clinical relevance of
MRI-detected subclinical inflammation in patients with arthralgia and early arthritis.
TOWARDS PREVENTION OF RA
Identification of patients at risk for RA-development
To study whether RA can be prevented, randomized trials are needed in patients at risk for RA. However, identification of these patients is challenging. To learn more about the symptomatic phase preceding arthritis development, the Leiden clinical suspect arthralgia (CSA)-cohort was set up in 2012, in which patient with recent-onset arthralgia were included and prospectively followed if the rheumatologist considered imminent
RA the most likely diagnosis72. The clinical expertise of the rheumatologist has proven to
be a very accurate tool in discriminating patients who are and who are not at risk for RA,
with an OR of ~5576. However, this approach also has downsides. First, it is a subjective
approach and will therefore differ between rheumatologists. Second, even though it is a very sensitive approach, meaning that almost no patients who will later develop RA are missed, only ~20% of patients who were considered at risk for RA, will eventually
develop arthritis73.
Another approach for identifying patients at risk for RA is by testing for the
14 Chapter 1
easy to do for GPs56. However, the downside is that test characteristics strongly depend
on the priori risk of RA-development, meaning that the risk of false-positives will be much higher in a GP population (where the risk of RA is low) than in a rheumatologist
population54. Furthermore, as ~40% of all RA-patients are seronegative, these patients
will by definition be missed by this approach, resulting in a low sensitivity.
The use of different approaches to identify patients at risk for RA can lead to incomparability of trials aimed at prevention of RA. With a growing amount of trials that are aimed at prevention of RA, it is important that homogeneous patient populations are
included54. For studies in RA-patients homogeneity can be achieved by only including
patients who fulfil classification criteria, but no classification criteria exist for patients who are at risk for developing RA. To this end, a clinical definition for arthralgia
suspicious for progression to RA has recently been developed by a EULAR taskforce78.
The definition translates clinical expertise in clinical parameters, thereby making it a more objective measure. It was developed in a secondary care setting through-out a three-phased approach resulting in seven clinical parameters that formed the final definition (Table 2). Similar as classification criteria for RA, the definition should only be applied on patients with a clinical suspicion on imminent RA. A combination of the seven parameters was accurate in identifying patients considered to be at risk for RA. The definition translates clinical expertise in clinical parameters, thereby making it a more objective measure. In Chapter 10 the definition will be discussed in more detail and will be validated in two sets of arthralgia patients.
Predicting RA-development
Besides including homogeneous groups of patients, it is also important to include patients who have a sufficient risk for RA-development, as inclusion of many
patients who will never develop RA, might dilute trial results79,80. Therefore, risk
prediction models are needed. While several risk factors for RA-development have been
Table 2: EULAR definition for arthralgia at risk for progression to RA
These paremeters are to be used in patients with arthralgia without clinical arthritis and without other more likely explanations for the arthralgia
History taking
• Joint symptoms of recent onset (duration <1-year) • Symptoms located in MCP-joints
• Duration of morning stiffness 60 minutes or more • Most severe symptoms present in the early morning • Presence of a first-degree relative with RA
Physical examination
1
identified, such as the presence of auto-antibodies and the presence of MRI-detected
inflammation73,77,81, no well validated prediction rule exists for arthralgia patients. In
Chapter 11 of the current thesis, the importance of risk stratification in trials aimed at
prevention of RA will be illustrated and discussed.
AIMS AND OUTLINE OF THIS THESIS
In general this thesis has three aims:
1. To improve understanding of mechanisms underlying DMARD-free sustained remission
2. To improve understanding of symptoms preceding RA-development 3. To explore what is needed to go towards trials aimed at prevention of RA This thesis contains three parts
In Part I, mechanisms underlying DMARD-free sustained remission are studied, which can be interpreted as the closest proxy to cure of RA. In Chapter 2 it is studied whether the use of different classification criteria for RA influences the ability to achieve DMARD-free sustained remission. Chapter 3 focuses on the effect of treatment strategy on the ability to achieve DMARD-free sustained remission, by comparing routine care
to an intensified treatment strategy as used within the IMPROVED-study82. In Chapter 4
the hypothesis that large joint involvement at diagnosis with RA associates with worse long-term outcomes is studied within the EAC-cohort. Finally, chapter 5 studies whether certain types or patterns of MRI-detected inflammation are associated with achieving DMARD-free sustained remission over time.
All studies described in Part I are performed within the Leiden EAC-cohort. This cohort was set-up already in 1993 and includes patients with recent-onset arthritis. Follow-up includes yearly visits were history is taken, questionnaires are filled out both by rheumatologists and patients, physical examination is performed, lab samples are taken, X-rays are performed and since 2010 MRIs are made. A more detailed description
of the EAC-cohort can be found elsewhere83.
