Rheumatoid arthritis-associated interstitial lung disease : assessment of the factors associated with the course of the disease

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DISSERTATIONS | HANNA NURMI | RHEUMATOID ARTHRITIS-ASSOCIATED INTERSTITIAL LUNG... | No 458

uef.fi

PUBLICATIONS OF

THE UNIVERSITY OF EASTERN FINLAND Dissertations in Health Sciences

ISBN 978-952-61-2758-3 ISSN 1798-5706

Dissertations in Health Sciences

PUBLICATIONS OF

THE UNIVERSITY OF EASTERN FINLAND

HANNA NURMI

RHEUMATOID ARTHRITIS-ASSOCIATED INTERSTITIAL LUNG DISEASE – ASSESSMENT OF THE FACTORS ASSOCIATED WITH THE COURSE OF THE DISEASE

Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) causes significant

morbidity and mortality in patients with RA. We investigated 60 RA-ILD patients of

whom those with a radiological pattern of usual interstitial pneumonia revealed more severe course of the disease. We observed that

certain risk predicting models are applicable for evaluating the risk of death of RA-ILD patients. The baseline diffusion capacity to carbon monoxide and several radiological

features predicted survival.

HANNA NURMI

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Rheumatoid Arthritis-associated

Interstitial Lung Disease – Assessment of the factors associated with the course of the

disease

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HANNA NURMI

Rheumatoid Arthritis-associated

Interstitial Lung Disease – Assessment of the factors associated with the course of the

disease

To be presented by permission of the Faculty of Health Sciences, University of Eastern Finland for public examination in Kuopio, on Friday, June 8^th, 2018, at 12 noon.

Publications of the University of Eastern Finland Dissertations in Health Sciences

Number 458

Department of Respiratory Medicine, Institute of Clinical Medicine, School of Medicine, Faculty of Health Sciences, University of Eastern Finland

Kuopio 2018

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Series Editors:

Professor Tomi Laitinen, M.D., Ph.D.

Institute of Clinical Medicine, Clinical Physiology and Nuclear Medicine Faculty of Health Sciences

Professor Hannele Turunen, Ph.D.

Department of Nursing Science Faculty of Health Sciences Professor Kai Kaarniranta, M.D., Ph.D.

Institute of Clinical Medicine, Ophthalmology Faculty of Health Sciences

Associate Professor (Tenure Track) Tarja Malm, Ph.D.

A.I. Virtanen Institute for Molecular Sciences Faculty of Health Sciences

Lecturer Veli-Pekka Ranta, Ph.D. (pharmacy) School of Pharmacy

Faculty of Health Sciences Distributor:

University of Eastern Finland Kuopio Campus Library

P.O.Box 1627 FI-70211 Kuopio, Finland http://www.uef.fi/kirjasto

ISBN (print): 978-952-61-2758-3 ISBN (pdf): 978-952-61-2759-0 ISSN (print): 1798-5706 ISSN (pdf): 1798-5714 ISSN-L: 1798-5706

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III

Author’s address: Center of Medicine and Clinical Research, Division of Respiratory Medicine, Kuopio University Hospital and Department of Respiratory Medicine, Institute of Clinical Medicine, School of Medicine, Faculty of Health Sciences University of Eastern Finland

KUOPIO FINLAND

Supervisors: Professor Riitta Kaarteenaho, M.D., Ph.D.

Research Unit of Internal Medicine Medical Research Center Oulu

Department of Internal Medicine and Respiratory Medicine University of Oulu and Oulu University Hospital

OULU FINLAND

Docent Minna Purokivi, M.D., Ph.D.

Center of Medicine and Clinical Research Division of Respiratory Medicine

Kuopio University Hospital KUOPIO

FINLAND

Reviewers: Professor Hannu Puolijoki, M.D., Ph.D.

University of Tampere

Central Hospital of Southern Ostrobothnia SEINÄJOKI

FINLAND

Docent Paula Rytilä, M.D., Ph.D., Adj. Prof.

University of Helsinki

Chief Medical Officer, Vice President

Global Medical Affairs and Pharmacovigilance, R&D Orion Corporation, Orion Pharma

ESPOO FINLAND

Opponent: Docent Maija Halme, M.D., Ph.D.

Department of Pulmonary Diseases University of Helsinki

Helsinki University Central Hospital HELSINKI

FINLAND

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V

Nurmi, Hanna

Rheumatoid Arthritis-Associated Interstitial Lung Disease – Assessment of the factors associated with the course of the disease

University of Eastern Finland, Faculty of Health Sciences

Publications of the University of Eastern Finland. Dissertations in Health Sciences 458. 2018. 81 p.

ABSTRACT

Interstitial lung disease (ILD) is one of the most common lung manifestations in patients with rheumatoid arthritis (RA), occurring in approximately 10% of patients with RA and increasing both their morbidity and mortality. RA-ILD is not considered as one single disease entity; instead it includes several different subtypes, each of which seems to have a distinct disease course. Moreover, the disease course even within the same subtype can be highly variable from patient to patient, which complicates the estimation of prognosis. The categorization into different subtypes is often performed by high-resolution computed tomography (HRCT).

