Remission in early rheumatoid arthritis: Predictors, definitions and treatment

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Remission in early rheumatoid arthritis

Predictors, definitions and treatment

Thesis by

Nina Paulshus Sundlisæter

2020

Diakonhjemmet Hospital Department of Rheumatology

Oslo, Norway

University of Oslo Faculty of Medicine

Oslo, Norway

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© Nina Paulshus Sundlisæter, 2020

Series of dissertations submitted to the Faculty of Medicine, University of Oslo

ISBN 978-82-8377-642-3

reproduced or transmitted, in any form or by any means, without permission.

Cover: Hanne Baadsgaard Utigard.

Print production: Reprosentralen, University of Oslo.

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Acknowledgements

The last months have been surrealistic. Thanks to the coronavirus, my eyes have opened up for what I usually take for granted, in particular how important weekdays are. All of you mentioned here play a valuable role in my weekdays. I am very proud of and thankful to work with so many brilliant, creative and adaptable colleagues with an impressive way of handling our clinical and research department in “good and bad days”. I am also extremely grateful to be surrounded by family and near friends giving me a feeling of safety and happiness even when the world seems falling apart.

So, due to the circumstances, I am going to defend my thesis in solitude. But, this work would not have come this far without the contribution of a great number of people to whom I am incredible grateful.

First of all, I would like to thank my impressive team of supervisors; Siri Lillegraven, Espen A. Haavardsholm, Anna-Birigtte Aga and Prof. emeritus Tore K. Kvien.

Siri Lillegraven, my main supervisor, to you I am incredible grateful. Tirelessly (at least that’s my impression) you have shared your wisdom, insight, valuable time and magical writing skills. It impresses me how you always manage to possess an extremely detailed overview of international as well as local research. Your critical look at methods and suggestions for improvements lifts the quality of abstracts, manuscripts, applications as well as presentations.

In addition, you have become a very good friend, listening and encouraging me whenever needed. Thank you for letting me be a part of the ARCTIC REWIND team, I really look forward to continue working with you and this trial.

Espen, your merit list is impressive – both in scientific and in social life. Thank you for sharing your wisdom and competence in such a friendly way. You (mostly) appear incredible calm and act as you have all time in the world, even if that is not at all the case.

Tore, thank you for such valuable input and discussions along the way – few PhD students are privileged by having a world’s expert on the field as a supervisor. By coincidence I met you and your wife Turid in 2010, and thank you so much for keeping the door into the Department of Rheumatology and the “Villa” open for me.

Anna-Birgitte, I miss you in the “Villa”. Your friendly, calm and all but patronizing way of being has meant a lot to me, especially in periods without any signs of progression.

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Further, I am grateful to all of my co-authors. Thanks to Prof. Hilde B. Hammer, Prof. Till Uhlig and Prof. Désirée van der Heijde for valuable input, viewpoints and discussions.

Thanks to Joe Sexton and Inge C. Olsen for your statistical contributions, for your endless attempts of making statistics understandable – and for teaching me to always question my own and others research.

Thanks to Ellen Moholt, Camilla Fongen and Bjørn Solvang for being helpful, patient and solution oriented.

This research would not have been possible without benevolent patients, and a great number of local investigators in the ARCTIC and ARCTIC REWIND trials, to whom I send warm thanks.

I always look forward going to work, even if papers are keeping returned and days are gray.

The reason is you fantastic colleagues in the “Villa”, which makes such an inspiring and innovative, but at the same time laid back and cozy environment. Thanks to Ulf Sundin and Maria K. Jonsson for all scientific and non-scientific conversations, and to Lena B. Nordberg – my good colleague and friend - sitting next to you has really spiced up my years as PhD student.

I am lucky to also be surrounded by good and intelligent colleagues in the clinical work, doctors, nurses and secretaries. A special thanks to Silje W. Syversen, Vera Halsaa, Marte S.Heiberg and Kjetil Bergsmark for valuable support and good advices in times when needed.

I am thankful to Diakonhjemmet for the excellent support they provide their researchers, and the University of Oslo for facilitating my PhD project.

Thanks to my good friends Ragnhild, Lene, Birgit, Hanne and Nina for running and talking me through all aspects of life while writing this thesis.

Finally, I want to thank my family. Thanks to my two brothers for inspiring me, and to my family-in-law for being supportive. The warmest thanks to my Mum and Dad, for always encouraging me and helping me find a solution, to see my needs, for your love and care.

Many hours spent working with this thesis I owe to you. Last, but not least, Ludvik, Eivind and Eirik – the best thing I know is to spend my time with you.

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Funding

This PhD-fellowship was funded by the Research Council of Norway. Institutional support was provided by the administration at Diakonhjemmet Hospital.

The ARCTIC trial was supported by the Research Council of Norway, the South-Eastern Norway Regional Health Authority, the Norwegian Rheumatism Association, and

investigator initiated research grants from AbbVie, UCB, Pfizer, MSD and Roche. Siemens Healthcare and GE Healthcare provided technical support regarding standardisation of ultrasound equipment.

The ARCTIC REWIND was financed through grants from the Research Council of Norway and the South-Eastern Norway Regional Health Authority.

The funders of the studies have not been involved in study design, data collection, data analyses, data interpretation, or writing of the manuscripts.