In Part II we aim to improve understanding of symptoms preceding
16 Chapter 1
of subclinical MRI-detected inflammation is tested. In Chapter 8, 67 patients from the CSA-cohort who developed arthritis during follow-up are studied. Within these patients symptoms during the phase preceding arthritis development are examined and compared between ACPA-positive and ACPA-negative patients.
In Part III we focus on the next step, namely prevention of RA-development. To start, Chapter 9 offers an overview of evidence for the window of opportunity including an overview of trials aimed at prevention that have so far been performed. In Chapter
10 the definition of arthralgia suspicious for progression to RA is validated in two
arthralgia cohorts. Finally, the importance of adequate risk stratification in trials aimed at prevention of RA is illustrated in Chapter 11. Here, a post-hoc analysis is performed
in the PROMPT-study84 that excludes UA patients with a low risk on RA-development
post-randomisation.
1
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54. van Steenbergen HW, da Silva JAP, Huizinga TWJ, van der Helm-van Mil AHM. Preventing progression from arthralgia to arthritis: targeting the right patients. Nat Rev Rheumatol [Internet] 2017 [cited 2017 Dec 18];Available from: https:// www.nature.com/articles/nrrheum.2017.185 55. Gerlag DM, Raza K, Baarsen LGM van, et al.
EULAR recommendations for terminology and research in individuals at risk of rheumatoid arthritis: report from the Study Group for Risk Factors for Rheumatoid Arthritis. Ann Rheum Dis 2012;71(5):638–41.
56. Mankia K, Nam J, Emery P. Identifying arthral-gia suspicious for progression to rheumatoid arthritis. Ann Rheum Dis 2016;annrheum-dis-2016-210853.
57. Janssens H, Lagro H, van Peet P, et al. NHG-standaard artritis [Internet]. 2009;Available from: https://www.nhg.org/standaarden/volledig/ nhg-standaard-artritis
58. Nies JAB van, Brouwer E, Gaalen FA van, et al. Improved early identification of arthritis: evalu-ating the efficacy of Early Arthritis Recognition Clinics. Ann Rheum Dis 2013;72(8):1295–301. 59. Haavardsholm EA, Østergaard M, Ejbjerg BJ, Kvan NP, Kvien TK. Introduction of a novel magnetic resonance imaging tenosynovitis score for rheumatoid arthritis: reliability in a multireader longitudinal study. Ann Rheum Dis 2007;66(9):1216–20.
60. Østergaard M, Edmonds J, McQueen F, et al. An introduction to the EULAR–OMERACT rheu-matoid arthritis MRI reference image atlas. Ann Rheum Dis 2005;64(suppl 1):i3–7.
61. Østergaard M, Peterfy C, Conaghan P, et al. OMERACT Rheumatoid Arthritis Magnetic Resonance Imaging Studies. Core set of MRI acquisitions, joint pathology definitions, and the OMERACT RA-MRI scoring system. J Rheuma-tol 2003;30(6):1385–6.
62. Baan H, Bezooijen R, Avenarius JKA, Dubbeldam R, Drossaers-Bakker WK, Laar MAFJ van de. Magnetic Resonance Imaging of the Rheumatic Foot According to the RAMRIS System Is Relia-ble. J Rheumatol 2011;38(6):1003–8.
63. McQueen FM, Stewart N, Crabbe J, et al. Mag-netic resonance imaging of the wrist in early rheumatoid arthritis reveals a high prevalence of erosions at four months after symptom onset. Ann Rheum Dis 1998;57(6):350–6.
64. McQueen FM. Bone marrow edema and osteitis
in rheumatoid arthritis: the imaging perspective. Arthritis Res Ther 2012;14(5):224.
65. Krabben A, Stomp W, van Nies JAB, et al. MRI-detected subclinical joint inflammation is associated with radiographic progression. Ann Rheum Dis 2014;73(11):2034–7.
66. Hetland ML, Stengaard-Pedersen K, Junker P, et al. Radiographic progression and remission rates in early rheumatoid arthritis – MRI bone oedema and anti-CCP predicted radiographic progres-sion in the 5-year extenprogres-sion of the double-blind randomised CIMESTRA trial. Ann Rheum Dis 2010;69(10):1789–95.
67. Hetland ML, Ejbjerg B, Hørslev-Petersen K, et al. MRI bone oedema is the strongest predictor of subsequent radiographic progression in early rheumatoid arthritis. Results from a 2-year randomised controlled trial (CIMESTRA). Ann Rheum Dis 2009;68(3):384–90.
68. Bøyesen P, Haavardsholm EA, Heijde D van der, et al. Prediction of MRI erosive progression: a comparison of modern imaging modalities in early rheumatoid arthritis patients. Ann Rheum Dis 2011;70(1):176–9.
69. Nieuwenhuis WP, van Steenbergen HW, Mangnus L, et al. Evaluation of the diagnos-tic accuracy of hand and foot MRI for early Rheumatoid Arthritis. Rheumatol Oxf Engl 2017;56(8):1367–77.