Different kinds of scoring systems for ILDs have been developed over the years, trying to help in the evaluation of an individual´s prognosis. These scoring models have, however, mainly been developed for idiopathic pulmonary fibrosis (IPF), and their suitability for RA- ILD is largely unknown.

Our aim was to evaluate the course of the disease of RA-ILD patients in Kuopio University Hospital (KUH) health care district. The study material consisted of retrospectively gathered data of 60 RA-ILD patients treated between the years 2000-2014 in the KUH pulmonology clinic. Clinical, pulmonary function tests and death certificate data were gathered using a specially designed form. The HRCTs of the patients were re- evaluated and the radiological re-categorization was conducted according to the current criteria. Firstly, we evaluated comorbidities and causes of death, as well as investigated the course of the disease in different subtypes. Secondly, we tested the applicability of three different prediction models, previously mostly applied in patients with IPF, and searched for other factors that could be useful for evaluating the prognosis of RA-ILD patients.

Finally, we compared the presence and extent of various HRCT observations in different subtypes and compared radiological findings with clinical data.

Most of the patients (36/60%) showed a radiological pattern of usual interstitial pneumonia (UIP). These patients had higher numbers of hospitalizations for respiratory reasons and deaths as well as greater use of oxygen than patients with other subtypes. RA- ILD was the most common primary cause of death, even though several comorbidities co- existed. We observed that the risk predicting models, such as the gender-age-physiologic variables model (GAP), were applicable for evaluating the risk of death of patients with RA-ILD in a similar manner as in those with IPF. The baseline diffusion capacity to carbon monoxide (DLCO), the composite physiologic index (CPI) and several radiological findings, such as the extents of reticulation and traction bronchiectasis also predicted survival.

Moreover, the extents of honeycombing, traction bronchiectasis and architectural distortion correlated with hospitalizations due to respiratory reasons.

This thesis clarified the numbers and subtypes of RA-ILD patients in KUH region as well as revealing the variable course of the disease. Our study may help clinicians to identify those patients at the highest risk of death which could lead to more individualized follow- up and treatment protocols in the future.

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National Library of Medicine Classification: WE 346, WF 600, WN 206

Medical Subject Headings: Lung Diseases, Interstitial; Arthritis, Rheumatoid; Risk Factors; Prognosis;

Tomography; Respiratory Function Tests; Death Certificates; Cause of Death; Comorbidity;

Hospitalization; Retrospective Studies; Humans; Finland

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VII

Nurmi, Hanna

Nivelreumaan liittyvän interstitiaalisen keuhkosairauden luokittelu ja taudinkulku Itä-Suomen yliopisto, terveystieteiden tiedekunta

Publications of the University of Eastern Finland. Dissertations in Health Sciences 458. 2018. 81 s.

TIIVISTELMÄ

Interstitiaalinen keuhkosairaus on yksi nivelreuman tärkeimpiä keuhkoilmentymiä, jota esiintyy n. 10 %:lla nivelreumaa sairastavista potilaista. Nivelreumaan liittyvä interstitiaalinen keuhkosairaus (RA-ILD) lisää merkittävästi näiden potilaiden sairastavuutta ja kuolleisuutta. Se ei kuitenkaan ole yksi yhtenäinen sairaus, vaan ryhmä monia eri alatyyppejä, joilla on erilainen taudinkulku ja ennuste ja joista osa johtaa keuhkojen fibrotisoitumiseen. Yksittäisen sairastuneen kohdalla taudin kulun ja oletetun eliniän ennustaminen on erittäin haastavaa. Potilaiden luokittelu eri alatyyppeihin tehdään pääasiallisesti ohutleike-tietokonetomografian (HRTT) perusteella.

Aiemmin on kehitetty useita riskinarviointimenetelmiä, joilla on pyritty arvioimaan ILD- potilaita suuremman ja pienemmän kuoleman riskin luokkiin. Nämä menetelmät on kuitenkin valtaosin kehitetty idiopaattista keuhkofibroosia (IPF) sairastaville, eikä niiden soveltuvuudesta RA-ILD:ssä ole aikaisempaa tutkittua tietoa.

Tavoitteenamme oli selvittää RA-ILD:n taudinkulkua Pohjois-Savon sairaanhoitopiirin alueelta kerätyssä kohortissa. 60 potilaan aineisto kerättiin retrospektiivisesti vuosina 2000- 2014 Kuopion yliopistollisen sairaalan keuhkoklinikassa hoidetuista potilaista, joiden kliiniset sekä kuolintodistusten tiedot ja keuhkojen toimintakokeiden tulokset kerättiin yksityiskohtaista tiedonkeruukaavaketta käyttäen ja joiden HRTT-kuvat arvioitiin uudelleen. HRTT-kuvien perusteella potilaat luokiteltiin nykysuositusten mukaisesti eri ILD alatyyppeihin. Ensimmäisessä osatyössä kartoitimme liitännäissairauksia ja

kuolinsyitä, sekä vertasimme taudinkulkua eri alatyypeissä. Toisessa osatyössä testasimme miten IPF: iin kehitetyt ennustemallit toimivat RA-ILD potilaiden kohdalla ja selvitimme muita tekijöitä, joita mahdollisesti voitaisiin hyödyntää yksittäisen potilaan kuoleman vaaraa arvioidessa. Kolmannessa tutkimuksessa tarkastelimme radiologisia löydöksiä RA- ILD:n eri alatyypeissä, sekä niiden korrelointia kliinisiin tekijöihin.

