Dissertations in Health Sciences - UEF · Interstitial lung disease (ILD) is one of the most common...

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uef.fi

PUBLICATIONS OF THE UNIVERSITY OF EASTERN FINLAND

Dissertations in Health Sciences

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



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

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

To be presented by permission of the Faculty of Health Sciences, University of Eastern Finland

for public examination in Kuopio, on Friday, June 8th, 2018, at 12 noon.

Publications of the University of Eastern Finland


Number 458

Department of Respiratory Medicine, Institute of Clinical Medicine, School of Medicine, Faculty

of Health Sciences, University of Eastern Finland

Kuopio

2018

Grano Oy

Jyväskylä, 2018

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


Professor Kai Kaarniranta, M.D., Ph.D.

Institute of Clinical Medicine, Ophthalmology


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

A.I. Virtanen Institute for Molecular Sciences


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

School of Pharmacy


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

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

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.

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

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.

VI

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

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.

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

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

VIII

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

IX

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

Ja mielen vapaus, ja mielen vapaus”

Vexi Salmi

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.

XII

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

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.

XV

Contents

1 INTRODUCTION ................................................................................................................... 1

2 REVIEW OF THE LITERATURE .......................................................................................... 3

2.1 RHEUMATOID ARTHRITIS ........................................................................................ 3

2.2 INTERSTITIAL LUNG DISEASES ............................................................................... 3

2.3 EXTRA-ARTICULAR MANIFESTATIONS IN RA ................................................... 4

2.4 OVERVIEW OF RA-ILD ................................................................................................ 5

2.4.1 History ................................................................................................................... 5

2.4.2 Definition .............................................................................................................. 5

2.5 EPIDEMIOLOGY ............................................................................................................ 6

2.6 PATHOPHYSIOLOGY AND RISK FACTORS........................................................... 9

2.6.1 Genetics ................................................................................................................. 9

2.6.2 Citrullination and autoimmune response ........................................................ 9

2.6.3 Smoking and other patient-dependent risks ................................................. 11

2.6.4 Factors relating severity of RA ......................................................................... 12

2.6.5 Other potential biomarkers for RA-ILD ......................................................... 12

2.7 CLINICAL FEATURES ................................................................................................ 14

2.7.1 Symptoms and clinical findings ...................................................................... 14

2.7.2 PFT and chest radiography .............................................................................. 14

2.7.3 Bronchoalveolar lavage ..................................................................................... 14

2.8 CLASSIFICATION OF RA-ILD .................................................................................. 15

2.9 DIAGNOSTICS ............................................................................................................. 16

2.9.1 HRCT ................................................................................................................... 16

2.9.2 The radiological features of the RA-ILD subtypes ........................................ 16

2.9.3 The histological features of most common RA-ILD subtypes..................... 18

2.9.4 The role of surgical lung biopsy ...................................................................... 19

2.10 THE COURSE OF THE DISEASE ............................................................................... 19

2.10.1 Disease progression ........................................................................................... 19

2.10.2 RA-ILD and prognosis ...................................................................................... 20

2.10.3 Acute exacerbations ........................................................................................... 20

2.11 ASSESSMENT OF PROGNOSIS ................................................................................. 21

2.11.1 Radiological predictors of mortality ............................................................... 21

2.11.2 Histopathological predictors of mortality ...................................................... 22

2.11.3 Pulmonary function tests, 6MWT and prognosis ......................................... 22

2.11.4 Patient- and RA-related predictors of mortality ........................................... 22

2.12 THE RISK PREDICTION MODELS IN ILDS ........................................................... 23

2.13 COMORBIDITIES ......................................................................................................... 25

2.13.1 Comorbidities in RA-ILD.................................................................................. 25

2.13.2 Comorbidities in RA .......................................................................................... 25

2.14 CAUSES OF DEATH .................................................................................................... 25

2.15 TREATMENT ................................................................................................................ 25

2.15.1 Whom and how to treat? .................................................................................. 25

2.15.2 Immunosuppressive agents ............................................................................. 27

XVI

2.15.3 Synthetic disease modifying antirheumatic drugs (DMARDs) .................. 27

2.15.4 Biologic agents ................................................................................................... 27

2.15.1 Pulmonary rehabilitation ................................................................................. 29

2.15.2 Lung transplantation ......................................................................................... 30

2.15.3 Antifibrotic drugs .............................................................................................. 30

2.15.4 Treatment of RA-ILD exacerbation ................................................................. 30

2.15.5 Other treatments ................................................................................................ 30

2.15.6 Palliative care ..................................................................................................... 31

3 AIMS OF THE STUDY ......................................................................................................... 33

4 MATERIAL AND METHODS ........................................................................................... 34

4.1 DATA SOURCES AND PATIENT SELECTION ..................................................... 34

4.2 GATHERING OF DEMOGRAPHIC INFORMATION (I, II, III) ........................... 35

4.3 RADIOLOGICAL EVALUATION ............................................................................. 36

4.3.1 Re-classification of HRCTs (I, II, III) ............................................................... 36

4.3.2 Further interpretation of the CTs and the scoring system (III) ................... 36

4.4 STAGING SYSTEMS (II) .............................................................................................. 36

4.5 STATISTICAL ANALYSIS .......................................................................................... 37

4.6 ETHICAL CONSIDERATIONS .................................................................................. 38

5 RESULTS ................................................................................................................................. 39