70. Gent YYJ, ter Wee MM, Ahmadi N, et al. Three-Year Clinical Outcome Following Baseline Mag-netic Resonance Imaging in Anti–Citrullinated Protein Antibody–Positive Arthralgia Patients: An Exploratory Study. Arthritis Rheumatol 2014;66(10):2909–10.
71. van Steenbergen HW, van Nies JAB, Huizinga TWJ, Reijnierse M, van der Helm-van Mil AHM. Subclinical inflammation on MRI of hand and foot of anticitrullinated peptide antibody–neg-ative arthralgia patients at risk for rheumatoid arthritis. Arthritis Res Ther 2014;16(2):R92. 72. van Steenbergen HW, van Nies JAB, Huizinga
TWJ, Bloem JL, Reijnierse M, van der Helm-van Mil AHM. Characterising arthralgia in the pre-clinical phase of rheumatoid arthritis using MRI. Ann Rheum Dis 2015;74(6):1225–32.
73. van Steenbergen HW, Mangnus L, Reijnierse M, Huizinga TWJ, van Der Helm-van Mil AHM. Clinical factors, anticitrullinated peptide anti-bodies and MRI-detected subclinical inflamma-tion in relainflamma-tion to progression from clinically suspect arthralgia to arthritis. Ann Rheum Dis 2015;annrheumdis-2015-208138.
74. Mangnus L, van Steenbergen H w., Reijnierse M, van der Helm-van Mil A h. m. MR-detected features of inflammation and erosions occur in symptom-free persons from the general popula-tion. Arthritis Rheumatol 2016;n/a-n/a. 75. Boer AC, Burgers LE, Mangnus L, et al. Using a
20 Chapter 1
study in two cohorts at risk for rheumatoid ar-thritis. Rheumatology [Internet] [cited 2017 Aug 11];Available from: https://academic.oup.com/ rheumatology/article/doi/10.1093/rheumatology/ kex235/3896392/Using-a-reference-when-defin-ing-an-abnormal-MRI
76. van Steenbergen HW, van der Helm-van Mil AHM. Clinical expertise and its accuracy in differentiating arthralgia patients at risk for rheumatoid arthritis from other patients pre-senting with joint symptoms. Rheumatology 2016;55(6):1140–1.
77. Bos WH, Wolbink GJ, Boers M, et al. Arthritis de-velopment in patients with arthralgia is strongly associated with anti-citrullinated protein antibody status: a prospective cohort study. Ann Rheum Dis 2010;69(3):490–4. 78. van Steen-bergen HW, Aletaha D, Beaart-van de Voorde LJJ, et al. EULAR definition of arthralgia suspi-cious for progression to rheumatoid arthritis. Ann Rheum Dis 2016;annrheumdis-2016-209846. 79. Fergusson D, Aaron SD, Guyatt G, Hébert P.
Post-randomisation exclusions: the intention to treat principle and excluding patients from analysis. BMJ 2002;325(7365):652–4.
80. Cohen J, Guyatt G, Bernard GR, et al. New strat-egies for clinical trials in patients with sepsis and septic shock. Crit Care Med 2001;29(4):880–6. 81. van de Stadt LA, Witte BI, Bos WH, van
Schaardenburg D. A prediction rule for the de-velopment of arthritis in seropositive arthralgia patients. Ann Rheum Dis 2013;72(12):1920–6. 82. Akdemir G, Heimans L, Bergstra SA, et al.
Clini-cal and radiologiClini-cal outcomes of 5-year drug-free remission-steered treatment in patients with early arthritis: IMPROVED study. Ann Rheum Dis 2017;annrheumdis-2017-211375.
83. de Rooy DPC, van der Linden MPM, Knevel R, Huizinga TWJ, van der Helm-van Mil AHM. Predicting arthritis outcomes—what can be learned from the Leiden Early Arthritis Clinic? Rheumatology 2011;50(1):93–100.
PART I
CHAPTER 2
Long-term outcome of RA defined according
to the 2010-classification criteria
LE Burgers*, JAB van Nies*, LY Ho, de Rooy DP,
TWJ Huizinga, AHM van der Helm-van Mil
Ann Rheum Dis. 2014 (Feb;73 (2): 428-432)
26 Chapter 2
ABSTRACT Objective
The 2010 ACR/EULAR-criteria for RA have been thoroughly studied for the test characteristics but it is unclear whether ‘2010-RA’ has a different phenotype than ‘1987-RA’ when assessing the severity of the disease course. Therefore this study compared two long-term disease outcomes.
Methods
1502 early arthritis patients that had no other diagnoses than RA or UA were studied on fulfilling the 1987-ACR-criteria, 2010-criteria or both. The severity of joint damage was studied with yearly radiographs over 7-years. Achieving DMARD-free sustained remission was assessed over 10-years follow-up. Multivariate normal regression and Cox-proportional hazard regression were used, adjusting for age, gender and treatment.
