Epidemiology of Comorbidities in Early Rheumatoid Arthritis with Emphasis on Cardiovascular Disease

Recent Publications in this Series ANNE KEROLA Epidemiology of Comorbidities in Early Rheumatoid Arthritis with Emphasis on Cardiovascular Disease

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Helsinki 2015 ISSN 2342-3161 ISBN 978-951-51-0899-9

cover.indd 1 2.4.2015 7:27:38 Internal Medicine Department of Medicine Faculty of Medicine Doctoral Programme in Clinical Research University of Helsinki Helsinki, Finland

EPIDEMIOLOGY OF COMORBIDITIES IN EARLY RHEUMATOID ARTHRITIS

WITH EMPHASIS ON CARDIOVASCULAR DISEASE

Anne Kerola

ACADEMIC DISSERTATION

To be presented, with the permission of the Faculty of Medicine of the University of Helsinki, for public examination in Lecture Hall 1, Haartman Institute, Haartmaninkatu 3, Helsinki, on May 6th 2015, at 12 noon.

Helsinki 2015 Supervisors Professor Tuomo Nieminen, MD, PhD Department of Medicine, Faculty of Medicine, University of Helsinki, Helsinki Department of Medicine, South Karelia Central Hospital, Lappeenranta, Finland

Professor Markku Kauppi, MD, PhD Department of Internal Medicine, Päijät-Häme Central Hospital, Lahti School of Medicine, University of Tampere, Tampere, Finland

Docent Tuomas Kerola, MD, PhD Department of Internal Medicine, Päijät-Häme Central Hospital, Lahti School of Medicine, University of Tampere, Tampere, Finland

Reviewers Docent Tuomas Kiviniemi, MD, PhD Heart Center, Turku University Hospital and University of Turku, Finland

Docent Pekka Kurki, MD, PhD Finnish Medicines Agency (FIMEA), Helsinki, Finland

Opponent Professor Tore Kvien, MD, PhD Department of Rheumatology, Diakonhjemmet Hospital, Oslo University of Oslo, Norway

Published in the series Dissertationes Scholae Doctoralis Ad Sanitatem Investigandam Universitatis Helsinkiensis

ISBN (paperback): 978-951-51-0899-9 ISSN (print): 2342-3161 ISBN (PDF): 978-951-51-0900-2 ISSN (online): 2342-317X

Hansaprint Oy Helsinki, 2015 Finland To my family Contents

Abstract Tiivistelmä List of original publications Abbreviations Introduction ...... 1 Review of the literature ...... 2 1 Rheumatoid arthritis ...... 2 1.1 Overview ...... 2 1.2 Etiology ...... 2 1.3 Pathophysiology ...... 3 1.3.1 Autoimmunity ...... 3 1.3.2 Infl ammation and joint destruction ...... 3 1.4 Epidemiology ...... 4 1.5 What is early RA? ...... 4 1.6 RA pharmacotherapy ...... 5 1.7 Work disability ...... 6 1.8 Mortality ...... 6 2 Comorbidities in early RA ...... 7 2.1 Overview ...... 7 2.2 Cardiovascular disease ...... 7 2.2.1 Etiology and pathogenesis ...... 7 2.2.2 Cardiovascular risk in early RA ...... 9 2.2.2.1 Traditional cardiovascular risk factors ...... 9 2.2.2.2 Non-traditional cardiovascular risk factors ...... 14 2.2.2.3 Preatherosclerotic processes...... 15 2.2.2.4 Subclinical atherosclerosis ...... 15 2.2.2.5 Subclinical myocardial damage ...... 18 2.2.2.6 Symptomatic cardiovascular disease ...... 20 2.2.2.7 Coronary heart disease and stroke ...... 20 2.2.2.8 Congestive heart failure ...... 24 2.2.2.9 Cardiac arrhythmias ...... 24 2.2.2.10 Cardiovascular mortality ...... 24 2.2.3 RA medications and risk for CV morbidity and mortality ...... 27 2.2.4 Assessment and treatment of CV comorbidities in RA ...... 29 2.3 Autoimmune thyroiditis and hypothyroidism ...... 30 2.4 Psychiatric disorders ...... 31 2.5 Comorbidities and work disability ...... 31 Aims of the study ...... 33 Materials and methods ...... 34 3 Background ...... 34 3.1 Register of special reimbursements for medicine expenses ...... 34 3.1.1 Rheumatoid arthritis ...... 35 3.1.2 Cardiovascular disease and its risk factors ...... 35 3.1.3 Hypothyroidism ...... 36 3.2 Pension registers ...... 36 3.3 Statistics Finland’s archive of death certifi cates and annual statistics on causes of death ...... 37 3.4 Prescription register ...... 37 4 Patient cohorts ...... 37 5 Outcomes ...... 38 5.1 Comorbidities at diagnosis of RA ...... 38 5.2 Work disability caused by comorbidities ...... 38 5.3 Cardiovascular mortality ...... 39 6 Ethical considerations ...... 39 7 Statistical analysis ...... 39 Results ...... 41 8 Characteristics of the patient cohorts ...... 41 9 Comorbidities at diagnosis of RA ...... 41 9.1 Coronary heart disease ...... 41 9.2 Hypertension ...... 43 9.3 Other CV diseases and risk factors ...... 43 9.4 Hypothyroidism ...... 44 10 Work disability caused by comorbidities ...... 47 11 Cardiovascular mortality ...... 50 Discussion ...... 56 12 General discussion ...... 56 13 Comorbidities at diagnosis of RA ...... 57 13.1 Coronary heart disease ...... 57 13.2 Chronic hypertension ...... 59 13.3 Congestive heart failure ...... 60 13.4 Diabetes and dyslipidemia ...... 60 13.5 Assessment and management of CV risk in RA ...... 60 13.6 Hypothyroidism ...... 61 14 Comorbidities as causes of work disability ...... 63 15 Cardiovascular mortality ...... 65 16 Limitations of the study ...... 67 Conclusions ...... 71 Acknowledgements ...... 72 References ...... 74 Abstract

Background: Rheumatoid arthritis (RA) is associated with a substantially increased risk for cardiovascular (CV) morbidity and mortality. Th is cannot be fully explained by traditional CV risk factors, but a key driver behind the excess risk is systemic infl ammation. Along with their CV burden, RA patients are at increased risk for other comorbidities such as hypothyroidism and depressive symptoms. Th e aim of this study was to evaluate the prevalence of CV comorbidities, CV risk factors, and hypothyroidism among RA patients in comparison to those of the general population at the time of RA diagnosis. We also aimed to determine, among patients with early RA, the contribution of psychiatric and CV comorbidities as causes of long-term work disability (WD). Lastly, we assessed CV mortality rates in early RA and the impact of RA medications on CV mortality.

Methods: Between 2000 and 2007, all patients diagnosed with RA in Finland were possible to identify from a Finnish nationwide register on special reimbursements for medicine expenses. Th e same register provided information on the presence of comorbidities antedating RA diagnosis. From the pension registers, we identifi ed those RA patients who were, by the end of 2008, granted permanent or temporary disability pensions. Th e incidences of disability pensions were assessed as those with CV diseases or psychiatric disorders as their main causes. Causes of death were obtainable until the end of 2008. A multivariable competing-risks model served to assess the impact of variables such as RA medications on CV mortality. We compared the main outcomes, that is, the prevalence of comorbidities at RA diagnosis, the incidence of comorbidity- related disability pensions, and CV mortality rates to those of the age- and sex-specifi c Finnish population, and calculated standardized rate, incidence and mortality ratios (SRRs, SIRs, and SMRs).

Results: In a population of 7,209 RA patients, the risk of having coronary heart disease (CHD) at RA diagnosis was slightly elevated, the SRR being 1.10 (95% confi dence interval [CI] 1.01–1.20). Higher SRRs for CHD seemed to relate to younger age at RA onset. Th e SRR for levothyroxine- treated hypothyroidism at RA diagnosis was 1.51 (95% CI 1.35 to 1.67). SRR was highest, almost 2.5, among women with RA aged 20 to 49, the excess prevalence of hypothyroidism decreasing steadily and fading in older age groups. From 2000 to 2008, of 7,831 RA patients, 1,095 (14.0%) were granted a disability pension. Aft er adjusting for competing risks, the 9-year cumulative incidence of WD resulting from RA was 11.9%, from a psychiatric comorbidity 1.3%, and from a CV disease 0.5%. SIR of WD resulting from CV disease was 1.75 (95% CI 1.23 to 2.51) and SIR of WD resulting from psychiatric disorders was 0.99 (95% CI 0.80 to 1.23). By the end of 2008, of 14,878 RA patients, 1,157 had died, 501 (43%) from CV causes. Th e SMR in the entire RA cohort was 0.57 (95% CI 0.52–0.62). Th e RF-positive men had the highest SMR (0.70, 95% CI 0.60–0.83), whereas the RF-negative women had the lowest SMR (0.43, 95% CI 0.35–0.53). Glucocorticoids were, along with the presence of CV comorbidities, diabetes, and RF, associated with increased CV mortality, whereas methotrexate was associated with decreased CV mortality.

Conclusions: Th e risks for CHD and hypothyroidism were already higher among RA patients at RA diagnosis. Psychiatric and CV comorbidities were the primary causes of long-term WD much less frequently than was RA itself; the risk for WD due to CV disease, however, was higher in RA than in the general population. During the era of modern treatment regimens for RA, the risk of CV death during the early years of RA was not elevated. Th ese fi ndings highlight the importance of alertness for comorbid conditions and their optimized care in RA, already in the early years of the disease. Tiivistelmä

Tausta ja tavoitteet: Nivelreumaan liittyy lisääntynyt sydän- ja verisuonitautisairastavuus ja -kuolleisuus. Tämä ei selity pelkästään perinteisillä sydänsairauksien riskitekijöillä, vaan nivelreumaan liittyvä systeeminen tulehdusreaktio lisää voimakkaasti sydäntapahtumien riskiä. Nivelreumapotilaat kärsivät muistakin liitännäissairauksista, kuten kilpirauhasen vajaatoiminnasta ja masennuksesta enemmän kuin muu väestö keskimäärin. Tavoitteenamme oli tutkia sydän- ja verisuonitautien ja kilpirauhasen vajaatoiminnan esiintyvyyttä nivelreumapotilailla taudin diagnoosihetkellä. Pyrimme myös selvittämään, kuinka yleisiä sydän- ja verisuonisairaudet ja psykiatriset sairaudet ovat nivelreumapotilaiden pitkäaikaistyökyvyttömyyden aiheuttajina. Lisäksi tutkimme nivelreumapotilaiden sydän- ja verisuonitautikuolleisuutta ensimmäisinä sairastamisvuosina ja nivelreuman lääkehoidon vaikutusta sydän- ja verisuonitautikuolleisuuteen.

Menetelmät: Tunnistimme Kelan erityiskorvattavuusrekisteristä kaikki Suomessa vuosina 2000- 2007 diagnosoidut nivelreumapotilaat ja heillä todetut liitännäissairaudet. Diagnoosihetkellä työkykyisten potilaiden sydän- ja verisuonitautien ja psykiatristen sairauksien takia myöhemmin myönnettyjen työkyvyttömyyseläkkeiden ja kuntoutustukien ilmaantuvuus tunnistettiin Eläketurvakeskuksen eläkerekistereistä. Sydän- ja verisuonitautikuolemien ilmaantuvuus analysoitiin vuoden 2008 loppuun asti. Erilaisten tekijöiden, kuten nivelreuman lääkehoidon vaikutusta sydän- ja verisuonitautikuolleisuuteen arvioitiin kilpailevien kuolemansyiden regressiomallilla. Tärkeimpien päätetapahtumien yleisyyttä nivelreumakohortissa verrattiin Suomen väestön vastaaviin lukuihin.

Tulokset: Sepelvaltimotauti oli 7209 potilaan nivelreumakohortissa 10 % yleisempi kuin vertailuväestössä jo taudin diagnoosihetkellä. Alhaisempi nivelreuman puhkeamisikä näytti liittyvän korkeampaan sepelvaltimotaudin riskisuhteeseen. Kilpirauhasen vajaatoiminta oli 50 % yleisempää nivelreuman diagnoosihetkellä kuin vertailuväestössä, suhteellisen riskin ollessa lähes 2,5-kertainen 20-49-vuotiaiden naispotilaiden ikäryhmässä. Diagnoosihetkellä työkykyisestä 7831 potilaasta työkyvyttömyyseläkkeelle jäi vuosina 2000-2008 1095 potilasta. Yhdeksän vuoden seurannassa nivelreuman aiheuttamien työkyvyttömyyseläkkeiden kumulatiivinen ilmaantuvuus oli 12 %, kun taas psykiatristen sairauksien ja sydän- ja verisuonitautien kohdalla vastaavat luvut olivat pienemmät, 1,3 % ja 0,5 %. Sydän- ja verisuonitautien aiheuttaman työkyvyttömyyden ilmaantuvuus oli nivelreumapotilailla 75 % korkeampi kuin väestössä keskimäärin, mutta psykiatristen syiden aiheuttaman työkyvyttömyyden ilmaantuvuudessa ei ollut eroa. Vuoden 2008 loppuun mennessä 14878 potilaan kohortista kuoli 1157 potilasta. Heistä 501 (43 %) potilaalla oli peruskuolemansyynä sydän- ja verisuonitaudit. Nivelreumapotilaiden sydän- ja verisuonitautikuolleisuus ei ollut korkeampi kuin vertailuväestössä. Suurin suhteellinen sydän- ja verisuonitautikuoleman riski oli reumatekijäpositiivisilla miehillä ja pienin reumatekijänegatiivisilla naisilla. Glukokortikoidien käyttö liittyi lisääntyneeseen sydän- ja verisuonitautikuoleman riskiin, kun taas metotreksaatin käyttö liittyi pienentyneeseen riskiin.

Johtopäätökset: Sepelvaltimotaudin ja kilpirauhasen vajaatoiminnan riski oli nivelreumapotilailla lisääntynyt jo taudin diagnoosihetkellä. Psykiatriset sairaudet ja sydän- ja verisuonitaudit olivat nivelreumapotilaiden pitkäaikaistyökyvyttömyyden syinä huomattavasti harvinaisempia kuin itse nivelreuma. Silti sydän- ja verisuonisairauksien aiheuttaman pitkäaikaistyökyvyttömyyden riski oli korkeampi nivelreumassa kuin väestössä keskimäärin. Sydän- ja verisuonitautikuolleisuus sen sijaan ei ollut koholla ensimmäisinä nivelreuman toteamista seuraavina vuosina. Havaintomme korostavat huolellisen liitännäissairauksien kartoituksen ja hoidon tärkeyttä jo nivelreuman alkuvaiheista lähtien. Original publications

Th is thesis is based on the following publications:

I Kerola AM, Kerola T, Kauppi MJ, Kautiainen H, Virta LJ, Puolakka K, Nieminen TVM. Cardiovascular Comorbidities Antedating the Diagnosis of Rheumatoid Arthritis. Annals of the Rheumatic Diseases 2013;72:1826-9. II Kerola AM, Nieminen TVM, Kauppi MJ, Kautiainen H, Puolakka K, Virta LJ, Kerola T. Increased Risk of Levothyroxine-Treated Hypothyroidism Preceding the Diagnosis of Rheumatoid Arthritis - a Nationwide Register Study. Clinical and Experimental Rheumatology 2014;32:455-9. III Kerola AM, Kauppi MJ, Nieminen TVM, Rantalaiho V, Kautiainen H, Kerola T, Virta LJ, Pohjolainen T, Puolakka K. Psychiatric and Cardiovascular Comorbidities as Causes of Long-Term Work Disability among Individuals with Recent-Onset Rheumatoid Arthritis. Scandinavian Journal of Rheumatology 2015;44:87-92. IV Kerola AM, Nieminen TVM, Virta LJ, Kautiainen H, Kerola T, Pohjolainen T, Kauppi MJ, Puolakka K. No Increased Cardiovascular Mortality among Early Rheumatoid Arthritis Patients—a Nationwide Register Study in 2000–2008. Clinical and Experimental Rheumatology, in press.

Th e original publications are published with the permission of the copyright holders and are referred to in the text by their Roman numerals. In addition, some unpublished data are presented.

Section 2.2 in the literature review is in part based on the following review article: Kerola AM, Kauppi MJ, Kerola T, Nieminen TVM. How early in the course of rheumatoid arthritis does the excess cardiovascular risk appear? Annals of the Rheumatic Diseases 2012;71:1606-15. Abbreviations

ACE Angiotensin-converting enzyme ACPA Anti-citrullinated protein antibodies ACR American College of Rheumatology ADMA Asymmetric dimethylarginine AMP Adenosine monophosphate ATC Anatomical Th erapeutic Chemical CD Cluster of diff erentiation CI Confi dence interval CRP C-reactive protein CHD Coronary heart disease CHF Congestive heart failure COPD Chronic obstructive pulmonary disease CV Cardiovascular DAS28 Disease activity score in 28 joints DMARD Disease-modifying antirheumatic drug DSM Diagnostic and Statistical Manual ESR Erythrocyte sedimentation rate EULAR European League Against Rheumatism FIN-RACo Finnish Rheumatoid Arthritis Combination Th erapy Trial HAQ Health Assessment Questionnaire HDL High-density lipoprotein HLA Human leukocyte antigen HR Hazard ratio ICD-10 International Classifi cation of Diseases, 10th revision Ig Immunoglobulin IL-1 Interleukin-1 IL-6 Interleukin-6 IMT Intima-media thickness IRF5 Interferon regulatory factor 5 Kela Th e Social Insurance Institution of Finland LDL Low-density lipoprotein Lp(a) Lipoprotein(a) MMP Matrix metalloproteinase MTHFR Methylenetetrahydrofolate reductase NFKB1 Nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 NSAID Non-steroidal anti-infl ammatory drug NT-proBNP N-terminal prohormone of the brain natriuretic peptide OR Odds ratio PAI-1 Plasminogen activator inhibitor-1 PHQ Patient Health Questionnaire PTPN22 Protein tyrosine phosphatase, non-receptor type 22 RA Rheumatoid arthritis RANK Receptor Activator of Nuclear Factor κ B RF Rheumatoid factor SCORE Systematic COronary Risk Evaluation SD Standard deviation sHR Sub-hazard ratio SIR Standardized incidence ratio SMR Standardized mortality ratio SRR Standardized rate ratio TgAb Th yroglobulin antibodies TGFβ1 Transforming growth factor-beta 1 TNF-α Tumor necrosis factor α TNFRII Tumor necrosis factor receptor-II TPOAb Th yroid peroxidase antibodies WD Work disability Introduction

INTRODUCTION

Rheumatoid arthritis (RA), a chronic knowledge, no study has yet confi rmed infl ammatory autoimmune disease primarily whether this association already exists in aff ecting the joints, is associated with a early phases of RA. plethora of comorbidities, especially of Comorbidities have profound eff ects on cardiovascular (CV) origin. RA patients many important outcomes of RA including suff er excessively from coronary heart disability, quality of life, and mortality.7,8 disease (CHD), congestive heart failure Regarding the high rates of work disability (CHF) and stroke, and compared to the (WD) related to RA, initial data suggest that general population’s, their CV mortality is comorbidities may further elevate the risk for 50% higher.1 Th e increased CV risk cannot WD.9 Existing studies on this topic, however, be fully explained by traditional CV risk are small in size and mostly concern only factors, even though some of these occur in psychiatric comorbidities,10-12 thus leaving RA more frequently than one would expect. considerable gaps in current knowledge. Accumulating evidence points to a key A great number of studies spanning mechanism accelerating atherosclerosis in half a century demonstrate that patients with RA; that is, systemic infl ammation, perhaps established RA are at increased risk of CV elevating CV risk even in the early phases of death.13 Knowing that treatment of RA has the disease. Th e important question of how improved notably during the past two decades early in the course of RA the excess CV risk and that a similar improvement has occurred emerges, however, remains unanswered. in RA patients’ health status,14 the question Along with CV burden, RA patients arises whether the CV survival of RA patients experience increased risk for other has truly improved. Results of many mortality comorbidities like autoimmune diseases and studies may not be reliably generalizable to psychiatric disorders. Depressive symptoms RA patients alive during the era of modern are 2 to 3 times as common in RA as in RA treatments. the general population.2,3 Another disease From this background, we focused that clusters with RA more frequently than on elucidating selected epidemiological expected is chronic autoimmune thyroiditis, aspects of early RA, including risk for CV commonly causing hypothyroidism.4,5 disease and hypothyroidism, contribution of Hypothyroidism itself may also be excessively comorbidities to WD, and CV mortality. prevalent in established RA.6 Again, to our

1 Review of the literature

REVIEW OF THE LITERATURE

1 Rheumatoid arthritis associate with RA. None of the single risk alleles is suffi cient to cause RA, since their 1.1 Overview eff ects at the individual level are only modest RA is a systemic, chronic progressive or minor. Some risk loci are linked to infl ammatory disease that is characterized by susceptibility to other autoimmune diseases, persistent synovitis in the small and medium- and some to infl ammatory pathways.16 For sized joints, systemic infl ammation, and, example, the shared epitope-containing in the majority of patients, autoantibodies HLA-DRB1 alleles are strongly associated to rheumatoid factor (RF) or citrullinated with the production of anti-citrullinated proteins or to both. RA typically aff ects the protein antibodies (ACPAs),16 and the small joints of the hands and feet, ankles, PTPN22 gene locus residing outside of the knees, wrists, elbows, shoulders, and upper HLA complex is a strong risk factor for many cervical spine.15 Joint pain, swelling, and autoimmune diseases.17 Epigenetic factors morning stiff ness are common symptoms also play a role in RA development.18 among patients with RA. Th e disease usually As to environmental risk factors, begins insidiously, and the severity of the smoking is undoubtedly the most important symptoms oft en fl uctuates over time. Along – it doubles the risk for ACPA-positive RA,16 with joint symptoms, various extra-articular a risk that may increase up to 21-fold when manifestations and comorbidities modify double copies of the HLA-DRB1 shared RA’s clinical phenotype. Systemic expression epitope are present.19 Moreover, one risk of RA may include fatigue, fever, and anemia. factor for RA is porphyromonas gingivalis Without eff ective treatment, ongoing joint infection.20 Epstein-Barr virus infection infl ammation leads to destruction of cartilage may be associated with RA, a possible and of articular bone, limited motility, mechanism for this association’s being deformity, chronic pain, disability, and molecular mimicry.21 Limited evidence exists decreased quality of life. that other environmental risk factors such as vitamin D defi ciency, high birthweight, and 1.2 Etiology low socioeconomic status elevate the risk 22 Genetic factors account for approximately for RA. Interestingly, initial data suggest 50% of the risk for developing RA. Many that consumption of alcohol may be dose- susceptibility polymorphisms in more than dependently associated with reduced RA 23 30 genetic regions both inside and outside risk. Oral contraceptives may also reduce its 22 the human leukocyte antigen (HLA) region risk.