5.1 PATIENT CHARACTERISTICS ................................................................................. 39

5.1.1 Demographics .................................................................................................... 39

5.1.2 Medication for RA ............................................................................................. 39

5.1.3 PFT ....................................................................................................................... 39

5.1.4 Radiological subtypes ....................................................................................... 39

5.1.5 GAP and ILD-GAP (II) ...................................................................................... 39

5.1.6 Comparison of the demographics in UIP and non-UIP patients (I) ........... 40

5.1.7 Comparisons within RA-UIP subgroup ......................................................... 40

5.2 RADIOLOGICAL FINDINGS ..................................................................................... 42

5.2.1 Disease progression ........................................................................................... 42

5.2.2 Inter-observer agreement (III) .......................................................................... 42

5.2.3 The HRCT findings in different subtypes (III) .............................................. 42

5.2.4 Original radiological reports ............................................................................ 42

5.3 HISTOLOGICAL DATA AND BAL .......................................................................... 46

5.4 COMORBIDITIES (I) .................................................................................................... 46

5.5 CAUSES OF DEATHS (I)............................................................................................. 47

5.6 CORRELATIONS BETWEEN CLINICAL DATA, PFT AND RADIOLOGY (III)47

5.7 THE COURSE OF THE DISEASE .............................................................................. 48

5.7.1 Differences between RA-UIP and non-UIP patients (I) ............................... 48

5.7.2 Survival (I, II) ..................................................................................................... 48

5.7.3 Predictors of mortality (II, III) .......................................................................... 50

5.8 VALIDATION OF THE GAP AND ILD-GAP MODELS (II) ................................. 50

6 DISCUSSION ........................................................................................................................ 52

6.1 GENERAL DISCUSSION OF THE STUDY DESIGN .............................................. 52

6.1.1 Search for the patients and sample size ......................................................... 52

6.1.2 Data gathering and missing data .................................................................... 53

6.1.3 Implication of the RA medication ................................................................... 53

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6.1.4 Diagnostics .......................................................................................................... 53

6.1.5 Reliability of the radiological re-categorization ............................................ 54

6.2 CLINICAL FEATURES OF THE COHORT .............................................................. 54

6.2.1 Subject characteristics and PFT ........................................................................ 54

6.2.2 Radiological features and their correlation to RA duration (III) ................ 54

6.2.3 BAL results .......................................................................................................... 55

6.2.4 Original radiological reports ............................................................................ 55

6.2.5 Disease course in UIP and non-UIP patients (I) ............................................ 55

6.3 COMORBIDITIES AND CAUSES OF DEATHS (I) ................................................. 56

6.4 SURVIVAL (I) ................................................................................................................ 57

6.5 PREDICTORS OF MORTALITY (II, III) .................................................................... 57

6.5.1 Pulmonary function tests and CPI .................................................................. 57

6.5.2 Clinical factors .................................................................................................... 57

6.5.3 Radiological factors associating with decreased survival ........................... 58

6.6 VALIDATION OF THE GAP AND ILD-GAP MODELS (II) ................................. 58

6.7 FUTURE PERSPECTIVES ............................................................................................ 59

7 CONCLUSIONS .................................................................................................................... 61

8 REFERENCES ......................................................................................................................... 62

XIX

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


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

XX

IIP Idiopathic interstitial

pneumonias

IL Interleukin

ILD Interstitial lung disease

iNSIP Idiopathic nonspecific


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

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

2

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.

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.

4

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.

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).

6

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.

7

Table

3.

Sum

mary

of

stu

die

s in

vestigating th

e pre

vale

nce and/o

r in

cid

ence of

RA

-ILD

in

diffe

rent

stu

dy popula

tions usin

g diffe

rent

dia

gnostic

meth

ods.

Stu

dy,

year

Nu

mb

er

of

the

pati

en

ts

Du

rati

on

of

RA

Meth

od

P

revale

nce o

f R

A-I

LD

In

cid

en

ce

Sym

pto

ms

Walk

er,

1969

(26)

516

Not

report

ed

Chest

X-r

ay

1.6

%

- N

ot

cle

arl

y

report

ed

Fra

nk,

1973

(36)

41

Not

report

ed

DLCO

41.4

%

- “U

sually n

ot

sym

pto

matic”

Suzuki, 1

994

(8)

81

13.7

± 1

1.0

Auto

psy

34.6

%

- N

ot

report

ed

Saag,

1996

(42)

336

Not

report

ed

Chest

X-r

ay a

nd P

FT

Chest

X-r

ay a

bnorm

ality

12%

. FVC <

80%

% p

red.

12.5

%,

DLCO

<80%

%pre

d.

19.0

%,

any o

f th

e a

bove 3

2.4

%

- N

ot

report

ed

Gabbay,

1997

(7)

36

< 2

years

Chest

X-r

ay,

HRCT,

PFT,

BAL a

nd/o

r 99Tc-D

TPA s

can

Abnorm

alities in 5

8%

(one o

r m

ore

investigations),

22%

PFT,

6%

X-r

ay,

33%

HR

CT.