Results
550 patients fulfilled the 1987-criteria, 788 patients the 2010-criteria and 489 both criteria sets. Patients fulfilling the 2010-criteria developed less severe radiological joint damage (p=0.023) and achieved DMARD-free sustained remission more often (HR=1.18 (0.93-1.50)) than patients fulfilling the 1987-critera, though the latter was not statistically significant. All 1987+2010-patients were ACPA-negative. When also applying the radiologic criterion of the 2010-criteria half of the 1987+2010- patients became 2010-criteria positive, but results on the long-term outcome remained similar.
Conclusion
‘2010-RA’ has a milder disease course than ‘1987-RA’. This may have important
2
INTRODUCTION
Presently Rheumatoid Arthritis (RA) can be classified according to either the 1987 ACR-criteria or the 2010 ACR/EULAR-ACR-criteria. Both sets of ACR-criteria are being used and multiple
studies have evaluated the performance of the 2010-criteria1-5. A formal meta-analysis on
the test-characteristic is in progress (personal communication H. Radner), but the current impression is that the 2010-criteria, compared to the 1987-criteria, are more sensitive
and less specific in classifying RA1. It is yet insufficiently clear whether the phenotype
of RA is different when the disease is classified according to the 2010-criteria or the 1987-criteria. Several studies observed that some disease characteristics at disease onset
of 2010 RA-patients were milder than of 1987 RA-patients2-5. Some authors reported that
erosions at baseline and after 2-years are more often present in 1987-RA compared to
2010-RA2,4-6. Together, these data lead to the presumption that RA defined according to
the 2010-criteria is milder in nature than that defined according to the 1987-criteria, but there is insufficient data to draw definite conclusions on this matter. Particularly, there are no studies comparing the long-term outcome of RA-patients when RA is classified either to the 1987-criteria or the 2010-criteria. The most characteristic hallmarks of RA are progression of joint damage and disease persistency. We aimed to compare these two long-term disease outcomes in relation to the classification of RA and performed the present longitudinal study to this end.
METHODS Patients
Early arthritis patients included in the Leiden Early Arthritis Clinic Cohort7 between
1993 and May 2011 were studied. Inclusion took place when arthritis was confirmed at physical examination and symptom duration was <2 years. At the first visit, patients and rheumatologists completed questionnaires, physical examination was performed, and serum and radiographs were taken. Follow-up visits were performed yearly. For further
description see reference 7. The treatment differed for different inclusion periods. Patients
included between 1993 and 1995 were initially treated with NSAIDs, patients included between 1996 and 1998 were initially treated with chloroquine or sulphasalazine and patients included after 1999 were promptly treated with methotrexate or sulphasalazine. The inclusion period was used as a proxy for the applied treatment strategy in the analyses.
28 Chapter 2
excluded (n=397) as the treatment of these patients was more tightly controlled and the medications used more potent; affecting the disease course . Patients with a follow-up <1 year were also excluded (n=10). Thus, 1502 patients were studied (Figure 1A) and classified on fulfilling the 1987 ACR-criteria and/or the 2010 ACR/EULAR-criteria.
Outcome
Two outcome measures were studied. The first was the severity of radiological damage during 7-years of follow-up. Hand and feet X-rays were taken at baseline and yearly thereafter and scored according to the Sharp-van der Heijde method by two
Figure 1: Flowchart of patient selection (A) and the number of patients studied that fulfilled the 1987 and/or 2010 classification criteria at baseline.
(A) The 2010 ACR/EULAR criteria state that these criteria should not be applied in patients that have
2
readers with known time order, blinded to clinical data. Intraclass-observer correlation coefficients (ICC) within the readers were 0.91 and 0.87 and between the two readers 0.89.
The second outcome was achieving a DMARD-free sustained remission during 10-years of follow-up. Remission was defined as the sustained absence of synovitis (by physical examination) after discontinuation of DMARD-therapy. Synovitis had to be
absent for the entire period of follow-up and at least during one year8; in general these
patients were also discharged from the outpatient clinic. Patients that achieved such a remission but relapsed (n=13) were included in the non-remission group. This stringent definition of remission is the best possible outcome of RA as it approximates ‘cure’; it is the opposite of disease persistency. Medical files of all patients were studied on remission, and this was determined until the fifth of April, 2012.
Statistical analyses
Analyses on remission were done using a Cox proportional hazard regression
analysis8. Analyses on joint destruction were done using a multivariate normal regression
analysis as described previously, including all radiographs in one analysis and taking
advantage of serial measurements9. Another advantage is that it allowed to study all
patients, also in case of missing radiographs, preventing selection bias that would be
induced by a completers-only-analysis10. All analyses were adjusted for age, gender,
and treatment strategy. First the long-term outcomes of patients with RA according to the 1987-criteria and RA according to the 2010-criteria were compared. In this analysis, patients that fulfilled both criteria sets were included in both groups. Subsequently all patients were split in three groups (1987+2010-, 1987-2010+ and 1987+2010+) and analyses repeated. SPSS version 20.0 was used. P values <0.05 were considered significant.