2 Review of the literature

1.3 Pathophysiology cornerstone autoantibody pathogenetically – one of the key mechanisms in the induction RA is characterized not only by local of synovitis may be loss of tolerance to infl ammation damaging small and citrullinated proteins.21 Of note, citrullination medium-sized joints but also by systemic reactions are expedited both by smoking and infl ammation. Diff erent autoimmune and by porphyromonas gingivalis infections,21 infl ammatory processes are variably active in thus providing a mechanism by which these RA, making the entire disease entity clinically environmental risk factors can magnify and pathobiologically heterogeneous.16 the risk for ACPA-positive RA. Although Th e common denominators of diff ering citrullinated proteins occur not only in the RA subsets, such as autoimmunity and synovia but also in other organs, an immune infl ammation, are of key interest. response against them somehow arises only locally in the synovia.21 1.3.1 Autoimmunity Within the joint soon to become To date, what remains to be fully elucidated is infl amed, citrullinated proteins and other when and where autoimmunity in RA emerges. possible autoantigens activate cluster of It may occur at mucosal sites including diff erentiation 4 (CD 4) helper T cells, the lung, gastrointestinal tract, and oral mostly of Th 1 and Th 17 subsets.15 Th e cavity, but as RA progresses, autoimmunity activated helper T cells produce cytokines primarily targets joints.24 Th e production and activate an army of other cells of the of two known groups of autoantibodies, immune system to attack the self-antigens.15 RF and ACPAs, is characteristic of RA. Synovium may be able to act as a secondary Approximately 50 to 80% of all RA patients lymphoid organ and to serve as a platform have RF, ACPA, or both, and RF and ACPA for the stimulation of T and B cells.21 overlap in individuals frequently.16 Th ey Adaptative immunity—the action of B and both target common autoantigens expressed T lymphocytes—is pivotal, especially during not only inside but also outside the joints.21 the preclinical and early phases of RA, but is RF, the classic autoantibody in RA, is an also involved in perpetuation of the disease.21 IgM, IgA, or IgG antibody against the Fc In the later phases of RA, innate immunity fragment of the IgG antibody.16 ACPAs are a eff ector cells, especially macrophages, usually group of autoantibodies against citrullinated predominate.21 proteins, that is, proteins in which arginine RA pathogenesis is a slow process— residues are post-translationally modifi ed the sera of RA patients already show both into citrulline by peptidylarginine deiminase RF and ACPAs more than ten years before enzymes.25 Citrullinated proteins recognized clinical RA onset.28 Despite this, in a minority by ACPAs include extracellular proteins such of seronegative patients, seroconversion to as fi laggrin, type II collagen, fi brinogen, and seropositive disease occurs aft er RA’s clinical fi bronectin, as well as cytoplasmic and nuclear eruption.29 proteins such as vimentin and histones.26 ACPAs were discovered later than was 1.3.2 Inflammation and joint RF, but are becoming increasingly important destruction for several reasons. Firstly, they are more Th e local autoimmune response in the sensitive and specifi c for the diagnosis of synovium leads to homing of leukocytes RA than is RF, and they are better predictors as well as to infl ammatory cascades and 27 of poor prognosis. Secondly, they are a amplifi cation loops. In addition to B and T

3 Review of the literature lymphocytes, neutrophils, macrophages, and the destruction of soft tissue structures may fi broblast- and macrophage-like synoviocytes result in joint deformities.15 accumulate in the synovium.15 Macrophages are very important eff ector cells of synovitis, 1.4 Epidemiology acting via secretion of tumor necrosis factor RA aff ects approximately 0.5 to 1% of the α (TNF-α), interleukin 6 (IL-6), interleukin population worldwide, with women 2 to 3 1 β (IL-1β), and metalloproteinases. Th ey times as likely as men to develop the disease.30 also carry out phagocytosis and antigen Its annual incidence in Finland is estimated 21 presentation. Besides macrophages, other at 44.5 per 100 000 (58.6 for women, 29.5 for innate eff ector cells such as natural killer men).31 Studies in industrialized countries cells, neutrophils, and mast cells reside in show annual incidences between 5 and 50 21 rheumatoid synovial tissue. per 100 000,16 with results varying based on Leukocytes produce an armamentarium case identifi cation methods and geographical of cytokines forming a redundant and diff erences. RA is especially common in pleiotropic network of a predominantly northern Europe and North America.16 Age proinfl ammatory nature. Important at onset is usually between 30 and 70, but at proinfl ammatory cytokines in RA include no age is one immune. Evidence suggests that TNF-α, IL-1, and IL-6, which induce RA incidence may be declining, with disease angiogenesis and synovial hyperplasia by onset shift ing towards older age groups.32,33 stimulating the production of growth factors including vascular endothelial growth factor, 1.5 What is early RA? platelet-derived growth factor, fi broblast growth factor and insulin-like growth factor, Th e signs and symptoms of RA develop over resulting in the formation of rheumatoid a variable period of time, in some cases even 34 pannus.21 Histologically, rheumatoid over several years. To predict the outcome pannus consists of proliferating synovial and prognosis of early infl ammatory arthritis cells and infl ammatory cells, granulation at the onset of the symptoms is challenging: tissue, and fi brotic tissue.15 Aggregates of some patients may achieve remission, while organizing fi brin may also be visible on others progress to classifi able RA or other 34 the synovial surface and in the synovial clinical forms of chronic arthritis. For these fl uid.15 Furthermore, in a rheumatoid joint, reasons, defi ning the beginning and duration the synovial architechture and synoviocyte of RA explicitly is demanding. phenotypes undergo changes.21 For case identifi cation of incident Finally, pannus supersedes the normal RA, methods are many and heterogenous. synovium, and cartilage subjacent to the Th ey identify RA patients with diff erent pannus is eroded.15 Cartilage erosion and sensitivities and specifi cities, and this is destruction may be mediated by fi broblast- likely to be refl ected in the duration of RA like synoviocytes.21 Infl ammation aff ects symptoms before inclusion. In some studies, chondrocyte function and impairs collagen RA onset refers to the onset of any symptom synthesis and cartilage repair. It may also attributable to RA or patient-reported attack subarticular bone: bone destruction fi rst joint swelling, and in others, it means is performed by osteoclasts and regulated by fulfi llment of RA classifi cation criteria or 35 the Wnt, RANK ligand, and osteoprotegerin clinical RA diagnosis. As a consequence, pathways.21 Such fi brosis and ossifi cation may comparison of disease duration between potentially lead to permanent ankylosis, and studies is challenging.

4 Review of the literature

Fulfi llment of at least four out of the seven collection of agents that reduce synovitis Americal College of Rheumatology (ACR) and systemic infl ammation by diverse 1987 classifi cation criteria has been widely mechanisms of action. Th ey comprise used for case identifi cation earlier. Th ese the core of the RA pharmacotherapy. Th e criteria were devised for RA classifi cation most important conventional DMARD is in research,36 not as diagnostic tools, so the undoubtedly methotrexate, administered sensitivity of the ACR 1987 criteria in the either perorally or subcutaneously. It can early phases or mild forms of RA is relatively be used alone or in combinations with low.37 In 2010, the ACR and the European other conventional DMARDs such as League Against Rheumatism (EULAR) sulfasalazine, hydroxychloroquine, or developed new classifi cation criteria, aiming lefl unomide. Biochemically, methotrexate is a at earlier patient identifi cation, treatment, and folic acid antagonist, and it has diverse anti- study inclusion. Indeed, the ACR/EULAR infl ammatory eff ects, enhancing extracellular 2010 criteria are more sensitive in recognizing adenosine release and inhibiting various early RA than are the 1987 criteria.38 proinfl ammatory cytokines.39,40 In clinical work, rheumatologists Biological DMARDs such as TNF-α may make the diagnosis of RA without blockers, abatacept, rituximab, or tocilizumab strict fulfi llment of the ACR 1987 or ACR/ are considered if response to conventional EULAR 2010 criteria.34 As a consequence, DMARD strategies is insuffi cient.41 Some of the clinical diagnosis is likely to result in an them are given by infusion, and others self- RA population including earlier and milder administered by injection. Methotrexate forms of RA than the population provided is oft en combined with them. Th e most by ACR 1987 criteria. As in the case of ACR/ important adverse events related to biological EULAR 2010 criteria,38 defi ning the onset of DMARDs are various infections. RA by the clinical diagnosis is likely to lead Like DMARDs, glucocorticoids also to more sensitivity than with the ACR 1987 reduce RA-related infl ammation. Because criteria. of their notorious adverse eff ects in long- Th is work uses the concept of early term use, glucocorticoids are suggested for RA relatively liberally, depending on the only short-term use at their lowest eff ective outcome explored. For example, regarding dose, mainly for early and active RA or for atherosclerosis or preatherosclerotic fl are-ups. Intra-articular glucocorticoids, changes, focus was mainly on studies in RA on the other hand, have only minor adverse populations with disease duration under one risks, and are a highly eff ective treatment for year. On the other hand, when examining active synovitis. long-term outcomes such as CV mortality, Non-steroidal anti-infl ammatory drugs RA was considered as early if disease duration (NSAIDs) reduce pain and stiff ness in the was less than ten years. rheumatoid joint, improving function, mobility, and quality of life among some RA 1.6 RA pharmacotherapy patients with chronic joint pain. Although Th e target of the modern pharmacotherapy they relieve RA symptoms quite eff ectively, in RA is remission, defi ned as the absence they do not improve the course of RA and of clinical symptoms, of active joint have potentially dangerous eff ects on renal infl ammation and of erosive or functional function as well as on the gastrointestinal deterioration. Disease-modifying and CV systems. Long-term use of NSAIDs, antirheumatic drugs (DMARDs) are a especially COX-2 selective inhibitors, has

5 Review of the literature been associated with increased cardiovascular 1.7 Work disability morbidity and mortality.42 Th is has even led Without eff ective treatment, RA leads to to the withdrawal of some COX-2 selective functional disability and diminished work inhibitors, such as rofecoxib, from the market. capacity. It emerges as loss of productivity For these reasons, the long-term use of while at work (presenteeism), lost work NSAIDs is, in most cases, undesirable. Even in days (absenteeism), and, possibly, as loss short-term use, simultaneous use of proton- of employment and permanent WD. Th ese pump inhibitors is a recommendation to work-related consequences are closely related reduce risk for gastrointestinal bleeding. Most to the social welfare system, and consequently, importantly, the patient’s renal function, and their occurrence diff ers among countries.47,48 CV and gastrointestinal status always needs Moreover, studies assessing WD may diff er assessment before prescribing NSAIDs.42 greatly with regard to methodology, causing Besides NSAIDs, treatment options for a large heterogeneity in their results. In a chronic pain in RA include paracetamol and, review including mostly studies from the late in rare cases, opioid analgesics. 1990s, the incidence of WD in longitudinal RA treatment guidelines highlight studies was 4.3 to 26% when RA duration the fact that initiating aggressive was 2.0 to 2.5 years, and 30 to 50% when RA pharmacotherapy early in the disease course duration was 10 years.47 In a Finnish register plays a pivotal role in halting the development study from 2000-2007, the 2-year incidence of erosive joint damage.43 Th is concept of of continuous WD in RA was 4.8 to 9.4%, an early period in the RA disease course and the risk for WD was 2.77 to 3.69 times when the possibility of achieving complete as high as in the age- and sex-specifi c general remission with eff ective pharmacotherapy population.49 Furthermore, the same study is especially high, is oft en referred to as demonstrated a declining incidence of WD in the window of opportunity.44 Th e Finnish successive RA cohorts.49 Variables associated Rheumatoid Arthritis Combination Th erapy with WD in RA include clinical factors such (FIN-RACo) Trial has promoted from 1999 as disease severity and physical disability, a combination of methotrexate, sulfasalazine, female sex, socioeconomic factors such as hydroxychloroquine, and low-dose education, and work-related factors such prednisolone in early and active RA, with the as the physical demands of the job pursued. target designated as swift remission.45,46 Th is 47,50-53 treatment protocol is also embedded in the heart of Th e Finnish Current Care Guideline 1.8 Mortality for RA.45 Biologic agents are generally considered in Finland if remission is either Evidence for increased mortality rates in RA not achieved or not sustained with the triple has been accumulating for many decades.54 therapy or another methotrexate-based Meta-analyses have shown that RA patients combination therapy. carry an approximately 45 to 50% increased Although pharmacotherapy is essential risk for mortality.55,56 Th e major causes of in the treatment of RA, its optimal care death in RA and in the general population requires a multidisciplinary approach, seem to be similar. Th e specifi c diseases that including also non-pharmacological seem to confer excess risk of death include treatments such as patient education, exercise, hematological, gastrointestinal, respiratory, occupational therapy, physical therapy, diet, infectious, and, most importantly, CV and, in DMARD refractory cases, surgery. diseases.54,57

6 Review of the literature

Along with the same risk factors for 2 Comorbidities in early RA death as in the general population, many 2.1 Overview disease-related factors predict risk of death in RA patients. Higher levels of infl ammation RA is associated with a wide spectrum of or disease activity as measured by C-reactive coexisting diseases, that is, comorbidities, protein (CRP) and disease activity score in with profound eff ects on many important 28 joints (DAS28) seem to independently RA outcomes, including quality of life, predict mortality.58,59 Many studies have WD, and mortality.7,8,69 Apart from CV shown that ACPA- and RF-positivity are disease, which is well acknowledged to associated with increased risk of death.54,60 be linked to RA, the patients suff er from Other predictors of mortality include extra- infections, anemia, lymphoproliferative articular manifestations of RA,61 rheumatoid malignancies, gastrointestinal disorders, cachexia,62 and genetic factors such as the osteoporosis, depression, and various HLA-DRB1 gene.63 autoimmune diseases at a higher rate than How mortality rates in RA have changed does the general population. Some of these over time remains controversial. On the comorbidities may be treatment-associated: one hand, several studies from diff erent for example, NSAID use is an important risk continents indicate reductions in mortality factor for gastrointestinal ulceration, and in successive RA cohorts.60,64-66 On the other glucocorticoids predispose to osteoporosis hand, as a dramatic decline in mortality has and cataract. also occurred in the general population, a widening all-cause mortality gap between 2.2 Cardiovascular disease RA patients and the general population has 2.2.1 Etiology and pathogenesis even been suggested.59,67 A meta-analysis of 11 studies from 1955 to 1995 reported a Many cross-sectional and longitudinal decline in the incidence of all-cause mortality epidemiological studies have confi rmed, but no decrease in standardized mortality among patients with established RA, an ratio (SMR) in successive RA cohorts.55 One elevated risk for atherosclerosis, clinical 70,71 registry study from Finland suggested no CV disease, and CV mortality. Although increased mortality in patients with incident under wide investigation, the underlying RA diagnosed between 2000 and 2007 and causes of the increased CV burden are not yet observed through 2008, the SMR being 0.97 completely clear. Th e association of RA and (95% confi dence interval [CI] 0.91-1.02).60 A CV disease may originate from both causal recent British study found no change in SMRs and non-causal elements. One proposal is but a sustained excess mortality in successive that RA-specifi c factors such as immune RA or early infl ammatory polyarthritis dysregulation, systemic infl ammation, inception cohorts diagnosed in 1990-1994, or treatment with oral glucocorticoids or 1995-1999, and 2000-2004.68 NSAIDs enhance CV risk during the course of RA. On the other hand, RA and CV disease may share risk factors such as smoking, genes, or diet which could elevate the risk for CV events already before the onset of RA.63,72-74 Supporting evidence exists for both of these theories, suggesting a combination of the two.

7 Review of the literature

One of the most important receptors modulating antibody formation pathophysiologic mechanisms of CV risk in RA reside also in atherosclerotic plaques, in RA is the interplay between systemic and autoantibodies against oxidized LDL infl ammation and atherosclerosis. may be involved in the development of both Atherogenesis is nowadays recognized not atherosclerosis and RA.79 as a passive lipid accumulation but an active Although synovium is the harbor infl ammatory process characterized by of infl ammation in RA, when RA is pathogenetic steps such as endothelial injury, active, various amounts of infl ammatory recruitment of various infl ammatory cells, cytokines are released into the systemic proliferation of smooth muscle cells, and lipid circulation. Th ese cytokines have multiple oxidation.75 pro-atherogenic eff ects (Figure 2). Firstly, An atherosclerotic plaque and an cytokines mediate endothelial dysfunction RA-aff ected infl amed joint show noteworthy by upregulating endothelial adhesion similarities in their infl ammatory events molecule expression, attracting leukocytes.80 (Figure 1). Not only the same types of Secondly, they impair the insulin sensitivity infl ammatory cells but also the same of skeletal muscle and adipose tissue, cytokines such as TNF-α and IL-6 leading to increasing glucose and lipid levels mediate injury in both atherosclerosis and in the blood.80 Infl ammation promotes synovitis.76 Neoangiogenesis, expression pro-atherogenic oxidative modifi cation of of adhesion molecules, and extracellular low-density lipoprotein (LDL) and impairs matrix degradation are also involved in both the ability of high-density lipoprotein processes.76,77 In addition to infl ammation, (HDL) particles to remove cholesterol from another factor linking atherosclerosis atherosclerotic lesions.81,82 TNF-α raises the and RA may be autoimmunity: for levels of asymmetric dimethyl-L-arginine example, citrullinated proteins that can be (ADMA), an endogenous inhibitor of nitric recognized by ACPAs may occur within an oxide synthase and an indicator of oxidative atherosclerotic plaque.78 Moreover, toll-like stress and CV risk. ADMA, in turn, may

Similar factors between a joint affected by RA and an atherostatic plaque

Figure 1. Schematic illustration of similarities between the histology and biochemical features of a rheumatoid joint and atherosclerotic plaque. Abbreviations: RA, rheumatoid arthritis; TNF-α, tumor necrosis factor alpha; IL-1, interleukin-1; IL-6, interleukin-6; MMPs, matrix metalloproteinases; LDL, low-density lipoprotein; oxLDL, oxidized low-density lipoprotein. 8 Review of the literature

Figure 2. Proatherogenic processes caused by the release of infl ammatory cytokines into the systemic circulation. reduce levels of endothelial progenitor cells, study investigating the extent of coronary thereby preventing them from repairing artery atherosclerosis in RA, hypertension endothelial injury.80 Furthermore, TNF-α prevalence was 67.6% among established RA induces the expression of tissue factor on patients, 38.6% among early RA patients, monocytes and endothelium, leading to and 38.4% among controls.86 Higher disease increased coagulation.80 activity is associated with hypertension, and furthermore, blood pressure may be reduced 2.2.2 Cardiovascular risk in early RA by successful antirheumatic treatment.87 Since this thesis focuses on comorbidities in Blood pressure levels have been reported as future and early RA patients, the following covariate data in several studies that show, sections describe recent evidence on CV despite their methodological diff erences, changes closely preceding and following the mainly similar prevalences of hypertension diagnosis of RA. in newly onset RA compared with those of non-RA controls (Table 1). 2.2.2.1 Traditional cardiovascular risk In general, LDL particles expedite factors the formation of atherosclerotic plaque Data are somewhat inconsistent as to whether by transporting cholesterol into arterial the prevalence of hypertension is higher in RA walls, whereas HDL particles dampen than in the general population.83 Regarding atherosclerosis by eliminating cholesterol established RA, a meta-analysis that included from the vessel wall. Besides high LDL seven RA case-control studies failed to and low HDL cholesterol levels, elevated demonstrate an increase in prevalence of lipoprotein(a) (Lp(a)) levels are a marker hypertension among RA cases compared of CV risk. Reduced HDL cholesterol and with that of controls.84 Among newly increased Lp(a) levels correlate with elevated diagnosed RA patients, few studies have infl ammatory activity in RA measured by 84,88 investigated the prevalence of hypertension as serum CRP levels. Interestingly, despite a primary outcome. In a Swedish prospective higher CV risk, active infl ammation in study of 442 RA patients, prevalence of RA also leads to a reduction in the levels of antihypertensive treatment during the 5-year triglycerides, LDL, and total cholesterol, period aft er RA diagnosis increased from suggesting a paradoxical inversion of the 24.5% to 37.4%.85 In a small case-control relationship between CV risk and lipid levels.89 In line with this, an American

9 Review of the literature retrospective cohort study from 2005-2010 HDL cholesterol increased, and the ratio of showed a non-linear J-shaped association total cholesterol to HDL cholesterol fell.95 between LDL levels and risk for myocardial Furthermore, Lp(a) levels decrease aft er infarction, the lowest risk being observed inhibition of IL-6 signaling with biologic among patients with LDL between 1.8 and agents.96 Although antirheumatic treatment 2.6 mmol/l.90 Comparable fi ndings have come may raise total and LDL cholesterol and from studies on infl ammatory and infectious thus theoretically elevate CV risk, this is diseases other than RA.91 less likely to represent an increased CV risk It is not yet fully clear why infl ammation than a response to successful suppression of aff ects lipid levels in such radical ways, but the infl ammation.89 activation of the reticuloendothelial system Interestingly, some have observed may play an important role in the changes.89 derangements in lipid profi les even in In addition to quantitative infl ammation- preclinical phases of RA. Van Halm and related lipid level changes, changes may also coworkers reported that 79 blood donors with be qualitative: for example, changes in the future RA showed a more atherogenic lipid subfraction composition of HDL may result profi le than did controls even 10 years prior in a decrease in its anti-infl ammatory and to clinical eruption of RA (Table 1).97 One reverse cholesterol-transport function.91 study within the Rochester Epidemiology Similarly, in early RA, many studies Project showed that levels of total and LDL show levels of HDL cholesterol lower than cholesterol decreased during the 5 years in non-RA controls, whereas results for before the fulfi llment of the ACR 1987 total or LDL cholesterol have been more criteria in 577 RA patients, but not among ambiguous (Table 1). Some have observed a 540 non-RA controls. HDL cholesterol levels typical proatherogenic lipid profi le in early in the RA group, however, remained similar, RA compared with control profi les, more resulting in a decreasing atherogenic total specifi cally higher serum levels of total cholesterol/HDL ratio before RA onset.98 cholesterol, LDL cholesterol, and triglycerides Th e systemic infl ammatory burden but lower serum HDL cholesterol92 as well in RA may enhance insulin resistance as smaller LDL particle size.93 Other studies, and therefore promote type II diabetes however, suggest in early RA relatively low mellitus.99-101 Initial data suggest higher levels of both total cholesterol and HDL fasting insulin levels and more insulin cholesterol.94 Despite this heterogeneity, a resistance even during the fi rst year of RA common feature in many studies has been than found among non-RA controls.102 higher atherogenic total cholesterol/HDL Furthermore, the insulin-resistant state may ratio in early RA. be more severe among patients with high Antirheumatic pharmacotherapy and versus moderate disease activity.102 Besides subsequent control of disease activity seems systemic infl ammation, glucocorticoid use to improve blood lipids by raising HDL in RA may promote insulin resistance.103 cholesterol.92,94 Th is was recently shown Whether diabetes is more common in RA in a 24-week randomized controlled trial than in the general population, the consensus involving 459 patients with early, untreated is not yet unanimous – reports both RA: shortly aft er initiation of either support4,104 and oppose105,106 an association methotrexate monotherapy, of a combination between RA and both type I and type II of methotrexate and etanercept, or of triple diabetes. A meta-analysis of 15 case-control therapy; the levels of both total, LDL, and studies suggests that in RA the prevalence of

10 Review of the literature adapted by by adapted 13 38.4 % in controls, 38.6% in early RA, and RA, and 38.6% in early 38.4 % in controls, RA cohort. 67.6% in established in 24% vs. 25% hypertension diastolic vs. controls. RA patients SystBP/diastBP 139/76 mmHg in long- 139/76 mmHg SystBP/diastBP RA, in early RA, 129/75 mmHg standing (P = 0.003/P in controls 129/73 mmHg and = 0.21). in RA patients hypertension of Prevalence 49%. in controls 52%, and Prevalence of hypertension 5.4% in RA hypertension of Prevalence 5.5% in controls. and patients, 8.3% in controls. er 10 min BP >140/90 mmHg in 45% vs. 43 % and hypertension Systolic Use of of Use antihypertensive BP or agents >140/90 mmHg antihypertensives antihypertensives criteria JNC or a diagnosis of or hypertension measurements 5 measurements in supine min apart aft position rest Evaluation methodEvaluation Results Discharge Hospital Register of IP of and >10 yrs for for >10 yrs and RA established observation onset symptom indicate studies not included in the original publication. in the original included not studies indicate 86 RA early for <5 yrs 85 ** 2 of Average 91 182 the onset to Prior established RA established and 66 long- and RA) standing joints ≥4 weeks ≥4 weeks joints Studies on traditional CV risk factors near the onset of RA (updated version of a table published in a review by Kerola et al., Kerola in a review by published a table of version RA (updated of the onset near CV risk factors traditional on Studies Goodson 2004 [109] ≥2 swollen IP: Gonzalez 2008 [105]Gonzalez 1987 ACR 603 2005 [86]Chung 1987 ACR 603 RA, 71 70 early date Incidence of Use Holmqvist 2009 [72]Holmqvist 1987 ACR 2008* [108]*Chung 1987 ACR 2,025 154 (88 early 2,760 RA Newly-diagnosed Self-reported in RA 9.0% and hypertension of Prevalence Author, year (ref.)Author, RA diagnosisHypertension 2009 [72]Holmqvist Patients 1987 ACR Controls 8,454 end-point of Timing 42,267 <18 mos from Table 1. Table Asterisks Limited). Group BMJ Publishing permission from

11 Review of the literature er treatment, treatment, er in changes er RA diagnosis. No groups. between erences Patients with RA had 3.8% higher TC, RA had 3.8% higher TC, with Patients HDL-C 9.0% lower and 16.8% higher TG, controls’. than lower but TG, and LDL-C TC, Higher Aft controls’. than HDL-C LDL-C/ and TC/HDL-C ratios atherogenic increased. decreased as HDL-C HDL-C CRP and with inversely correlated Changes ESR. high. ratio TC/HDL-C all RA cohorts, trial with controlled 1-yr randomized RA 155 early among antirheumatics the reduced and HDL-C raised patients ratio. TC/HDL-C No diff No Decline in TC and LDL during 5 yrs 5 yrs during LDL and Decline in TC in not but patients among RA onset before within group in either change No controls. aft 5 yrs levels. TG or HDL-C levels, HDL-C lower and TG Higher LDL similar. levels LDL-C and while TC in than size smaller in RA patients particle controls. Increase in mean TC, HDL-C and and HDL-C TC, in mean Increase of in ratio decrease and levels LDL-C groups in all 3 treatment HDL-C to TC MTX and therapy, triple (MTX+ETA, baseline. versus monotherapy) TC, HDL-C, TG, TG, HDL-C, TC, apolipoproteins HDL-C, LDL-C, TC, TG TG, Lp(A) TG, TG, LDL size LDL TG, TC, LDL-C, HDL-C, HDL-C, LDL-C, TC, TG TC, LDL-C, HDL-C, HDL-C, LDL-C, TC, TG Evaluation methodEvaluation Results er er DMARDs er 1 yr of 7.5 at e 1st sample inclusion, follow-up follow-up inclusion, aft Th before (0.1–14.5) yrs RA symptoms During the 5 yrs the 5 yrs During aft 5 yrs and before RA incidence initiation of DMARDs of initiation observation RA active Early HDL-C TC, in normal low HDL-C Baseline and TC 1,071 serum samples 85 ** HDL-C, LDL-C, TC, 540, 3,048 lipid measurements in three early in three early RA cohorts 1,078 serum samples and 66 long- and RA) standing measurements measurements 459 aft 24 weeks ACR 1987, ACR DMARD-naive patients Georgiadis 2006 [92]Georgiadis 1987 ACR 58Boers 2003 [94] 63 <1 yr at RA duration 155 26, 21 and van Halm 2007 [97] Halm van 1987 ACR 79 patients, Rizzo 2009 [93] 1987 ACR 2008 [108]*Chung 25 1987 ACR 154 (88 early 22 <1 yr RA duration HDL-C, LDL-C, TC, Myasoedova 2010 [98]Myasoedova 1987 ACR 577, 3,088 lipid Author, year (ref.)Author, RA diagnosisDyslipidemia 2013 Navarro-Millan Patients[95]* Controls end-point of Timing