- 14%

Daw

son,

2001

(39)

150

8 ±

12.7

H

RCT

18.7

%

- 71.4

% d

yspnoea,

46.4

% p

roductive

cough

Ture

sson,

2003

(5)

609

Not

report

ed

Clinic

al ju

dgem

ent

and

decre

ased V

C o

r D

LCO

by

15%

fro

m n

orm

al

- 30-y

ear

cum

ula

tive

incid

ence 6

.8%

Not

report

ed

Bilgic

i, 2

005

(41)

54

8.4

± 8

.2

HRCT

67

.3%

-

42.6

%

sym

pto

matic

Mori

, 2008

(43)

126

65 <

1 y

ear,

61 >

3 y

ears

H

RCT

11.9

%

- 23.8

%

sym

pto

matic

Bongart

z,

2010

(4)

582

not

report

ed

Pro

bable

ILD

= X

-ray +

treating p

hysic

ian´s

dia

gnosis

of IL

D.

Definite I

LD

= D

iagnosis

of

ILD

by a

pulm

onolo

gis

t +

2/3

of fo

llow

ing:

ILD

on C

T /

x-r

ay,

restr

ictive P

FT, bio

psy

confirm

ation

4.0

% d

efinite,

7.9

% d

efinite +

pro

bable

10-,

20-

and

30-

year

cum

ula

tive

incid

ences

3.5

%,

6.3

%

and 7

.7%

not

report

ed

Koduri

, 2010

(37)

1460

<2 y

ears

H

RCT

2.9

%

Annual

incid

ence

4.1

/1000,

15-

year

cum

ula

tive

incid

ence 6

.3%

All s

ym

pto

matic

8

Habib

, 2011

(34)

40

<2 y

ears

H

RCT a

nd/o

r PFT

Abnorm

al H

RCT 2

7.5

%,

abnorm

al PFT 3

2.5

%,

abnorm

al

PFT a

nd H

RCT 2

0%

, abnorm

al PFT a

nd H

RCT w

ith

sym

pto

ms 1

0%

- 90%

asym

pto

matic

Ols

on,

2011

(10)

>162 0

00

Not

report

ed

ICD

-9 a

nd I

CD

-10 c

odes

6.8

% in w

om

en,

9.5

% in m

en

- N

ot

report

ed

Restr

epo,

2015

(44)

779

12.6

± 1

0.8

Chest

X-r

ay,

CT,

HRCT o

r

lung b

iopsy

8.8

%

- All s

ym

pto

matic

Zhang,

2017

(35)

550

8 ±

9 (

range

2 w

eeks –

40 y

ears

)

HRCT

43.1

%

-

41%

sym

pto

matic

of patients

with

HRCT c

hanges

DLCO

= d

iffu

sio

n c

apacity t

o c

arb

on m

onoxid

e;

HRCT =

hig

h-r

esolu

tion c

om

pute

d t

om

ogra

phy;

PFT =

pulm

onary

function t

ests

;

BAL =

bro

nchoalv

eola

r la

vage;

VC

= v

ital capacity;

FVC =

forc

ed v

ital capacity;

RA =

rheum

ato

id a

rthri

tis;

ILD

= inte

rstitial lu

ng d

isease;

99Tc-D

TPA

scan =

technetium

-99-m

-labelled d

ieth

yle

netr

iam

ine p

enta

aceta

te s

can;

ICD

= inte

rnational cla

ssific

ation o

f dis

eases.

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

10

growth factors, such as tumor necrosis factor (TNF), vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF) and interleukins (IL). These influence the differentiation and proliferation of fibroblasts, increased synthesis and deposition of extracellular matrix, as well as increased activity of matrix metalloproteinases resulting in ILD (60,61) (Figure 2).

In a recent study, tissue samples were obtained from lung and synovial biopsies of RA patients and identical citrullinated protein contents were found in both specimens (62). Some investigators have suggested that RA begins in the lungs, by descripting cohorts of ACPA positive patients with lung disease without RA, some of whom developed articular disease afterwards (63,64). However, the initiation point of the autoimmunity process in RA has also been suggested as being in the oral mucosa or gastrointestinal system (65).

Figure 2. Schematic illustration of the concepts in the pathogenesis of RA-ILD. Original figure

reproduced from the review article of Shaw et al (60), with permission of the © ERS 2015

(European Respiratory Review Mar 2015, 24 (135) 1-16; DOI: 10.1183/09059180.00008014).

RA-ILD = rheumatoid arthritis-associated interstitial lung disease; HLA = human leukocyte

antigen; ECM = extracellular matrix; MMP = metalloproteinases; TNF = tumor necrosis factor;

VEGF = vascular endothelial growth factor; PDGF = platelet derived growth factor; IL =

interleukins; CCP = anti-cyclic citrullinated peptide.

11

2.6.3 Smoking and other patient-dependent risks Smoking has been shown to promote citrullination of lung proteins, thus leading to the appearance of ACPAs (66,67). Moreover, the risk of developing ACPAs is increased in heavy smokers carrying at least one copy of the HLA-DRB1 SE alleles (68). Thus, it seems that smoking, the HLA-DRB1 SE and ACPAs interact to increase the risk of RA (44,68). The exact relationship between tobacco smoke and the development of RA-ILD is unknown but a dual effect has been proposed, with one explanation being the above-mentioned smoking-induced protein citrullination in the lungs and the subsequent ACPA-promoted lung injury and another pathway being the independent elevated risk of lung injury and fibrosis caused by smoking (69) (Figure 3).

Smoking has associated with RA (70), its severity (71), RA-ILD (42,71-73) as well as other ExRAs (21), in many studies. However, the development of ILD does not require smoke exposure but can also be encountered in lifelong non-smokers (74).