RESULTS
Baseline characteristics
30 Chapter 2 Patient characteristic 1987-RA (n=550) 2010-RA (n=788) 1987-/2010+ (n=299) 1987+/2010+ (n=489) 1987+/2010- (n=61) Age at inclusion, y ears, mean ± SD 57.9 ± 16.2 56.6 ± 16.4 54.7 ± 16.4 57.8 ± 16.2 58.9 ± 15.8 Female sex 377 (68.5) 536 (68.0) 198 (66.2) 338 (69.1) 39 (63.9) Symptom duration in w eeks, median (IQR) 21.9 (12.7-38.1) 19.9 (10.6-37.3)* 15.0 (5.9-31.3) 22.0 (13.0-40.0) 15.7 (10.8-31.8) Symptom duration < 12 w eeks 120 (23.5) 221 (29.7)* 119 (41.2) 102 (22.4) 18 (33.3)
Swollen joint count of 66 joints, median (IQR)
10.0 (6.0-15.0)
9.0 (4.0-15.0)
4.0 (2.0-10.0)
11.0 (7.0-16.0)
6.0 (4.0-8.0)
Acute onset of symptoms
287 (53.8)
408 (53.5)
159 (55.4)
249 (52.3)
38 (66.7)
Onset of symptoms in small joints
306 (57.0)
443 (57.2)
170 (57.2)
273 (57.1)
33 (55.9)
Symmetric onset of symptoms
377 (74.8) 519 (71.8) 183 (66.8) 336 (74.8) 41 (74.5) RF positiv e 307 (55.9) 444 (56.5) 138 (46.3) 306 (62.7) 1 (1.6) ACP A positiv e 264 (52.3) 379 (52.1) 115(41.7) 264 (58.5) 0 (0)
ESR, mm/hour, mean ± SD
41.1 ± 28.8 38.1 ± 28.2 32.0 ± 26.3 42.0 ± 28.7 34.7 ± 28.8 CRP, mg/L, median (IQR) 19.0 (8.0-42.8) 16.0(6.0-37.0)* 12.0 (4.0-26.3) 19.0 (9.0-43.0) 19.0 (6.5-37.0)
Morning stiffness, minutes, median (IQR)
90 (60-180)
60 (30-120)*
30 (10-82.5)
90 (60-180)
90 (60-150)
HAQ (0-3), median (IQR)
1.0 (0.6-1.6) 1.0 (0.5-1.5) 0.8 (0.4-1.4) 1.0 (0.6-1.6) 0.9 (0.6-1.3) Erosiv
e joints, median (IQR)
3 (1-7)
3 (1-6)
1.5 (0-4)
4 (1-7)
4 (1-6)
Table 1: Baseline characteristics of patients classified with RA according to either the 1987 and/or the 2010-criteria Unless indicated otherwise, v
alues are the number (%) of patients.
*p<0.05 for comparison betw
een 1987-RA and 2010-RA (Student t-test or
Mann-Whitney U-test as applicable). Some data w
ere missing: for symptom duration (n=48), for acute onset of symptoms (n=29), for symptom onset in small joints
(n=15), for symmetric onset of symptoms (n=71), for RF (n=2), for
ACP
A (n=68), for ESR (n=3), for CRP (n=35), for morning stiffness (n=24) and for HAQ
2
Comparison of 1987 and 2010 RA
RA-patients according to the 2010-criteria had less severe radiological joint destruction over 7-years of disease than RA-patients classified using the 1987-criteria (p=0.023, Figure 2A). When evaluating DMARD-free sustained remission, more remission was achieved in 2010+ RA-patients than in 1987+ RA-patients, though this difference was not statistically significant (HR=1.18(0.93-1.50) p=0.17, Figure 2B).
Subanalyses
Subsequently, the RA-patients were stratified in three groups (1987+2010-, 1987-2010+, 1987+2010+) and the analyses were repeated. As presented in Figure 2C&D, 1987+2010+ RA-patients developed more severe joint destruction and achieved DMARD-free sustained remission less often than patients fulfilling one criteria set for RA (p<0.001 for both outcomes and comparison of three groups). Moreover, when analysing these subgroups in more detail, the severity of joint damage was not different between the 1987+2010+ and 1987+/2010- patients (p=0.35) but differed between the 1987+2010+ and 1987-/2010+ patients, p<0.001, Figures 2C&D). Interestingly, 1987+2010- RA-patients achieved DMARD-free sustained remission most frequently. However, this small subgroup contained only ACPA-negative patients. When the analysis was also adjusted for ACPA, this effect was no longer present (Figure 2F).
Thus far the 2010-criteria were applied using the point system. When applying
the radiological criterion for RA-specific erosiveness (≥3 erosive joints)11,12 in addition
to the point system, 30 of the 61 1987+2010- RA were now 2010-criteria positive. All analyses on joint damage and remission were repeated; this did not influence the results (Supplementary Figures 1 and-2).