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Abbreviations

ACPA Anti-Citrullinated Peptide Antibodies

ACR American College of Rheumatology

AE Adverse Event

ARA American Rheumatism Association

ARCTIC Aiming for Remission in rheumatoid arthritis: a randomised trial examining the benefit of ultrasonography in a Clinical TIght Control regimen

ARCTIC REWIND REmission in rheumatoid arthritis – assessing WIthdrawal of disease- modifying antirheumatic drugs in a Non-inferiority Design

bDMARD biologic Disease Modifying Anti-Rheumatic Drug

BMI Body Mass Index

CDAI Clinical Disease Activity Index

CI Confidence Interval

CR Conventional Radiographs

CRP C-Reactive Protein

csDMARD conventional synthetic Disease Modifying Anti-Rheumatic Drug

DAS Disease Activity Score

DI Disability Index

DMARD Disease Modifying Anti-Rheumatic Drug ESR Erythrocyte Sedimentation Rate

EQ-5D EuroQol-5 Dimensions

EudraCT European Union Drug Regulating Authorities Clinical Trials EULAR EUropean League Against Rheumatism

GCP Good Clinical Practice

GS Grey Scale (ultrasound)

HAQ Health Assessment Questionnaire HCQ HydroxyChloroQuine

HLA Human Leukocyte Antigen

IL InterLeukin ITT Intention-to-treat

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IQR InterQuartile Range

JAK JAnus Kinase

JSN Joint Space Narrowing

LEF LEFlunomide MBDA Multi-Biomarker Disease Activity MCP MetaCarpoPhalangeal MTX MetoThreXate

MRI Magnetic Resonance Imaging

MTP MetaTarsoPhalangeal

NA Not Applicable

NSAID NonSteroidal AntiInflammatory Drugs OMERACT Outcome Measures in Rheumatology

OR Odds Ratio

PD Power Doppler (ultrasound)

PGA Patient Global Assessment

PhGA Physician Global Assessment

PROMIS Patient-Reported Outcomes Measurements Information System

RA Rheumatoid Arthritis

RAID Rheumatoid Arthritis Impact of Disease

RAMRIS Rheumatoid Arthritis Magnetic Resonance Imaging Score RCT Randomised Controlled Trial

RF Rheumatoid Factor

SA Single Arm

SAP Statistical Analysis Plan

SD Standard Deviation

SDAI Simplified Disease Activity Index

SDC Smallest Detectable Change SDD Smallest Detectable Difference

SE Standard Error

SF-36 Short-Form 36

SJC Swollen Joint Count

SSZ SulfhaSalaZine

STAT Signal transducers and activators of transcription

TNF Tumor Necrosis Factor

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11 tsDMARDs targeted synthetic Disease Modifying Anti-Rheumatic Drug

TJC Tender Joint Count

VAS Visual Analogue Scale

vdHSS van der Heijde-modified Sharp Score

WPAI Work Productivity and Activity Impairment Questionnaire

∆vdHSS change in the total van der Heide-modified Sharp Score

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List of papers

I. Nina Paulshus Sundlisæter, Inge C. Olsen, Anna-Birgitte Aga, Hilde B. Hammer, Till Uhlig, Désirée van der Heijde, Tore K. Kvien, Siri Lillegraven*, Espen A.

Haavardsholm* and the ARCTIC study group. *Shared last authors. Predictors of sustained remission in patients with early rheumatoid arthritis treated according to an aggressive treat-to-target protocol.Rheumatology 2018;57:2022-31.

II. Nina Paulshus Sundlisæter, Anna-Birgitte Aga, Inge Christoffer Olsen, Hilde Berner Hammer, Till Uhlig, Désirée van der Heijde, Tore K. Kvien, Siri

Lillegraven*, Espen A Haavardsholm*, the ARCTIC study group. *Shared last authors. Clinical and ultrasound remission after 6 months of treat-to-target therapy in early rheumatoid arthritis: associations to future good radiographic and physical outcome. Ann Rheum Dis 2018;77:1421–25.

III. Siri Lillegraven*, Nina Paulshus Sundlisæter*, Anna-Birgitte Aga*, Joseph Sexton, Inge C. Olsen, Hallvard Fremstad, Cristina Spada, Tor Magne Madland, Christian A. Høili MD, Gunnstein Bakland, Åse Lexberg, Inger Johanne Widding Hansen, Inger Myrnes Hansen MD, Hilde Haukeland, Maud-Kristine Aga Ljoså, Ellen Moholt, Till Uhlig, Daniel H. Solomon, Désirée van der Heijde, Tore K. Kvien, Espen A. Haavardsholm. *Shared first authors. Stable versus half-dose conventional synthetic disease-modifying antirheumatic drugs in rheumatoid arthritis remission (ARCTIC REWIND): a randomised, open-label, phase 4, non-inferiority trial. [Submitted]

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1. Introduction and background

1.1 Rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by joint

inflammation with subsequent joint destruction and functional loss. RA might also include extra-articular manifestations, and there is an increased risk of cardiovascular disease and mortality.(1, 2) In the past two decades there has been a therapeutic revolution in the treatment and management of RA patients, with improved articular and systemic

outcomes.(1) Remission and sustained remission have become achievable targets due to modern treatment strategies and available drugs. The optimal definition of remission aims to minimize future joint destruction and disability without compromising possible side-effects for the patients and costs for the society. With an increasing number of patients reaching the therapeutic target, the question of treatment withdrawal is engaging both rheumatologist and patients. At the present, there is a great focus on personalized medicine, and the possibility to predict outcomes and treatment effects at the patient level is central.

1.1.1 Classification

New classification criteria for RA were developed in 2010 to accommodate the increasing evidence that early recognition of the disease with immediate therapeutic intervention would improve clinical outcomes and prevent joint damage and disability.(3-6) The 2010

American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria have improved sensitivity in early disease capturing features predictive of chronicity and radiographic damage, rather than defining the disease by its late stage features as was the case in the 1987 ACR classification criteria for RA.(6) The 2010

ACR/EULAR classification criteria focus on joint involvement and distribution, and should be applied on patients with confirmed presence of clinical synovitis in at least one joint.