Higher risks for the ILD development associating with male sex (7,73,75) and aging (37,73,76) have been confirmed in many studies (Table 4). In the study of Koduri et al. the likelihood of having ILD increased by 64% for every 10-year increase in age (37). In another study, more than a four-fold risk of ILD was detected in patients over 65 years (50).

Figure 3. Schematic illustration of the dual role of smoking in the pathogenesis of RA-ILD.

Original figure adapted and modified from review article of Johnson et al. 2017 (69). ACPA =

anticitrullinated protein antibodies; HLA-DRB = human leukocyte antigen-D-related beta alleles;

SE = shared epitope; RA-ILD = rheumatoid arthritis-associated interstitial lung disease.

12

2.6.4 Factors relating severity of RA Different kinds of measurements have revealed that the RA severity is related to the development of RA-ILD (45). High disease activity and extensive disability within the first 2 years after RA diagnosis were shown to predict subsequent development of severe ExRA (77). Similarly, the presences of erosive joint disease and/or rheumatoid nodules, as well as high levels of erythrocyte sedimentation rate (ESR) have been identified as risk factors for the development of ILD (4,37). Commonly used scores, such as “disease activity score in 28 joints” (DAS28) and “Health Assessment Questionnaire Disability Index score” (HAQ-DI) are also associated with RA-ILD (37,42,44).

There is also some evidence that high levels of circulating RF increase the risk of ILD development in RA, as well as the risk of other ExRAs (78-80). The explanation or exact mechanism for this association is unclear but might be due to the formation of circulating immune complexes (60). However, the interpretation of the RF titer is challenging, since e.g. tobacco smoking can increase RF serum titer in the general population as well as in patients with RA (81,82).

2.6.5 Other potential biomarkers for RA-ILD A study by Harlow et al. described citrullinated versions of Heat Shock Protein 90 isoforms as potential biomarkers for RA-ILD (83). The levels of Krebs von den Lungen (KL-6) have been shown to correlate with the severity of CT findings in RA-ILD (84). Previously Oyama et al reported that an increase in serum KL-6 levels in RA associated with the presence of active interstitial pneumonitis (85). Moreover, elevated KL-6 levels have been claimed to associate with the presence of pulmonary fibrosis in patients with systemic sclerosis (SSc) (86), although they can also be present in IIPs, hypersensitivity pneumonitis, radiation pneumonitis and Pneumocystis jirovecii pneumonia (86).

In a quite recent study, multiplex enzyme-linked immunosorbent assays (ELISAs) and Luminex xMAP technology were used to assess 36 cytokines/chemokines, matrix metalloproteinases (MMPs) and acute-phase proteins in two different cohorts. In this study, levels of MMP-7 and interferon-γ-inducible protein 10 (IP-10)/CXCL10 were elevated in the serum of RA patients with ILD, versus RA patients without ILD (87).

13

Table

4.

Diffe

rent

risk f

acto

rs a

ssocia

ted w

ith inte

rstitial lu

ng d

isease r

ela

ted t

o r

heum

ato

id a

rthri

tis (

RA).

Table

part

ly a

dapte

d a

nd e

xte

nded f

rom

the r

evie

w a

rtic

le o

f C.

Johnson (

69).

C

lin

ical

facto

rs

Stu

dy (

first

au

thor)

n

Ag

e

Male

sex

Late

r

on

set

RA

RA

du

rati

on

RF

tite

r

AC

PA

s

DA

S-

28

HLA

-

DR

B1

SE

Cig

arett

e

sm

okin

g

HA

Q-D

I

score

Hig

h

ES

R

Tu

mo

ur

markers

Kelly (

73)

230

+

+

+

+

+

Restr

epo (

44)

779

+

+

+

+

+

+

+

+

+

Bongart

z (

4)

582

+

+

+

Koduri

(37)

1460

+

+

+

Wang (

88)

544

+

+

+

+

+

+

+

Wang (

89)

41

+

Song (

90)

116

+

+

+

+

+

Mori

(50)

356

+

+

+

+

Akiy

am

a (

91)

395

+

+

+

+

+

Doyle

(72)

113

+

+

+

+

+

Rocha-M

unoz (

92)

81

+

+

+

+

Wang (

93)

111

+

+

Saag (

42)

336

+

+

+

+

RA =

rheum

ato

id a

rthri

tis;

RF =

rheum

ato

id f

acto

r; A

CPAs =

anticitru

llin

ate

d p

rote

in a

ntibodie

s;

DAS-2

8 =

dis

ease a

ctivity s

core

in 2

8 j

oin

ts;

HLA

DRB1 S

E =

hum

an l

eucocyte

antigen D

RB1 s

hare

d e

pitope;

HAQ

-DI

= H

ealth A

ssessm

ent

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14

2.7 CLINICAL FEATURES

RA-ILD most commonly occurs in patients in their late 50s to 60s (94,95). The onset of ILD has been shown to appear at an average of 10 years after RA diagnosis (94,96). ILD may, however, precede the development of arthritis in RA, as was the case in 10 out of 111 patients (9.0%) initially diagnosed as IPF (97). Others have reported ILD predating the articular disease in approximately 10-17% of the patients (73,96), and the time interval from ILD to RA diagnosis has varied from 6 months to 8 years (96,97).

2.7.1 Symptoms and clinical findings Many patients with RA display no respiratory symptoms despite the presence of radiographic or PFT abnormalities. In a study of 52 RA patients, HRCT abnormalities were observed in almost 70% of the patients of whom only 40% experienced respiratory symptoms (41). In another study, approximately one-third of asymptomatic patients with RA had interstitial lung changes in their CT scan, and of those, more than half progressed within 2 years (6).