12 Review of the literature ammatory in 42%/42% of ned MetS imentation rate; HOMA-IR, HOMA-IR, rate; imentation , year; IP, infl , year; IP, O, World Health Organization; Organization; Health World O, groups. between erences TG, trigycerides; Lp(a), lipoprotein(a); trigycerides; lipoprotein(a); TG, Lp(a), WHO/NCEP-defi RA, 31%/30% long-standing with patients (P controls 11%/22% of RA, and early with < 0.001/P = 0.03). No diff No Mean (SD) BMI had increased from BMI had increased from (SD) Mean 26.0 (4.5) kg/m2 (P=0.000). 25.4 (4.2) to BMI >30 kg/m2 was 12.9% at of Prevalence follow-up. 15.8% at baseline and total but BMI similar, and weight Mean mass higher and truncalbody fat and in RA mass lower lean appendicular patients. legs, and and arms mass of lean Lower high truncal mass and high fat body fat RA. early with in women distribution Disease activity linked with insulin insulin Disease with linked activity resistance. rough medical rough criteria for MetS for criteria examination examination Physical Physical total examination, lean regional and mass fat mass and Physical total examination, lean regional and mass fat mass and Evaluation methodEvaluation Results Th a and records self-assessment questionnaire 3 yrs mos observation 9.5 (3.7) years of mass index; SD, standard deviation; MetS, metabolic syndrome; WH metabolic syndrome; MetS, deviation; standard mass index; SD, 85 ** III NCEP and WHO 85 ** Physical follow-up (SD) mean and 66 long- and RA) standing and 66 long- and RA) standing 1.596 at 1.596 at 1,333 inclusion, follow- end of at up duration <1 yr <1 yr duration

Metabolic syndrome Metabolic 2008 [108]*Chung 1987 ACR 154 (88 early Dao 2011 [111] Book 2009 [112] 2008 [108]*Chung 105 1987 ACR 154 (88 early 132 105 132 ≤ disease duration ≤ 12 disease duration Author, year (ref.)Author, RA diagnosis resistance Insulin Patients Controls end-point of Timing Shahin 2010 [102]Shahin 66 40 <1 yr RA duration HOMA-IR patients. among greater values HOMA-IR Body composition 2013 [110]*Ajeganova 1987, RA ACR *Studies not included in the original publication. in the original included not *Studies RA in long-standing 20 (14-24) yrs RA, and in early 2 (1-3) yrs duration (IQR) **median yr Committee; Negotiating Joint JNC, Rheumatology; month; of College American arthritis; ACR, mo, RA, rheumatoid Abbreviations: Panel Treatment Adult Program Education Cholesterol National NCEP, polyarthritis; TC, total cholesterol; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; cholesterol; lipoprotein high-density HDL-C, cholesterol; lipoprotein low-density LDL-C, cholesterol; total TC, polyarthritis; ESR, erythrocyte protein; sed C-reactive CRP, etanercept; ETA, disease-modifying drug; MTX, methotrexate; anti-rheumatic DMARD, BMI, body resistance; insulin model for homeostasis assessment

13 Review of the literature diabetes is increased, although studies were bystander but is associated with higher CRP statistically signifi cantly heterogeneous.84 levels and a more severe disease course.118,119 Regarding RA and type I diabetes mellitus, convincing evidence from recent population- 2.2.2.2 Non-traditional cardiovascular risk based studies indicates a positive association factors between these diseases.4,107 Th e frequency of Although traditional CV risk factors type I diabetes, however, was similar among contribute to development of CV disease also 1,460 Finnish RA patients when compared among RA patients, they do not fully explain with that of the general middle-aged the excess CV risk.105 Th is has led to the population in Finland.106 Interestingly, in a theory that RA patients carry additional risk preliminary study of 11 non-diabetic patients factors for CV disease. Th e two main culprits with rheumatoid disease, inhibition of IL-6 indicated to induce atherosclerotic damage in signaling with biologic agents improved systemic rheumatic diseases are infl ammation insulin sensitivity.96 and autoimmunity.120,121 Th ese are activated Smoking is more prevalent among prior to the onset of RA symptoms122-124 RA patients than among the general and may enhance atherosclerosis already in population84,113,114 in part because smoking is a preclinical or early phases of RA.125 Traditional risk factor for ACPA-positive RA.115 Smoking and non-traditional risk factors do not lead may be even more prevalent among those who to increased CV risk independently of each will have RA in the future than among those other: for example, both insulin resistance and who have already been diagnosed, as implied atherogenic lipid levels increase with higher by a Swedish prospective study in which the CRP values,102,125,126 and insulin resistance has prevalence of smoking decreased from 29.8% been linked to seropositivity.127 to 22.4% during the 5 years following the RA Markers of systemic infl ammation diagnosis.85 and disease activity might be useful when Obesity is recognized nowadays as evaluating in RA the magnitude of CV risk. a chronic low-grade infl ammatory state, An American retrospective cohort study mediated by adipokines produced by on 44,000 RA patients found a CRP level of adipose tissue.116 In early RA, an unhealthy >10 mg/L compared with <1 mg/L and an body-composition phenotype may be more erythrocyte sedimentation rate (ESR) level frequent than in controls, as indicated by of >42 mm/h compared with <14 mm/h to lower appendicular lean mass, higher body be associated with a twofold risk for MI.90 fat mass, and higher truncal fat mass.111,112 In a recent Swedish ten-year observational Metabolic syndrome seems to be more study among 741 patients with early RA, the prevalent in established RA than in non-RA area under the curve for both CRP and ESR controls.117 Th is may also be the case in early values was associated with higher CV disease RA, as indicated by a study among 154 RA risk.128 In a Swedish prospective 5-year study patients, in which the prevalence of metabolic among 442 patients with newly diagnosed syndrome was 42% in patients with a median RA, independent predictors of a CV event RA duration of 20 years, 31% for a median included raised ESR at baseline, higher RA duration of two years, and 11% in non-RA cumative disease activity, and progression controls (P<0.001).108 Again, a possible of extra-articular disease.85 Subclinical mediator for this association is the frequent atherosclerotic changes such as higher carotid use of glucocorticoids in RA. Abnormal body intima-media thickness (IMT) and impaired fat composition in RA is not an innocent vasodilatory responses have been generally

14 Review of the literature shown to associate with higher CRP, ESR, and these studies, endothelial dysfunction DAS among early RA patients,129-133 although was reversed aft er 6 to 12 months of some studies have demonstrated no such antirheumatic drug therapy.130,142,143 In line association.134,135 with these results, coronary fl ow reserve, As to immune-mediated mechanisms, as measured by dipyridamole transthoracic a plethora of epidemiological data show that stress echocardiography, may be lower RF and ACPA positivity are associated with among recent-onset RA patients than increased risk for CV events in RA.128,136-138 among controls.144 As with brachial artery Interestingly, in a study on 40 patients with vasodilatory responses, aft er treatment with early RA, antibodies against oxidized LDL DMARDs, vascular function of coronary independently predicted atherosclerosis as arteries improved.135 measured by carotid ultrasound (p=0.0089).131 Noteworthy is that these studies In the Swedish 5-year prospective study, had relatively small numbers of patients however, CV events were not linked to RF, (Table 2). Besides, in one population of ACPA, or anti-nuclear antibodies during 79 RA patients whose symptoms had the fi rst years of RA.85 Still, the same group developed in less than one year, brachial found that low longitudinal levels of IgM artery endothelium-dependent dilation anti-phosphorylcholine, an antibody that was preserved both at baseline and aft er 18 may protect from atherosclerosis and chronic months of follow-up.145 Furthermore, an infl ammation, may independently predict observational study among 18 RA patients the presence of bilateral carotid plaque,139 with median symptom duration of only a fi nding in line with fi ndings in non-RA two months showed preserved micro- and populations.140 macrovascular endothelial function.146 Th e same study, however, revealed increased 2.2.2.3 Preatherosclerotic processes levels of molecular markers of endothelial Endothelial dysfunction, an early step damage and abnormal endothelium- of atherogenesis, is linked to increased independent vasodilatory responses expression of adhesion molecules, production (induced by sublingual glyceryl trinitrate for of proinfl ammatory and prothrombotic macrovascular assessment and iontophoresis molecules, oxidative stress, diminished of sodium nitroprusside for microvascular production of nitric oxide, and impaired assessment).146 A study among 15 patients modulation of vascular tone.121 It can with early RA and low-grade infl ammation be assessed by measuring endothelium- (CRP <20mg/dl) found no diff erences dependent vasodilatory responses in between patients and controls in skin both micro- and macrocirculation.121 microvascular function.147 In the light of these Endothelial dysfunction seems to be more studies, whether endothelial dysfunction is prevalent in established RA patients than in present in excess during the fi rst years of RA healthy controls, and to be associated with remains inconclusive. infl ammation.141 As to the fi rst few years of RA, the state of endothelial function is still 2.2.2.4 Subclinical atherosclerosis unclear (Table 2, Figure 3). Non-invasive methods for assessing Th ree studies have found among the extent of atherosclerosis include patients with newly diagnosed untreated echocardiography of the carotid arteries and RA signifi cantly impaired brachial artery evaluation of coronary artery calcifi cation vasodilatory responses.130,134,142 In all in computer tomography scans. Th e related

15 Review of the literature ammatory RA er 1 yr of treatment. er 18 mos of ammatory therapy. ammatory rst evaluation. In follow-up; follow-up; In evaluation. rst adapted by permission by adapted 13 anti-infl er 1 yr of the fi at erences anti-infl er 6 mos of ow reserve reduced compared with controls’. with compared reserve reduced ow ow reserve improved aft reserve improved ow cant diff cant function in skin microvascular erence cant improvement aft improvement cant Levels of soluble VCAM-1, vWF, and pentraxin-3 elevated elevated pentraxin-3 and vWF, VCAM-1, soluble Levels of E-selectin, MCP-1, soluble ADMA, controls’. to compared high disease in RA with increased only activity. OPG and treatment, response improved. response treatment, Brachial artery vasodilation response lower among RA among lower artery response Brachial vasodilation Aft baseline. at controls among than patients Both micro- and macrovascular endothelial function endothelial macrovascular Both and micro- abnormal. responses endothelium-independent preserved but damage endothelial of markers molecular some contrast, In raised. No signifi No No diff No unchanged. vasodilatory responses in IMT but increase an therapy. RA patients had lower vasodilatory responses at baseline. baseline. at vasodilatory responses had lower RA patients Signifi Vasodilatory responses in RA patients impaired at baseline, baseline, at impaired in RA patients responses Vasodilatory aft normal but ow-mediated ow-mediated ow-mediated ow-mediated ow-/nitrate- ow-/nitrate- ow-/nitrate- ow reserve Coronary fl reserveow Coronary fl Biochemical markers of of markers Biochemical VCAM- activation: endothelial ADMA, pentraxin-3, 1, vWF, OPG, E-selectin, MCP-1, soluble cystatin C, homocysteine Evaluated parameterEvaluated Results Brachial arteryBrachial fl dilation Microvascular endothelium- Microvascular endothelium- and dependent and vasodilatation independent artery fl brachial dilatation mediated Brachial arteryBrachial fl IMT carotid and dilation Microvascular endothelium- Microvascular endothelium- and dependent vasodilatation independent Brachial arteryBrachial fl dilation mediated Coronary fl Coronary Coronary fl Coronary Brachial arteryBrachial fl dilation mediated er er 1 er er er 6 mos of ammatory therapy ammatory e studies not included in the original publication. publication. in the original included not e studies DMARDs er 1 yr of duration 12 (4-18) mos duration observation baseline; follow-up aft baseline; follow-up treatment DMARD yr of Symptoms >1 month, >1 month, Symptoms 2 (1.2-3.0) (IQR) median mos baseline, follow-up aft follow-up baseline, 18 mos duration 5 (4-12) mos duration inclusion, follow-up follow-up inclusion, aft treatment

inclusion, follow-up aft follow-up inclusion, DMARDs 18 mos of follow-up aft follow-up anti-infl Controls endpoint of Timing and 25 type and 2 diabetic, hypertensive controls 44 <12mos at Symptoms RA RA patients 18 48 healthy, baseline, baseline, 27 in follow-up 15 15 symptom (IQR) Median diagnosis ACR 1987ACR 35 35 <1 yr at RA duration to an early- an to arthritis clinic criteria and and criteria CRP ≤20 mg/l ACR 1987ACR 25 25 <1 yr Disease duration ACR 1987ACR 20 25 <1 yr at RA duration Studies on subclinical CV changes near the onset of RA (updated from a table published in a review by Kerola et al., Kerola in a review by published a table from RA (updated of the onset near subclinical CV changes on Studies Author, year (ref.)Author, RA Pre-atherosclerotic changes Pre-atherosclerotic Klimek 2014 [164]* 1987 ACR 29 29 disease (SD) Mean Chatterjee Adhikari Adhikari Chatterjee 2013 2012 [134], Guin [143]* Foster 2012 [146]Foster Referrals van Eijk 2011 [147] Eijk van 1987 ACR Södergren 2010 [145] 1987 ACR 79 at Hannawi 2009 [130]Hannawi 1987 ACR 20 20 <1 yr at RA duration Turiel 2009 [144] Turiel Turiel 2010 [135] Turiel Bergholm 2002 [142] 1987 ACR 10 33 <18 mos, RA duration Table 2. Table indicat Asterisks Limited). Group BMJ Publishing from

16 Review of the literature in RA. cantly with anti- with cantly treatment. er 18 mos of cantly from baseline. baseline. from cantly erence in EF. E/A ratio and disease and E/A ratio in EF. erence cantly with disease activity. Global disease with activity. cantly cation not increased in early RA but in RA but increased in early not cation er 1 yr of therapy, a decrease in IMT. a decrease therapy, er 1 yr of er. er. n Willebrand factor; ADMA, asymmetric factor; dimethyl- ADMA, n Willebrand erence in EF, LVEDD, or LVESD. E/A ratio and disease and E/A ratio LVESD. or LVEDD, in EF, erence decreased signifi er 1 year established RA. established baseline. Aft aft early RA, and 0.78±0.01mm in later RA. All patients were were RA. All patients 0.78±0.01mm in later RA, and early postmenopausal women. EF correlated non-signifi EF correlated signifi correlated strain systolic longitudinal disease of activity. markers CCP and Greater LA, LVEDD, LVESD, A, and IVRT but lower E/A lower but IVRT A, and LVESD, LA, LVEDD, Greater diff No controls’. than ratio negatively. correlated duration LV end-systolic radial and longitudinal myocardial strains strains myocardial longitudinal radial and end-systolic LV E’/A’ and E’ S’, reduced showed TDI in controls. than lower did parameters echocardiographic in RA. Conventional ratio diff not Greater LA, A, and DT but lower E/A ratio than controls. No No controls. than E/A ratio lower but DT LA, A, and Greater diff negatively. correlated duration range; IMT, intima-media thickness; DMARD, disease- thickness; DMARD, intima-media IMT, range; cationcalcifi Coronary id plaque in RA. plaque more and IMT values carotid Higher diastole in early velocity ow ventricle; S’, systolic annulus velocity; E’, early diastolic annulus velocity; A’, late diastolic diastolic late velocity; A’, annulus diastolic early velocity; E’, annulus systolic S’, ventricle; ventricular end-systolic dimension; EF, ejection fraction; IVRT, isovolumic relaxation time; E, relaxation isovolumic fraction; IVRT, ejection EF, dimension; end-systolic ventricular Carotid IMTCarotid plaque carotid IMT, Carotid at plaque of in prevalence no increase IMT but Elevated aft unchanged IMT levels Carotid Carotid IMTCarotid baseline; cIMT values at in controls than IMT greater Carotid Evaluated parameterEvaluated Results Carotid IMT Carotid 0.72±0.03mm in IMT was 0.68±0.14mm in controls, Coronary arteryCoronary calcifi Echocardiography: LV systolic systolic LV Echocardiography: as EF and function measured strain systolic global longitudinal Echocardiography: LA diameter, LA diameter, Echocardiography: LVESD, LVEDD, aorta diameter, E, IVRT, fractional shortening, EF, A, E/A ratio 2D speckle tracking 2D speckle tracking TDI, echocardiography, echocardiography conventional Echocardiography: LA diameter, LA diameter, Echocardiography: LVESD, LVEDD, aorta diameter, E, A, E/A ratio DT, EF, er DMARDs er 1 yr of of Rheumatology; VCAM, vascular cell adhesion molecule; vWF, vo molecule; vWF, vascular Rheumatology;cell adhesion of VCAM, inclusion, follow-up aft follow-up inclusion, DMARDs 18 mos of treatment follow-up inclusion, aft treatment <1 yr; 1-yr follow-up observation or more for early RA patients and and RA patients early for RA established for >10 yrs naive early RA early naive 5.1 (1-17) yrs 34.2 (4.2) mos 76 (85) mos, range 3-324 76 (85) mos, range mos ow velocity; DT, deceleration time of fl time of deceleration velocity; DT, ow Controls endpoint of Timing 86 was <5 yrs RA duration ventricular end-diastolic dimension; LVESD, left LVESD, dimension; end-diastolic ventricular RA RA patients RA,71 RA 53 DMARD- and Steroid- diagnosis ACR 1987ACR 35 35 Baseline disease duration

ACR 1987ACR 45 45 RA duration (range) Mean atrium; LVEDD, left LVEDD, atrium; ow velocity; A, late diastolic mitral fl mitral diastolic velocity; A, late ow Author, year (ref.)Author, RA Ahmed 2010 [131] 2010 [135]Turiel 1987 ACR 40 1987 ACR 20 2009 [144]Turiel 2008 [129]Georgiadis 40 1987 ACR 1987 ACR 40 25 25 <12mos Symptoms 45 25 <1 yr at RA duration carot IMT, Carotid <1 yr at RA duration <1 yr Disease duration IMT Carotid in controls. than IMT greater Carotid Atherosclerosis Adhikari Chatterjee 2013 2012 [134], Guin [143]* Park 2002 [150]Park 1987 ACR 53 53 <1 yr either RA duration Hannawi 2007 [132]Hannawi 1987 2005 [86] ACR Chung 40 1987 ACR 70 early 40 <1 yr Disease duration plaque carotid IMT, Carotid plaque increased atherosclerotic and IMT greater Myocardial dysfunction Myocardial Løgstrup 2014 [160]* Udayakumar 2007 Udayakumar [153]* Sitia 2012 [158]*Sitia 1987 ACR 22 20 RA duration (SD) Mean Arslan 2006 [154]*Arslan 1987 ACR 52 47 RA duration (SD) Mean *Studies not included in the original publication. in the original included not *Studies College American ACR, arthritis; RA, rheumatoid Abbreviations: L-arginine; MCP-1, monocyte chemotactic protein-1; OPG, osteoprotegerin; yr, year; CRP, C-reactive protein; IQR, interquartile interquartile IQR, protein; C-reactive year; CRP, yr, osteoprotegerin; OPG, protein-1; monocyte chemotactic MCP-1, L-arginine; left LV, imaging; tissue doppler TDI, lipoprotein; high-density HDL, modifying month; drug; mo, velocity; LA, left annulus early diastolic mitral fl mitral diastolic early

17 Review of the literature measurements, more specifi cally carotid clinically evident heart disease present with IMT and coronary artery calcifi cation more left ventricular fi lling abnormalities score, are strongly associated with risk for than do healthy controls.153-155 Moreover, CV disease.148,149 Carotid IMT has been diastolic dysfunction seems to correlate with quite extensively studied in early RA, and disease duration, suggesting a subclinical four129,131,132,144 of the seven129,131,132,135,144,145,150 myocardial involvement with the progression case-control studies included in this review of RA.153-155 In addition, RA patients are more found IMT to be signifi cantly higher in RA likely to have higher systolic pulmonary artery patients with a disease duration of under one pressures, increased left ventricular mass year than in controls (Table 2, Figure 3). With and larger left atrial size than controls across longer disease duration, the carotid IMT may studies, but their left ventricular ejection increase even further.150 In line with this, fractions have usually been similar.156,157 coronary artery calcifi cation may be more Interestingly, recent studies assessing prevalent and severe in RA cohorts of long- myocardial function by speckle-tracking standing disease than among those with RA echocardiography strain imaging have shown for less than fi ve years.86 reduced myocardial strain in patients with Again, confl icting results exist: the both early158 and established159 RA without 79 early-RA patients who had preserved known CV disease. In early and untreated endothelial function had no higher carotid RA, left ventricular function measured by IMT values than did controls at baseline.145 global longitudinal systolic strain correlates During 18 months of follow-up, however, with disease activity and ACPA-positivity.160 their carotid IMT rapidly increased, with no Of note, myocardial infl ammation and similar increase apparent among controls.145 fi brosis in cardiac magnetic resonance scans Carotid plaque prevalence is another may be frequent in RA patients without marker of atherosclerosis and predictor of CV known cardiac disease, and be linked to RA events that can be measured by ultrasound disease activity.161 examination.151 Two studies observed more NT-proBNP is a marker of ventricular prevalent plaques in the carotid arteries of dysfunction and CV risk that has prognostic RA patients with disease duration less than signifi cance both in heart failure and acute one year than among healthy controls,131,132 coronary syndrome. A study of 90 patients whereas one study found no diff erence with early RA (duration < 5 years), 69 with between early RA patients and controls.129 long-standing RA (duration > 10 years), and In established RA, carotid plaque prevalence 88 controls has indicated that NT-proBNP associates with disease activity.152 concentrations are elevated also in early RA To conclude, it seems that morphological when compared with control values, although atherosclerotic changes occur rapidly aft er or the increase is even more pronounced even prior to onset of RA symptoms (Figure in established disease.162 Patients with 3) and are likely to become aggravated along established RA without heart failure also with longer disease duration. show elevated high-sensitivity troponin I levels.163 2.2.2.5 Subclinical myocardial damage Several echocardiographic studies have demonstrated that RA patients without

18 Review of the literature

BiomarkersBiomarkers of ofendothelial endothelial activation activation Klimek 2014 [164]*

Endothelium-dependentEndothelium-dependent vasodilation vasodilation Chatterjee Adhikari 2012 [134], Guin 2013 [143]* Foster 2012 [146] van Eijk 2011 [147] Södergren 2010 [145] Hannawi 2009 [130] Bergholm 2002 [142] Bergholm 2002 [142]

CoronaryCoronary flow flow reserve reserve Turiel 2010 [135] Turiel 2009 [144]

CarotidCarotid IMT Chatterjee Adhikari 2012 [134], Guin 2013 [143]* Ahmed 2010 [131] Södergren 2010 [145] Turiel 2010 [135] Turiel 2009 [144] Georgiadis 2008 [129] Hannawi 2007 [132] Park 2002 [150]

CarotidCarotid plaque plaque Ahmed 2010 [131] Georgiadis 2008 [129] Hannawi 2007 [132]

CoronaryCoronary artery artery calcificationcalcification Chung 2005 [86]

DiastolicDiastolic dysfunction dysfunction Udayakumar 2007 [153]* Arslan 2006 [154]*

MyocardialMyocardial strainstrain Sitia 2012 [158]*

-10 -8 -6 -4 -2 0 2 4 6 8 Years from symptom onset

Figure 3. Overview of studies on subclinical CV changes near RA onset (updated from a review by Kerola et al.,13 adapted by permission from the BMJ Publishing Group Limited). Red bars show increased CV risk, green bars unincreased risk. Starting point and length of bars represent observation period. Asterisks indicate studies not included in the original publication.