Aineistostamme valtaosa (36/60%) kuului ns. tavallisen interstitiaalisen pneumonian (UIP) alaryhmään, jossa esiintyi muihin alaryhmiin verrattuna enemmän keuhkoperäisistä syistä johtuvia sairaalahoitojaksoja, happihoidon tarvetta ja kuolemantapauksia. Yleisin peruskuolinsyy oli RA-ILD, vaikka erilaiset liitännäissairaudet olivat yleisiä. Toisessa tutkimuksessa osoitimme, että erilaiset kuolemanriskin arviointimallit, kuten ”gender-age- physiologic variables”- malli (GAP), ovat käyttökelpoisia myös RA-ILD-potilaiden kuolemanriskin arviossa samaan tapaan kuin IPF-potilailla. Lisäksi havaitsimme lähtötason kokonaisdiffuusiokapasiteetin ja ns. ”composite physiologic index” (CPI)- pistemäärän ennustavan kuolleisuutta. Kolmannessa osatyössä todettiin useiden radiologisten löydösten, kuten retikulaation ja traktiobronkiektasioiden laajuuden, olevan yhteydessä lyhentyneeseen elinikään sekä hunajakennojen, traktiobronkiektasioiden ja arkkitehtuurin vääristymän laajuuksien korreloivan keuhkoperäisten osastohoitojaksojen määrään.

Tutkimuksen myötä tiedämme, minkä verran ja minkä typpisiä RA-ILD potilaita alueellamme on. Saimme lisätietoa taudinkulun eroista eri alatyypeissä ja toivottavasti

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pystymme jatkossa tunnistamaan paremmin suuressa riskissä olevat potilaat. Tämä voisi mahdollistaa seurantakäytäntöjen ja hoitojen yksilöllisemmän suunnittelun.

Luokitus: WE 346, WF 600, WN 206

Yleinen Suomalainen asiasanasto: keuhkosairaudet; keuhkofibroosi; nivelreuma; riskitekijät;

riskinarviointi; tietokonetomografia; ennusteet; kuolintodistukset; kuolemansyyt; kuolleisuus;

liitännäistaudit; elinikä; sairaalahoito; happihoito; Pohjois-Savo; Suomi

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IX

“Maailma on kaunis ja hyvä elää sille, jolla on aikaa ja tilaa unelmille.

Ja mielen vapaus, ja mielen vapaus”

Vexi Salmi

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XI

Acknowledgements

This study was carried out in the Department of Respiratory Medicine, University of Eastern Finland and in the Center of Medicine and Clinical Research, Division of Respiratory Medicine, Kuopio University Hospital during the years 2014-2018.

First of all, I would like to express my deepest gratitude to my supervisor Professor Riitta Kaarteenaho. You have provided both guidance and support in the first steps of my research career and advised me carefully throughout the process. You have always found the time to answer my questions and your dedication made possible the completion of this study. Your devotion to science is truly inspirational.

I am also deeply grateful to my other supervisor Docent Minna Purokivi. You have encouraged and supported me in many ways. I am sincerely thankful for your empathy and advice when life delivered a number of misfortunes. You often understand my temper.

Moreover, you have arranged my leaves of absence; these allowed me to complete this study at full speed.

I wish to thank all my co-authors and study group members for their collaboration and support. This study would not have been possible without the excellent radiologists Hannu-Pekka Kettunen and Sanna Suoranta, who performed the enormous job of screening and re-categorizing the HRCTs. Many thanks to Tuomas Selander for his patience when guiding me through the basics of SPSS. The cheerful peer support of Miia Kärkkäinen has helped me carry on and the assistance of research nurse Satu Nenonen saved a lot of my time and energy at the beginning of this project.

I sincerely thank Ewen MacDonald for reviewing English language in all the original publications as well as this thesis.

I express my gratitude to the official reviewers of this dissertation, Professor Hannu Puolijoki and Docent Paula Rytilä, who gave me professional, constructive and helpful comments about this manuscript. I am also grateful to the anonymous reviewers of the original publications for their comments, which helped me improve the manuscripts.

I warmly thank all funders of my research: the Foundation of the Finnish Anti- Tuberculosis Association, the Jalmari and Rauha Ahokas Foundation, the Väinö and Laina Kivi Foundation, the Research Foundation of the Pulmonary Diseases, the Kuopio region Respiratory Foundation, the North Savo Regional Fund of the Finnish Cultural Foundation and a state subsidy to the Kuopio University Hospital.