Even though some of the patients are asymptomatic, many patients suffer from shortness of breath during exercise or cough, which is commonly dry and insidious (48,98). Once present, the symptoms usually progress over time. Less common respiratory symptoms include chest tightness/pain, wheezing and sputum secretion. In addition, fatigue or generalized weakness can also be seen (98,99). In particular, dyspnoea on exertion can be difficult to notice in patients whose joint disease limits exercising.

Common physical examination findings include bi-basilar crackles, which are present in most of the patients (17). Finger clubbing can also be seen, but not as frequently as in IPF patients (100). Hypoxemia can be seen either during exercise, for example using the 6-minute walking test (6MWT), or also at rest in the advanced cases (9,22,101).

2.7.2 PFT and chest radiography In the majority of the patients, spirometry usually demonstrates a restrictive defect with a lowered forced vital capacity (FVC), although the spirometry can also be completely normal, especially in the early stage of the disease. Decreased DLCO has been reported to be the most sensitive test for predicting the presence of ILD on HRCT (39) as well as predicting the extent of disease (102); this has been detected in up to 25-60% of asymptomatic RA patients (7,39).

The chest X-ray is often normal in patients with early RA-ILD and has a low sensitivity for detection of ILD since more than 50% of patients with a normal chest X-ray will have abnormalities visible in their HRCT (7,39). When present, the common X- ray changes are reticular, reticulonodular or honeycomb changes, mainly in the basal area of the lungs (17).

2.7.3 Bronchoalveolar lavage BAL is not routinely performed in RA-ILD patients as BAL patterns are nonspecific and abnormalities in BAL can be present also in the absence of ILD (103). Increased concentrations of neutrophils, eosinophils and lymphocytes, as well as a decreased CD4/CD8 ratio have been described in RA-ILD patients (7,96,104,105). RA patients with advanced interstitial lung disease on HRCT have been shown to have significantly higher BAL fluid cellular concentrations as their counterparts with mild or no ILD changes (105). Some investigators have found an increased cellularity in BAL compared to healthy controls but not when compared to RA patients without ILD (106). Another report investigated 24 RA patients; nine with significant ILD with symptoms showed increased

15

percentages of neutrophilia, five asymptomatic patients with evidence of ILD showed elevated BAL lymphocyte numbers, whereas those without any evidence of ILD had normal BAL (104). In the study of Gabbay et al 29 out of 36 recent onset RA-patients underwent a BAL and of those 52% showed elevations in the numbers of neutrophils, eosinophils and/or lymphocytes (7). Moreover, an abnormal cell profile in BAL was present in all clinically significant RA-ILD patients, whereas 10 out of 13 subclinical cases and none of 11 RA patients without evidence of ILD displayed any signs of BAL pathology (7).

The results of BAL analysis may have a modest ability to distinguish between the different subtypes of ILD, as a slight neutrophilia may be more frequent in usual interstitial pneumonia (UIP) while lymphocytosis is more common in non-specific interstitial pneumonia (NSIP) and organizing pneumonia (OP) (75), but convincing studies are lacking which would have correlated BAL findings with HRCT patterns of disease (107).

As most of the RA patients are immunosuppressed because of the RA medication, they experience an increased risk of developing various infections. Thus, the most useful role of BAL in clinical practice is in patients with an acute/subacute respiratory worsening when the clinician needs to rule out the appearance of an opportunistic infection (45,75). Moreover, a significant eosinophilia in BAL could suggest a drug reaction rather than ILD (108)

2.8 CLASSIFICATION OF RA-ILD

The subtypes of RA-ILD have been categorized according to the subdivisions of the IIPs. Since 2002, the IIPs have been classified into seven different entities according to the ATS/ERS International Multidisciplinary Consensus Classification of the IIPs (18) and the guidelines were updated in 2013 (20). In the updated IIP Consensus Classification, the previously used term “cryptogenic fibrosing alveolitis” was removed and the different entities are categorized as the major, rare and unclassifiable IIPs. The major IIPs can further be categorized as chronic fibrosing IIPs, smoking-related IIPs and acute/subacute IIPs (Table 5).

Of these IIP patterns, UIP, NSIP, OP and diffuse alveolar damage (DAD) are the most commonly observed patterns in RA-ILD, but respiratory bronchiolitis (RB), lymphocytic interstitial pneumonia (LIP) and desquamative interstitial pneumonia (DIP) are also possible, although rare (109). Unlike the situation in other CTDs, the most common radiologic and histopathologic pattern of RA-ILD is UIP (31,96,101,110,111).

Table 5. Categorization of major idiopathic interstitial pneumonias according to the ATS/ERS

updated International Multidisciplinary Classification (20).

Category Radiologic and/or histologic pattern Multidisciplinary diagnosis

Chronic fibrosing Usual interstitial pneumonia (UIP)

Nonspecific interstitial pneumonia (NSIP)

Idiopathic pulmonary fibrosis (IPF)

Idiopathic nonspecific interstitial

pneumonia (iNSIP)

Smoking-related Respiratory bronchiolitis (RB)

Desquamative interstitial pneumonia (DIP)

Respiratory bronchiolitis-interstitial lung

disease (RB-ILD)

Desquamative interstitial pneumonia

(DIP)

Acute/subacute Organizing pneumonia (OP)

Diffuse alveolar damage (DAD)

Cryptogenic organizing pneumonia (COP)

Acute interstitial pneumonia (AIP)

16

2.9 DIAGNOSTICS

2.9.1 HRCT The development of HRCT techniques has reduced the need for lung biopsies and the diagnostics of RA-ILD is nowadays mainly performed radiologically. According to the official diagnostic criteria, IPF can be diagnosed without biopsy in the presence of a typical HRCT pattern, i.e. “definite UIP”, the characteristics of which are shown in table 6. Similar criteria are used in RA-UIP diagnosis due to the lack of its own criteria (32).