Furthermore, the criteria take duration of symptoms, the presence of autoantibodies and elevated acute phase reactants into account (table 1).(6) A limitation in the performance of the new criteria could be the great emphasis on the serological status, with delayed

diagnosis of seronegative patients as a possible consequence.(7) However, classification is

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14 not synonymous with diagnosis. Diagnostic criteria have the goal of being correct at the level of the individual patient, while classification criteria aims to maximise homogenous populations for study purpose.(1)

Table 1: The 2010 ACR/EULAR classification criteria for RA*

JOINTS (0–5) †

1 large joint 0

2–10 large joints 1

1–3 small joints (large joints not counted) 2 4–10 small joints (large joints not counted) 3

>10 joints (at least one small joint) 5

SEROLOGY (0–3)

Negative RF AND negative ACPA 0

Low positive RF OR low positive ACPA 2

High positive RF OR high positive ACPA 3

SYMPTOM DURATION (0–1)

<6 weeks 0

≥6 weeks 1

ACUTE PHASE REACTANTS (0–1)

Normal CRP AND normal ESR 0

Abnormal CRP OR abnormal ESR 1

* The criteria apply to patients with at least one joint with clinical synovitis not related to a specific aetiology. A patient must achieve a score of 6 or more points to be classified as RA.(6) In the presence of erosions typical of rheumatoid arthritis, no other points are needed for classification.(8)

† Joint involvement includes any tender or swollen joints, except from DIP of hand and feet, CMC1, MTP1, and MRI/ultrasound may be used to determine a more complete joint involvement.(9)

Abbreviations: ACPA: Anti-Citrullinated Peptide Antibodies, CRP: C-reactive protein, ESR: Erythrocyte Sedimentation Rate, RF: Rheumatoid factor.

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15 1.1.2 Epidemiology

Epidemiology is the study of health-related states and the prevalence and causes of disease in specified populations.(10) RA is one of the most prevalent chronic inflammatory

diseases, generally reported to affect 0.5-1% of the adult population of developed

countries.(1, 11) The incidence in Northern America and Northern Europe range from 20-50 per 100 000 persons per year, with lower incidence rates reported in Southern Europe.(11- 14)

RA is more common in women than in men,(15, 16) and the incidence increases with age, with a peak in the 60-79 years age group.(13, 14) Assessment of heritability in RA shows a prevalence of 2-5% for dizygotic twins and other first-degree relatives, meaning that a positive family history gives a two- to fivefold increase in risk. Monozygotic twins share RA on about 12%-15% of occasions. Genetic factors have a substantial contribution to RA accounting for approximately 40-65% of the liability of disease for seropositive RA, and approximately 20% for seronegative RA. The relatively low concordance suggests that other factors, such as environmental exposures, are also important in the pathogenesis of RA.(1, 17-21) Especially patients with highly active RA have an increased mortality risk compared to the general population, mainly due to the elevated risk of cardiovascular disease,

lymphoproliferative malignancies, pulmonary complications and adverse events of RA treatment such as infections and gastrointestinal bleeding.(22-24) Over the last decades a decrease in mortality has been observed, probably due to earlier diagnosis, modern treatment and treatment strategies, and increased knowledge of modifiable cardiovascular and lifestyle risk factors.(25-27)

1.1.3 Pathogenesis

RA is a complex disease, with several genetic and environmental risk factors found to be associated with its development.(18, 28) The environmental triggers (e.g. smoking, periodontitis, viral infections and the microbiome) contribute to local tissue stress which might lead to epigenetic modifications and post-translational protein modifications as citrullination of arginine by peptidyl arginase deiminase. In genetically susceptible individuals, these modified proteins could be presented via the human leukocyte antigen (HLA)-DR shared epitope on antigen-presenting cells to T-cells, with subsequent activation

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16 of T-cells and B-cells resulting in generation of autoantibodies.(18, 28, 29) Autoantibodies, such as anti-citrullinated peptide antibodies (ACPA) and antibodies to the Fc fragment of IgG (rheumatoid factor (RF)) might develop many years before signs and symptoms of RA occur, a stage termed “pre-RA” in patients who subsequently develop the disease.(30, 31) In this stage the immunological tolerance is broken with immune complex formation and complement activation, leading to an immune response against “self”-antigens culminating with inflammation and clinical synovitis.(29, 32) It is also proposed that ACPA might have a direct activating effect on osteoclasts, potentially inducing bone resorption and pain independent of inflammation.(32-35)

The process whereby autoreactivity transforms a paucicellular synovium into a chronically inflamed joint and symptomatic arthritis is poorly understood and immune-histochemical analyses of the synovium in seropositive individuals at risk of developing RA show no clear-cut synovial inflammation before clinical signs or symptoms of arthritis is present.(36) The articular localisation might arise from a “second hit”, such as a local microtrauma or microvascular insult (figure 1).(18, 28, 29)

The synovial inflammation is regulated by a complex cytokine and chemokine network with inhibitors of tumor necrosis factor alfa (TNFα) and interleukin (IL)-6 particular potent in the treatment of RA. Furthermore, as T- and B-cells are involved in RA pathogenesis, a T-cell- co-stimulator blockade and a cell-depleting agent binding CD20-antigen on B-cells are effective. Inhibitors of the Janus kinase (JAK) pathways are also potent.(18)

Based on the diversity of clinical manifestations and responses to highly targeted therapeutic agents, RA probably does not comprise of a single entity, but should be

considered a syndrome with a common clinical phenotype arising from diverse pathways in individual patients.(18) In particular seronegative RA is less understood, but also likely to involve discrete genetic and environmental factors. Further insight into disease pathogenesis is crucial for the vision of future RA therapeutics: restoration of immunologic homeostasis with drug-free remission.(28)

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17 Figure 1 Pathways to rheumatoid arthritis.