I am grateful for being a part of the Department of Respiratory Medicine personnel. I am surrounded by skillful clinicians, enthusiastic researchers and warm and intelligent people.

You have believed in me, supported me and offered me much useful advice. Your company in every-day work as well as in numerous parties has made me laugh and relax, which has been very important during this process. Special thanks to Professor Heikki Koskela, who acted as a mentor when I first started my resident´s training in respiratory medicine; his guidance has continued since that time and he is partially responsible for planting the seed of a scientific way of thinking.

I also wish to thank my parents-in-law Orvokki and Kari for their support and love, not to mention taking care of our children which has enabled me and Samipetteri to enjoy some time together as well as coping with the long working hours.

I thank all my dear friends and relatives, especially Jenni, Juha, Annukka, Anne, Anniina, Laura, Tiina and Jussi, for their friendship, support, listening ears, delicacies, sparkling wine, enjoyable company, sharing all the precious moments in life and giving me other things to think outside my scientific work. A big thank you to the Sawotta girls for their companionship in music, the power of which is astonishing.

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I am extremely grateful to my parents, Eeva and Kalervo, for their love and support during my whole life. You have taught me the importance of both hard work and relaxing in the summer cottage. I was fortunate to grow up in a stable and loving home.

Most importantly, I thank my spouse Samipetteri for sharing his life with me in both the good times and the bad ones, for your unconditional love and patience. When facing a hill, you push me forward, when plunging downhill, you slow down my speed. You make me laugh and boost my spirits. Your worlds´ best cinnamon buns have comforted me on so many occasions. You have been the best father to our precious children, Iita and Paavo, for whom I´m more grateful than anything else. You three are the loves of my life.

Hanna Nurmi Kuopio, March 2018

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XIII

List of the original publications

This dissertation is based on the following original publications:

I Nurmi H, Purokivi M, Kärkkäinen M, Kettunen H-P, Selander T, Kaarteenaho R.

Variable course of disease of rheumatoid arthritis-associated usual interstitial pneumonia compared to other subtypes. BMC Pulm Med 16:107-016-0269-2, 2016.

II Nurmi H, Purokivi M, Kärkkäinen M, Kettunen H-P, Selander T, Kaarteenaho R.

Are risk predicting models useful for estimating survival of patients with rheumatoid arthritis-associated interstitial lung disease? BMC Pulm Med 17:16- 016-0358-2, 2017.

III Nurmi H, Kettunen H-P, Suoranta S-K, Purokivi M, Kärkkäinen M, Selander T, Kaarteenaho R. Several high-resolution computed tomography findings associate with survival and clinical features in rheumatoid arthritis-associated interstitial lung disease. Resp Med 2018;134:24-30

The publications were adapted with the permission of the copyright owners.

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XV

Abbreviations

6MWT Six-minute Walk Test ACPA Anticitrullinated protein

antibodies

AE Acute exacerbation ALAT Latin American Thoracic

Association

ANA Antinuclear antibodies ARDS Acute respiratory distress

syndrome

ATS American Thoracic Society BAL Bronchoalveolar lavage CAD Coronary artery disease CI Confidence interval COPD Chronic obstructive pulmonary disease cNSIP Cellular nonspecific

interstitial pneumonia CPI Composite physiologic index CRP Clinical-radiologic-

physiologic scoring system

CT Computed tomography

CTD Connective tissue diseases DAD Diffuse alveolar damage DAS-28 Disease activity score in 28

joints

DIP Desquamative interstitial pneumonia

DLCO Diffusion capacity to carbon monoxide

DMARD Disease modifying antirheumatic drug

ERS European Respiratory Society ESR Erythrocyte sedimentation

rate

ExRA Extra-articular manifestations in rheumatoid arthritis FEV1 Forced expiratory volume in 1

second

FIN-RACo Finnish rheumatoid arthritis combination therapy fNSIP Fibrotic nonspecific

interstitial pneumonia FPF Familial pulmonary fibrosis FVC Forced vital capacity GAP Gender, age, and

physiological variables GER Gastro-esophageal reflux GGO Ground-glass opacity HAQ Health-assessment

questionnaire

HAQ-DI HAQ Disability Index score HLA Human leukocyte antigen HR Hazard ratio

HRCT High-resolution computed tomography

ICD International Classification of Diseases

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IIP Idiopathic interstitial pneumonias

IL Interleukin

ILD Interstitial lung disease iNSIP Idiopathic nonspecific

interstitial pneumonia IPF Idiopathic pulmonary fibrosis JRS Japanese Respiratory Society KL-6 Krebs von den Lungen KUH Kuopio University Hospital LDH Lactate dehydrogenase LEF Leflunomide

LIP Lymphocytic interstitial pneumonia

LTx lung transplantation

MDD Multidisciplinary discussion MMF Mycophenolate mofetil MMP Matrix metalloproteinase MTX Methotrexate