A good correlation between histopathological and radiological features has been previously observed and a definite UIP pattern in HRCT has been demonstrated to be a sensitive and specific technique for detecting the histopathologic UIP pattern in both IPF and RA-ILD (112-115). For example, Hozumi et al showed that the specificity and sensitivity of HRCT for the histological UIP pattern were 100% and 41.7%, respectively (116). In another study conducted by Assayag et al. the definite UIP pattern in HRCT was highly predictive of the histological UIP pattern, having a 96% specificity and a 45% sensitivity (113). Thus, HRCT provides a useful non-invasive tool for diagnosing RA-ILD patients, especially those with a definite UIP pattern.

A multidisciplinary discussion (MDD) between pulmonologists, radiologists and pathologists increases the accuracy of the diagnosis and is recommended as a part of the diagnostic work in ILDs (117). The group of experts is recommended to include also a rheumatologist when handling the CTD-ILD cases.

Table 6. The radiological criteria of UIP pattern according to the ATS/ERS/Japanese Respiratory

Society (JRS)/Latin American Thoracic Association (ALAT) guidelines 2011 (32).

UIP = usual interstitial pneumonia.

Definite UIP Possible UIP Not UIP

Subpleural basal predominance Subpleural basal predominance Upper- or mid lung predominance

Reticular abnormalities Reticular abnormalities Peribronchovascular predominance

Honeycombing with or without

traction bronchiectasis

No inconsistent findings

(column 3)

Severe ground glass opacities (ground

glass pattern > reticulation)

No inconsistent findings (column 3) Profuse micronodules

Cysts (other than honeycombing)

Mosaic-attenuation pattern/air

trapping

Consolidation

2.9.2 The radiological features of the RA-ILD subtypes The typical radiological features of the most common RA-ILD subtypes are shown in Table 7 and Figure 4. The UIP pattern occurs in 40-62% of the patients with RA-ILD (48). As described above, the distribution of UIP on HRCT is typically basal and peripheral, often also patchy. UIP is characterized by the presence of reticular opacities, which often are associated with traction bronchiectasis. Honeycombing is common and essential for making a definite diagnosis.

17

Ground-glass opacities (GGO) are also common, but usually less extensive than the reticulation (Figure 4a) (32).

Table 7. Prevalences and radiological features of the four most common RA-ILD subtypes.

Adapted and modified from review articles of Cavagna et al (75) and Lake & Proudman 2014

(22).

GGO = ground-glass opacities.

The NSIP pattern, comprising 11-38% of the RA-ILD cases (48), is characterized by basilar bilateral predominant GGO, reticulation with or without traction bronchiectasis, little or no architectural distortion or honeycombing and often a subpleural sparing distribution (Figure 4b) (31,118,119). Sometimes, the features are less typical and can overlap with the UIP pattern (120).

The characteristic radiological findings of OP pattern, which is clearly less common than UIP and NSIP, covering approximately 0-11% of RA-ILDs (22), include patchy, peripheral and often migratory consolidations, nodules and sometimes a central GGO surrounded by a ring shaped denser airspace consolidation, also called as the atoll sign/reversed halo sign (Figure 4c) (22,121-123).

DAD pattern is the fourth commonest, although rare, RA-ILD subtype and its typical radiological appearance in the early phases includes patchy or diffuse ground glass changes with basal consolidation and a rapid progression (Figure 4d) (22,124). Later, the DAD appearance can change to the organizing stage associated with distortion of bronchovascular bundles and traction bronchiectasis (20).

The rest of the subtypes are rare in RA-ILD patients (37,96,101,111). The CT findings of smoking-related RB include centrilobular nodules, patchy ground glass attenuation, and thickening of the walls of central and peripheral airways (125). These findings can be reversible if the patient stops smoking or is treated with corticosteroids (18). In all cases of DIP, the lower zone distributed GGO is present on CT (126). Irregular linear opacities and a reticular pattern are frequent but not extensive and usually present only in the basal parts. Honeycombing can also be seen in less than one-third of cases, and usually is quite limited in extent (18,126). Finally, the dominant CT finding of LIP is usually GGO, but perivascular cysts or perivascular honeycombing can also be observed and a reticular abnormality is seen in about half of the patients (127).