19 Review of the literature

2.2.2.6 Symptomatic cardiovascular disease main focus, which is atherosclerotic CV Clinical CV disease is estimated to be 1.5 to 2 disease and other common CV conditions. times as prevalent in established RA as in the general population, and the CV disease risk 2.2.2.7 Coronary heart disease and stroke in RA is comparable to that exerted by type According to a recent systematic review 2 diabetes mellitus.165,166 Similar phenomena and a meta-analysis, the risk for myocardial appear in the early years of RA. For instance, infarction in RA is 2.1-fold and for stroke the rates of hospital admissions for CV 1.9-fold that of the general population.171 disease among patients with infl ammatory Another meta-analysis, however, indicated polyarthritis of less than seven years are no increased risk for stroke but only for double those of the general population.167 In myocardial infarction.172 In a cohort of a cohort of 553 newly-onset RA patients from approximately 4,000 RA patients from Rochester, Minnesota, USA, the absolute 17 countries, the average prevalence of ten-year risk for a CV event was as high as myocardial infarction or stroke was 6.6%, and that of non-RA patients who were 5 to 10 prevalence by country was generally higher years older.168 in European countries and in the US than in Many temporal aspects of RA-related Asia or South America.173 CV risk are not yet fully clarifi ed. Initial Th e CHD phenotype may diff er among data are controversial as to whether CV patients with and without RA. Data from disease is more prevalent than expected the Rochester Epidemiology project have before RA onset.72,169 CHD in established shown RA patients to be less likely to RA may occur at a younger age than in the report symptoms of angina and more likely general population,168 and the rate ratio for to experience unrecognized myocardial CV events and death is highest in young RA infarction and sudden cardiac death than were patients, albeit the rate diff erence increases non-RA controls.169 Moreover, RA patients with age.165 Young age at RA onset may be may exhibit poorer long-term outcomes aft er associated with increased risk of CV death.138 myocardial infarction, despite similar rates Furthermore, RA duration may act as a risk of reperfusion therapy and cardioprotective factor for CV disease, since long-standing medications.174 disease leads to longer exposure to chronic RA patients may carry an increased risk infl ammation.86 A recent study involving for CHD already in the proximity of the RA 855 RA patients discovered, however, that diagnosis (Figure 3).175,176 Maradit-Kremers disease activity over time rather than disease and coworkers conducted a population- duration may contribute to excess CV risk, based cohort study in which they showed since neither occurrence nor hazard for a CV that RA patients were already at increased event correlated independently with disease risk for myocardial infarction during the duration.170 two-year period before fulfi llment of the RA may present with extra-articular ACR 1987 criteria for RA.169 Holmqvist and manifestations that involve the CV system coworkers, however, in two large Swedish such as vasculitides, pericarditis, pericardial cohorts, found no increased risk for CHD eff usion, valvular heart disease, conduction before onset of RA symptoms,72 whereas defects, and myocardial fi brosis or their subsequent investigation disclosed amyloidosis. Th ese diseases are relatively rare an increased myocardial infarction risk complications of RA, and are not this study’s aft er one year following fulfi llment of ACR criteria for RA.175 Supporting these fi ndings,

20 Review of the literature

CV disease Franklin 2010 [167] Maradit-Kremers 2008 [168] Gonzalez 2008 [105]

Coronary heart disease Lindhardsen 2011 [177] Holmqvist 2010 [175] Holmqvist 2009 [72] Maradit-Kremers 2005 [169]

Congestive heart Failure Nicola 2005 [178]

CV death Humphreys 2014 [68]* Franklin 2010 [167] Naz 2008 (RF+) [138] Naz 2008 (RF -) [138] Young 2007 [189] Goodson 2005 [190] Goodson 2002 (RF +) [191] Goodson 2002 (RF -) [191]

-4 -2 0 2 4 6 8 10 12 Years from symptom onset

Figure 4. Overview of studies on symptomatic CV disease risk during the fi rst decade of RA (updated from a review by Kerola et al.,13 adapted by permission from the BMJ Publishing Group Limited). Red bars represent increased CV risk compared with controls, green bars unincreased risk. Follow-up for the fading bars continues beyond the scale (Tables 3, 4). Asterisks indicate studies not included in the original publication.

21 Review of the literature erence erence er RA er cant), all cant), was 2.53 CV event rst cantly increased compared increased compared cantly erence at 1 yr. At 1-4 yrs RR was 1-4 yrs At 1 yr. at erence er diagnosis was 0.64% vs. 9.4%. RR for CV disease was 1.9, RR for admission signifi 1.1 (not CHD 1.9, stroke vascular disease 2.0. admission diff RR 1.6. No 5-12 yrs at 1.6, and RF status. by Elevated absolute, excess, and relative relative and excess, absolute, Elevated of CV disease.10-yr risk of Incidence soon aft was elevated the outcome incidence date. pectoris, or in MI, angina increase No did not RA. RF status to CHD prior total modify risk. excess this of lack Similar prevalence of CV disease. of prevalence Similar angina for MI 3.40, and hospitalized pectoris 0.59. Risk for ACS in both TNFi users and in both TNFi users and ACS Risk for patients biologics-naive signifi were TNFi- HR for populations’: general to the biologics- exposed for was 1.61 and 2.03. patients naïve Probability of an CV event in 1 vs. 10 CV event an of Probability yr aft fi time to Median 0.02–8.31). (range years ed adapted by permission from BMJ Publishing BMJ Publishing permission from by adapted ed from from ed 13 ned as primary defi ACS; rst Evaluation methodEvaluation Results CV disease identifi admission care a local acute of records from hospital MI diff No Combined CV outcome including including CV outcome Combined MI, revascularization, coronary CV death CHF and CHD events reported Combined CHD eventCombined MI was 5.5, for unrecognized for OR failure, etc. before incidence date before etc. failure, Any fi Any MI, acute diagnosis of discharge pectoris, acute or angina unstable death of cause MI as underlying Unstable angina, MI, cardiac arrest, arrest, MI, cardiac angina, Unstable identifi death cardiac or codes 410- ICD-9 records; hospital codes I20-21 413, ICD-10 MI 0-3. yrs MI was 1.7 during for OR ned. At inclusion, inclusion, At ned. er symptom onset, onset, er symptom observation Median 7.0 yrs from from 7.0 yrs Median RA incidence date range (interquartile 5.8–8.1). aft 6 mos median incidence date onset symptom Before self- and register Nationwide RA diagnosis defi 19.6% vs. 16.7% had and had RA >10yrs, was follow-up median in TNFi 3.9 vs. 2.7 yrs exposed vs. biologic- group. naive mean RA duration RA duration mean 5.8 yrs 0-3 yrs e Norfolk population 42267 and 42267 and 2760 38,520 not RA duration

Population duration Treatment 800 Th 7469 37024 Diagnosis <18 mos 553 574 since RA 0-10 yrs 8454 and 2025 603 603 RA incidence date MI, heart pectoris, Angina CHD, 603 603 the 2-yr period before 7,704 TNFi exposed, 23,112 biologics- naive 653 10477 total, 10477 total, 295 in case-control study joints ≥4 wk. joints if not Exclusion RA. RA diagnosis Patients Controls end-point of Timing 1987 ACR criteria ACR 1987 ACR criteria 1987 ACR criteria ACR 1987 ACR criteria 1987 ACR criteria two or more more or two or visits clinical hospitalizations RA as a with diagnostic code ICD-9 code 714 ICD-9 ICD-10 and codes M5-M6 ICD codes ICD M5-M6 and prescription of DMARDs

NOAR-cohort ≥2 swollen IP: Population studied ERAR Swedish cohort Rochester, Rochester, Minnesota, residents EAR and Swedish EIRA cohort Rochester, Rochester, Minnesota, residents Rochester, Minnesota, residents Swedish RA Swedish basedcohorts on the National Register Patient the Swedish and Register Biologics Based on inpatient Based inpatient on database, hospital Zealand New Danish population Studies on symptomatic CV disease near the onset of RA (updated from a review by Kerola et al., Kerola a review by from RA (updated CV disease of the onset near symptomatic on Studies CV disease 2010 Franklin [167] Author, year Author, (ref.) [175] Maradit- 2008 Kremers [168] 2009 Holmqvist [72] Gonzalez 2008 Gonzalez [105] Maradit- 2005 Kremers [169] Coronary heart disease Ljung 2014 Ljung [182]* Khan 2013 Khan [183]* Lindhardsen Lindhardsen 2011 [177] Holmqvist 2010 Holmqvist Table 3. Table publication. in the original included not studies indicate Asterisks Limited). Group

22 Review of the literature ammatorypolyarthritis; ; MI, myocardial infarction; yr, yr, infarction; ; MI, myocardial 1.7-fold incidence of CHF. Risk higher CHF. incidence of 1.7-fold the RF+. among ster; IP, infl ster; IP, rheumatoid factor; ERAR, Rheuma- Early rheumatoid Evaluation methodEvaluation Results Framingham Heart criteria Study observation diagnosis (median diagnosis (median 11.8 yrs) follow-up American College of Rheumatology; CHD, coronary heart disease coronary Rheumatology; CollegeAmerican of CHD, cation of Diseases; WHO, World Health Organization; BP, blood pressure; JNC, Joint Negotiating Commit- Negotiating Joint JNC, blood pressure; BP, Organization; Health World Diseases; of WHO, cation ; EIRA, Epidemiological Investigation of Rheumatoid Arthritis; RF, Rheumatoid of Investigation ; EIRA, Epidemiological 575 583 from 6-46 yrs ACR 1987 ACR criteria RA diagnosis Patients Controls end-point of Timing Rochester, Rochester, Minnesota, residents Population studied Congestive heart failure 2005 Nicola [178] Author, year Author, (ref.) *Studies not included in the original publication. publication. in the original included not *Studies ACR, cardiovascular; CV, arthritis; RA, rheumatoid Abbreviations: Arthritis Regi the Norfolk NOAR, syndrome; coronary acute ACS, inhibitors; TNF alpha TNFi, heart failure; congestive year; CHF, Classifi International ICD, Arthritis month; Register;toid mo, tee RR, risk ratio; OR, odds ratio; EAR, OR,RR, odds Arthritis Early risk ratio; ratio; Register

23 Review of the literature a Danish register study revealed an odds ratio infl ammation.184 A considerable number of for myocardial infarction of 1.7 among RA studies show that two important risk factors patients with treatment duration of less than for life-threatening arrhythmias, that is, three years.177 CV autonomic dysfunction and ventricular repolarization abnormalities, are excessive 2.2.2.8 Congestive heart failure among RA patients as measured by heart Patients with established RA are at increased rate variability analysis, heart-rate-corrected risk for CHF and this contributes to the excess QT-interval, and QT-interval dispersion.184,185 mortality in RA.178,179 Risk for heart failure Th ese mechanisms may underlie the is associated with certain RA characteristics increased risk of sudden cardiac death in RA such as RF positivity, ESR levels, and populations. severe extra-articular manifestations.180 Infl ammation may drive the Compared to that of the general population, pathogenesis of atrial fi brillation, the most their presentation of heart failure may be common sustained arrhythmia in the general more subtle, with fewer typical signs and population.186 To date, two large cohort symptoms.181 In addition, their left ventricular studies have evaluated the risk for atrial systolic function is more likely to be preserved fi brillation in RA. A Danish study including (ejection fraction ≥50%).181 18,000 patients with RA disclosed a 40% Elevated risk for CHF may also occur higher incidence of atrial fi brillation than in early RA. In a population-based study of that of the general population. Moreover, they 575 RA patients within the framework of observed higher relative risks in younger age the Rochester Epidemiology project, relative groups, but higher absolute risk diff erences in risk for CHF remained fairly constant, older groups.187 A study of nearly 21,000 RA almost twice as high as among the controls, patients from the USA revealed an unadjusted throughout the long follow-up of 6 to 46 incidence rate ratio for atrial fi brillation of years.178 Cumulative incidence of CHF had 1.4, but aft er adjustment for comorbidities, already begun to rise more sharply among medications, and healthcare use, no increased the RA group aft er the fulfi llment of ACR risk for atrial fi brillation was associated with 1987 criteria for RA.178 Furthermore, a greater RA.188 Both of these studies were conducted percentage of RA patients were excluded among cohorts with established RA, and no from the study because of pre-existing CHF, studies to date have assessed the risk for atrial implying that CHF may already be more fi brillation in early RA. frequent among them before the clinical eruption of RA.178 2.2.2.10 Cardiovascular mortality A recent meta-analysis of observational 2.2.2.9 Cardiac arrhythmias studies on CV mortality in RA reported a 50% RA patients are at increased risk of sudden increase in risk of CV death in comparison cardiac death,169 implying that their increased to that of the general population.1 Another incidence of malignant arrhythmias may meta-analysis showed the risk for fatal contribute to their excess mortality.184 myocardial infarction in RA to be increased Th e prevalences in RA of two important by almost 80%, whereas risk for fatal stroke arrhythmogenic conditions, CHD and CHF, was increased by 46%.171 However, in the are increased, thus indirectly promoting former meta-analysis, if considering only arrhythmias. Nevertheless, cardiomyocyte inception cohorts, risk of CV death was not electrophysiology may be directly aff ected by elevated.1

24 Review of the literature

Studies of RA inception cohorts have decade of the disease (Table 4, Figure 4). displayed contradictory results as to whether What therefore remains controversial is how CV mortality is increased in the early years of early the CV mortality rates in RA actually RA. In one British multicenter study, mortality begin to rise. was increased within the fi rst seven years aft er During the past few decades, improved RA diagnosis, and CHD appeared to be a key treatment strategies controlling infl ammation promoter of this early excess mortality.189 have reduced RA disease activity considerably. A study of the Norfolk Arthritis Register Evidence to fully confi rm a reduction in cohort from the UK showed that patients all-cause or CV mortality in established RA diagnosed in 1990-1994 with infl ammatory over time, however, is still lacking. A meta- polyarthritis had increased CV mortality analysis of cohort studies including mostly during a median follow-up of 11.4 years, and cases with established RA reported that SMR that, in seropositive patients, their increased for CV death did not change between 1945 CV mortality was already apparent fi ve years and 1995, the pooled SMR being 1.6.57 In a aft er symptom onset (SMR of 1.93, 95% CI large American study, mortality due to acute 1.08-3.19).138 However, a cohort identifi ed myocardial infarction declined from the 1970s from the same register but diagnosed in to the 1990s, and patients with RA diagnosed 1995-1999 appeared to have no increased aft er the 1990s had no longer an elevated CV mortality during the fi rst seven years of risk of fatal acute myocardial infarction.66 infl ammatory polyarthritis, neither in the Interestingly, a Finnish study conducted as seropositive nor the seronegative subgroup.167 early as in the late 1980s observed an increased Th e most recent analysis from the same CV mortality over a 10-year follow-up in 500 register but including patients from 1990- men but not in 500 women with established 1994, 1995-1999, and 2000-2004 revealed no RA.192 Regarding CV case fatality, a recent signifi cant elevation in 7-year CV mortality prospective analysis of 480 RA patients from in the early infl ammatory polyarthritis or RA 2009-2011 revealed a case fatality rate aft er cohorts as a whole.68 In the antibody-positive the fi rst CV event of only 6.9%, which was, subgroup, however, the risk of CV death was in the light of a literature review comprising almost doubled (SMR 1.87, 95% CI 1.30- six studies, considerably lower than in studies 2.69).68 A total of six studies that assessed CV with observation periods from the years mortality rates among inception cohorts with 1955-2006.193 Th at study may have been, some form of arthritis was found,68,138,167,189-191 however, statistically underpowered, since and three of them138,189,191 suggested a slightly only 29 patients experienced a fi rst CV event, increased risk of CV death during the fi rst of which no more than two were fatal.

25 Review of the literature c cant cant in CV erence RA. of 7 yrs rst e antibody-postive antibody-postive e ollege of Rheumatology of ollege erences. erences. 7-year SMR: 1.09 (0.92-1.30) in the SMR: 7-year 1.13 (0.91-1.42) in and cohort EIA Th the RA cohort. increased risk, had a borderline group being 1.31 (1.00-1.73). SMR CV disease for in increase in SMR No sex or by in subgroups or RA patients RF status. mortality all-cause cohort, the entire In CVD mortality increased but was not 1.25 [95% CI 1.01–1.54]. In was (SMR CV disease for 5-yr SMR RF+ patients, 2.00. was 1.93, 10-yr SMR 1.49 and all-causes was 1.27 for SMR was increased, Mortality CHD. for in the fi CHD, by driven death. for RF was a predictor in CV disease men SMR was 1.36 for were SMRs women. 1.93 for and diff higher in the RF+. No rates. admission RF+ CV disease for among SMR signifi was 2.02, no other women diff er adapted by permission from BMJ Publishing BMJ Publishing permission from by adapted 13 Follow-up Results interquartile interquartile 5.8–8.1. range 5 follow-up aft 10 yrs and disease onset 19 yrs, to Up 9.1 yrs median 11.4 yrs median 5-10 yrs, 6.9 yrs ammatory polyarthritis; wk, week; RF, rheumatoid factor; mo, factor; mo, rheumatoid polyarthritis; wk, RF, ammatory week; relation to symptom onset 7.0 yrs increase in CV-disease-specifi No delay Median symptom from 5 mos onset 7.0 yrs, Median <2 RA symptoms 6 mos median yrs, delay Median symptom from median 6-22 yrs, 6.2 mos onset Norfolk population population Norfolk population sex- matched population population of Stockport Norfolk population RA patients Controls in Inclusion 2,519 with whom of EIA, 1,419 had RA 2010 to according criteria 8001098 (267 RF- positive) Norfolk 1429 CV 1010; 515 for admissions and Age- 1236 (320 RF positive) ammatory arthritis; CV, cardiovascular; IP, infl IP, cardiovascular; CV, arthritis; ammatory IP: ≥2 swollen joints joints ≥2 swollen IP: EIA, ≥4 wks for 2010 ACR/EULAR RA for criteria Criteria to enter Criteria enter to cohort IP: ≥2 swollen joints joints ≥2 swollen IP: if ≥4 wks. Exclusion RA not joints ≥2 swollen IP: ≥4 wks. Patients required later were meet the ACR to criteria RA symptoms no prior <2 yrs, treatment Clinical diagnosis a rheumatologist by joints ≥2 swollen IP: if ≥4 wks. Exclusion RA not RA e early Norfolk Arthritis Arthritis Norfolk UK, Register, 1990-1994, 1995- 1999, 2000-2004 Population studied Norfolk Arthritis Arthritis Norfolk UK, Register, 1995-1999 Arthritis Norfolk UK, Register, 1990-1994 Th inception study cohort, UK multicentre, at Patients Stockport rheumatology in clinics UK Manchester, Arthritis Norfolk UK, Register, 1990-1994 Studies on CV death rates in arthritis inception cohorts (updated from a review by Kerola et al., Kerola a review by from (updated cohorts inception in arthritis rates CV death on Studies ) CV death Humphreys 2014 [68]* Franklin Franklin 2010 [167] 2008 Naz [138] 2007 Young [189] Goodson 2005 [190] Goodson 2002 [191] Author, Author, year (ref. Table 4. Table Group Limited). Asterisks indicate studies not included in the original publication. in the original included not studies indicate Asterisks Limited). Group Abbreviations: RA, rheumatoid arthritis; EIA, early infl early arthritis; EIA, RA, rheumatoid Abbreviations: heart disease-modifying disease; coronary C American ACR, drug; CHD, DMARD, ratio; mortality year; SMR, standardized yr, month;

26 Review of the literature

2.2.3 RA medications and risk for with CHF showed no diff erences between CV morbidity and mortality the methotrexate and placebo groups for the primary end-point: the 6-minute walk-test Accumulating data demonstrate that distance.204 Currently, a large, randomized, antirheumatic therapy eff ectively reduces double-blind, placebo-controlled trial known several markers of CV risk.130,135,143 Regarding as the CV Infl ammation Reduction Trial clinical CV outcomes, better control of is testing methotrexate (15-20mg/week) as systemic infl ammation, especially during cardioprotective therapy in 7,000 non-RA the fi rst few years of RA, may confer CV and patients with stable CHD and diabetes survival benefi ts.128 Both exposure to each RA mellitus or metabolic syndrome.205 Th is fl are and cumulative disease activity seem to study will, if methotrexate does improve lead to increased risk for CV events.194 Th e CV outcomes, not only strongly support the importance of achieving sustained remission infl ammatory hypothesis of atherothrombosis in RA is highlighted also by observation of but also provide innovative directions for CV higher NT-proBNP levels, higher brachial and disease management. central systolic blood pressure, and indicators TNF blockers can reduce the likelihood of arterial stiff ness among patients with of CV outcomes.206 In a recent German active RA than among patients in remission study of 8,908 RA patients, TNF-inhibitor and controls.195 Furthermore, the notion that and rituximab users had signifi cantly lower early uncontrolled infl ammation predicts mortality rates than did methotrexate users.207 progression of arterial stiff ness in later A retrospective cohort study of 2,101 RA stages of RA emphasizes the importance of patients demonstrated that, when compared introducing aggressive antirheumatic therapy to patients using non-biologic DMARDs as early in the disease course as possible.196 other than methotrexate, the use of TNF Emerging epidemiologic evidence among inhibitors was associated with a decreased RA patients indicates that methotrexate may risk for CHD (hazard ratio [HR] 0.45 [95% CI reduce CV risk.197 When the results of the 0.21-0.96]).202 A similar but not statistically most relevant studies are combined, reduction signifi cant decrease was observable for in clinical CV events is approximately 20%.198 methotrexate (HR 0.54 [95% CI 0.27-1.09]).202 In one prospective study of 1,240 RA patients, In one Swedish study, 7,704 RA patients CV mortality was reduced by as much as 70% treated with TNF inhibitors were at lower and overall mortality by 60% in patients ever risk for acute coronary syndrome than were vs. those never treated with methotrexate.199 those never exposed to biologics (HR 0.8, A more recent 25-year prospective study of 95% CI 0.7 to 0.95), but at higher risk than more than 5,000 RA patients revealed similar was the general population (HR 1.6, 95% CI results, that is, that methotrexate use was 1.4 to 1.9).182 In another Swedish cohort of associated with a 70% reduction in overall 6,000 early RA patients, patients on anti-TNF mortality.200 Not all studies, however, have therapy had, however, a similar risk for acute reported methotrexate to be associated with coronary syndrome during the fi rst years of decreased rates of CV events or deaths.201,202 RA as did those never undergoing anti-TNF To date, no randomized controlled trial therapy.208 has directly evaluated whether methotrexate Hydroxychloroquine may have reduces CV event rates in RA or non-RA cardioprotective properties through its patients.203 An initial trial on the use of benefi cial eff ects on fasting lipid profi les.209,210 methotrexate among 50 non-RA patients In an American RA cohort predominantly

27 Review of the literature white, male, and elderly, hydroxychloroquine randomized trial involving prednisolone 7.5 use for at least three months was associated mg/day in addition to DMARDs compared with improved lipid profi les irrespective of to DMARD therapy without prednisolone disease activity and statin use.211 Th e authors found, however, a similar incidence of suggested that, given the safety and low cost ischemic coronary artery events but a higher of hydroxychloroquine, its continuous use incidence of ischemic cerebrovascular events as part of an RA treatment regimen might in those assigned to prednisolone compared be a reasonable means of reducing CV risk. to DMARDs alone.219 Initial data suggest that hydroxychloroquine Despite epidemiological fi ndings may also reduce platelet aggregation when regarding the deleterious eff ects of administered alone or when combined with glucocorticoids on CV outcomes,207,217,220 the aspirin.212 extent to which confounding by indication is Not all medications for RA are favorable refl ected in these results remains unclear.221 for the CV system. A recent meta-analysis In theory, glucocorticoids may even have indicated that although NSAIDs have positive CV eff ects in RA populations via slightly diff erent CV risk profi les, none attenuation of infl ammation.221,222 In fact, of them is completely safe in CV terms.213 a recent Dutch study on 353 RA patients Unfavorable side eff ects can include addressing this question reported that even hypertension, heart failure, and weakening though recent, current, and cumulative of the antithrombotic eff ect of aspirin.214 exposure to glucocorticoids associated with As promoters of thrombotic CV events, incident CV disease, adjustment for DAS28 cyclo-oxygenase-2 selective inhibitors and and the Health Assessment Questionnaire traditional NSAIDs do not seem to diff er.215 (HAQ) – Disability Index negated this Cytotoxic immunosuppressive agents may association, thus refl ecting channeling also aggravate CV risk.216 bias.222 Th e German study on 8,909 RA Glucocorticoids are well known patients, however, reported that treatment for their unfavorable eff ects on CV risk; with glucocorticoids (dosage >5 mg/day) among their many important CV side- was signifi cantly associated with increased eff ects are hypertension, insulin resistance, all-cause mortality in a dose-dependent hypercholesterolemia, and weight gain.80 manner, and this study reduced the impact Accumulating epidemiological data suggest of channeling bias by taking into account a positive association between glucocorticoid disease activity and functional capacity as use and CV events and mortality. A recent time-varying covariates.207 study on this topic demonstrated a dose- In sum, emerging data indicate that tight dependent increase in mortality rates disease control is benefi cial for RA patients associated with glucocorticoids among 779 also in CV terms. Furthermore, methotrexate RA patients.217 Furthermore, they found a and TNF inhibitors may improve CV minimum daily prednisone dose threshold outcomes, whereas most evidence suggests of 8 to 15 mg associated with an increase in that glucocorticoids and NSAIDs have mainly mortality.217 Another recent study including detrimental CV eff ects. Until results from over 8,000 RA cases observed for more than well-designed, randomized controlled trials 50,000 person-years suggested that both are available, however, it is impossible to fully current dosage and cumulative exposure to determine the CV risks and benefi ts of these glucocorticoids associate with risk for CV agents. events.218 A 10-year follow-up of a 2-year