NSIP Nonspecific interstitial pneumonia

OP Organizing pneumonia PDGF Platelet derived growth factor PFT Pulmonary function test RA Rheumatoid arthritis RA-ILD Rheumatoid arthritis-

associated interstitial lung disease

RB Respiratory bronchiolitis RF Rheumatoid factor ROSE Risk stratification score

RTX Rituximab

SD Standard deviation SE Shared epitope SLB Surgical lung biopsy

SSc-ILD Systemic sclerosis-associated interstitial lung disease TBB Transbronchial biopsy TBCx Transbronchial cryobiopsy TERT Telomerase reverse

transcriptase TLC Total lung capacity TNF Tumor necrosis factor UIP Usual interstitial pneumonia VAS Visual analogue pain scale VATS Video-assisted thoracoscopic

surgery

VEGF Vascular endothelial growth factor

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XXI

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1

1 Introduction

Rheumatoid arthritis (RA) is a systemic inflammatory disease that affects approximately 1%

of the global population (1) and about 0.8% of the Finnish population (2). Patients with RA have greater mortality than the healthy population and their average life expectancy is shortened by approximately 10 years (3). The majority of deaths are due to extra-articular manifestations (ExRA) of the disease, of which interstitial lung disease (ILD) is one of the most important (4).

Approximately every tenth patient with RA develops clinically evident ILD with respiratory symptoms and/or a decline in pulmonary function tests (PFT) during the course of the rheumatoid disease (5). In a substantial percentage i.e. 30-55% of asymptomatic RA patients, high-resolution computed tomography (HRCT) scans have revealed evidence of interstitial lung involvement and a large proportion of those patients with subclinical disease deteriorate with time (6,7). Similarly, as in HRCT-based studies, autopsy studies have detected high prevalences of up to 35% for rheumatoid arthritis-associated interstitial lung disease (RA-ILD) (8).

RA-ILD greatly affects the lives of RA patients, increasing both morbidity and mortality (9). Recent studies have shown that despite the decline in overall mortality in RA, deaths attributable to RA-ILD have substantially increased (10). However, the course of the disease is highly heterogenic, as some patients remain stable for years or even decades, while others develop an insidious progressive disease (11).

Predicting the survival of an individual patient with ILD is challenging (9). Several factors i.e. physiological, radiological and histopathological characteristics, as well as demographic variables have been proposed to predict disease progression and survival (12). Several indexes combining single factors into multifaceted scoring systems have been developed over the past years to help in the risk prediction (13), but these models have primarily been developed for idiopathic pulmonary fibrosis (IPF) and have not been previously investigated or validated in RA-ILD patients.

There has been very little research conducted concerning RA-ILD in Finland after some studies that were conducted in the 1980s (14). Subsequently, radiological technology has developed, significantly improving the diagnostic accuracy and enabling a modern classification of the ILDs. Moreover, the first randomized controlled studies of combination therapy on RA were performed in the late 1990s, the long-term effects of which have been documented in a Finnish study (15). Since then, the recommended treatment of newly diagnosed RA has involved a combination of methotrexate (MTX), sulfasalazine, hydroxychloroquine plus prednisolone; this recommendation has stabilized treatment protocols and thus may have an impact on the course of disease on RA and RA-ILD as well.

In addition, the repertoire of drugs has expanded with the arrival of biological drugs, the first of which was taken into use in 1999 (16) and therefore results from the studies from the 1980s are no longer completely applicable.

The purpose of the present study was to evaluate a cohort of RA-ILD- patients treated in Kuopio University Hospital (KUH) health care district, re-classify the cases with ILD according to the current criteria, evaluate the course of the disease, comorbidities, causes of death, prognostic factors for survival in different subtypes as well as testing the suitability of the prediction models previously developed for IPF. We wanted to evaluate how many and which subtype of patients with RA-ILD exist in the KUH region, information which was formerly unknown due to the non-standardized diagnosis coding. We wanted to explore the course of the disease and examine how the lung disease has affected the patients´ lives and lifespans. A secondary aim was to seek means to help clinicians in the difficult estimation of an individual’s prognosis and to test the prediction models of IPF in

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RA-ILD patients. The identification of the high-risk patients could help to plan individualized monitoring and in particular, to consider when to proceed to lung transplantation (LTx) or perhaps to a treatment trial. Hopefully, this thesis will improve the recognition of RA-ILD and provide clinicians with tools for identifying those patients who are at the highest risk of death.

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3

2 Review of the literature

2.1 RHEUMATOID ARTHRITIS

RA is a systemic, chronic progressive inflammatory disease that is characterized by destructive joint disease, systemic inflammation, and in most of the patients, the presence of autoantibodies to either rheumatoid factor (RF) or citrullinated proteins or to both (17).

The prevalence of clinically significant RA is about 0.8% and the incidence of RA is about 40 / 100 000 of the adult Finnish population (2).