Prevalence Radiological pattern

Usual interstitial pneumonia (UIP) ++++ Subpleural, peripheral, basal predominance,

reticulation, honeycombing with or without traction

bronchiectasis, architectural distortion, less diffuse

GGO, absence of inconsistent features

Nonspecific interstitial pneumonia

(NSIP)

+++ Bilateral GGO, possible reticulation, may have

traction bronchiectasis, little or no honeycombing,

often subpleural sparing

Organizing pneumonia (OP) ++ Patchy multiple peripheral consolidations, subpleural

and peribronchial, often migratory, air bronchograms

can be seen

Diffuse alveolar damage (DAD) + Patchy or diffuse ground glass changes with basal

consolidation, rapid progression

18

Figure 4. Representative high-resolution computed tomography (HRCT) images from the

subjects with rheumatoid arthritis- associated interstitial lung disease. A) 64-year-old female

with fibrotic changes of usual interstitial pattern (UIP) pattern in basal and subpleural

predominance, traction bronchiectasis and honeycombing. B) 69-year-old male revealing

peripheral ground glass opacity and typical subpleural sparing representing the nonspecific

interstitial pneumonia (NSIP) pattern. C) 55-year-old female showing evidence of bilateral

peribronchovascular and peripheral patchy consolidations typical for organizing pneumonia

(OP). D) 59-year-old male patient with diffuse alveolar damage (DAD) shows diffuse ground

glass opacity, reticulation and traction bronchiectasis.

2.9.3 The histological features of most common RA-ILD subtypes In patients who undergo a lung biopsy, the criteria of IPF, i.e. a definite UIP pattern, are applied in RA-ILD patients. They include marked fibrosis / architectural distortion with or without honeycombing, predominantly subpleural / paraseptal distribution, patchy involvement of lung parenchyma by fibrosis and presence of fibroblast foci in the absence of features suggesting alternative diagnosis (32).

The histopathological diagnostics of other RA-ILD subtypes are made using the consensus classification of IIPs (18). Accordingly, histological features of NSIP can show either cellular (cNSIP) or fibrosing (fNSIP) patterns the first showing primarily chronic inflammation and the latter usually homogenous interstitial fibrosis lacking the UIP features. The typical histological features of OP are patches involving alveolar ducts and alveoli with the preservation of lung architecture, mild interstitial inflammation and a uniform temporal appearance. The histopathological appearance of DAD contains alveolar

19

septal thickening due to organizing fibrosis, airspace consolidation and hyaline membranes with the features being uniform temporal appearance and diffuse (18).

2.9.4 The role of lung surgical biopsy As the traditional bronchoscopic transbronchial forceps lung biopsy (TBB) has only sensitivity for UIP detection of 30% (128), the golden standard for the classification or diagnosis of an IIP subtype has historically been a surgical lung biopsy (SLB) (9), although nowadays HRCT has reduced its necessity. Even though it is recommended in non-definite UIP cases, its utilization has significantly declined and most patients do not undergo SLB due to the risks associated with it, as well as due to the adoption of MDD and clinical-radiologic criteria for definitive diagnosis of IPF (129). The most feared feature of SLB is the mortality which is reported to be 1.5% for elective and 16% for non-elective procedures (130). There is evidence that the high mortality is particularly present in patients with IPF i.e. with the UIP pattern (131). Acute exacerbations (AE) are partly responsible for the mortality. Kondoh et al. observed AEs in 2.1% of the 236 ILD patients who underwent a surgical biopsy (132). In a retrospective analysis of 10 patients with AE (6 idiopathic NSIP (iNSIP), 3 RA-UIP, 1 SSc-ILD), eight of them had undergone SLB prior to AE and in two of them the AE occurred shortly after the SLB and thus was thought to be induced by the SLB (133). It is suggested that a higher risk of AE is associated with a lower baseline DLCO and lower vital capacity and that the risk of AE is increased in patients who exhibited AE signs and symptoms prior to biopsy (134). If a biopsy is to be performed, the preferred method is video-assisted thoracoscopic surgery (VATS), rather than open-lung biopsy (75).

Nowadays, in some centers, a new diagnostic method has become available, namely transbronchial cryobiopsy (TBCx), in which the sample size is much larger than in standard TBBs (135). One study compared TBCx and SLB in a series of 117 IPF-patients (58 TBCx, 59 SLB) with fibrotic and not definite UIP on HRCT and observed a major increase in diagnostic confidence after TBCx, similar to SLB, highlighting the usefulness of TBCx in the diagnostics (136). The mortality from cryobiopsy is significantly less (0.1%) (137) than that for SLB (130) and moreover, a decreased length of hospital stay and less adverse events such as persistent fever, prolonged air leak and acute exacerbation of ILD have been reported in TBCx compared to SLB (137). Some risks are, however, attached also to TBCx, the most common of which are pneumothorax (10-20%) and mild-to-moderate bleeding (4-12%) (135,137).

2.10 THE COURSE OF THE DISEASE

2.10.1 Disease progression Retrospective studies on the natural course of RA-ILD have revealed a variable clinical course, with some patients having a stable or slowly progressive course for a decade, and others having a fulminant course with death less than six months after the onset of respiratory symptoms (11). For example, in a small study cohort (28 RA-ILD patients) of Fujii et al, 57% of patients had no change in HRCT after a 1 year of follow-up, whereas nine patients had progressed and three improved (138). In a study of initially asymptomatic early RA-ILD patients, over 50% had a radiological disease progression on HRCT during a mean follow-up of 1.5 years (6). In another study, 34% of patients progressed radiographically over the 2-year follow-up and the progressive disease was more commonly associated with reticular abnormalities than with ground glass changes, suggesting that UIP patients have a greater risk of progression (11). In a retrospective study of 84 RA-UIP patients monitored for 33 months, Song et al. observed 44% of the patients

20

being stable, 33% progressing, 17% deteriorating with an AE and 6% improving during the follow-up (139).