Finally, all analyses were repeated including the 397 patients that were treated in clinical trials, yielding similar results as described above (data not shown).
DISCUSSION
The present study evaluated the long-term outcome of patients classified to the 1987-criteria or the 2010-criteria and observed a statistically significant difference in the severity of joint damage and a non-significant difference with regard to disease persistency. For both outcomes, patients classified as RA using the 2010-criteria had a less severe disease course. Thereby the present data suggest that RA, when using the most recent classification criteria, has become a milder disease.
32 Chapter 2
Figure 2: Comparison of long-term outcomes of RA according to fulfillment of the 1987- and/or 2010 classification criteria for RA.
All analyses were adjusted for age, gender and treatment. Depicted in A, C and E are the predicted (by the multivariate normal regression model) Sharp-van der Heijde scores during 7-years of follow-up. Depicted in B,D,F are the percentage of patients achieving DMARD-free sustained remission A-B: Comparison of patients fulfilling the 1987-criteria and patients fulfilling the 2010-criteria. C-D: Comparison of patients fulfilling either one or both criteria sets for RA. E-F: Comparison of patients fulfilling either one or both criteria sets for RA, after also adjusting for the presence of ACPA. C,D,E,F; Presented are the overall p-values when comparing three groups.
2
criteria have a lower specificity than the 1987-criteria and can be positive in patients
that later on have other diagnoses (associated with a less destructive course)1,5,6,13-15.
Alternatively patients fulfilling the 2010-criteria, in particular the 1987-2010+ patients, may simply represent a milder set of patients. The milder outcome observed was not due to an earlier diagnosis and earlier treatment initiation, as the 2010-criteria were applied after the follow-up data were obtained.
In our study we did not observe large differences in baseline characteristics, though the 1987-RA patients experienced more morning stiffness than 2010-RA patients. This may be a consequence of morning stiffness being part of the 1987-criteria. Adding morning stiffness as an additional adjustment factor to the analyses did not gave different results (data not shown); hence the findings done were not driven by this baseline difference.
The 2010-criteria were derived with MTX-usage as outcome; by using this outcome some level of circularity could not be prevented. Advantages of the two outcomes used here is that they are independent of any set of classification criteria and therefore do not suffer from circle reasoning.
A limitation is that patients were treated. Ideally, the present study question was evaluated in patients that were not treated over many years, as this completely represents the natural disease course. We excluded patients that were treated in clinical trials and studied only patients treated according to routine care. Nonetheless the treatment strategies used in these patients had changed over time, therefore analyses were adjusted for these differences in treatment. Importantly, the proportion of 1987+ and 2010+ patients was similar for the different inclusion periods (data not shown). Moreover, including patients who were treated in clinical trials did not influence the findings.
All 1987+2010-patients were ACPA-negative, which is in line with another
recent report16. When the radiological criterion of the 2010-criteria was also applied, half
of this group of patients became 2010-criteria positive. This supports the relevance of the radiological criterion as the frequency of this misclassification reduced.
In conclusion, the present longitudinal study showed that RA classified according to the 2010-criteria has less severe joint destruction and is less often persistent than RA classified according to the 1987-criteria. This may have important implications, both for basic scientific studies and randomized clinical trials in RA.
SUPPLEMENTARY DATA
34 Chapter 2
REFERENCES
1. van der Helm-van Mil AHM, Huizinga TWJ. The 2010 ACR/EULAR criteria for rheumatoid arthritis: do they affect the classification or diag-nosis of rheumatoid arthritis? Ann Rheum Dis 2012;71(10):1596–8.
2. Britsemmer K, Ursum J, Gerritsen M, van Tuyl L, van Schaardenburg D. Validation of the 2010 ACR/EULAR classification criteria for rheuma-toid arthritis: slight improvement over the 1987 ACR criteria. Ann Rheum Dis 2011;70(8):1468– 70.
3. Cader MZ, Filer A, Hazlehurst J, de Pablo P, Buckley CD, Raza K. Performance of the 2010 ACR/EULAR criteria for rheumatoid arthri-tis: comparison with 1987 ACR criteria in a very early synovitis cohort. Ann Rheum Dis 2011;70(6):949–55.
4. de Hair MJH, Lehmann KA, van de Sande MGH, Maijer KI, Gerlag DM, Tak PP. The clinical picture of rheumatoid arthritis according to the 2010 American College of Rheumatology/ European League Against Rheumatism criteria: Is this still the same disease? Arthritis Rheum 2012;64(2):389–93.
5. van der Linden MPM, Knevel R, Huizinga TWJ, van der Helm-van Mil AHM. Classification of rheumatoid arthritis: comparison of the 1987 American College of Rheumatology criteria and the 2010 American College of Rheumatology/ European League Against Rheumatism criteria. Arthritis Rheum 2011;63(1):37–42.