28 Review of the literature

2.2.4 Assessment and treatment of evaluating CV risk in RA, total cholesterol/ CV comorbidities in RA HDL ratio may therefore give a better estimate of CV risk than would total cholesterol As the increased CV burden related to RA alone.234 Moreover, it is advisable to reassess has become widely acknowledged among cholesterol levels aft er suppression of rheumatologists, the question arises how to infl ammation and only then decide whether deal with this risk in daily practice. Because to start lipid-lowering therapy, because aft er of the mechanisms underlying CV risk the initiation of eff ective antirheumatic related to RA, suppression of disease activity therapy, lipid levels usually increase.91 and systemic infl ammation are crucial for Th e need for preventive CV CV disease prevention. Equally important is pharmacotherapy in infl ammatory joint the treatment of traditional CV risk factors. diseases is high,235 but alarmingly, RA patients Evidence suggests that statins provide a are less likely to be prescribed CV medications cholesterol-reducing eff ect in infl ammatory than are non-RA patients both for primary joint diseases similar to that in healthy and for secondary prevention.236,237 Moreover, controls,223,224 and the statin dosage to obtain RA patients meeting guideline-based recommended lipid targets is not aff ected hypertension criteria are less likely to receive by the level of systemic infl ammation.225 a diagnosis of hypertension in primary Interestingly, statins may also have anti- care than are those without RA, despite infl ammatory and immunomodulatory more frequent visits.238 Th ese fi ndings are properties that could attenuate RA-related worrisome not only because of the elevated infl ammation and disease activity.226,227 Statins risk for CV events, but also because long- as primary prevention in RA are associated term outcomes aft er a CV event may be with lower risk for CV events and mortality;228 poorer among RA patients.174 In the future, statin discontinuation is associated with closer collaboration between rheumatologists, higher risk of CV death.229 Th is emphasizes cardiologists, and primary-care physicians, the importance of compliance with statin and nurse-led programs may aid in better therapy also among RA patients. Some studies prediction and management of CV risk in have shown that exercise and treatment RA.239,240 Th is may involve establishment of with angiotensin-converting enzyme (ACE) preventive cardio-rheuma clinics, two of inhibitors confer positive CV eff ects in RA.230 which already exist in Oslo, Norway, and in For smokers with RA, smoking cessation Rochester, Minnesota, USA.235,239 is undoubtedly very important in CV risk Specifi c guidelines have been developed reduction.231 to enhance the management of CV risk in RA. Th e interpretation of lipid levels in RA is In 2010, EULAR provided evidence-based not a straightforward process. Th e association recommendations for CV risk management between total cholesterol and risk for CV for RA and other forms of infl ammatory events is weaker in RA than in the general arthritis.231 Th ey emphasized aggressive population,232 since infl ammation distorts the control of RA-related infl ammation, and relationship between lipid levels and CV risk. smoking cessation, and refraining from One American study of a predominantly male use of high doses of glucocorticoids. CV RA cohort comprising 37,000 patients showed risk management, including treatment of no evident association between CHD and hyperlipidemia and hypertension, was to LDL cholesterol, but an inverse association be according to local guidelines. An annual between CHD and HDL cholesterol.233 When CV risk assessment was recommended, and

29 Review of the literature additional risk assessment if antirheumatic or by the Framingham Risk Score for those treatment changed. who fulfi ll two of the following criteria: 1) Th e Finnish Current Care Guideline RA disease duration >10 years, 2) presence for RA has a viewpoint toward CV risk of RF or ACPA, and 3) presence of severe quite similar to that of the EULAR extra-articular manifestations. Even aft er recommendations.241 It states that CV risk applying this multiplication factor, however, assessment should be a part of routine the SCORE risk factor equation may still not general assessment in RA. In contrast to estimate CV risk in RA accurately.246,247 Such the EULAR recommendations, the Finnish a risk underestimation may at least in part be guidelines suggest that treatment goals explained by the fact that increased CV risk for hyperlipidemia should be the same as is confi ned not only to patients with RA for for other groups at high CV risk. What over ten years, but also to early RA patients.169 remains unclear, however, is how oft en Carotid ultrasonography together with risk these guidelines are implemented in clinical prediction equations may improve CV-risk practice. Furthermore, randomized controlled stratifi cation.248 trials are warranted to evaluate whether, for preventing CV events in RA, stricter-than 2.3 Autoimmune thyroiditis and normal blood pressure and lipid treatment hypothyroidism 230 targets are superior to current practice. Autoimmune diathesis, a theory suggesting It is not yet clear what would be the best a tendency for autoimmune diseases to method in RA to detect CV risk. Many of the co-exist within individuals in excess of levels established CV risk-prediction tools such as expected by chance, is generally accepted in the Systematic COronary Risk Evaluation clinical work.5 Indeed, thyroid abnormalities (SCORE), Reynolds risk score, and the in RA are most commonly autoimmune, Framingham risk score may underestimate and may present with hypo-, eu-, or risk for CV disease in RA, because they hyperthyroidism.249 take into account only traditional CV Epidemiological studies since the 1960s risk factors, not those related to systemic have shown that RA and chronic autoimmune 242,243 infl ammation or autoimmunity. Th is thyroiditis (i.e. Hashimoto’s thyroiditis), a is especially true among seropositive and common cause of hypothyroidism, co-occur 242 elderly patients, and among patients more frequently than expected.4,250-253 For categorized as in low or medium CV risk instance, Shiroky and coworkers studied 244 groups in these risk-prediction models. 91 Canadian women with RA in the early Validated and more discriminating CV risk 1990s and found that thyroid dysfunction assessment tools for this purpose are thus was three times as common in this RA vital. Aiming at responding to this need, A cohort as in patients of similar demographic TransAtlantic Cardiovascular risk Calculator characteristics with non-infl ammatory for Rheumatoid Arthritis (ATACC-RA) rheumatic diseases.254 Of note, this excess consortium, including 13 rheumatology risk was entirely due to hypothyroidism centers from 10 countries, is currently or confi rmed Hashimoto’s thyroiditis.254 developing an RA-specifi c algorithm for CV Prevalence estimates for autoimmune 245 risk estimation. thyroiditis in RA vary substantially between Th e EULAR recommendations suggest studies from various countries and with a multiplication factor of 1.5 to be added to diff ering methodologies. In a recently the CV risk estimate measured by SCORE conducted literature review, estimates for the

30 Review of the literature prevalence of autoimmune thyroid disease in Prevalence estimates for depression in RA ranged from 0.5% to 27% across studies RA are highly variable across studies, partly from diff ering areas.255 due to diff erences in methods for identifying Th e etiology underlying co-occurrence depression and partly due to variation in study of RA and autoimmune thyroiditis has quality.263 According to a recent systematic been investigated, for example, with review and a meta-analysis evaluating 72 respect to interrelating genes251,256 and studies of RA, the pooled prevalence (95% autoantibodies.257 Common susceptibility CI) of a major depressive disorder was 16.8% alleles to these diseases include PTPN22 (10.0-24.0%) according to the Diagnostic and and HLA-DR.249,250,258 Initial data imply that Statistical Manual (DSM) criteria, and 38.8% CTLA4 gene polymorphisms may also play (34.0-43.0%) according to the Patient Health a role.259 Moreover, fetal microchimerism has Questionnaire 9 (PHQ-9) depression scale.263 been linked to the pathobiology of both RA Schizophrenia, on the other hand, seems and Hashimoto’s thyroiditis.260 to be negatively associated with RA. In a Investigating the coexistence of Taiwanese registry study of more than 10,000 autoimmune diseases typically involves schizophrenia patients, when compared with patients with an index disease such as 100,000 age-matched controls, the OR for RA; assessment of comorbid autoimmune RA was 0.52 (95% CI 0.35-0.76).264 Similar disorders occurs when the index disease fi ndings appear in several other studies.265,266 is fully established.250 Initial autoimmune Some studies have tried to investigate whether processes in RA may, however, activate genetics explains this negative relationship, years before its clinical onset.123 Th is may with no major breakthroughs.267 Moreover, thus already be aff ecting the development it has been suggested that autoimmune of autoimmune thyroiditis and its clinical mechanisms play a role in the development of manifestation, hypothyroidism, even in schizophrenia.268 preclinical RA phases. To our knowledge, studies on this topic are lacking. 2.5 Comorbidities and work disability 2.4 Psychiatric disorders An issue investigated surprisingly little is Depressive symptoms may be up to 2 to 3 whether the high prevalence of comorbidities times as common in RA as in the general contributes to the development of WD in population.2,3 A recent population-based RA. A Dutch study on 508 RA patients who study on more than 3,300 infl ammatory- were using TNF inhibitors demonstrated arthritis patients showed, during a median that having comorbidities is associated with follow-up of 2.8 years from disease onset, an stopping working.269 In one small case- increased risk for developing both anxiety control study among patients with established and depressive disorders (HRs 1.4 and RA, the odds ratio for permanent WD in 1.4, respectively).261 Depression in RA is patients with any comorbidity vs. without associated with physical disability, fatigue, comorbidities was as high as 7.54.9 disease activity, and, above all, the experience Depressive symptoms and anxiety have of chronic pain.2 Emerging evidence indicates associated with WD in some relatively small that bidirectional interactions exist between RA populations.10-12 In one German study on mood disorders and infl ammation, and this 356 patients with an infl ammatory rheumatic might also in part explain the high prevalence disease, a psychiatric comorbidity as assessed of depression in RA.262 by the PHQ was an independent predictor

31 Review of the literature of WD.10 More specifi cally, a comorbid assessed the eff ect of CV comorbidities on psychiatric disorder raised WD from 25% work participation in patients with rheumatic to 50% in severe infl ammatory rheumatic diseases in a cohort of 12,140 employees from disease and from 5% to 17% in mild disease, 45 companies and organizations. Th ere, a self- rheumatic-disease severity being assessed reported CV comorbidity did not additively by the treating physician on a 5-step rating aff ect the length and frequency of sick leave scale. In addition, the severity of depression episodes or long-term WD among patients was an independent predictor of WD.10 In with a self-reported rheumatic disease, one Norwegian study comprising 474 RA although both CV and rheumatic diseases patients aged 18 to 45, WD pension risk elevated sick leave and WD rates separately.270 was associated with worse mental health as However, because rheumatic diseases other assessed by patient-reported Short Form (36) than RA such as osteoarthritis, fi bromyalgia, Health Survey.53 and gout constituted the majority of the No literature yet exists on the role of CV rheumatic diagnoses in the study, the diseases as leading to WD in RA cohorts. generalizability of the results to RA patients is A Dutch prospective study in 1998-2008 limited.

32 Aims of the study

AIMS OF THE STUDY

Th e main aim of this work was to elucidate the epidemiology of comorbidities in early RA, with emphasis on CV disease. Specifi c aims were to discover:

1. Th e prevalence of CHD, chronic hypertension, and CHF at RA diagnosis, and to compare this with fi gures for an age- and sex-specifi c general population.

2. Th e prevalence of hypothyroidism at RA diagnosis, and to compare it with that of the general population.

3. Th e contribution of psychiatric and CV comorbidities to long-term WD in recent-onset RA, and to compare rates of WD resulting from these diseases with those of the general population.

4. CV mortality in the early years of RA, to compare it to the general populations’, and to evaluate the impact of RA medications on CV mortality.

33 Materials and methods

MATERIALS AND METHODS

3 Background the pharmacotherapy of certain chronic and severe diseases such as CHD, CHF, RA, and Th e data for this work came solely from diabetes with an examination-based doctor’s nationwide Finnish registers and statistics, certifi cate. e.g. the register of special reimbursements To qualify for special reimbursement, for medicine expenses, the pension registers the patient must fulfi ll Kela’s set of predefi ned maintained by Kela (Th e Social Insurance medical criteria for his/hers condition. Institution of Finland) and the Finnish Th e criteria for special reimbursement are Centre for Pensions, the archive of death oft en not the same as the medical criteria certifi cates, the statistics on causes of death, for starting medication. According to good and the prescription register. Th ese registers clinical practice, if the patient fulfi lls the are maintained primarily for administrative criteria for special reimbursement, the needs but also serve research purposes. As treating physician routinely fi lls in the the data in the registers are coded according required certifi cate (Medical Certifi cate B). to the personal identifi cation number of every For many diseases, the medical certifi cate permanent Finnish resident, it was possible to must be issued either in a specialist-level combine all of each person’s data. health care unit or by a specialist, but for some common diseases such as hypertension 3.1 Register of special or hypothyroidism, any physician can reimbursements for medicine complete the certifi cate. Th e certifi cate must expenses describe the signs, symptoms, and course of All permanent residents of Finland are the disease, diagnostic procedures, and the covered under general sickness insurance, relevant ICD-10 code(s). It must also include which includes reimbursements for the a plan for disease monitoring and treatment. costs of outpatient prescription medicines It is possible to apply special reimbursements for the treatment of illness. Th ese medicine for more than one disease with only one costs are reimbursed by Kela at three rates certifi cate. Th e Medical Certifi cate B costs the of reimbursement: the basic, the lower, and patient typically 30 euros when received from higher special reimbursements. Th e basic public health care,272 and from 60 to 140 euros reimbursement is granted from Kela without from private health care.273 a doctor’s certifi cate. Between 2000 and Before granting of the special 2007, this covered 42 to 50% of the price of reimbursement, the medical certifi cate is the medicinal product.271 Lower and higher submitted to Kela, where a medical examiner special reimbursements can be applied for physician or pharmacist at Kela checks and 34 Materials and methods approves it. Th e special reimbursements for medication costs. Regarding CHD, the are granted independently of the patient’s doctor’s certifi cate sent to Kela is usually socioeconomic status or place of residence. completed in a clinic of cardiology or Between 2000 and 2007, the lower special internal medicine. It must describe the signs, reimbursement covered 72 to 75% of the symptoms, and diagnostic procedures for price of the medicine, and the higher special the patient with chronic CHD. For example, reimbursement covered 100%.271 To qualify patients who have suff ered a myocardial for reimbursement, the medicine must be infarction, undergone a percutaneous purchased in the most economical package coronary intervention or coronary artery size for a maximum of 3 months’ use. bypass graft ing, or patients with chronic Special reimbursement decisions are angina pectoris whose rest or exercise recorded in a nationwide register by date of electrocardiogram shows signs of CHD are reimbursement decision and a set of Kela entitled to the special reimbursement. Th e codes for the diseases qualifying for special medical certifi cate must also include one of reimbursement. From 2000 onwards, this has the ICD-10 codes: I20–I22, I24.0, or I25. also included the respective ICD-10-codes for Chronic hypertension is the most diagnoses of chronic diseases. common disease entitling patients to special reimbursement of medications in Finland, 3.1.1 Rheumatoid arthritis covering more than 10% of the population. In order to establish entitlement to To establish this particular entitlement, special reimbursement for antirheumatic the patient must have received treatment medications, a patient must fi le an for at least 6 months with antihypertensive examination-based medical certifi cate agents. Th e medical certifi cate must include issued by a rheumatologist or physician with an ICD-10 code of I10–I13, I15, or I27.0 experience of rheumatology. Th e certifi cate and describe either clearly elevated blood must describe the proper diagnostic pressures, additional CV risk factors or the procedures and ICD-10 code (M05 for presence of an end-organ complication. Th us, RF-positive RA and M06 for RF-negative RA) patients with only mild hypertension are as well as a treatment plan in accordance with ineligible for reimbursement. good clinical practice. Th e reimbursement Similarly, patients with CHF are entitled system covers any antirheumatic medication to special reimbursement by an ICD-10 necessary to control the disease activity code of I11.0, I13, I50, or I97.1. Chronic of each patient, also during remission. cardiac arrhythmias entitle patients to special Practically all Finnish patients with reimbursement of medications by ICD-10 antirheumatic medications are eligible for the codes I47 to I49. For diabetes, the special special reimbursement from the early phases reimbursement is granted if the medical of the disease, because it is a routine policy certifi cate shows that either the 1) fasting in the rheumatology clinics of Finland to plasma glucose is >7.0 or fasting blood complete this certifi cate at the diagnosis of an glucose >6.1 mmol/l, 2) plasma/blood glucose infl ammatory rheumatic disease. is >11.1/10.0 mmol/l in one measurement, 3) glucose tolerance test 2-hour plasma/ 3.1.2 Cardiovascular disease and its blood glucose is >11.1/10.0 mmol/l, or 4) risk factors HbA1c is >48 mmol/l. Th is certifi cate must include one of the ICD-10 codes E10-E14, or For many chronic CV diseases, a diagnosis E89.1, that includes both type I and type II entitles patients to special reimbursement 35 Materials and methods diabetes. Patients with chronic CHD-related the patients with future RA and the general dyslipidemia were, until 2011, entitled to a population. separate special reimbursement for lipid- lowering agents. Nowadays, treatment 3.2 Pension registers of dyslipidemia is included in the special Th e statutory pension system in Finland reimbursement for CHD medications. consists of two main parts – an earnings- related pension and a residence-based 3.1.3 Hypothyroidism national pension. Th e earnings-related Patients with clinical hypothyroidism pension, managed by various earnings- are entitled to special reimbursement for related pension providers that belong to the levothyroxine substitution. A medical Finnish Centre for Pensions, covers the entire certifi cate describing the etiology, the clinical workforce, including the self-employed. Th e picture of hypothyroidism, and the levels of national pension provides minimum security thyroid-stimulating hormone and thyroid and income for those who have an insuffi cient hormone T4 is sent to Kela as an enclosure earnings-related pension. Th e national in the application for special reimbursement. pension is managed by Kela.275 Because of the high prevalence of Disability pensions are granted for hypothyroidism, this certifi cate can be issued permanent Finnish residents of working age not only by an endocrinologist but also by a who have a long-term disease that prevents general practitioner. them from working. At fi rst, employees are Th e special reimbursement for paid an allowance for a maximum of 300 days levothyroxine is granted for patients under of illness. Disability pensions can be applied ICD-10 codes C73, E03, and E89.0. Th us, not for at Kela or the Finnish Centre for Pensions only chronic autoimmune thyroiditis, but also with an examination-based doctor’s certifi cate other, rarer forms of primary hypothyroidism aft er 150 weekdays of sickness allowance. (inadequate function of the thyroid gland Usually, when the allowance period ends, the itself) qualify for the special reimbursement, work-disabled person will receive a temporary including postprocedural hypothyroidism, disability pension entitled a rehabilitation hypothyroidism aft er radioiodine therapy, allowance in Finnish legislation. During the and hypothyroidism caused by medications rehabilitation allowance, the pension recipient or malignant neoplasms of the thyroid gland. receives rehabilitation in order to restore work Iodine-defi ciency-related hypothyroidism capacity from either the earnings-related or and subclinical hypothyroidism, on the the national pension scheme. other hand, do not qualify for special Later, if the medical treatment and reimbursement. Central hypothyroidism is vocational rehabilitation cannot restore the covered under the special reimbursement for patient’s ability to earn a reasonable living, a hypopituitarism and is thus excluded from permanent disability pension follows. If the our data. Because levothyroxine is such a pension recipient has an illness, defect, or low-priced medicine (in 2007, a 100-tablet injury that causes a 60% reduction in work package of either 25 or 100 μg strength cost capacity, a full-time permanent disability 4.97 euros274), not all hypothyroid patients pension can be issued. If work capacity is on levothyroxine may apply for the special reduced by 40% but by less than 60%, a reimbursement. Th is is likely to result in a low partial disability pension is issued. Data coverage of hypothyroid patients both among on sick leaves, rehabilitation allowances,

36 Materials and methods and disability pensions are gathered in the 3.4 Prescription register pension registers maintained by Kela and the Kela maintains a prescription register Finnish Centre for Pensions. recording outpatient medicine purchases of 3.3 Statistics Finland’s archive reimbursable medicines from pharmacies. It of death certificates and was established in 1994, and serves primarily annual statistics on causes administrative purposes. Medicine purchases of death are fi led according to the Anatomical Th erapeutic Chemical (ATC) code,279 and When a person dies, the treating physician date of purchase and number of purchased writes a death certifi cate which includes the packages are retrievable. Th e prescriptions are underlying cause of death, causes leading valid for 1 year from the day on which they to death, the immediate cause of death, a were prescribed, but Finnish reimbursement possibility to enter contributory causes of regulations restrict the maximum number death, a short case-history of the deceased, of packages supplied per redemption to and a description of the circumstances cover only a 3-month period. Intravenous 276 of death. Causes of death are classifi ed medicines such as infl iximab are reimbursed according to the ICD-10 code system. Causes by hospitals and outpatient clinics, and of death are oft en based on the diseases their use is therefore not recorded in this known before death, but in some cases, register. Further, the register does not include a post-mortem investigation is necessary over-the-counter medicines. If the patient because the cause of death is unknown, or presents his/hers Kela card when purchasing unexpected, or if the deceased was not under medicines, the reimbursement can oft en a doctor’s care during his/her last illness. be credited directly at the pharmacy. Th e In 2008, a medical autopsy was performed reimbursement can also be claimed aft erwards for 7.0% and a forensic autopsy for 24.0% of from Kela within six months of the purchase. 277 those deceased. Th e coverage of prescription medicine Statistics Finland maintains an archive purchases in the register is approximately 75 of death certifi cates that includes death to 95%, and varies according to calendar year 278 certifi cates from 1936 onwards. From and medicinal product.280 this archive, information on mortality and causes of death can be obtained for scientifi c purposes with written permission from 4 Patient cohorts Statistics Finland. Statistics Finland also produces annual Th e case identifi cation method of this statistics on causes of death in the entire study relied on the special reimbursement Finnish population, covering all permanent decisions for RA medications. We identifi ed Finnish residents who have died in Finland all the adult RA patients under ICD-10 or abroad during the calendar year. Data codes M05 and M06 who were granted the on causes of death for these statistics are special reimbursement of medications for RA compilations of data in the death certifi cates from the register of special reimbursement according to underlying cause of death. Th e decisions, using the date of the reimbursement statistics contain data on mortality according decision as the RA index date (Figure 5). to cause of death (54-group classifi cation of ICD-10 codes), age, and sex.278

37 Materials and methods

Finnish population

Index date Eligibility for special Index date 1 Jan 2004─31 Dec 2007 reimbursement for 1 Jan 2000─31 Dec 2007 antirheumatic medication ≥20 years of age (M05 or M06) ≥18 years of age

Excluded if retired or >64 years of age

Studies I and II Study III Study IV

7,209 incident RA cases 7,831 incident RA cases 14,878 incident RA cases

Figure 5. Case identifi cation protocol for Studies I-IV.