In a genetically predisposed host with susceptibility genes, environmental insults, epigenetic modifications, and post-translational modifications can lead to loss of tolerance with subsequent activation of the immune system, ultimately leading to clinically overt arthritis.

First published by Smolen et al in the Lancet, 2016 (1). Reprinted with permission from Elsevier.

1.1.4 Prognosis and prognostic factors

RA prognosis is related to long-term outcomes as joint damage and physical function, and evaluation of prognostic factors is important to inform treatment decisions. If RA is left insufficiently treated, 80% of patients will have joint deformities and 40% will be unable to work within 10 years from disease onset.(29) These patients may also be affected by

multiple comorbidities such as cardiovascular disease, interstitial lung disease and

lymphoma. Over the last 20-30 years RA prognosis has improved considerably, with a more than two-fold increase in the Disease Activity Score with 28 joints (DAS28) remission rates (18% to 40%) observed among Norwegian RA patients in the period 2000-2010.(37)

Despite this impressive prognostic improvement at the population level, it does not apply to all individuals with RA.(38) In addition, some patients might experience adverse effects of synthetic and/or biologic disease modifying anti-rheumatic drugs (DMARDs), and the latter drugs may be expensive. It would be a great advantage to increase the ability to distinguish

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18 patients who will develop severely destructive RA from those in whom the disease will follow a milder course, and to predict treatment response.(38) Therefore, identification of prognostic factors is important for the possibility of individualizing treatment, as well as making the patients expectations more realistic.(39)

High disease activity, autoantibody positivity and early presence of radiographic damage are well-known negative prognostic factors in early RA, as reflected both in the 2010

classification criteria and in the present EULAR treatment recommendations.(6, 40)

Inflammatory markers, such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), are not highly predictive as they are not specific to RA,(41) while the level of calprotectin and the multibiomarker disease activity (MBDA) score are found to be associated with radiographic progression.(42, 43) Several studies indicate the ability of power Doppler (PD) ultrasound to predict disease activity and structural damage,(44, 45) and magnetic resonance imaging (MRI) bone marrow edema are shown to be highly

predictive of radiologic progression both in randomised controlled trials (RCTs) and cohort studies.(46, 47) Smoking is found to be associated with the development of RA and with response to methotrexate (MTX), but the impact on clinical or radiological outcomes has not been clarified.(48, 49) In a Swedish early RA cohort, smoking was demonstrated as an independent risk factor for radiographic progression, while other studies have shown rather a protective effect of smoking on RA outcome.(50-52) Adipose tissue is an

endocrine/paracrine organ which secrets important pro-inflammatory signals such as TNF- alfa and IL-6; in contrast adipose tissue can also produce cortisol which is a potent antiinflammatory substance. Thus, overweight might have a dual influence on disease activity and joint damage progression in RA.(53) Underweight has been associated with increased mortality in RA.(53, 54) A population-based study indicates a genetic predisposition for disease severity, not only for the development of RA.(55) The Health Assessment Questionnaire (HAQ) physical function score is historically seen as an outcome of the disease reflecting joint damage, especially with increasing disease duration.(56) Today, with treatment initiation in earlier stages of the disease, patient reported outcomes (e.g.

pain) are shown to be more consistent predictors of long-term physical disability than erosions and serology markers.(57) An overview of poor prognostic factors is shown in table 2. Most of the included prognostic factors are also found to be predictive of long-term physical function. However, functional outcome was not included in the table as results were less consistent between studies, partly due to confounding by disease duration.(56-59)

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19 Table 2 Overview of a selection of prognostic factors in RA*

Prognostic factor Outcome assessed

Disease activity

Composite measure↑ Absence of remission(60)

Radiographic progression(61, 62) Acute phase reactants↑ Absence of remission(60, 63)

Radiographic progression(46, 64, 65) Number of swollen joints↑ Radiographic progression(66) Number of tender joints↑ Absence of remission(60, 63, 67-70) ACPA and/or RF positivity Absence of remission

Radiographic progression(46, 52, 58, 59, 61, 64, 65, 71, 72)

Delayed diagnosis/ treatment initiation EULAR response(49)

Absence of remission(68, 70, 73, 74) Radiographic progression(73)

Smoking EULAR response(49)

Absence of remission(75) Radiographic progression(52) Body mass index

High BMI Absence of remission(53, 54, 75)

Low BMI Radiographic progression(61, 72)

Radiographic joint damage

Erosions Absence of remission(67)

Radiographic progression(52, 59, 65, 72) Joint space narrowing

Total radiographic score Absence of remission(60) Radiographic progression(71) Magnetic resonance imaging

MRI Bone marrow edema Radiographic progression(46, 47, 58, 71, 76) MRI Synovitis Radiographic progression(46)

Ultrasound

Power Doppler Disease activity(44)

Radiographic progression(44, 45) Grey scale synovitis Disease activity (44)

Radiographic progression(44) Genetic predisposition Radiographic progression(55) HAQ physical function score↑ Absence of remission(63, 70, 75)

MBDA score↑ Radiographic progression(42)

*This table is based on a selection of studies with adjusted analyses of potential baseline predictors (most of them including patients before treatment initiation), and not on a systematic literature search.

Abbrevations: ACPA: Anti-Citrullinated Protein Antibody, BMI: Body Mass Index, EULAR: EUropean League Against Rheumatism, HAQ: Health Assessment Questionnaire, MBDA: Multi Biomarker Disease activity, MRI: Magnetic Resonance Imaging, RF: Rheumatoid Factor.