2.2 INTERSTITIAL LUNG DISEASES

ILDs are a heterogeneous group of differently behaving rare diseases, characterized by varying degrees pulmonary inflammation and fibrosis formation. Most of the cases are idiopathic, but ILDs can also be attributable to exogenous factors, such as connective tissue disorders (CTD) (e.g. RA), exposure to organic dusts (e.g. asbestos), or exposure to certain drugs. ILDs are commonly categorized into four categories: idiopathic interstitial pneumonias (IIP), ILDs of known causes, granulomatous diseases and a remnant group of other ILDs (Figure 1) (18,19).

Figure 1. Classification of ILDs. Modified from the 2002 consensus classification of the IIPs (18) and the 2013 update (20). IIP = idiopathic interstitial pneumonias; ILD = interstitial lung disease; CTD = connective tissue diseases; LAM = lymphangioleiomyomatosis; HX = Langerhans´ histiocytosis; IPF = idiopathic pulmonary fibrosis; NSIP = nonspecific interstitial pneumonia; RB-ILD = respiratory bronchiolitis interstitial lung disease; DIP = desquamative interstitial pneumonia; COP = cryptogenic organizing pneumonia; AIP = acute interstitial pneumonia; LIP = lymphocytic interstitial pneumonia; PPFE = pleuroparenchymal fibroelastosis.

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2.3 EXTRA-ARTICULAR MANIFESTATIONS IN RA

Since RA is a systemic inflammatory disease, it is recognized that there can be extensive variability between different ExRAs (21). There is a wide spectrum of pulmonary (Table 1), as well as cardiac and other organ manifestations (Table 2). RA-ILD is one of the most important ExRAs significantly impacting on morbidity and mortality of the patients with RA (9).

Table 1. Frequency and impact of pulmonary manifestations in patients with rheumatoid arthritis (RA). Adapted and modified from Lake et al. 2014 (22).

Frequency Impact Pleural abnormalities

Pleuritis Effusion

Pleural thickening

Other (unexpandable lung, empyema, chyliform effusion, pneumothorax, hemothorax, pyopneumothorax, bronchopleural fistula)

++

+++

+

++

+ +++

Upper airway

Crico-arytenoid immobility with vocal cord abnormality, cord nodules,

recurrent laryngeal or vagus nerve vasculitis, cord paralysis

+ ++

Lower airway Airflow obstruction Obliterative bronchiolitis Bronchiectasis

++

+ +

+ +++

+ Parenchymal

Interstitial lung disease

Apical fibrosis and Caplan syndrome Nodules

+++

+ +++

+++

+ + Vascular

Pulmonary hypertension Vasculitis

+ +

+++

Musculoskeletal related

Chest wall immobility and respiratory failure + +

Infection Related to RA Related to treatment

+ ++

Treatment related Pneumonitis Pleuritis / effusion

++

+

+++

+ Increased risk

Lung cancer

Pulmonary thromboembolism

+ +

+++

++

RA = rheumatoid arthritis.

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5

Table 2. Other organ manifestations in addition to those classified as pulmonary extra-articular manifestations (ExRA) in patients with rheumatoid arthritis. Adapted and modified from Prete et al. 2011 (23).

Affected tissue or organ ExRA Not severe

ExRA Severe

Skin Nodules

Raynaud´s phenomenon

Petechiae, purpura Ulcers, gangrene

Heart Valvular heart disease

Myocarditis Arrhythmias

Pericarditis

Coronary vasculitis and aortitis

Nervous system - Mono/polyneuritis multiplex

Central nervous system vasculitis

Eyes Secondary Sjögren syndrome

Sicca syndrome

Episcleritis or scleritis Retinal vasculitides

Hematological system - Felty´s syndrome

Kidneys - Glomerulonephritis

Interstitial nephritis Amyloid deposition

2.4 OVERVIEW OF RA-ILD

2.4.1 History

The first descriptions of three RA patients with “rapidly progressive fibrosing pneumonitis” were published in 1948 by Ellman and Ball (24). The first review article concerning a few sporadic cases was published in 1965 (25). In the 1960s, there were some doubts about whether there was any association between RA and pulmonary fibrosis, even though several research groups had investigated the relationship between these two disorders and moreover, risk factors for the RA-related pulmonary fibrosis could already be detected (26). By the end of the 1970s, typical symptoms and clinical signs, PFT findings and typical radiological and histological findings were defined. In that era, the common appearances in the chest X-rays were described as “non-specific diffuse bilateral shadows in the lower zones” (27) which was likely a mixture of the currently known different entities.

A pivotal change in the field of pulmonary fibrosis research occurred in the early 1990s with the development of the HRCT technique (28). Gradually, the computed tomography (CT) findings of RA-ILD were described (29,30) resulting in a more uniform terminology and enabling the identification of different subtypes (31).

2.4.2 Definition

Currently, there is no official international accepted definition or criteria for RA-ILD or its different subtypes. The definitions are commonly adopted from the American Thoracic Society/European Respiratory Society (ATS/ERS) statement on IPF (32) and the IIPs (18), the latter being updated in 2013 (20). These criteria include an underlying RA diagnosis and ILD on HRCT scan or lung biopsy or both, without any identifiable etiology to account for the lung changes. With this definition, respiratory infections, treatment-related ILDs and e.g. rheumatoid nodules can be distinguished from RA-ILD (33).