5 Outcomes disability pensions that had continued for at least one year at the end of follow-up. 5.1 Comorbidities at diagnosis Hereaft er, these disability pensions are of RA designated as WD. Th e patients were followed Data on comorbidities were retrievable up until the beginning of a disability pension, from the register of special reimbursement of normal retirement, until death, or until the decisions. Data on existence of CHD, chronic end of 2008. From the same registers came hypertension, and hypothyroidism at the RA data on periods of sickness allowance longer index date were collected by requiring that the than ten days. Compensation of lost income medicine reimbursement decision antedates is not granted for sick leaves shorter than or the medicine reimbursement decision for equal to ten days, and data on those short sick RA (Studies I and II). We also present similar leaves were thus unavailable. unpublished data on CHF, other CV diseases, Th e primary outcomes for Study III and CV risk factors. were WD-causing CV disease and psychiatric disorders. Th e leading cause for the disability 5.2 Work disability caused by pension of each patient was identifi ed by comorbidities the fi rst (i.e. the most important) diagnostic From the pension registers, we obtained data ICD-10 code in the pension registers. CV on any kind of pension in the RA cohort diseases were identifi ed by the codes I00– as well as in the entire Finnish population I99 and RA by M05/M06. We identifi ed up until December 31, 2008. In analyses psychiatric disorders by ICD-10 codes F20– of these data, we included all incident F69, including schizophrenia; schizotypal permanent disability pensions occurring aft er and delusional disorders; mood disorders; the diagnosis of RA and those temporary neurotic, stress-related, and somatoform

38 Materials and methods disorders; behavioral syndromes associated administered biologic agents. CV disease with physiological disturbances and physical medications were categorized by ATC code factors; and disorders of adult personality subgroups. For each purchase, Kela provides and behavior. Th is composite outcome will reimbursement for medications for only be referred to as “psychiatric disorders” or three-month use. Th erefore, we assumed “psychiatric comorbidities.” that one medicine purchase corresponds to three months of medication use. In assessing 5.3 Cardiovascular mortality the total duration of use for each RA or We obtained the underlying cause of death CV medication, the number of medicine for each RA patient from the archive of death purchases was multiplied by a three-month certifi cates maintained by Statistics Finland period, and the medication-use duration was (Study IV). Th e validity of this register, determined as a percentage of patient-years. particularly regarding CV causes, has been Because of the frequency of combination demonstrable.276,281 CV disease was identifi ed therapies, this method would have yielded as the underlying cause of death by ICD-10 falsely high results for evaluating the duration codes I00 to I99. Th e CV disease-specifi c of treatment with any RA medication (data in death rates in the age- and sex-specifi c general Figure 19). For this reason, we estimated the population came from the annual statistics on duration of any RA medication by calculating causes of death (Statistics Finland). Patients the remainder of the last and fi rst medicine were followed up until death or the end of purchases and adding a three-month period. December 2008, whichever occurred fi rst. We assessed the eff ect of several factors 6 Ethical considerations on CV mortality, including RA medications and comorbidities. Th e comorbidities We used only offi cially archived register data, comprised cardiac diseases (CHD, CHF, which are available without any patient- or chronic arrhythmias with or without specifi c consent. Permission for use of these hypertension), hypertension without cardiac data came from the administrator of each disease, diabetes, asthma, chronic obstructive register, i.e., Kela, Statistics Finland, and pulmonary disease (COPD), and prior the Finnish Centre for Pensions. Every malignancies. We were unable to distinguish patient was given an identifi cation number, between patients who had cardiac disease according to which the data were analyzed with or without hypertension, because anonymously. the medications for these diseases overlap substantially, and a patient may have both conditions but be eligible only for the special 7 Statistical analysis reimbursement for cardiac disease. In analysis of the use of RA medications From the prescription register and number of WD days, the statistical maintained by Kela, we extracted data on signifi cance of diff erences between groups the use of RA and CV disease medications. was evaluated by bootstrap type analysis Th e specifi c RA medications included of variance (ANOVA) or co-variance methotrexate, hydroxychloroquine, (ANCOVA) with appropriate contrast; sulfasalazine, glucocorticoids, and 95% CIs were obtained by bias-corrected subcutaneous TNF inhibitors. Th e register bootstrapping (5000 replications). contains no information on intravenously

39 Materials and methods

For estimation of cumulative incidence used Poisson regression models and yielded functions and adjusted sub-hazard ratios standardized rate ratios (SRRs) with 95% CIs. (sHRs), we used the Fine and Gray Th e standardized mortality ratio (SMR) is the competing-risks regression model (Studies III ratio of the number of observed deaths in a and IV). In general, competing-risks analyses study population divided by the number of are suitable for settings in which subjects are expected deaths. Expected numbers of deaths at risk for more than one mutually exclusive were calculated by multiplying patient-years event such as competing causes of death.282 at risk by the age- (in 5-year categories), For estimating cumulative incidences of sex-, and calendar-year-specifi c death rate. WD (Study III), competing risks comprised Similarly, to compare WD incidence rates WD due to causes other than the disease of in the RA cohort to those in the general interest and death before age 65. Similarly, for population, we analyzed the standardized estimating the cumulative incidence of CV incidence ratio (SIR) based on observed death (Study IV), competing risks comprised and expected incidences of WD in the RA causes of death other than CV disease. population. In order to compare the rates of primary outcomes to the general population, we

40 Results

RESULTS

8 Characteristics of the 9.1 Coronary heart disease patient cohorts Of the 7,209 RA patients, a total of 553 (7.7%) Our RA populations consisted of had a validated diagnosis of CHD at RA predominantly female RA patients, with more diagnosis. Of these, 287 were women (CHD RF-positive than RF-negative patients (Table prevalence 5.9%), and 266 were men (11.5%). 5). Across the RA populations, mean age Risk for CHD was slightly higher in the RA among women ranged from 45.5 to 56.6 years, cohort than in the general population (SRR and among men from 47.2 to 58.2 years. 1.10, 95% CI 1.01 to 1.20). Th e SRR point estimates were similar in the RF-positive and 9 Comorbidities at diagnosis RF-negative subgroups, but only that of the of RA RF-negatives was statistically signifi cantly In the cohort of 14,878 RA patients diagnosed elevated (Table 7). between 2000 and 2007 in Finland, quite Figure 6 illustrates the SRRs for CHD a few patients had been granted special in subgroups by gender and age at RA onset. reimbursements for medicine expenses due Although the SRRs were mostly no longer to some other disease before the RA diagnosis signifi cantly elevated in the age subgroups, (Table 6). Th e most common diseases that patients with earlier RA onset seemed to have had led to special reimbursements were higher SRR point estimates than did patients hypertension, asthma and COPD, CHD, who were older at RA diagnosis, especially in hypothyroidism, and diabetes mellitus. the group of patients aged 20 to 49. Absolute prevalence of CHD was, however, only 0.5% among patients aged 20 to 49, and it increased

Table 5. Characteristics of RA cohorts in Studies I-IV

Patients Women Men n n (%) Age, mean RF+ n (%) Age, mean RF+ (SD) (SD) Studies I and II 7,209 4,887 (68) 56.6 (15.0) 64 % 2,322 (32) 58.2 (13.5) 66 % Study III 7,831 5,552 (71) 45.5 (11.1) 60 % 2,279 (29) 47.2 (10.2) 63 % Study IV 14,878 10,119 (68) 55.8 (15.8) 62 % 4,759 (32) 57.5 (13.9) 64 %

41 Results

Table 6. Eligibilities for special reimbursements of medication expenses in the cohort of 14,878 patients at RA diagnosis (unpublished results).

Percentage, % Men Women Total Disease (N=4,759) (N=10,119) (N=14,878) Cardiovascular diseases Congestive heart failure 2.8 2.3 2.4 Hypertension 20.8 19.9 20.2 Coronary heart disease 11.6 5.9 7.7 Chronic cardiac arrhythmias 2.3 1.5 1.8 Neoplasms Breast cancer - 0.6 0.4 Prostate cancer 1.1 - 0.4 Neoplasms of lymphoid, haematopoietic and related tissue 0.2 0.1 0.1 Neoplasms of female genital organs - 0.2 0.1 Other malignant neoplasms 0.2 0.1 0.1 Mental and behavioural disorders Psychoses and other severe mental disorders 1.7 2.4 2.1 Mental retardation 0.2 0.1 0.1 Diseases of the nervous system Multiple sclerosis 0.1 0.1 0.1 Parkinson’s disease and related movement disorders 0.4 0.3 0.3 Epilepsy 1.2 1.3 1.3 Trigeminal and glossopharyngeal neuralgia 0.1 0.1 0.1 Alzheimer’s disease 0.4 0.3 0.3 Endocrine, nutritional and metabolic diseases Diabetes mellitus 6.3 5.1 5.5 Hypothyroidism 1.2 6.2 4.6 Hypoparathyroidism 0.0 0.2 0.1 Pernicious anemia and other causes of vitamin B12 malabsorbtion 0.8 1.1 1.0 Hypogonadism 0.1 0.8 0.6 Chronic disorders of vitamin D metabolism 0.1 0.1 0.1 Hereditary dyslipidemias 0.2 0.1 0.1 Dyslipidemia related to coronary heart disease 5.0 2.3 3.2 Other Glaucoma 1.9 2.6 2.4 Sarcoidosis 0.1 0.2 0.2 Asthma and other chronic obstructive pulmonary diseases 7.7 9.0 8.6 Chronic cystitis 0.2 3.1 2.2 Infl ammatory bowel diseases 0.5 0.4 0.5 Gout 1.6 0.5 0.8 Other 1.2 0.9 1.0

42 Results

8 8, separately for men and women aged < and Females ≥70 years. 7 Males

6 9.2 Hypertension

5 A total of 1,383 (19.2%) patients had hypertension at RA diagnosis. Its prevalence 4 was similar in men (465 cases, 20.0%) and

3 women (918 cases, 18.8%). Th ere emerged no excess prevalence of chronic hypertension Standardized Rate Ratio 2 at RA diagnosis in the entire RA population

1 or in the RF-positive subgroup. Among the RF-negative subgroup, however, the 0 prevalence of chronic hypertension was 20-49 50-59 60-69 70-79 80+ Total slightly elevated (SRR 1.19, 95% CI 1.10–1.30) Age (Table 7). Figure 6. Standardized rate ratios (SRRs) for CHD at RA diagnosis by sex and age. SRRs are 9.3 Other CV diseases and risk shown with 95% confi dence intervals. factors We observed no increased prevalence of CHF, steeply towards older age groups, reaching chronic arrhythmias, diabetes, or chronic 23% among those aged ≥80 years at RA dyslipidemia among newly diagnosed RA diagnosis (Figure 7). We found no diff erences patients compared with that of the general in the SRR of CHD between men: SRR (95% population. Aft er stratifi cation by RF status, CI) 1.11 (0.98 to 1.25) and women: SRR 1.10 the SRRs for these comorbidities remained (0.97 to 1.23). Th e cumulative percentage of unchanged, despite slight but nonsignifi cant CHD before RA diagnosis is shown in Figure

Table 7. Prevalence and standardized rate ratios of CV comorbidities and risk factors in a population of 7,209 RA patients and in subgroups according to RF status at RA diagnosis.

Total (N=7,209) RF-positive (N=4,650) RF-negative (N=2,559) Disease n SRR (95% CI) n SRR (95% CI) n SRR (95% CI) CHD 553 1.10 (1.01 to 1.20) 355 1.08 (0.97 to 1.19) 198 1.15 (1.00 to 1.32) CHF* 141 1.01 (0.85 to 1.19) 89 0.99 (0.79 to 1.21) 52 1.06 (0.79 to 1.39) Chronic arrythmias* 121 1.03 (0.86 to 1.23) 69 0.90 (0.70 to 1.13) 52 1.29 (0.96 to 1.69) Hypertension 1,383 1.05 (0.99 to 1.10) 846 0.97 (0.90 to 1.04) 537 1.19 (1.10 to 1.30) Diabetes* 415 1.02 (0.92 to 1.12) 260 0.96 (0.85 to 1.09) 155 1.12 (0.95 to 1.31) Dyslipidemia* 285 1.07 (0.95 to 1.21) 186 1.06 (0.91 to 1.22) 99 1.10 (0.90 to 1.34) Abbreviations: RF, rheumatoid factor; SRR, standardised rate ratio; CI, confi dence interval; CHD, coronary heart disease; CHF, congestive heart failure. *A. M. Kerola et al. unpublished results.

43 Results

30 Women 25 Men

Percentage 10

0 20-49 50-59 60-69 70-79 ≥80 Age, years

Women 1445 1374 978 833 257 - with CHD 2 23 74 133 55 Men 571 685 554 414 98 - with CHD 7 29 95 108 27

Figure 7. Percentages of RA patients with coronary heart disease (CHD) at RA diagnosis by gender and age at RA onset. elevations in the SRR point estimates of the not reach statistical signifi cance (Figure 9). RF-negative subgroup (Table 7, unpublished Of the RF-positive patients, 220 (4.7%) were results). treated with levothyroxine, corresponding to a SRR of 1.46 (95% CI 1.27 to 1.66). Among 9.4 Hypothyroidism the RF-negative patients, the prevalence of Of the 7,209 patients with incident RA, hypothyroidism was similar; 130 (5.1%) were a total of 350 (4.9%) had levothyroxine- treated with levothyroxine substitution, the treated hypothyroidism, as identifi ed from SRR being 1.61 (95% CI 1.34 to 1.91). the register of special reimbursements for As to the eff ect of age, we found the medicine costs, at the time of RA diagnosis. highest rate ratios of hypothyroidism among Th is corresponds to a SRR of 1.51 (95% CI the youngest age groups (Figure 9), similar 1.35 to 1.67). As in the general population, to our fi ndings regarding CHD. Among hypothyroidism was far more common women, the excess prevalence was almost 2.5 among women than among men; 321 (6.6%) among patients aged 20 to 49, it decreased female and 29 (1.2%) male patients had both steadily with aging, and subsided completely RA and hypothyroidism. Among women, in the oldest patients, aged >80 (Figure 9). the prevalence of hypothyroidism was higher Th e absolute prevalence of hypothyroidism, than in the general population (SRR 1.52, 95% however, seemed to increase with aging, the CI 1.36 to 1.69). Among men, excess risk did highest prevalence being among patients

44 Results

100 <70 100 70+ Male (N=144) Male (N=135) 90 Female (N=102) 90 Female (N=191)

80 80

70 70

60 60

50 50

40 40

30 30 Cumulative percentage Cumulative percentage 20 20

10 10

0 0 -25 -20 -15 -10 -5 0 -25 -20 -15 -10 -5 0 Time before RA, years Time before RA, years

Figure 8. Cumulative percentage of coronary heart disease before RA diagnosis in men and women at age < and ≥70 years (unpublished results).

8 aged 70-79 years at RA onset (Figure 10). Th e Females cumulative percentage of hypothyroidism Males 7 before RA is shown in Figure 11, separately

6 for men and women aged < and ≥70 years. We found 30 RA patients who 5 had a validated diagnosis of both CHD

4 and hypothyroidism at RA diagnosis, corresponding to 8.6% of all the 3 levothyroxine-treated RA patients.

Standardized Rate Ratio 2 Among RA patients without levothyroxine substitution, the prevalence of CHD was 1 essentially similar, 7.6%.

20-49 50-59 60-69 70-79 80+ Total Age Figure 9. Standardized rate ratios (SRRs) for levothyroxine-treated hypothyroidism by sex and age. SRRs are shown with 95% confi dence intervals at RA diagnosis among 7,209 RA patients.

45 Results

10 Women 8 Men

Percentage 4

0 20-49 50-59 60-69 70-79 ≥80 Age, years

Women 1445 1374 978 833 257 - with HT 62 85 81 76 17 Men 571 685 554 414 98 - with HT 47891

Figure 10. Percentages of RA patients with levothyroxine-treated hypothyroidism (HT) at RA diagnosis by gender and age at RA onset.

Since the insidious symptoms of early Table 8. Absolute numbers of patients with RA or undiff erentiated arthritis may resemble hypothyroidism at the rheumatoid arthritis those of hypothyroidism, screening for (RA) index date and one year (yr) before the index date. hypothyroidism might have occurred more frequently among those with oncoming RA Cases with hypothyroidism than among the general population, causing a At the RA index 1 yr before the RA biased SRR for hypothyroidism. To assess the date index date eff ect of this bias, the SRRs for hypothyroidism Total 350 319 were calculated one year before the RA index Women 321 292 date. Th ese SRRs were similar to those at RA Men 29 27 diagnosis: the SRR (95% CIs) was 1.38 (1.23 to 1.54) for the entire population, 1.39 (1.23 to RF + 220 203 1.56) for women, 1.30 (0.86 to 1.89) for men, RF - 130 116 1.35 (1.17 to 1.55) for RF-positives, and 1.44 (1.19 to 1.73) for RF-negatives. Th e absolute numbers on which these estimates are based are shown in Table 8.

46 Results

100 <70 100 70+ Male (N=23) Male (N=10) 90 Female (N=237) 90 Female (N=93)

80 80

70 70

60 60

50 50

40 40

30 30 Cumulative percentageCumulative percentageCumulative 20 20

10 10

0 0 -45 -40 -35 -30 -25 -20 -15 -10 -5 0 -45 -40 -35 -30 -25 -20 -15 -10 -5 0 Time before RA, years Time before RA, years

Figure 11. Th e cumulative percentage of hypothyroidism before RA diagnosis in men and women at age < and ≥70 years (unpublished results).

10 Work disability caused by Aft er adjustment for competing risks, comorbidities the 9-year cumulative incidence of WD resulting primarily from RA was 11.9%, During follow-up (median 4.0 years, range from a psychiatric disorder 1.3%, and from <1 to 9 years), 1,095 (14%) of the 7,831 a CV disease 0.5% (Table 10, Figure 12). patients became disabled for work. Of them, Cumulative incidences of WD are shown 681 (12%) were women and 414 (18%) were separately for men and women in Figure men. In 739 (67%) of the cases, the leading 13. WD resulting from RA was less frequent cause was RA (462 women, 277 men). among women than among men (age- and Other musculoskeletal diseases were the RF-adjusted sHR 0.72, 95% CI: 0.62 to 0.83, leading causes of WD in 134 (12%) cases. p<0.001). Th e incidence of WD resulting from Aft er musculoskeletal diseases, psychiatric psychiatric disorders did not diff er by gender disorders were the second-most frequent (sHR 1.06, 95% CI: 0.65 to 1.71, p=0.82). CV cause of disability pension (82 cases), of disease resulted rarely in WD among both which 90% were mood disorders. In only 30 men (16 cases) and women (14 cases). It was (2.7%) cases were CV diseases the leading clearly less frequently the leading cause for cause of WD, mainly represented by ischemic WD among women than among men (sHR heart diseases and cerebrovascular diseases. 0.40, 95% CI: 0.19 to 0.81, p=0.012). Besides musculoskeletal, psychiatric and CV Th e mean (standard deviation [SD]) age diseases, other causes of WD were relatively at the beginning of a disability pension was rare (Table 9). Of note, 25 (2.3%) patients 52.4 (7.5) years. Th e mean (SD) age diff ered received a WD pension due to infl ammatory according to the leading cause of WD: it was polyarthropathies other than RA, seven of 47.6 (10.2) for psychiatric disorders, 52.4 which were due to psoriatic and enteropathic (7.2) for RA, 55.8 (4.6) for CV disease, and arthropathies (M07), three due to juvenile 53.4 (6.8) years for other diseases (p < 0.001). arthritis (M08), two due to other specifi c arthropathies (M12), and 13 due to other arthritis (M13). 47 Results

Table 9. Th e number of disability pensions for diseases according to ICD-10 disease class in the cohort of 7,831 RA patients.

% of all disability Leading cause of disability pension Total pensions Diseases of the musculoskeletal system (M00-M99) 873 79.7 Seropositive rheumatoid arthritis (M05) 539 49.2 Seronegative rheumatoid arthritis (M06) 200 18.3 Other infl ammatory polyarthropathies (M07-M14) 25 2.3 Arthrosis (M15-M19) 37 3.4 Systemic connective tissue disorders (M30-M36) 8 0.7 Dorsopathies (M40-M54) 42 3.8 Other diseases of the musculoskeletal system 22 2.0 Psychiatric disorders (F20-F69) 82 7.5 Schizophrenia, schizotypal and delusional disorders (F20-29) 6 0.5 Mood disorders (F30-F39) 74 6.8 Other psychiatric disorders 2 0.2 Cardiovascular diseases (I00-I99) 30 2.7 Ischemic heart diseases (I20-I25) 14 1.3 Cerebrovascular diseases (I60-I69) 11 1.0 Other cardiovascular diseases 5 0.5 Neoplasms (C00-D48) 28 2.6 Diseases of the nervous system (G00-G99) 18 1.6 Injuries (S00-T98) 14 1.3 Diseases of the respiratory system (J00-J99) 13 1.2 Diabetes mellitus (E10-E14) 8 0.7

Table 10. Numbers and cumulative incidences of work disability (WD) due to rheumatoid arthritis (RA), psychiatric disorders, and cardiovascular (CV) diseases in the cohort of 7,831 RA patients. A competing risks analysis.

Cumulative incidence of WD Main cause of WD n (%) % (95%CI) 5-year follow-up 9-year follow-up RA 739 (67.5) 10.3 (9.5, 10.9) 11.9 (11.1, 12.8) Psychiatric disorders 82 (7.5) 1.2 (0.9, 1.4) 1.3 (1.0, 1.7) CV diseases 30 (2.7) 0.4 (0.3, 0.6) 0.5 (0.3, 0.7) Other 244 (22.3) 3.6 (3.1, 4.1) 5.5 ( 4.7, 6.4)

48 Results

Figure 12. Competing-risks cumulative incidence functions for work disability 14 Rheumatoid arthritis (WD) because of rheumatoid arthritis (RA), 12 psychiatric and cardiovascular (CV) diseases aft er RA diagnosis among 7,831 RA patients. 10 Competing risks were WD caused by diseases other than the disease of interest and death 8 before age 65. Th e gray area represents the 95% confi dence intervals. 6

Th e incidence of WD caused by CV 2 Psychiatric disorders disease was higher than in the general population, the SIR being 1.75 (95% CI incidenceCumulative disability, of work % 0 CV diseases 1.23 to 2.51). Th e incidence ratios remained 0123456789 increased among both men (1.81, 95% CI: Time since RA diagnosis, years 1.11 to 2.95) and women (1.69, 95% CI: 1.00 to 2.86). Th e incidence of WD due to RA diagnosis among patients who had a psychiatric disorders was similar to that of the psychiatric disorder, a CV disease or neither general population (SIR 0.99, 95% CI: 0.80 to of these as evaluated by their eligibility for 1.23). It remained similar in both sexes, the special medicine reimbursements at RA SIR being 1.25 (95% CI: 0.83 to 1.88) among diagnosis. Regardless of the presence of men, and 0.92 (95% CI: 0.71 to 1.18) among comorbidities, the mean number of annual women. WD days was substantially higher one year Figure 14 shows the mean numbers of aft er than one year before the diagnosis of RA. annual WD days one year before and aft er Although the mean number of annual work

Rheumatoid arthritis Psychiatric disorders CV diseases 20

4 Cumulative incidenceCumulative of WD, % Men 2 Women 0 5-year 9-year 5-year 9-year 5-year 9-year Follow-up time, years

Figure 13. Five- and nine-year cumulative incidences (with 95% confi dence intervals) of work disability (WD) due to rheumatoid arthritis, psychiatric disorders, and cardiovascular (CV) diseases in men and women with RA, as competing risks analysis.

49 Results

Psychiatric disorders

CV diseases

Other

0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150

Mean annual work disability days per patient-years

Figure 14. Unpublished results. Mean annual work disability days one year before (white squares) and aft er (black squares) RA diagnosis among patients who had a baseline psychiatric disorder (n=33), a baseline cardiovascular (CV) disease (n=796) or who had neither of these comorbidities (n=7,002). Th e results are presented with 95% confi dence intervals. disability days was numerically slightly higher was CV disease with 501 cases, representing in the group of patients with a psychiatric 43% of deaths due to any cause (Figure 15). disorder at baseline, no statistically signifi cant Another major group of causes of death was inter-group diff erences emerged either one neoplasms (27%). year before (age-, sex- and rheumatoid Of the 501 CV deaths, 314 (63%) resulted factor-adjusted p=0.061) or one year aft er the from ischemic heart disease (Table 11). diagnosis of RA (p=0.17). Cerebrovascular disease was the underlying cause of death in 105 cases, comprising 21% of all CV deaths (Table 11). CV diseases 11 Cardiovascular mortality other than CHD and cerebrovascular diseases Th e median (range) follow-up was 4 (<1–9) caused less than 20% of all CV deaths. Th e years for individual patients. A total of 1,157 relative proportions of diff erent CV diseases patients died during a total of 71,769 person- as causes of death were similar in men and years (22,471 for men and 49,298 for women). women (Table 11). Only one death was caused Th e most common underlying cause of death by carditis, specifi cally recorded as chronic adhesive pericarditis (I31.0).

Neoplasms (C-D) 308

Mental and behavioural (F) 26

Nervous (G) 32

Circulatory (I) 501

Respiratory (J) 83

Digestive (K) 43

Musculoskeletal (M) 53

Accidents (V-X) 47

Other 64

0 1020304050 Percentage

Figure 15. Proportions of ICD-10 disease groups as underlying causes of death in the early rheumatoid arthritis cohort (n=14,878). Absolute numbers of deaths are at the ends of each column.

50 Results

Table 11. Proportions of diff erent cardiovascular diseases as causes of cardiovascular deaths in the early rheumatoid arthritis cohort.

n (%) ICD-10 Disease Men Women All I05-I09 Chronic rheumatic heart diseases 1 (0.5) 1 (0.3) 2 (0.4) I10-I15 Hypertensive diseases 1 (0.5) 7 (2.4) 8 (1.6) I20-I25 Ischemic heart diseases 150 (70.0) 164 (57.1) 314 (62.7) I26-I28 Pulmonary heart disease and diseases of 3 (1.4) 2 (0.7) 5 (1.0) pulmonary circulation I30-I52 Other forms of heart disease 12 (5.6) 25 (8.7) 37 (7.4) I60-I69 Cerebrovascular diseases 37 (17.3) 68 (23.7) 105 (21.0) I70-I79 Diseases of arteries, arterioles, and capillaries 10 (4.7) 16 (5.6) 26 (5.2) I80-I89 Diseases of veins, lymphatic vessels and lymph 0 (0.0) 4 (1.4) 4 (0.8) nodes, not elsewhere classifi ed Total 214 (100) 287 (100) 501 (100)

Th e SMR for CV deaths in the entire for those who died of a CV cause, 72.4 (11.0) RA cohort was 0.57 (95% CI 0.52–0.62). Th e years for those who died of another cause, SMR in subgroups according to sex and RF and 59.5 (14.5) years for those who survived. status was highest among RF-positive men Women who died of CV diseases were (0.70, 95% CI 0.60 to 0.83) and lowest among generally older (mean 80 years) than the men RF-negative women (0.43, 95% CI 0.35 to who died of CV diseases (mean 74 years). 0.53) (Figure 16). Women and men who died of causes other Th e proportion of CV deaths of all deaths than CV disease were more nearly the same increased towards older age groups in both age (mean ages at death 74 and 72 years). Th e men and women (Figure 17). At the end of cumulative incidence of CV death was 2.6% follow-up, mean (SD) age was 77.0 (9.6) years among women and 4.4% among men at fi ve

CV deaths SMR (95 % CI) SMR 95% CI

Men 214 0.63 (0.55 to 0.72) Women 287 0.53 (0.48 to 0.60)

RF-positive men 148 0.70 (0.60 to 0.83) RF-positive women 198 0.60 (0.52 to 0.69)

RF-negative men 66 0.51 (0.40 to 0.65) RF-negative women 89 0.43 (0.35 to 0.53)

All 501 0.57 (0.52 to 0.62)

0.0 0.2 0.4 0.6 0.8 1.0

Figure 16. Number of cardiovascular (CV) deaths and standardized mortality ratios (SMR) by sex and rheumatoid factor (RF) status.