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20 A good predictive model should determine absolute risk, i.e. the probability that a particular event will occur in the individual patient of interest. Risk model matrices provide estimates of the probability of treatment response or radiographic progression if one predictor or combinations of predictors are present. Models developed in RCT datasets have shown poor discriminative ability in validation cohorts representative of a wider RA population

resembling daily clinical settings.(38, 77) Enhanced precision regarding prediction of rapid radiographic progression has been shown for a matrix developed using pooled data from several RCTs and cohorts, but achievement of sufficient discriminatory power remains a challenge.(78) The relevance of poor prognostic factors for the outcome of RA is

challenging as treatment strategies always interfere as confounders.(48)

With an increasing number of RA patients with excellent disease control, a common question has become how to best manage patients in sustained remission. Which patients who profit most from tapering of treatment remains to be defined, but at present the most important factors to predict successful tapering of DMARD therapy are remission state and duration of remission.(79) ACPA negativity and absence of subclinical inflammation on ultrasound are associated with higher chances of drug-free remission with less risk of relapse.(80-83)

1.2 Assessment of disease activity and physical function

Assessment of disease activity is crucial to evaluate treatment efficacy and to monitor the course of the disease both in clinical practice and research.

1.2.1 Clinical examination

The most characteristic clinical signs of an inflamed joint are swelling and tenderness. The evaluation of these two features is therefore fundamental in the diagnosis and daily care of RA patients.(6) However, there are disagreements regarding how many joints should be assessed at each visit, and how accurate these measurements are in detecting true

inflammation. Bony swelling and joint deformities can for example complicate the count of swollen joints, while the number of tender joints may be affected by comorbidities as pain hypersensitivity.(84) In the 1960s, the American Rheumatism Association agreed on measuring disease activity in all peripheral synovial joints (66/68 joint count), but many studies have since then aimed to develop a more pragmatic reduced joint count, as the

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21 extensive 66/68 joint count is time consuming.(84) The Ritchie Articular Index and 44

swollen joint count are implemented in the original Disease Activity Score (DAS),(85, 86) and an even more reduced joint count based on 28 swollen and tender joints are part of several commonly used composite scores; DAS28, Simplified Disease Activity Index (SDAI), and the Clinical Disease Activity Index (CDAI).(87, 88) The 28 joint count has been shown as a valid and reliable measure of joint assessment compared to the traditional 66/68 joint count,(84, 89) however, the 28 joint count is criticised for not including

information about feet.(90) The Ritchie Articular Index uses a different approach to examination of joint tenderness than the other methods mentioned, as the assessments of tenderness are graded and certain joints are treated as a single unit.

Other single clinical measures usually assessed at a study visit include the patient’s

assessment of pain, and patient’s and physician’s global assessment of disease activity on a visual analogue scale (VAS).

1.2.2 Laboratory measurements

The most commonly measured acute phase reactants to evaluate inflammation are ESR and CRP. These markers are usually, but not always, elevated in RA patients with active

disease. As values usually decline with DMARD treatment, they can be used to monitor disease over time. ESR and CRP are criticized for being nonspecific and insensitive as they can be elevated due to other inflammatory conditions, e.g. infections.(41) The MBDA score is a novel blood test developed to objectively assess RA disease activity. The score is calculated using an algorithm that combines 12 individual serum biomarkers involved in the pathogenesis of RA. However, discrepant validity is reported for the MBDA in measuring RA disease activity, and further research regarding its ability to improve RA management is needed.(91) Calprotectin has gained interest as a marker of inflammation in RA, but more studies are needed to validate its clinical relevance.(43)

The autoantibodies RF and ACPA are important when diagnosing and classifying RA, but are also of prognostic value as both are associated with more aggressive, destructive disease.

The concentrations of these autoantibodies have been shown to decrease with effective therapy,(92) and seroconversion with respect to autoantibodies has been proposed as

“immunological remission”.(79)

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22 1.2.3 Physical function and health-related quality of life

Physical function in RA is often evaluated by a version of the HAQ. The most common is the disability index (DI) of this instrument, the HAQ-DI , that includes questions concerning the ability of patients to perform 20 activities of daily living with four response categories for each question.(93) A substantial “ceiling-effect” (i.e. a considerable group of patients have good/normal scores), is a limitation of HAQ. Thus it may not be the most appropriate scale for use in patient populations with relatively good functional capacity.(94) The newer Patient-Reported Outcomes Measurement Information System (PROMIS) assesses physical function using the 20 items in the original HAQ, but with a fifth response option of “with a little difficulty” added. It also uses a different scoring algorithm where the total raw score (the sum of the values of the response to each question) is translated into a T-score with a mean of 50 and a standard deviation (SD) of 10.(95, 96) The SF-36, EuroQol 5-dimension (EQ-5D) and the RA Impact of Disease (RAID) scores are patient reported outcome measures that capture other aspects of RA such as pain, fatigue, social functioning, emotional well-being and sleep disturbance as well as physical functioning.(97-99) The impact of RA on work productivity is assessed by the Work Productivity and Activity Impairment Questionnaire (WPAI).(100)

1.2.4 Composite disease activity scores

No single marker reflects all aspects of the inflammatory process in RA. The development of composite scores for assessment of disease activity has significantly improved the ability of the clinicians to evaluate the course of RA.(87) DAS28, DAS, SDAI and CDAI are the most commonly used indices, both in clinical practice and clinical trials. They all include tender and swollen joint count, acute phase reactants (except for CDAI), patient’s evaluation of disease activity, and for SDAI and CDAI the physician’s evaluation are also included. In addition, the categorical Boolean based definition of remission was developed in 2011 by an ACR/EULAR task force.(101) In a modern treat-to-target strategy, the mentioned indices are used to monitor disease activity, guide treatment decisions and to define the treatment goal. The thresholds for disease activity states by each composite score are shown in table 3.