6. Mäkinen H, Kaarela K, Huhtala H, Hannonen PJ, Korpela M, Sokka T. Do the 2010 ACR/EU-LAR or ACR 1987 classification criteria predict erosive disease in early arthritis? Ann Rheum Dis 2013;72(5):745–7.
7. de Rooy DPC, van der Linden MPM, Knevel R, Huizinga TWJ, van der Helm-van Mil AHM. Predicting arthritis outcomes—what can be learned from the Leiden Early Arthritis Clinic? Rheumatology 2011;50(1):93–100.
8. van der Woude D, Young A, Jayakumar K, et al. Prevalence of and predictive factors for sus-tained disease-modifying antirheumatic drug– free remission in rheumatoid arthritis: Results
from two large early arthritis cohorts. Arthritis Rheum 2009;60(8):2262–71.
9. Knevel R, Krabben A, Brouwer E, et al. Genetic variants in IL15 associate with progression of joint destruction in rheumatoid arthritis: a multi-cohort study. Ann Rheum Dis 2012;71(10):1651– 7.
10. Knevel R, Tsonaka R, le Cessie S, et al. Compari-son of methodologies for analysing the progres-sion of joint destruction in rheumatoid arthritis. Scand J Rheumatol 2013;42(3):182–9.
11. Knevel R, Lukas C, van der Heijde D, Rincheval N, Combe B, van der Helm-van Mil AHM. De-fining erosive disease typical of RA in the light of the ACR/EULAR 2010 criteria for rheumatoid arthritis; results of the data driven phase. Ann Rheum Dis 2013;72(4):590–5.
12. van der Heijde D, van der Helm-van Mil AHM, Aletaha D, et al. EULAR definition of erosive dis-ease in light of the 2010 ACR/EULAR rheuma-toid arthritis classification criteria. Ann Rheum Dis 2013;72(4):479–81.
13. Fautrel B, Combe B, Rincheval N, Dougados M, ESPOIR Scientific Committee. Level of agree-ment of the 1987 ACR and 2010 ACR/EULAR rheumatoid arthritis classification criteria: an analysis based on ESPOIR cohort data. Ann Rheum Dis 2012;71(3):386–9.
14. Kennish L, Labitigan M, Budoff S, et al. Utility of the new rheumatoid arthritis 2010 ACR/EULAR classification criteria in routine clinical care. BMJ Open 2012;2(5):e001117.
15. Zeidler H. How can misclassification be pre-vented when using the 2010 American College of Rheumatology/European League Against Rheumatism rheumatoid arthritis classification criteria? Comment on the article by van der Lin-den et al. Arthritis Rheum 2011;63(8):2544–2546; author reply 2456.
CHAPTER 3
Does treatment strategy influence the
ability to achieve and sustain DMARD-free
remission in patients with RA? - results
of an observational study comparing an
intensified treatment regimen with
treat-to-target in routine care
LE Burgers, JA van der Pol, TWJ Huizinga, CF Allaart,
AHM van der Helm-van Mil
38 Chapter 3
ABSTRACT Objectives
To study the impact of treatment strategy on achieving and sustaining disease modifying antirheumatic drug (DMARD)-free remission in patients with rheumatoid arthritis (RA).
Methods
279 RA-patients (median follow-up 7.8-years) were studied. Of these, 155 patients participated in a DAS<1.6-steered trial aimed at DMARD-free remission. Initial treatment comprised Methotrexate with high-dose prednisone (60mg/day) and a possibility to start biologicals after 4-months. In the same period and hospital, 124 patients were treated according to routine care, comprising DAS<2.4-steered treatment. Percentages of DMARD-free remission (absence of synovitis for≥1-year after DMARD-cessation), late flares (recurrence of clinical synovitis≥1-year after DMARD-cessation) and DMARD-free
sustained remission (DMARD-free remission sustained during complete follow-up) were
compared between both treatment strategies.
Results
Patients receiving intensive treatment were younger and more often ACPA-positive. In ACPA-positive RA an intensive treatment regimen resulted in more DMARD-free remission (25% vs 6%, HR 4.9, 95%CI 1.4-17, corrected for age). No significant differences were observed in the whole group (35% versus 29%) or in the ACPA-negative stratum (49% versus 44%). Intensive treatment was associated with more late flares (20% versus 8%, HR 2.3, 95%CI 0.6-8.3). Subsequently, there was no difference in DMARD-free
sustained remission on group level (28% versus 27%), nor in the ACPA-negative (43%
versus 42%) or ACPA-positive stratum (17% versus 6%, HR 3.1, 95%CI 0.9-11, corrected for age).
Conclusions
3
INTRODUCTION
Over the last decades, treatment of rheumatoid arthritis (RA) has changed dramatically. Treatment targets have shifted from mere relief of symptoms towards treat-to-target
therapy aimed at remission and prevention of structural joint damage1–3. The recent
EULAR recommendations for the management of RA state that treatment should be aimed at sustained remission or low disease activity, defined according to Boolean
or index-based definitions, which correspond with absence of radiologic damage2,4.