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2.5 EPIDEMIOLOGY

The reported prevalence and incidence of RA-ILD have varied in different studies. The differences derive from different study populations as some studies have included only asymptomatic patients or those with recently diagnosed RA, whereas in other reports, the cohorts have consisted of longstanding and/or symptomatic RA patients. Naturally, the development of modern and more sensitive diagnostic technology has increased the estimations of RA-ILD prevalence. Moreover, the variable RA-ILD definitions used in the past make any comparison of the reported prevalences difficult.

The prevalence has been estimated as low as 4.5% (25) or 1.6% in those studies that used chest radiographs in ILD diagnostics (26). In one investigation using CT-based diagnostics, only one fifth of the RA-patients with abnormal CT scans had visible ILD changes in their chest X-rays (7); nowadays the prevalence has been shown to be much higher with the evolution of more sensitive HRCT imaging (34,35).

One study which applied the diffusion capacity to carbon monoxide (DLCO), estimated the prevalence of RA-ILD to be as high as 41% (36), whereas another investigation using autopsy material of 81 RA patients found ILD in every third RA patient with advanced disease (8). In a cohort exploring RA patients diagnosed less than two years earlier, 58% of the patients had changes suggestive of ILD in either chest X-ray, HRCT, PFT, bronchoalveolar lavage (BAL) and/or 99Tc-DTPA (technetium-99-m-labelled diethylenetriamine pentaacetate) scan. Of these, 76% were asymptomatic (7). Another study with recent onset RA patients detected HRCT abnormalities and/or abnormal PFTs in 45%

of the patients, of which 10% were symptomatic (34).

The prevalence of clinically relevant ILD was estimated between 4 and 7.9%, with a 30- year cumulative incidence of 7.7% in a large population-based cohort of RA patients (4).

Similar results were reported in another study in which clinically significant ILD was observed in approximately 6.8% of women and 9.5% of men with RA (10). A subsequent report from Turesson et al. described comparable results estimating the 30-year cumulative incidence as 7% (5). In the cohort study of Koduri et al, the annual incidence rate for the development of RA-ILD was 4.1/1000 (95%CI: 3.0-5.4), with a 15-year cumulative incidence of 62.9/1000 (95%CI: 43.0-91.7) (37).

Overall, the lifetime risk of a clinically significant RA-ILD is nowadays shown to be approximately 10% (9), whereas in unselected populations, subclinical ILD has been detected in 20-30% (10,38,39) although in some reports it has been estimated to be present in two thirds of RA patients (40,41). Selected studies reporting the prevalence and/or incidence of RA-ILD are shown in table 3.

(33)

7 Table 3. Summary of studies investigating the prevalence and/or incidence of RA-ILD in different study populations using different diagnostic methods. Study, yearNumber of the patients

Duration of RAMethodPrevalence of RA-ILDIncidenceSymptoms Walker, 1969 (26) 516Not reportedChest X-ray1.6%- Not clearly reported Frank, 1973 (36) 41Not reported DLCO41.4%- “Usually not symptomatic” Suzuki, 1994 (8) 8113.7 ± 11.0Autopsy34.6%- Not reported Saag, 1996 (42) 336Not reportedChest X-ray and PFTChest X-ray abnormality 12%. FVC <80% % pred. 12.5%, DLCO <80% %pred. 19.0%, any of the above 32.4%

- Not reported Gabbay, 1997 (7) 36 < 2 yearsChest X-ray, HRCT, PFT, BAL and/or 99Tc-DTPA scanAbnormalities in 58% (one or more investigations), 22% PFT, 6% X-ray, 33% HRCT.

- 14% Dawson, 2001 (39) 1508 ± 12.7 HRCT18.7%- 71.4% dyspnoea, 46.4% productive cough Turesson, 2003 (5) 609Not reportedClinical judgement and decreased VC or DLCO by 15% from normal

- 30-year cumulative incidence 6.8%

Not reported Bilgici, 2005 (41) 548.4 ± 8.2HRCT 67.3%- 42.6% symptomatic Mori, 2008 (43) 12665 <1 year, 61 >3 yearsHRCT11.9%- 23.8% symptomatic Bongartz, 2010 (4) 582not reportedProbable ILD = X-ray + treating physician´s diagnosis of ILD. Definite ILD = Diagnosis of ILD by a pulmonologist + 2/3 of following: ILD on CT / x-ray, restrictive PFT, biopsy confirmation

4.0% definite, 7.9% definite + probable 10-, 20- and 30- year cumulative incidences 3.5%, 6.3% and 7.7%

not reported Koduri, 2010 (37) 1460<2 yearsHRCT2.9%Annual incidence 4.1/1000, 15- year cumulative incidence 6.3%

All symptomatic

(34)

8 Habib, 2011 (34) 40 <2 yearsHRCT and/or PFTAbnormal HRCT 27.5%, abnormal PFT 32.5%, abnormal PFT and HRCT 20%, abnormal PFT and HRCT with symptoms 10%