51 Results

160 160 Men with RA (N=4,759) Women with RA (N=10,119) 140 Other cause 140 Other cause Cardiovascular cause Cardiovascular cause 120 120

100 100

80 80

60 60 Number of deaths deaths of Number 40 40

20 20

0 0 <50 50- 55- 60- 65- 70- 75- 80- 85+ <50 50- 55- 60- 65- 70- 75- 80- 85+ Age at death Age at death

Figure 17. Number of cardiovascular (CV) and other deaths by sex and age. years aft er RA diagnosis, and at nine years, it patient-years (Figure 19). Only 7.3% of the was 5.8% and 8.4%, respectively (Figure 18). patients used antirheumatic medications Based on their medicine purchases, for less than 50% of their individual patient- 82.3% of the patients were using some kind years. Glucocorticoid use was more common of RA medication (including glucocorticoids) among those who died than among those for a period exceeding 90% of their individual who survived, whereas methotrexate use was most common among those who survived (Figure 20).

Figure 18. Cumulative incidence 14 functions for cardiovascular death with adjustment for competing causes of death 12 aft er RA diagnosis among men (N=4,759) and women (N=10,119). 10 Men

4 Women

2 Cumulative cardiovascularCumulative mortality, %

0 0123456789 Time, years 52 Results

100 Figure 19. Proportions of rheumatoid arthritis (RA) patients treated with any 90 RA medication (antirheumatic agents or 80 glucocorticoids). Th e X axis represents the duration of medicine use as a 70 percentage of individual patient-years 60 (pyrs) at risk.

Percentage of Percentage RA %patients, 20

0 <10 10- 20- 30- 40- 50- 60- 70- 80- ≥90 Drug treatment time/individual pyrs, %

70 Figure 20. Percentages of medicine-use Survivors duration per individual patient- Cardiovascular death 60 years (pyrs) in patients who died of Other death p<0.001 cardiovascular disease (n=501), those 50 who died of other causes (n=656), and those who survived (n=13,721). For p<0.001 p=0.009 40 diff erences between groups, age- and sex-adjusted p-values were calculated. p=0.001 30 p=0.10 MTX, methotrexate; SASP, sulfasalazine; HCQ, hydroxychloroquine; TNF,

20 tumor necrosis factor inhibitors; GC, prednisolon.

10 p<0.001

Drug treatment time/individual pyrs, %pyrs, time/individual treatment Drug 0 MTX SASP HCQ TNF Other GC Drug

Th e prevalences of cardiac disease, CV medications was, as expected, generally hypertension, and diabetes were higher more common among those who died of CV among RA patients who died of CV disease disease than among those who died of other than among those who died of other causes causes or survived, but with statins most oft en or who survived (Table 12). Asthma or used by those who survived (Table 12). COPD and prior malignancies, on the other In the multivariable competing-risks hand, were most prevalent among those who model (Figure 21), the highest HRs for died of causes other than CV disease. Use of CV death were linked to cardiac disease,

53 Results

Table 12. Percentages of comorbidities and duration of medicine use for cardiovascular disease medications in patients who died of CV disease, those who died of other causes, and those who survived.

Survivors CV death Other death Total (n=13,721) (n=501) (n=656) (n=14,878) Comorbidity Prevalence in patient subsets, % Cardiac disease* 8.2 39.5 21.3 9.8 Hypertension without cardiac disease 15.0 26.6 15.8 15.4 Diabetes 4.9 15.6 9.8 5.5 Asthma or COPD 7.7 11.2 15.4 8.2 Prior malignancy 0.9 1.2 3.8 1.0 Medication Duration of medication use of individual pyrs, % Beta-blockers 44.6 62.0 46.2 45.6 Agents acting on the RAA system 42.6 47.6 36.0 42.4 Lipid-modifying agents 30.3 23.7 15.6 29.0 Diuretics 19.6 51.2 35.3 22.3 Calcium-channel blockers 21.0 22.4 19.6 21.0 Certain other CV drugs** 17.5 57.5 34.4 20.8 Diabetes medications, including insulin 18.9 34.9 22.7 20.1 Abbreviations: CV, cardiovascular; COPD, chronic obstructive pulmonary disease; pyrs, patient years; RAA, renin-angiotensin-aldosterone *includes CHD, chronic CHF, chronic cardiac arrythmias (with or without hypertension and hyperlipidemia) **ATC code C01: Cardiac glycosides, class I and III antiarrhythmic agents, sympathomimetics, vasodilators used in cardiac diseases including organic nitrates and other cardiac preparations hypertension, and diabetes. In addition, use of methotrexate. Prior malignancies age, male sex, RF positivity, and use of and treatment with sulfasalazine, glucocorticoids were associated with hydroxychloroquine, subcutaneous increased risk of CV death. A decreased TNF inhibitors, or other antirheumatic risk of CV death was associated with female medications did not modify risk of CV death. sex, the presence of asthma or COPD, and

54 Results

A sHR (95 % CI) Patient characteristics P Female sex <0.001 Age <0.001 RF 0.009

Comorbidities Cardiac disease* <0.001 Hypertension without cardiac disease <0.001 Diabetes <0.001 Asthma or COPD 0.024 Prior malignancy 0.154 01234 B sHR (95 % CI)

RA medications P MTX <0.001 OXI 0.963 Glucocorticoids <0.001 SASP 0.975 TNF inhibitors 0.267

0.8 1 1.2 1.4

Figures 21 A and B. Impact of patient characteristics, comorbidities, and RA medications on the risk of cardiovascular death in a multivariable competing-risks model. Regarding RA medications, sub-hazard ratios are given for impact of medicine-use duration of 10% of individual patient-years. *includes CHD, CHF, chronic cardiac arrhythmias (with or without hypertension and hyperlipidemia) Abbreviations: sHR, sub-hazard ratio; RF, rheumatoid factor; COPD, chronic obstructive pulmonary disease; RA, rheumatoid arthritis; MTX, methotrexate; OXI, hydroxychloroquine; SASP, sulfasalazine; TNF, tumor necrosis factor

55 Discussion

DISCUSSION

12 General discussion discovered no increased CV mortality. Th e CV disease-specifi c SMRs were, in fact, less Th e results of our study shed light on many than one in the entire RA population and in epidemiological aspects of comorbidities every subgroup sorted by sex and RF status. in early RA. Th e prevalence of clinical Th e interpretation of this result should best, comorbidities has mainly been investigated however, be fairly conservative, because in established RA cohorts. Nevertheless, the others’ studies have shown diff ering results, existing literature shows that many systemic and because our data do not provide suffi cient autoimmune and infl ammatory processes explanatory analyses. Nevertheless, CV activate well before the clinical onset of diseases remained the leading cause of death. RA, which may in theory lead to alterations We also observed that 10% of the in functions of many organs already in its disability pensions in our RA cohort were 13 preclinical phases. In the present study, caused by CV and psychiatric comorbidities, we observed that RA patients, already at and that the risk for becoming work disabled the time of diagnosis, have more clinical because of a CV disease was almost twice as CHD and hypothyroidism than the general high as in the general population. All these population. Moreover, their excess risk for fi ndings together stress the importance of hypothyroidism was more pronounced comprehensive clinical examinations and among younger RA patients. Th ese fi ndings alertness for comorbid conditions in patients emphasize the systemic nature of RA, and diagnosed with RA, already in the early years may also imply the presence of shared risk of the disease. factors or pathogenetic mechanisms in As multimorbidity has vast eff ects on preclinical RA phases that also elevate risk for disability, mortality, quality of life, and even CV diseases or hypothyroidism. the treatment of RA itself, it should become Numerous epidemiological studies have an important target in the medical care of shown that, compared to individuals without RA patients. Keys to optimize the prevention RA, individuals with RA are disadvantaged of comorbidities in RA include annual and, at many hard clinical end-points such as ideally, structured screening for comorbidities, mortality and WD rates. In other studies, and a multidisciplinary approach to the excess mortality in RA has stemmed comorbidity care, involving rheumatologists, mainly from excess CV deaths. Th e aim of other specialists, primary-care practitioners, our mortality study was to explore whether and allied health professionals.283 Because CV mortality is still increased among early systemic infl ammation seems an important RA patients diagnosed in the 2000s, and we

56 Discussion mechanism in the development of multiple medical records, were lower at RA diagnosis comorbidities in RA, tight control of than in our study: 9% of those patients had disease activity is central in order to prevent hypertension, 2% had asthma or COPD, 1% comorbidity. Paying attention to common had COPD, and 1% had diabetes.69 A recent risk factors for many diseases such as Dutch study among a cohort of 3,354 patients smoking, physical inactivity, and unnecessary with newly diagnosed infl ammatory arthritis use of glucocorticoids is also helpful. Based from 2001-2010 using data from electronic on the higher relative risk for comorbidity, patient records in general practice discovered attention should focus upon the prevention that the prevalence of a chronic comorbidity of comorbidities in young and early-onset at the onset of the disease was as high as RA patients, whereas among older patients, 70%.287 Th is was signifi cantly higher than in comorbidities should be targeted based on the controls without infl ammatory arthritis their higher absolute risk. matched at a 2:1 ratio by age, sex, and general Identifi cation of RA patients relied on practice, among whom the prevalence of any the combination of a rheumatologist’s clinical comorbidity was 59%.287 Th e most common diagnosis, commencement of antirheumatic comorbidities for infl ammatory arthritis were medication, and the allowance of special CV diseases (35%), musculoskeletal diseases reimbursement for those medications. Th is (27%), and neurological diseases (22%).287 is a sensitive case identifi cation method, as Prevalence estimates for comorbidities in indicated by the RA incidence of 44.5/100,000 that study may be higher than ours because patient-years over the years 2000 to 2007, of diff erences in their case identifi cation which is slightly higher than in earlier Finnish methods – our case identifi cation was based studies using the ACR criteria31,32 and similar on special medicine reimbursements, which to or slightly higher than incidence rates may result in a suboptimal coverage of some reported recently in north Europe or North comorbidities because not all chronic diseases America.284-286 A major strength of these or milder disease forms qualify for special studies was that we were able to compare the medicine reimbursements in Finland, and RA cohorts with the age- and sex-specifi c some diseases do not even require continuous general population regarding all important medication. outcomes, and thus gain reliable information on their relative risks. 13.1 Coronary heart disease We observed a slightly but signifi cantly increased risk for CHD among patients 13 Comorbidities at diagnosis with newly diagnosed RA already at the of RA time they were prescribed antirheumatic We observed that, based on the eligibilities for medication (Table 7). Although the literature special medicine reimbursements, 20% of the has implied that increased risk for CHD 14,878 RA patients already had hypertension, exists in the early years of RA,13,169,176 what 9% had asthma or COPD, 8% had CHD, 6% remains to be ascertained is how early this had diabetes, and 5% had hypothyroidism risk increases.175,176 An American population- before RA diagnosis. In another Finnish based cohort study in the framework of the cohort of 87 patients with early RA collected Rochester Epidemiology Project showed between 1986-1989 from the Helsinki area, the that patients with RA were at increased risk prevalences of comorbidities, as recognized for CHD already during the two-year period by interview and confi rmed from patients’

57 Discussion before the fulfi llment of the ACR 1987 criteria observations. Firstly, CHD prevalence for RA.169 During that period, the RA patients increased towards older age groups, as it were much more frequently hospitalized for does in the general population (Figure 7). acute MI (OR 3.17, 95% CI 1.16-8.68) and Secondly, the rate ratio of having CHD experienced more unrecognized MIs (OR prior to RA diagnosis seemed higher among 5.86, 95% CI 1.29-26.64) than did non-RA younger than among older age groups (Figure controls.169 On the other hand, a Swedish 6), but power to prove this trend statistically study on 7,469 RA patients disclosed an signifi cant was lacking. Similar fi ndings increased risk for myocardial infarction only emerge in established RA populations: one year aft er fulfi llment of ACR criteria for for example, Naz and coworkers studied a RA, but no increased risk before the onset cohort of 1,098 patients with infl ammatory of RA symptoms.72,175 Together with the polyarthritis from 1990-94 and observed study from Rochester, Minnesota, our study the highest CV death rates to be among the supports an increased risk of CHD already RF-positive patients who were younger than preceding the full clinical eruption of RA. 55 at RA-symptom onset.138 A large Swedish As CV risk seems to increase already study on almost 50,000 RA patients from before the clinical symptoms of RA, what 1964-95 reported a fi ve-fold risk for coronary mechanisms do underlie this fi nding? death among female patients who were age As shown by the presence of RA-related 20-39 at fi rst RA-related hospital discharge, autoantibodies as well as elevated cytokine whereas the risk of coronary death rose and chemokine levels, systemic infl ammation by only 80% in the entire RA cohort.64 In and autoimmunity in RA begin years before addition, in an American cohort of 25,385 the onset of detectable joint infl ammation.24,124 RA patients in 1999-2003, the rate ratio of In theory, these preclinical autoimmune and hospital admissions for CV disease was 3.3 infl ammatory processes may increase CV risk among patients aged 18 to 39 years vs. 1.6 before the clinical onset of RA. In addition, among those ≥75 years, whereas the absolute our fi nding brings forth the role of shared rate diff erence between RA patients and risk factors underlying the co-existence non-RA controls was 1.2 vs. 19.7 per 1,000 of RA and CV disease. One of these risk person-years in the respective age groups.165 factors is undoubtedly smoking.74,114 With Th ese studies suggest that earlier-onset regard to genetic factors, a British study on RA may confer a higher relative risk for more than 1,000 patients with infl ammatory CHD than does later-onset RA.64,138 Th is polyarthritis showed that carrying two copies premise is reasonable, since if sustained of SE alleles, a risk factor for the development remission is not achieved with antirheumatic of ACPAs,16 predicted death from CV disease therapy, the earlier a patient contracts RA, (HR 1.68, 95% CI 1.1-2.7).63 Th e combination the longer systemic infl ammation damages of SE, smoking, and anti-CCP antibodies the vasculature. Although we investigated elevated risk even further (HR 7.81, 95% CHD prevalence at the time of RA diagnosis, CI 2.6-23.2). Many other RA-related we nevertheless observed the highest SRR polymorphisms in genes such as TGFβ1, point estimates among the youngest patients. factor XIIIA, IRF5, PAI-1, TNF-α, TNFR II, One explanation for our suggestive fi nding NFKB1, and MTHFR apparently modulate is at least in part the concept of competing risk for CV disease in RA.74,288-292 risks: since age is such an important risk When we examined the eff ect of age factor for CHD, it leads to a reduction in at RA onset on CHD risk, we made two the relative contribution of other CHD risk

58 Discussion factors, including RA.165 Absolute excess risk, shortly aft er the fi rst RA symptoms emerge. however, might be even higher in patients Speculatively, because reversal in CV changes with late-onset RA than in those with early- may occur aft er successful antirheumatic onset RA, as indicated by our observation of treatment, a window of opportunity may a very low prevalence of CHD among patients exist not only for treatment of RA but also for aged less than 60 (Figure 7). RA-exacerbated CV disease.168,295 Our fi ndings Although both the RF-positive and highlight the importance of early prevention RF-negative patients had higher prevalences of atherosclerosis in RA, regardless of RF of CHD than expected based on the rates in status. the general population, only the RF-negative patients reached statistical signifi cance. Most 13.2 Chronic hypertension studies have found RF to associate with Based on special-reimbursement-decision higher risk for CV events. Our fi nding is not data, hypertension was the most common necessarily contradictory to theirs, because comorbidity at RA diagnosis in Finland in we looked at the CV risk before RA; earlier 2000-2007 with a prevalence of 20%. Similarly, 60 studies focused mainly on established RA. in another Finnish study on a cohort of 87 Since RF-positive RA is linked to higher patients with early RA, hypertension was the disease activity and a poorer prognosis than is most common comorbidity, its prevalence 293 RF-negative RA, the ongoing higher level of being 9% at RA diagnosis and 30% aft er 15 infl ammation may result in a higher risk for years of follow-up.69 Our fi ndings are also CV events as disease duration lengthens. Nor comparable to those of a Swedish prospective did one Swedish study examining myocardial cohort study, in which the prevalence of infarction risk at RA onset fi nd RF positivity antihypertensive treatment at RA diagnosis 175 linked to CV risk. was 24.6%.85 As in the general population, men with Th e existing literature is inconsistent RA had a considerably higher prevalence on whether hypertension, an important of CHD (11.5%) than did women with traditional CV risk factor, is less prevalent RA (5.9%). Rate ratios of CHD, however, with no RA than in RA patients.104,105,296,297 remained fairly similar by gender (Figure One meta-analysis pooling the results of 15 6). Th ese fi ndings are in line with previous case-control studies disclosed a prevalence fi ndings of higher absolute but similar relative of hypertension similar among RA patients risk for CV disease among male compared to and controls.84 In line with this, we found 165,175,177,294 female RA patients. For example, no increased risk for hypertension at RA in a population-based study on 25,000 RA diagnosis when looking at the entire RA patients from British Columbia, Canada, cohort. When looking at the subgroups of the rates of a combined CV outcome of RF-positive and -negative patients, however, myocardial infarction, stroke, and CV death we observed a slightly increased prevalence were 12.4 per 1,000 person-years among of chronic hypertension only among the women and 20.1 among men, whereas the RF-negative subgroup. Although we present 165 rate ratio was 1.6 among both sexes. no explanatory fi ndings for this observation, In short, relative risk for CHD was it is consistent with our observations already higher in RA patients at the time of regarding risk for CHD. Interestingly, a recent diagnosis. Based on the literature review, both study from the Rochester Epidemiology asymptomatic atherosclerosis and overt CV Project suggested that RA patients have more events occur at a higher than expected rate

59 Discussion long-term variability in blood pressure than have, however, observed no association do non-RA controls, and that this may be between the two conditions.105,106,297 With associated with adverse CV outcomes.298 regard to early RA, severe insulin resistance characterized 66 untreated RA patients with 13.3 Congestive heart failure disease duration less than one year.102 Various studies have reported that RA patients We observed no diff erence in risk carry an excess risk for CHF.104,178,299,300 A for diabetes between newly diagnosed population-based, retrospective incidence RA patients and the general population. cohort study in Rochester, Minnesota, Th is fi nding suggests that if the systemic indicated that the increased risk for CHF infl ammation of RA indeed accelerates the 100,101,304 among RA patients exists in all age groups development of insulin resistance, it and may already be present at the index may not manifest as type II diabetes mellitus date.178 Regarding the RA population as a very early in the course of RA. Th is hypothesis whole, they detected a 1.7-fold incidence of needs testing in even larger studies with better CHF. In addition, the higher risk for CHF was sensitivity to type II diabetes mellitus and its more pronounced among women and among early manifestations. Of note, we detected no those RF-positive.178 elevated prevalence of special reimbursement We observed a similar risk for CHF in for medications for dyslipidemia, although our RA inception cohort and in the general the prevalence of CHD was slightly higher population. Since CHF frequently results than in the general population. from injury to the myocardium resulting from 13.5 Assessment and ischemic heart disease or hypertension,301 management of CV risk in it seems logical that it is not highly frequent RA among RA patients until such diseases have been established for awhile. In addition, these CV risk assessment in RA is an important fi ndings are in line with the observation that clinical issue lacking unambiguous evidence- diastolic dysfunction may be linked to RA based treatment guidelines. Th e EULAR duration.153-155 recommendations for CV risk management in patients with RA and other forms of 13.4 Diabetes and dyslipidemia infl ammatory arthritis suggest that, along with early and eff ective antirheumatic Many studies examining associations treatment, an annual CV risk assessment between RA and diabetes mellitus have and intervention is necessary, following local reported them to co-exist at a rate higher than treatment guidelines.231 Furthermore, to take expected.4,84,104,302,303 In a large population- the additional RA-related CV burden into based study of over 28,000 RA patients account when using CV risk-score calculators, compared with more than 100,000 controls, these recommendations suggest adding a the prevalence ratio for diabetes was 1.4.104 multiplication factor of 1.5 if the RA patient According to a study on 48,718 RA subjects, meets two of the following three criteria: 1) a relative risk for diabetes mellitus, mostly disease duration of more than 10 years, 2) type II, was elevated in both genders but risk RF or ACPA positivity, and 3) the presence decreased with age.303 One meta-analysis of certain extra-articular manifestations.231 assessing the prevalence of CV risk factors Based on our conducted review13 and in RA concluded that the OR (95% CI) for results (Study I), however, atherogenesis diabetes was 1.74 (1.22 to 2.50).84 Some studies

60 Discussion and development of CV diseases may in fact cause of hypothyroidism, has been highly accelerate already in the earliest phases of RA. prevalent among established RA patients in Moreover, the increased CV risk seems not to numerous investigations. A systematic review be confi ned only to those seropositive, but to on this topic showed, however, that most of be elevated also among seronegative patients, these fi ndings are derived from uncontrolled as indicated by both our own fi ndings and case series or small case-control studies earlier studies.72,175,190,305 Th erefore, even aft er from tertiary care settings.5 Th ese authors applying a multiplication factor to CV risk- found eight studies between 1963 and 2001 score calculations by these three criteria, CV examining the prevalence of comorbid risk may still be underestimated, especially autoimmune thyroiditis among an RA index for patients with early RA and seronegative population; the prevalence of thyroiditis disease. ranged from 0.5% to 9.8%.252-254,307-311 Only Th e use of beta-blockers, of agents acting four of these were controlled studies,253,254,307,311 on the renin-angiotensin-aldosterone system, and only two of them showed a signifi cantly and of lipid-modifying agents was relatively higher prevalence of autoimmune thyroiditis common in our RA cohort – the duration of among the RA patients than among controls.5 their use covered 46%, 42%, and 29% of all When considering RA prevalence in an index patient-years in the cohort (Study IV, Table population with autoimmune thyroiditis, 12). As these medications have been shown the review authors observed no consistent to improve the prognosis of patients with association.5 Another meta-analysis showed CV disease,306 it is vitally important that RA that thyroid autoantibodies were more patients at risk receive them. Beta-blockers prevalent in RA than in healthy controls and agents acting on the renin-angiotensin- (OR 3.17, 95 % CI 2.24 to 4.49 for TgAb; aldosterone system were, however, only OR 2.33, 95 % CI 1.24 to 4.39 for TPOAb).312 moderately more oft en prescribed and, Few studies have, in fact, looked into the alarmingly, statin use was lower among those prevalence of hypothyroidism in an RA index who died of CV disease than among those population at RA onset. who survived (Table 12), perhaps refl ecting A pair of large high-quality studies off er inadequate secondary prevention of CV results similar to ours. Th e most important events among those patients. Th is speculation is undoubtedly the population-based cohort is supported by a nationwide Danish study on study from the United Kingdom, which more than 66,000 patients with fi rst-time MI, included, from 1990 to 1999, 22,888 patients in which an RA diagnosis was associated with with RA and 26,198 with autoimmune reduced initiation of aspirin, beta-blockers, thyroiditis. It found a moderate bidirectional and statins as secondary prevention.237 association between RA and autoimmune Moreover, in the same study, adherence to thyroiditis, the SIR for thyroiditis being 1.62 statin therapy was poorer among RA patients among the RA index population, and the than among non-RA patients.237 SIR for RA being 1.32 among the thyroiditis index population.4 In a recent Swedish study 13.6 Hypothyroidism among 1,998 patients with incident RA from Th e present study demonstrated a positive 1996 to 2006, individuals with levothyroxine association between RA and hypothyroidism substitution (6%) were at twofold risk for already at RA diagnosis. Chronic developing both ACPA-positive and ACPA- 251 autoimmune thyroiditis, the most common negative RA.