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23 Table 3 Composite measures of disease activity in RA

Disease activity level

Remission Low Moderate High

DAS <1.6 1.6 to 2.4 >2.4 to 3.7 >3.7

DAS28 <2.6 2.6 to 3.2 >3.2 to 5.1 >5.1

SDAI ≤3.3 >3.3 to 11 >11 to 26 >26

CDAI ≤2.8 >2.8 to 10 >10 to 22 >22

ACR/EULAR Boolean remission criteria

SJC≤1, TJC≤1, CRP

(mg/dl)≤1, PGA≤1

NA NA NA

Abbrevations: ACR: American College of Rheumatology, CDAI: Clinical Disease Activity Index, CRP: C- reactive protein, DAS: Disease Activity Score, DAS28: Disease Activity Score with 28 joints, EULAR:

European League Against Rheumatism, NA: Not applicable, PGA: Patient Global Assessment, SDAI:

Simplified Disease Activity Index, SJC: Swollen Joint Count, TJC: Tender Joint Count.

1.3 Imaging

Imaging modalities capture two main features in RA; structural damage and inflammation.

While conventional radiography (CR) only assesses structural changes that are the

cumulative results of preceding disease activity, modern imaging technics such as MRI and ultrasound additionally visualises ongoing inflammation.(102)

1.3.1 Ultrasound

With its low cost and good accessibility, ultrasound has been increasingly used in diagnosis and management of RA. In addition to structural pathology, such as erosions and

osteophytes, two aspects of synovitis can be assessed by ultrasound; morphology and

quantity using grey scale (GS) and synovial vascularity using PD. Tissues reflect and absorb the ultrasound waves at different extents, e.g. fluid and cartilage appear black as they are weak reflectors while bone appears white, causing a spectrum of grey scales arising in the two-dimensional image. Ultrasound Doppler signals appear as the transmitted wavelengths are changed by erythrocytes in motion before returning to the transducer.(103, 104) The EULAR-OMERACT (Outcome Measures in Rheumatology) ultrasound taskforce has

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24 agreed upon a combined scoring system for the grading of ultrasound synovitis, with the degree of GS synovitis and PD activity scored by a four-point semi-quantitative scale (0- 3).(105, 106) Which joints and tendons should be assessed for a sensitive and feasible evaluation of joint inflammation is still debated. Most rheumatology departments in Norway use the validated 0-3 semiquantitative scoring system of GS and PD, with standard probe placements and patient position and with an ultrasound atlas for reference.(107) Although ultrasound examination is an operator dependent method, high intra- and interrater

reliability has been found.(107)

1.3.2 Magnetic Resonance Imaging

MRI is a non-invasive tomographic imaging technique that yields cross-sectional images in any plane. MRI allows simultaneous examination of all components of the joint, including soft tissue, articular cartilage and bone, without ionising radiation and with minimal adverse effects. In addition to joint destruction (erosions and joint space narrowing (JSN)), synovitis and tenosynovitis, MRI is the only imaging technique that visualizes bone marrow

oedema/osteitis.(102) The OMERACT RA MRI scoring system (RAMRIS) is validated for assessment of MRI images of the wrist and metacarpophalangeal (MCP) joints in RA.

RAMRIS includes a core set of MRI sequences and a semiquantitative scoring system for erosions, JSN, bone marrow edema, synovitis, and tenosynovitis.(108, 109)

1.3.3 Conventional radiography

CR has been in use for a long time to assess structural joint damage in RA, which is a hard endpoint of the disease. Regular evaluation of structural changes by CR is recommended for monitoring of the disease course and to guide treatment decisions in clinical practice.(110) Radiographic progression is usually assessed in hands and feet because these joints are most often involved in RA, and allow for a high number of joints to be covered using a low number of radiographs.(111) In routine practice, radiographs are usually evaluated semi- quantitatively without any formal scoring. For clinical trials, several instruments are developed to measure radiographic progression, and can largely be divided into Larsen- based methods and Sharp-based methods (112, 113). The main difference between these two methods is that the Larsen score applies a global grading of joint damage, while the Sharp score quantifies number and size of erosions per joint and amount of JSN.(111) The Sharp-based methods, for example the van der Heijde-modified Sharp score (vdHSS), are

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25 sensitive for detecting changes over time, but more time-consuming compared to the

Larsen-based methods.(114)The vdHSS assesses erosions in 16 joints of each hand and six joints of each foot. Erosions are given a score of 1 to 5 depending on the amount of surface area affected, with complete collapse of the bone scored as 5. JSN is assessed in 15 joints for each hand, and six joints for each foot. JSN is combined with a score for subluxation from 0 to 4, were 4 means bony ankyloses or complete subluxation. The total vdHSS score is the sum of scores for erosions and JSN, with the maximum score being 448 as outlined in table 4.(115, 116) Evaluation of radiographic joint damage progression is usually based on simultaneous assessment of a series of films from an individual patient (“paired”), with or without known sequence. The degree of progression in an individual patient must be above the measurement error to be deemed as a “real” change, which is best determined by the smallest detectable change (SDC).(117)

Table 4 Maximum scores according to the van der Heijde-modified Sharp score(116)

Hands Feet Total

Erosions 160 120 280

Joint space narrowing 120 48 168

Total score 280 168 448

1.4 Treatment and treatment strategies

The management of RA has changed dramatically over the past three decades due to

development and implementation of new treatment strategies, optimized use of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and the availability of biologic disease-modifying antirheumatic drugs (bDMARDs) and more recently also targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs).

1.4.1 Treatment

DMARDs are the main pharmacological treatment of RA. Depending on how they are produced, these drugs are classified as synthetic or biological, with the synthetic DMARDs further defined as conventional or targeted. Besides, glucocorticoids are shown to target inflammation with reduction of structural progression, meaning they also have disease modifying effects.(118) They can be administrated systematically or as joint injections.