These treatment aims can be achieved while patients are still on disease modifying antirheumatic drugs (DMARDs).
Although RA is considered a chronic disease, there is growing evidence that a proportion of patients can achieve DMARD-free remission with reported percentages
ranging between 3.6-23%5–12. To note, varying definitions of DMARD-free remission
were used in these studies. DMARD-free sustained remission, which has been defined as the sustained absence of arthritis after cessation of DMARDs, may be interpreted as the closest proxy to cure of RA, especially as it also corresponds with a patient-perceived state of remission in terms of normalized levels of physical functioning, pain, fatigue
and stiffness13,14 Although studies have shown it is an achievable goal in part of
RA-patients, EULAR recommendations are cautious with regards to tapering and stopping DMARDs. The main reason for this being the lack of evidence about safely stopping
DMARD-therapy and the risk of flares 2,15–17.
The presence of RA-related autoantibodies associates with a decreased risk of
DMARD-free sustained remission10,13, but biologic mechanisms mediating resolution
of RA chronicity are mostly unknown5. Studies have shown that with better treatment
options and the introduction of DAS-steered treatment, DMARD-free remission has
become a more achievable outcome13. However, it is unclear if current DAS-steered
treatment, starting with Methotrexate (MTX) results in an optimum chance for achieving this outcome, or whether a more intensive DAS-steered treatment regimen can result in an even higher proportion of patients achieving and sustaining DMARD-free remission. Therefore, this study assessed if treatment strategy impacts on the chance of disease resolution. We compared the prevalence of DMARD-free remission, as well as DMARD-free sustained remission between patients treated according to an intensive DAS-steered treatment strategy as applied in the setting of a clinical trial (the
EULAR-40 Chapter 3
recommendations2. All studied patients were treated in the same centre by the same
rheumatologists. In short, trial patients were treated DAS(<1.6)-steered and started with high dose prednisone next to MTX, whereas routine care consisted of initial MTX and DAS(<2.4)-steered treatment.
METHODS Patients
All patients who were newly diagnosed with RA (according to the 2010-criteria) between March 2007-September 2010 in the Leiden University Medical Center and who were
included in the Leiden Early Arthritis Clinic (EAC)19 were selected for this study (n=313,
Figure 1). The EAC is a prospective, population based inception cohort that includes
Figure 1: Flowchart of patient selection
Figure depicting patient selection for the current study. EAC, early arthritis clinic; RA, rheumatoid arthritis; DAS, disease activity score; DMARD, disease modifying antirheumatic drug; MTX, methotrexate. Patients in the regular treatment group that did not fulfil the inclusion criteria of the IMPROVED-study were excluded for reasons of comparability.
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patients with clinically confirmed arthritis and a symptom duration <2-years19. Besides
regular visits with their rheumatologist, patients had scheduled study visits at least once a year, including questionnaires, physical examination and blood samples. All patients were treated by the same team of rheumatologists in the same center, but according to different treatment strategies; either according to an intensive DAS-steered treatment
regimen within the IMPROVED-study18 or according to up-to-date routine care (see
below for more details). In order to study a homogenous group of patients, those who did not fulfill the inclusion criteria of the IMPROVED-study (see below) or were not started on DMARD-therapy were excluded (n=34) (Figure 1). Thus, a total of 279 patients were studied. In principle, all patients could have been included in the IMPROVED-study. Nevertheless only 155 patients were included. Reasons why 124 patients were not included were not routinely documented, but could either be patient related (for example, patient did not want to participate), rheumatologist related (rheumatologist did not ask patient to participate) or both.
Intensive treatment
The IMPROVED-study is a multicenter randomized single-blinded clinical
trial that recruited 610 patients between March 2007-September 201018. For inclusion,
patients had to be≥18-years, have a diagnosis of early RA or UA, a DAS≥1.6 and no prior use of DMARDs. In the trial all patients were started on Prednisone 60mg/day which was tapered to 7.5mg/day in 7 weeks and MTX, starting at 7.5mg per week and escalated to 25mg/week. If patients were in early remission (DAS <1.6) after 4-months, Prednisone was tapered to stop and if patients were still in remission after 8-months MTX was tapered and stopped as well over the next 4-months. If patients were not in remission after 4-months, they were randomized either to adding Hydroxychloroquine and Sulphasalazine to MTX and Prednisone, or to switching to MTX plus Adalimumab. Patients had 4-monthly visits and medication was tapered or stopped in case of a DAS<1.6 and restarted, switched or increased in case of a DAS≥1.6. Primary outcomes were DAS-remission and drug-free DAS-remission based on a DAS<1.6. The study has previously been
described18,20 and was approved by the Medical Ethical Committee. All patients provided