- 90% asymptomatic Olson, 2011 (10) >162 000Not reportedICD-9 and ICD-10 codes6.8 % in women, 9.5% in men- Not reported Restrepo, 2015 (44) 77912.6 ± 10.8 Chest X-ray, CT, HRCT or lung biopsy8.8%- All symptomatic Zhang, 2017 (35) 5508 ±9 (range 2 weeks – 40 years)

HRCT43.1%- 41% symptomatic of patients with HRCT changes DLCO = diffusion capacity to carbon monoxide; HRCT = high-resolution computed tomography; PFT = pulmonary function tests; BAL = bronchoalveolar lavage; VC = vital capacity; FVC = forced vital capacity; RA = rheumatoid arthritis; ILD = interstitial lung disease; 99Tc-DTP scan = technetium-99-m-labelled diethylenetriamine pentaacetate scan; ICD = international classification of diseases.

(35)

9

2.6 PATHOPHYSIOLOGY AND RISK FACTORS

2.6.1 Genetics

The mechanism of pulmonary fibrosis in ILD is poorly understood. Available data suggest a role for both genetic and environmental factors. It has been speculated that there is some underlying genetic vulnerability with some form of injury to the lung triggering the fibrosis formation (45).

Specific human leukocyte antigen (HLA) variants, such as HLA-B40 and HLA-DR4, have been associated with RA-ILD (46,47). Some polymorphisms of the HLA-DRB shared epitope (SE) have been associated with an increased risk of ILD, while others seem to protect from ILD (48). In a Japanese study, HLA-DQB1*06, HLA-DRB1*15 and *16 alleles were associated with an increased risk of ILD, and HLA-DRB1*04 and HLA-DQB1*04 appeared to be protective against the development of RA-ILD, although the majority of the HLA-DRB1 subtype alleles had no significant, either negative or positive, associations (49).

An association between HLA-DRB1*1502 and ILD was also observed in the study of Mori et al. (50). In the study of Restrepo et al., the association between ILD and smoking was seen only in those patients with an HLA-DRB1 SE, which was speculated to reflect a gene- environment interaction (44).

The risk of RA-ILD was shown to be increased in patients with the non-M1M1 alpha one antitrypsin phenotype (51). One study has investigated the MUC5B polymorphism, which is associated with IPF, but found no association between it and RA-ILD (52). Other potential genetic factors believed to be associated with the development of ILDs include surfactant protein abnormalities (53), telomerase reverse transcriptase (TERT) mutations and telomere length (54), but not all of them have been investigated in cohorts containing of RA patients.

RA-ILD and IPF have many similarities in terms of their histopathology and epidemiology, thus raising questions about whether these two fibrotic lung diseases could have a similar genetic background. The recent study of Juge et al. performed whole exome sequencing on 101 patients with RA-ILD (55). Restricting their analysis to nine genes linked to familial pulmonary fibrosis (FPF), they found mutations in the TERT, RTEL1, PARN or SFTPC coding regions in 11.9% of patients with RA-ILD. Patients with mutations in the TERT, RTEL1 or PARN genes were also found to have short telomeres in their peripheral blood leukocytes, suggesting that these mutations were biologically relevant, although the findings will still need to be confirmed in the future. These results suggest shared genetic risk factors in RA-ILD and FPF (55).

2.6.2 Citrullination and autoimmune response

Citrullination is a post-translational modification of proteins in which arginine is converted to citrulline, resulting in a change in the structure of the protein and an increase in its immunogenicity. Several diseases including IPF have been associated with abnormal citrullination of peptides (22). Protein citrullination leads to the production of anticitrullinated protein antibodies (ACPA), which are commonly present in patients with RA and can be detected in the serum for several years before clinical disease onset (56).

High titers of ACPAs in patients with RA have been shown to be associated with an increased risk of ILD in several different studies (50,57,58), but this association was not detected in one publication (59).

ACPAs are thought to cause synovial inflammation through the deposition of immune complexes and targeting of citrullinated synovial proteins such as vimentin, filaggrin and fibronectin (22). As is the case in other ILDs, protein citrullination promotes autoimmune responses that further contribute to tissue damage through inflammatory responses characterized by cellular infiltration and the release of selected cytokines, chemokines and

Rheumatoid arthritis-associated interstitial lung disease : assessment of the factors associated with the course of the disease

uef.fi

Dissertations in Health Sciences

HANNA NURMI

RHEUMATOID ARTHRITIS-ASSOCIATED INTERSTITIAL LUNG DISEASE – ASSESSMENT OF THE FACTORS ASSOCIATED WITH THE COURSE OF THE DISEASE

HANNA NURMI

Rheumatoid Arthritis-associated

Interstitial Lung Disease – Assessment of the factors associated with the course of the

disease

Rheumatoid Arthritis-associated

Interstitial Lung Disease – Assessment of the factors associated with the course of the

disease

Acknowledgements

List of the original publications

Contents

Abbreviations

1 Introduction

2 Review of the literature