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26 Non-steroidal anti-inflammatory drugs (NSAIDs) reduces pain and improve physical

function, but do not modify joint damage and are thus only symptom modifying.(1) Contraindications should be considered in every patient before starting a new drug, and symptoms of drug toxicity should be monitored regularly.

Non-pharmacological approaches, such as patient education and physical activity, are also mandatory in the management of RA patients,(119) but will not be addressed in this thesis.

Conventional and targeted synthetic DMARDs

Based on a combination of its efficacy and safety, MTX is the anchor drug in the treatment of RA. It should be initiated as first line therapy in combination with oral glucocorticoids, unless contraindications are present.(40) A csDMARD should be started as soon as the diagnosis of RA is made, and an initial dose of MTX 15 mg per week, with a rapid escalation by 2.5 mg every second week to 25 mg/week is recommended.(40, 120) Oral glucocorticoids, which offer rapid symptomatic effects, is used as bridging therapy when awaiting optimal effect of csDMARDs, and should be tapered as rapidly as clinically feasible due to its association with serious long-term side-effects.(40, 121) If the target is not achieved with this strategy, other csDMARDs (which include sulfasalazine (SSZ), leflunomid (LEF) and hydroxychloroquine (HCQ)) should be considered in combination with MTX or in monotherapy.(40) Although csDMARDs have been used for decades, the modes of action are still largely unknown. In contrast, the new targeted synthetic DMARDs are developed to modulate a particular target in the inflammation cascade, e.g. JAK

inhibitors.(1) The four membrane-bound JAKs are parts of the JAK-signal transducers and activators of transcription (STAT) pathway which acts as a link between extracellular chemical factors and the nucleus, influencing gene expression.(122, 123) The different groups of DMARDs are presented in table 2.

Biologic DMARDs

In patients with persistent inflammatory disease activity and without sufficient response to csDMARD (monotherapy or combination therapy), the addition of a bDMARD should be considered. Preferably the bDMARD should be combined with a csDMARD as they are mostly more effective in combination with MTX than as monotherapy,(40) and the use of MTX reduces the incidence of anti-drug antibodies.(40) According to current treatment recommendations, bDMARD should be initiated as 2^nd line treatment in the case of poor prognostic factors.(40) Current available bDMARDs effective in the treatment of RA have

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27 the following modes of action (as outlined in table 5); TNF-inhibition, IL-6 receptor

inhibition, T-cell costimulation blocade and B-cell depletion.(1) A small proportion of patients also respond to inhibition of the IL-1 receptor. In patients treated with TNF-

inhibitors in combination with MTX, it has been noted that joint damage progression can be reduced or completely inhibited even if a state of remission is not achieved.(124, 125) Biological therapeutics is produced from native biological tissue or living cells, and the high molecular complexity of these drugs make them sensitive to changes in manufacturing processes. Thus, it is impossible to create an exact replication of the drug, but a growing group of follow-up products referred to as biosimilars are designed to match the originator protein drugs for which patents and exclusivity have expired. The biosimilars needs to fulfill stringent regulatory requirements regarding equivalence with their corresponding reference medicine.(126) An increasing number of biosimilar bDMARDs have become available and approved and these drugs reduce the pressure on health care budgets.(40)

Although the bDMARDs have revolutionized the treatment of RA, there are still patients who either do not respond sufficiently or in whom the drugs loose its efficacy over time.

Some of the treatment failures might be caused by individual variations in the serum drug concentrations on standard doses, or the potential development of anti-drug antibodies.(127, 128)

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28 Table 5: Overview of groups of DMARDs

Subgroup Target

Conventional synthetic DMARDs

Methotrexate Folate antagonism, adenosine signaling, polyamine production, reactive oxygen species generation, cytokine production, effects on matrix metalloproteinases, prostaglandin production, nuclear factor- κB activity, JAK/STAT pathway inhibitor, amphoterin alarmin effect inhibitor.(129, 130)

Sulfasalazine Exact mechanism unclear.

Folate antagonism, effects on nuclear factor-κB activity, inducing apoptosis of neutrophils and macrophages.(131)

Leflunomide Dihydroorotate dehydrogenase inhibitor

which affects lymphocyte proliferation.(131)

Hydroxychloroquine Exact mechanism unclear.

Influences cell function by raising pH levels, mainly preventing antigen presentation to CD4+ T cells.(131) Targeted synthetic DMARDs

Tofacitinib Janus kinase 1, 2 and 3 inhibitor

Baricitinib Janus kinase 1 and 2 inhibitor

Upadacitinib Janus kinase 1 inhibitor

Filgotinib† Janus kinase 1 inhibitor

Biologic DMARDs

Etanercept* TNF-inhibitor Infliximab* TNF-inhibitor Adalimumab* TNF-inhibitor Golimumab TNF-inhibitor Certolizumab TNF-inhibitor

Tocilizumab IL-6 receptor-inhibitor

Anakinra IL-1 receptor-inhibitor

Rituximab* Anti-B-cell (CD20)

Abatacept Anti-T-cell costimulation (CD80/86)

*Originator and biosimilar available and approved

†Not yet approved by the European Medicines Agency (EMA)

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29 1.4.2 Treatment strategies

Early recognition and initiation of DMARDs, with tight controls and defined treatment targets has become cornerstones in modern RA management.

Window of opportunity

There is strong evidence that prolonged symptom duration before treatment initiation is associated with a severe course of RA with joint damage progression and loss of function.