61 Discussion

Assuming that most of the Finnish RA with age. Vigilance for hypothyroidism is patients using levothyroxine substitution therefore equally justifi ed among old and have hypothyroidism resulting from chronic young RA patients. autoimmune thyroiditis,313 our results lend Th e prevalence of hypothyroidism further support to the hypothesis that the among our female RA patients was 6.6%. high co-existence of these diseases results A recent Dutch population-based study either from common risk factors or shared reported that in a cohort of 175,000 primary- pathogenetic mechanisms. For example, care patients, hypothyroidism prevalence the PTPN22 risk allele may be a common among female patients with infl ammatory susceptibility allele to RA and to autoimmune arthritis was surprisingly similar, 6.5%,316 thyroiditis.250,258 In addition, evidence from corresponding to a 2-fold higher risk than similar cytokine profi les in these diseases that of controls. Risk for hypothyroidism is suggests that both are Th 1-associated,5 well acknowledged to be many times higher although Th 17-cells may also play a part among women than men and, consistent in RA pathogenesis.314 In one study, the with that, the prevalence of hypothyroidism prevalence of antinuclear autoantibodies in was 5.5-fold among our female compared to autoimmune thyroiditis was as high as 45%,257 our male RA patients. SRR point estimates perhaps implying a higher vulnerability to were, however, similar by gender (1.39 for autoimmune rheumatic diseases among these men and 1.52 for women), but the lower patients. 95% confi dence limit was higher than 1.0 Our results demonstrate that the relative only among women, most likely because of risk for hypothyroidism among younger a lack of power among men. Th us, studies compared to older patients with newly conducted in even larger RA populations diagnosed RA is higher (Figure 9). In line are warranted to confi rm our fi nding among with this fi nding, particularly the young men. patients with an autoimmune disease may be We demonstrated similar prevalences at increased risk for comorbid autoimmune and SRRs of hypothyroidism among RA thyroiditis.315 Th e risk for hypothyroidism patients RF-positive and RF-negative. was 2.5-fold among women younger than Th e impact of RF status on risk for 50 at RA diagnosis. Our fi ndings should hypothyroidism has been only rarely noted. encourage clinicians to check thyroid In those relatively small study populations, hormone levels of RA patients with any RF has been either less or equally prevalent symptoms of hypothyroidism, and to be alert among RA patients with thyroid dysfunction to the possibility of RA as the underlying than among euthyroid RA patients.254,317 cause of joint symptoms in young patients In theory, the symptoms of insidious- with hypothyroidism. onset RA such as fatigue and arthralgia could Although the rate ratio of hypothyroidism mimic those of hypothyroidism and lead was higher among younger than among to more frequent testing and diagnosing of older age groups, its absolute prevalence thyroid disorders in some patients diagnosed followed the opposite trend (Figure 10). As with RA a few months later. Th is potential with CHD, high age being a risk factor for source of bias might have elevated SRRs for hypothyroidism, the relative impact of RA on hypothyroidism in our RA cohort. To validate overall risk for hypothyroidism may decrease our results in this respect, we evaluated as one ages. Th e absolute excess risk for SRRs for hypothyroidism one year before hypothyroidism, on the other hand, increases RA diagnosis. Compared to values at RA

62 Discussion diagnosis, the SRRs remained unchanged, WD cases. Our fi ndings are comparable with thus lending support to our results. those of a British study of an inception cohort Th yroid defi ciency may play a role of 1,460 RA patients diagnosed in 1986-1998 in the development of CV disease both in and followed up for a median of 10 years.320 In the general population318 and in RA.6,316,319 that study, comorbidity was the main reason One Dutch study including 236 women for stopping working for only 8.7%, and RA with RA disclosed that, in addition to a together with a comorbidity led to 13.8% threefold risk for hypothyroidism among of the work cessations. Th e comorbidities female RA patients compared to that of the were most oft en CV diseases, chronic general population, the presence of clinical lung diseases, and psychiatric disorders. hypothyroidism was associated with a Approximately 50% of the work cessations fourfold risk for CV disease compared with were related to RA without the contributory that of euthyroid women with RA (HR 4.1, eff ect of comorbidity, and the rest were due to 95% CI 1.2 to 14.3).6 In an American study reasons not related to health such as planned using data from the Rochester Epidemiology age-related retirement and personal or social Project, hypothyroidism was not more reasons.320 prevalent among the 650 RA patients than In established RA, depressive symptoms among 650 controls, but it was associated with are highly prevalent,321 and depression may CVD in patients with RA (HR 2.1, 95% CI be more common in RA than in the general 1.1 to 3.6).319 In the light of these studies, we population. In a Finnish study of an RA wanted to investigate whether any clustering cohort similar to ours, that is, all ≥50-year-old occurred between CHD and hypothyroidism RA patients diagnosed in Finland in 2000- in individuals with future RA. In this Finnish 2007, 10.0% used antidepressants during RA cohort, however, CHD prevalence was the year antedating their RA diagnosis, and similar among patients with and without by the end of 2008, 9.4% more had initiated levothyroxine substitution at RA diagnosis. antidepressant medication.322 Although an association between WD and depressive symptoms or anxiety as 14 Comorbidities as causes of evaluated by self-assessment questionnaires work disability has been apparent in some small RA 10-12 To date, the literature on the role of populations, no studies to date have comorbidities in leading to WD in RA assessed the role of clinical psychiatric has been surprisingly limited. Our study disorders as the leading causes of long-term addressed, to our knowledge for the fi rst WD in RA. Our results show that psychiatric time, the question of how oft en psychiatric disorders were, aft er musculoskeletal diseases, and CV comorbidities in RA lead to long- the second most frequent group of chronic term WD. We found that CV and psychiatric diseases leading to long-term WD in recent- comorbidities were the leading cause of onset RA. Nevertheless, they accounted for a disability pension in only 10% of all only some 8% of all disability pensions (Table permanently work-disabled RA patients; 9). and they therefore seem to play a relatively Compared to the general population, the modest role as the leading causes of long- risk for permanent WD caused primarily by term WD in RA. Noteworthy is that RA and a psychiatric disorder was not increased. Th is other diseases of the musculoskeletal system fi nding is in line with the Finnish study, in comprised the leading causes of 80% of all which the prevalence of antidepressant use

63 Discussion among RA patients was not higher than in WD caused by CV disease than did women. the general population.322 Our results indicate Men may also be occupied in more physically that even though depression and other demanding jobs,320 making their ability to psychiatric disorders are likely to contribute work aff ected to a greater extent by physical to the development of WD in RA, their eff ect limitations imposed of their CV disease. on work ability rarely exceeds that of RA Despite this, the percentage increase in itself. incidence of WD resulting from CV disease In our RA cohort, CV disease was the compared to that of the general population leading cause of WD almost twice as oft en was similar by gender. Th ese fi ndings are as it is in the general population. Th is can in line with those of higher incidences but be rather eff ortlessly explained by the widely similar incidence rate ratios of CV events documented increased CV morbidity in RA. among men than among women with As RA patients are reported to be at CV risk RA.323,324 As to WD resulting from psychiatric similar to that of individuals without RA disorders, both the absolute incidences and who are 5 to 10 years older,168 it is reasonable incidence ratios of WD were similar between to expect disparities in rates of WD caused genders. by CV disease. Th is fi nding provides RA patients who were granted a rheumatologists and other healthcare disability pension for a psychiatric disorder professionals an additional reason to target were considerably younger than those who CV comorbidities in RA aggressively. became work disabled because of RA or a When considering the absolute CV disease – mean age at the beginning incidences of WD instead of incidence of a disability pension was 48 vs. 52 and 56 ratios, CV disease accounted for less than years, respectively. When refl ected against 3% of all disability pensions, indicating that a common statutory retirement age of 65 its signifi cance as a leading cause of WD in years in Finland, these ages equal a mean RA is limited. Comorbidities may, however, number of 17 vs. 9 or 13 lost years at work. compromise the work capacity of RA Psychiatric disorders are therefore likely to patients without leading to long-term WD, lead to relatively higher productivity losses and it may be diffi cult to determine which and societal costs than expected based on disease reduces work capacity the most in mere WD incidences. For a rough estimate multimorbid patients. Hence, although only of lost productivity, the average monetary a small portion of the disability pensions in value of annual productivity of an employed our RA cohort resulted primarily from CV Finnish resident was 73,623 euros in 2000– or psychiatric comorbidities, these diseases 2008 (amount expressed at the 2012 level).278 may be more signifi cant when considering Of note, musculoskeletal diseases other their contributory impact on WD that results than RA were the leading WD cause in 12% primarily from RA or other musculoskeletal of this RA population, mainly represented by conditions. Th is theory, however, was not degenerative disorders such as back pain and supported by our observation of similar osteoarthritis (Table 9). Th is highlights the numbers of WD days one year before and fact that in the era of modern RA treatment aft er RA diagnosis in patient subsets with regimens and decreasing WD rates for RA,49 or without baseline CV or psychiatric not uncommonly does the disability of an RA comorbidities. patient result actually from a musculoskeletal Male sex being a risk factor for CV disease other than RA, these diseases disease, men with RA had higher rates of

64 Discussion commonly leading to WD also in the general because we had no suffi ciently explanatory population. fi ndings, and because most studies display Interestingly, the diagnostic ICD-10 code confl icting results. For example, a meta- in the pension register was for 25 patients analysis of 17 studies conducted mainly an infl ammatory polyarthropathy other among established RA cohorts revealed a CV than RA. Th is is 3.4% of the patients whose disease-specifi c meta-SMR of 1.6, with SMRs WD pension diagnosis was RA. Th is fi nding of individual studies ranging from 0.91 to refl ects the real-life diagnostic challenges 2.20.57 Another meta-analysis comprising 24 in infl ammatory rheumatic diseases. Some studies demonstrated a CV disease-specifi c patients may display features of more than meta-SMR of 1.5.1 Noteworthy is the fact that one infl ammatory arthritis, such as RA the latter meta-analysis detected no increased and psoriatic arthritis, so that selecting risk of CV death among the four inception the diagnosis for these patients is not cohort studies, the CV-disease-specifi c meta- straightforward. Mistakes may also appear in SMR’s being 1.19 (95% CI 0.86–1.68).1 Th e medical certifi cates. Overall, the number of comparability of our results to these meta- patients whose diagnosis changed from RA analyses is, however, limited, because almost to another infl ammatory polyarthropathy was all of these cohorts were studied before the small, suggesting that identifying RA patients 2000s and comprised patients with established based on special reimbursement decisions is RA, whereas our cohort was an inception adequately accurate. cohort from the 2000s. Of note, neither was In the aggregate, psychiatric and CV the overall survival in our RA cohort inferior comorbidities were the leading causes of to that of the general population.60 disability pensions much less frequently Our short follow up-period is than was RA itself. Risk for WD due to CV another important factor that may partly diseases was higher in early RA than in the explain the low SMRs we observed. Many general population, whereas WD risk due epidemiological studies have indicated that to psychiatric disorders was not increased. increased CV mortality emerges only 7 to 10 Optimized care of both CV and psychiatric years aft er RA diagnosis.59,175,183,189 A British comorbidities in RA may aid, among other multicenter inception cohort study has eff orts, in preventing WD. implied that, among RF-positive patients, increased CV mortality may already arise fi ve years aft er RA diagnosis.138 In our RA cohort, 15 Cardiovascular mortality as well, CV mortality may exceed that of the Our fi ndings demonstrate that Finnish general population aft er a longer follow-up. patients with early RA are at no increased risk Moreover, it would be most interesting to for CV mortality, at least during a follow-up see corresponding results with a fi ve-year of less than 10 years. In fact, the CV disease- follow-up extracted from similar research specifi c SMR and its confi dence intervals were, settings abroad. surprisingly, less than one in the entire RA Speculatively, a shift towards more population and in every subgroup according aggressive DMARD therapy during the to sex and RF status, implying a reduced CV past 20 years may have contributed to our mortality in this early RA cohort compared to RA cohort’s favorable CV prognosis. In one that in the Finnish population. Interpretation British register study among successive RA of this result, however, requires caution cohorts, all-cause and CV-disease specifi c mortality rates decreased from 1990 to

65 Discussion

2011, although the reduction was similar to RA medications were between 0.95 and 1.26 that of the general population.68 A decline (Figures 21 A and B). Th e fi ndings of male in deaths from acute myocardial infarction sex and RF as increasing the absolute risk of was shown in an earlier American study in CV death were unsurprising and consistent three successive RA cohorts followed up with previous reports on both RA128,138 and for almost 20 years: in the cohort with RA non-RA cohorts.326 RF positivity and male sex incidence before 1970, the SMR (95% CI) was appeared also to associate with higher SMR 1.60 (1.20 to 2.14); in the cohort from 1970 point estimates, although the only statistically to 1979, it was 1.83 (1.45 to 2.30); and in the signifi cant subgroup diff erence was between cohort from aft er 1980, it was 1.3 (0.94 to RF-positive men and RF-negative women 1.75), suggesting that the most recent cohort’s (Figure 16). Th is extends earlier observations risk was not statistically diff erent from that of RF’s associating with higher SMRs for CV of the general population.66 Rantalaiho and death,137 but diff ers from ones suggesting that coworkers have demonstrated that, in the SMRs for CV death among men are similar1 same RA population that we studied, the or lower67,190 than among women with RA. initial treatment strategy of RA has become Another factor associated with more modern between 2000 and 2007: during increased risk of CV death was use of the fi rst three months of RA, the proportion glucocorticoids. Th is is in line with many of RA patients using a combination therapy epidemiological fi ndings of an association of two or more DMARDs increased from between glucocorticoids and CV events and 38% to 55%, and the proportion receiving death.216,217,327 Th is association, however, is any DMARD was as high as 93 to 95%.325 at least partly explained by confounding Hydroxychloroquine use increased from 50% by indication, that is, confounding by high to 60%, and methotrexate use from 44% to disease activity being both an indication 69%.325 for glucocorticoids and a risk factor for Th eoretically, the fact that RA patients CV disease.222 Correcting such bias with usually visit a doctor on a regular basis statistical adjustments in observational may have led to intensifi ed diagnostics and studies is challenging, and suffi ciently prevention of CV disease. Furthermore, a powered randomized controlled trials are rheumatologist may consult a cardiologist thus warranted to discover the true benefi t- within a special healthcare setting more easily risk ratio of glucocorticoids in relation to CV than would a general practitioner who carries disease.328 out CV risk management in primary health Along with sulfasalazine, methotrexate care. Most data from other countries suggest, was the most commonly used antirheumatic however, that RA patients are less likely to drug: of all patient-years in the follow-up, be prescribed CV medicines than are non its use covered almost 40%. In contrast to RA-patients, not the converse.236,237 glucocorticoids, methotrexate was associated Factors associated with an increased with a slightly decreased risk of CV death risk of CV death included male sex, RF (Figure 21 B). Th is fi nding is parallel with positivity, diabetes, hypertension, and cardiac many epidemiological observations of an disease. Th e impacts of these comorbidities inverse association between methotrexate on CV mortality were stronger than those and CV morbidity or mortality.197-200 of RA medications: the sHRs for diabetes, Infl ammation’s being a major driver of hypertension, and cardiac disease were atherothrombosis, the protective eff ect of between 2.02 and 2.90, whereas the sHRs for methotrexate is likely from a reduction in

66 Discussion systemic infl ammation via its eff ects on TNF inhibitors especially in the fi rst years the IL-6 signaling pathway.329 It may also of our follow-up. According to data received have direct cardioprotective eff ects through from the Finnish national register for biologic facilitation of reverse cholesterol transport treatment in rheumatic diseases (ROB- and subsequent prevention of macrophages FIN), a prospective cohort study covering diff erentiating to lipid-loaded foam cells.330 the majority of Finnish patients on biologic A recent study in a murine model of agents, only 4.1 to 6.9% of RA patients infl ammatory vasculopathy indicated that treated with biologic agents in 2000-2002 methotrexate may protect endothelium received them subcutaneously.332 In 2003, the by upregulating cytoprotective genes via respective percentage increased to 44.7%, and activation of AMP-activated protein kinase in 2004-2008, it further increased to 71.6 to and cyclic AMP response element-binding 80.2%.332 For these reasons, our analysis may protein.40 misjudge the eff ect of TNF inhibitors on CV As in the case of glucocorticoids, we mortality. cannot exclude the possibility of confounding Hydroxychloroquine was prescribed by indication or contraindication as distorting frequently for patients in our cohort the relation between methotrexate and CV (Figure 20). Although it has theoretical mortality: those who stop using methotrexate cardioprotective properties through benefi cial due to adverse eff ects or ineffi cacy may eff ects on lipid metabolism, platelet function, develop more comorbidities or may suff er and diabetes control,209,210,212,333 in our analysis from uncontrolled infl ammation while it did not aff ect CV survival. searching for optimal RA pharmacotherapy, In sum, our fi ndings suggest that in the thus being at higher CV risk. In one German 2000s, CV mortality may not be elevated one-center mortality study, discontinuation during the early years of RA. Glucocorticoids of methotrexate during the fi rst year of its were associated with increased CV mortality use led to 5.6-fold mortality compared to in early RA, whereas methotrexate was that of an age- and sex-matched sample of associated with decreased CV mortality. the general population.331 Furthermore, not Mortality studies from the 2000s with longer all studies have found an association between follow-up and accounting for confounding methotrexate and risk for CV events.201,202 by indication are warranted to reveal causal Importantly, randomized controlled trials on eff ects of RA medications on CV mortality this topic are on their way.205 Before receiving and to determine CV death rates in longer- such studies’ results, no defi nitive conclusions standing RA. on the eff ect of methotrexate on CV events are possible. Accumulating evidence shows that TNF 16 Limitations of the study 201,206 inhibitors reduce the risk for CV events. Th e main limitations arise from defi ciencies Our fi ndings regarding subcutaneous TNF in our register data—we were unable to inhibitors, however, failed to demonstrate characterize our study populations based on such a protective eff ect. Th is is likely to result factors other than sex, age, RF status, and from TNF inhibitors’ being so infrequent in disease duration, nor have we additional data Finland during the follow-up period (Figure on their clinical characteristics. Th us, we 20). Moreover, we were unable to obtain were unable to account for many important data on intravenous TNF inhibitors, which confounders. comprised a substantial proportion of the

67 Discussion

Th e RA cases were those individuals Studies I and II, however, use of any other who had been diagnosed by a rheumatologist RA medication such as glucocorticoids to have RA, who had been prescribed long- induces no such bias since the patients get term antirheumatic medication and had their prescriptions and start on antirheumatic been granted the special reimbursement for medications synchronously with the antirheumatic medications. We have no data certifi cate entitling to special reimbursement on their fulfi lling of any RA classifi cation for those medications, this date being the end criteria. In addition, it must be noted that of the observation period. although we evaluated the prevalence of Identifying RA patients with comorbidities at RA diagnosis, or more hypothyroidism based on special medicine exactly, at the date of the granting of special reimbursements encompasses not only reimbursement for RA, this date may occur a cases of autoimmune thyroiditis but variable period of time aft er clinical onset of also hypothyroidism arising from other the disease, since the traditional hallmarks of etiologies. Chronic autoimmune thyroiditis, RA develop with time.334 however, is the most common reason for We were likely to underestimate CV acquired hypothyroidism,313 making most disease prevalence among both RA patients hypothyroid patients thus likely to represent and the general population to some extent, an autoimmune etiology behind the because their milder forms do not necessarily condition. At least thyroid cancer is quite rare entitle patients to special reimbursement in Finland, as indicated by its mean annual of medications. Especially noteworthy is incidence of 84 in men and 266 in women in that a signifi cant portion of hypertensive 2002-2006.335 Another important limitation is patients were likely to fall through our net. that coverage of clinical hypothyroidism may Since patients with mild hypertension are be relatively low because levothyroxine is so not eligible for the reimbursement, selection inexpensive that, in some cases, the patients bias might aff ect our results. Th eoretically, may choose not to pay for the doctor’s a possible overlap in medications for certifi cate needed to apply for the special various CV diseases may enable a patient reimbursement. Obviously, this is equally with two or more CV diseases to get their true both of the general population and of medication reimbursements with only one those who will later develop RA; hence, it will reimbursement diagnosis. However, any not cause bias in assessment of relative risk imperfect coverage of patients suff ering from for hypothyroidism. CV disease is likely to concern RA patients Absolute rates of disability pensions are and the general population equally. diffi cult to compare among countries because Smoking, NSAIDs, and obesity can their social insurance systems vary widely, interfere with the relation between CHD and diff erences exist in the process of sick and RA or RF status. Unfortunately, we listing. Th is makes generalizing our results to were unable to collect data on these. many other countries challenging. Further, Smoking is traditionally associated with in multimorbid patients, selecting the illness RF-positive RA114 and is therefore unlikely that restricts working ability the most may to contribute to increased CHD risk among not be straightforward. the RF-negative subset. Another potential In examining CV mortality rates, we confounder is the use of NSAIDs for joint were unable to account for disease severity or pain before RA diagnosis; all NSAIDs have degree of infl ammation. Th us, confounding somewhat unfavorable CV risk profi les.213 In by indication is most likely to have aff ected

68 Discussion our results for RA medications. One strength death among RA patients is a potential of the medication analyses was our being able source of error when comparing their CV to evaluate RA-medication use not only at mortality rates with the general population’s. baseline but during the entire follow-up. A methodological advantage to our mortality A Finnish study on autopsy fi ndings study was that we used, instead of normal from 1952-1991 indicated that RA patients survival analyses, competing-risks regression were less accurately diagnosed with CV models and cumulative incidence functions, and coronary deaths than were non-RA both better suited for situations in which patients by clinicians before autopsy, competing events can preclude the event of when compared with the causes of death interest.337 Competing causes of death such as suggested by pathologists aft er autopsy.336 malignancies may have, however, aff ected the Th erefore, less accurate diagnosis of CV point estimates of SMR for CV deaths.

69 70 Conclusions

Conclusions

1. Since comorbidities are relatively common in RA and have diverse eff ects on many crucial outcomes, preventing and targeting them should be an important aspect in the treatment of RA.

2. Th e prevalence of CHD was elevated among RA patients already at the time of diagnosis. Our fi ndings highlight the importance of CV risk detection and management as soon as RA is diagnosed, both in RF-positive and RF-negative patients.

3. Risk for hypothyroidism was already elevated at RA diagnosis, especially among the young women, regardless of RF status. Th is calls for attention to screening for hypothyroidism among RA patients, preferably even when RA is diagnosed.

4. Th e number of disability pensions resulting from psychiatric or CV comorbidities was minimal in comparison to the disability pensions for by RA itself. Compared to the general population, risk for WD due to CV disease was increased, but it was similar regarding psychiatric comorbidities.

5. During the era of modern RA treatment regimens, risk of CV death during the early years of RA was not increased. Th is risk may, however, increase in later stages of RA.

71 Acknowledgements

Acknowledgements

My deepest gratitude goes to my magnifi cent supervisors Professors Tuomo Nieminen and Markku Kauppi, and Docent Tuomas Kerola. Th ank you for all your eff orts to help me throughout this project. Tuomo, no words can describe how fortunate I have been to have you as my supervisor and custos. During the past few years, I have learned incredibly much from you about scientifi c thinking and research. I admire your intelligence, discipline, creativity, and passion for science. Under your guidance, I always felt heard, understood, and respected. You always had time to help me, no matter how trivial my problems. Markku, you are a source of inspiration for me as being an experienced scientist and an outstanding clinician; always considerate and warm-hearted. Both in research and in clinical fi elds, I have witnessed your positive presence and cooperative skills beyond comparison. You have been my professional role model, and encouraged my growing interest in rheumatology in so many ways that my gratitude overfl ows. Tuomas, you were the fi rst to introduce me to this project, and for that I am most grateful. You have off ered me invaluable guidance and support, especially in the fi eld of cardiology. I highly respect your effi cacy and your ability always to identify the essentials. I have also enjoyed being a part of your family’s life as your cousin and Mikaela’s godmother.

I have had the honor to work with Docent Kari Puolakka during this project, and I am deeply grateful for all his contributions. He provided me with detailed supervision and shared his extraordinary expertise in rheumatology, particularly in work disability related to rheumatoid arthritis. I was privileged to have Hannu Kautiainen as the statistician of this project. I owe him gratitude for the productive meetings at Äänekoski and for his excellent statistical analyses. I appreciate him for his wide knowledge of rheumatology research and biostatistics. I express my sincere appreciation to Docent Lauri Virta, whose important and constructive comments not only benefi ted the manuscripts but taught me a great deal about critical assessment of research methods. I also warmly acknowledge Vappu Rantalaiho, and Docent Timo Pohjolainen for their valuable comments and collaboration. My sincere thanks go to Kari, Timo, and Hannu for launching this rheumatologic register research line, which has already produced several dissertations, and for giving me the opportunity to use its data.

I was privileged to have Docents Tuomas Kiviniemi and Pekka Kurki as my pre-examiners. Th eir thorough inspection of the thesis and valuable comments helped me to improve this

72 Acknowledgements work tremendously. I am most grateful and honored that Professor Tore Kvien, a world- renowned rheumatologist from the University of Oslo, accepted the invitation to be my opponent.

I am deeply indebted to Carolyn Norris for her helpful English courses with enthusiastic atmosphere and for editing the language of this thesis. I am also thankful to Eeva Parviainen for her help with the language of the original manuscripts.

I am most grateful to Elina Ritvonen, a truly loyal friend with a golden heart. In this scientifi c journey that is rewarding but sometimes painfully frustrating, you have been the best possible peer support. You have made my evenings happy and fun despite all the studying and research work. I have simply loved these years living with you in our cozy student apartment, growing up together as medical experts, and, most of all, growing up as persons, both supporting each other.

I warmly thank all my friends and relatives for bringing a welcome balance to the research work. I want to give particular thanks to Salli Nurminen, Emmi Kainulainen, Eliisa Ollikainen, and Virva Kuusi for their irreplaceable friendship. I owe my sincere gratitude to Heidi Hietanen for the cover image of this book, and our unforgettable adventures in India.

I express a heartfelt thank-you to Antti Ruokanen for his love and support. Th ank you for making me happy in my every-day life. You have the ability to make me laugh even on the most diffi cult days. When I have felt overworked and tense, you have helped me change my perspective. You have never questioned the importance of this project, but you have defi nitely been there for me every step of the way. Moreover, your dedication to your work inspires me to reach the same dedication in mine.

I am forever thankful to my mother Marjatta, my father Paavo, and my sister Piia, to whom I dedicate this book. Piia, I simply adore you, and I have always looked up to you as a wonderful example for life. Towards others, you are always kind and genuine, and you like to see the best in people. My dear parents; throughout my life, your unconditional love has been my greatest support. You always said “Education is the greatest wealth a human being could ever have”. Your wise words have encouraged me to work to the best of my ability and strive for my goals, and your extensive practical help has made it possible. If I ever become half the parent you have been to me, I will consider myself successful.

I warmly acknowledge the fi nancial support by Competitive State Research Financing of the Expert Responsibility area of Tampere University Hospital, Grant number 3333, the Onni and Hilja Tuovinen Foundation, the Aarne Koskelo Foundation, the Finnish Society for Rheumatology, and the Finnish Foundation for Rheumatic Diseases.

Anne Kerola Helsinki, April 2015

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