The rationale for early treatment is that the biologic processes behind the disease might be in a more reversible or at least modifiable stage.(132, 133) A defined time frame do not yet exist, but data from RCTs supports the presence of a “window of opportunity” within 6-12 months after diagnosis, with observational studies suggesting a cut-off of 3 months after onset of symptoms.(134) The EULAR recommends initiation of DMARD therapy as soon as the diagnosis of RA is made, and The Norwegian Rheumatology Associations

recommends examination of patients with possible RA within 2 weeks, and immediate DMARD initiation when indicated.(40) A new definition of the “window of opportunity” is proposed in which the window lies in a phase preceding the diagnosis of RA, referring to a possibility that treatment could result in prevention of RA.(134)

Treat to target and tight control

Several studies have shown that a treatment strategy using a defined target with intensive disease monitoring conveys superior clinical, functional and structural outcomes compared with regular care.(135-137) Patients should be followed with tight controls aiming for a clinical state of remission, with low disease activity as an alternative target particularly in long-standing disease. According to the EULAR recommendations, therapy should be adjusted if there is no improvement by at most 3 months or if the pre-defined target has not been reached by 6 months.(40, 110) Continuing tight controls is important to ensure that the patients maintain the treatment target. The strategy with tight controls and treatment to a pre-defined target mimics the successful approach used for other areas of medicine, such as cardiology and diabetes care.(138)

Treatment tapering and discontinuation

RA is traditionally regarded a life-long disease which requires life-long immune modulation to control the inflammatory process and prevent joint damage. Thus, it is assumed that RA can be controlled but not cured.(79) As modern aggressive treatment strategies have made

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30 remission a realistic and reachable goal in early RA, questions about the optimal

management of patients in sustained remission are raised. Consequently, an increasing number of publications the last years have addressed dose reduction and withdrawal of DMARDs.(79, 83, 139) These studies show heterogeneity regarding design, disease activity threshold for inclusion and outcome definition.(140)

csDMARDs

Even though csDMARDs, especially MTX, are the cornerstones of RA treatment, data on tapering of csDMARDs are especially scarce with one of the main publications from 1996 (table 6).(141) In the RETRO study all DMARDs, both conventional and biologics, were reduced by 50% in the tapering arms, with no analysis addressing isolated csDMARD tapering. The study reports a significant elevated flare rate in the tapering (38%) and stopping arms (52%) compared to the stable arm (16%), and biologic treatment exposure was not identified as a predictor of a disease relapse.(81) Observational studies of newer dates provides similar estimates on disease flares of 41-46% upon csDMARDs tapering, and the proportion of patients who regains remission upon restarting treatment is reported to be 47-53% within 3 months.(80, 142) With the limited evidence regarding csDMARD

tapering, treatment choices are currently influenced by the patient’s and clinician’s preference.

bDMARDs

Several studies have addressed the role of bDMARD tapering over the past years, although only a few RCTs have been entirely dedicated to this research question. In the PRIZE study, showing a flare rate of 60% upon tapering TNF-inhibitor, patients were in remission

according to the DAS28 at inclusion. Sustained DAS28 remission over 6 months were claimed before spacing TNF-blocker injections in the STRASS study, nevertheless, the risk of relapse over the 18-moths follow-up were quite high both in the maintenance arm (47%) and the spacing arm (77%). Low disease activity has been used as threshold for tapering in several RCTs, such as the DOSERA, DRESS, PRESERVE and POET trials, but this disease state is not considered sufficient to justify the withdrawal of bDMARDs anymore as

substantial disease activity can be present potentially leading to radiographic

progression.(79) Available data support consideration of bDMARD tapering in a subset of early RA patients in deep stable remission, as reflected in the EULAR recommendations for management of RA and in the ACR guidelines.(40, 143)

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31 However, the risk of disease flare has to be weighed against the potential of overtreatment,

safety considerations and treatment costs and until the ideal profile of patients profiting on treatment tapering and withdrawal is defined, it is reassuring that in most cases

reintroduction of DMARDs allow rapid regain of the remission status.(79-81)

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32

Table 6Studies of tapering/withdrawal of conventional synthetic DMARDs in rheumatoid arthritis* Study name DesignPopulationOutcome Arms Results BeSt (80)SAN=115 (of 508) 2 year after inclusion, the last csDMARD could be tapered if; *csDMARDs in maintenance dose according to protocol *DAS<1.6 for 6 months or longer.

Proportion of patients restarting treatment during the total 5 year follow- up

All patients tapering csDMARDs46% restarted treatment after a median (IQR) period of 5 (2-6) months, 51% remained in drug- free remission for a median duration of 23 (15-25) months, 3% were lost to follow-up. Restarters: 74% regained remission within 3 to 6 months without suffering from joint damage progression. Study by ten Wolde et al. (141) RCT N=285 *Clinical remission due to ARA criteria *Stable disease≥ 1 year *Use of csDMARDs ≥ 2 years, prednisolone not allowed The most frequent csDMARD was HCQ, MTX only used in 5 patients.

Cumulative incidence of flare by 52 weeks.

1: Continued treatment 22% 2: Stop/Placebo38% tREACh (142)SAN=118 (of 281) tapered a csDMARD Early RA patients included in the tREACH were randomised to induction treatment with triple DMARD therapy (iTDT) or MTX monotherapy (iMM). During the 2-year follow-up the medication were step-wise tapered according to protocol (in the iMM group the first step were half-dose) if: *sustained remission (DAS<1.6 at two visits)

Flare rate during 1- year follow-up.All patients tapering csDMARD41% (95% CI 32% to 50%) Restarters: 53% regained DAS-remission within 3 months and 65% within 6 months. PRINT(144)RCT N=176 (of 346) RA patients fulfilling the 1987 criteria with DAS >5.1 received MTX + LEF + HCQ. They tapered MTX and were randomised to continue LEF plus HCQ combination or LEF monotherapy if: *DAS ≤3.2 Disease state retention rate 1:LEF mono36.8% 2: LEF + HCQ 37.1%

Remission in early rheumatoid arthritis: Predictors, definitions and treatment