Reduced DLCO, presence of bibasilar crackles and the extent and distribution of HRCT changes have been reported to associate with the disease progression (defined as >15% fall in DLCO) with evidence of increasing fibrosis changes on HRCT or ILD-related death (11). In a very recent retrospective study of 167 RA-ILD patients, the UIP pattern, unlike NSIP, was a risk factor for DLCO worsening. Moreover, a lower baseline DLCO, lower baseline FVC, and higher changes in PFT during the first 6 months increased the risk for progression (140).

2.10.2 RA-ILD and prognosis The available studies demonstrate that patients with RA-ILD have a 3-fold risk of death compared to RA patients without ILD (98). While the overall mortality in RA has declined, the numbers of deaths due to RA-ILD have increased, especially in women and in older aged patients (10). Hakala et al. showed that hospitalization was not that common among RA-ILD patients, but those who were hospitalized because of ILD had a median survival of only 3.5 years (141).

The results of studies investigating survival have, however, been variable and mostly conducted with several types of CTD, and not solely with RA. Several studies have previously observed better survival outcomes in CTD-ILD when compared to the idiopathic ILD subtypes (110,142,143), which might be a consequence of lesser fibroblastic foci observed in CTD-UIP compared to IPF (142). Often studies comparing the survival in CTD-ILD vs. IIP have included patients with SSc, polymyositis and dermatomyositis, in which the most common ILD subtype is NSIP, unlike in RA-ILD, which may influence the results. Some investigators have proposed the prognosis of CTD-ILD to be even worse than that of IPF/IIP after adjusting for age, gender, smoking habit and exposure to oral corticosteroids (144), or adjusting just for age (145).

RA-ILD may be a possible exception to the putative hypothesis of better prognosis of CTD-ILDs compared to IIPs having revealed similar survival rates than IPF, i.e. 2-3 years (4,37), especially in RA-UIP cases (95,110,146). The study of Song et al., however, calculated a median survival of 53 months in RA-UIP versus 41 months in IPF (139). Similarly, in the study of Rajasekaran et al. for example, RA-ILD had a higher median survival (60 vs. 27 months) when compared to identical patterns of IIPs (147) and some studies have described an even better prognosis, with median survival of approximately 6-8 years in patients with RA-ILD (143,148). Overall, the question concerning the prognosis of RA-ILD is controversial and therefore predicting of lifetime of an individual patient is challenging. On average it can be concluded that the median survival ranges between 2.6 and 8 years from the time of RA-ILD diagnosis (4,45,95,146,148).

2.10.3 Acute exacerbations AE has been previously defined as an acute, clinically significant, respiratory deterioration of unidentifiable cause, and has been mostly linked to IPF (32). Recently, an updated definition of AE in IPF was proposed and the exclusion of specific triggers of AE, such as infection, aspiration or drug toxicity, is no longer required (149). AE is characterized by newly developed bilateral GGO and/or consolidations on chest X-ray or CT scans and worsening / development of dyspnoea (150).

AE has also been detected in other ILDs than IPF, including iNSIP, chronic hypersensitivity pneumonitis and CTD-ILD, among which AE is most commonly present in RA-ILD (133,150,151). The one-year cumulative incidence of AE in IPF has been reported to be 9-16% depending on whether infections were included or excluded (152), whereas that of RA-ILD was 2.8% in a study by Hozumi et al (116). In the same study, AE was associated with a high mortality up to 64%, similarly as in IPF, and an older age at ILD diagnosis, the

21

UIP pattern on HRCT and the use of MTX correlated with the development of AE (116). Suda et al. investigated 83 CTD-ILD patients (including 25 RA-ILD); five RA-ILD patients developed AE with a one-year incidence of 2.6% and 75% mortality (151).

2.11 ASSESSMENT OF PROGNOSIS

Most studies investigating the prognostic factors in ILD have focused on IPF, but some studies on RA-ILD have also been published and reviewed quite recently (12). Several factors have been proposed to predict disease progression and survival which can be categorized as patient-specific, RA-specific and ILD-specific variables (Figure 5).

2.11.1 Radiological predictors of mortality A retrospective study of 144 RA-ILD, whose diagnosis was based on either HRCT (n=120) or lung biopsy (n=24), revealed that patients with DAD had the worst prognosis following UIP-patients, whose survival was significantly shorter than that of NSIP-patients (148). Several other investigators have demonstrated that the UIP-pattern on HRCT is associated with worse survival than the NSIP- or non-UIP-patterns (73,95,153).

The extent of the disease has also been shown to be related with increased mortality in RA-ILD with extensive disease (>20% of lung affected) associating with a two-fold relative risk of dying compared with limited disease (73,154,155). Similar results have been observed in SSc-ILD (156), IPF (157,158) and fNSIP (158) as well.

In a study conducted by Walsh et al., 168 patients with CTD-ILD, including 39 patients with RA-ILD were examined, and the extents of honeycombing and severity of traction bronchiectasis were associated with increased mortality (159). The presence and extent of traction bronchiectasis and honeycombing, as well as the presence of reticulation were all significantly associated with worse survival time on bivariate survival analysis of Kim et al. investigating 82 patients with RA-ILD (95).

Figure 5. Predictors of mortality in RA-ILD in the unadjusted analysis. Original figure adapted

and modified from review article of Assayag et al. 2014 (12). RA = rheumatoid arthritis; ILD =

interstitial lung disease; ESR = erythrocyte sedimentation rate; LDH = lactate dehydrogenase;

HAQ DI = Health-assessment questionnaire disability index score; DLCO % = diffusion capacity

to carbon monoxide, percent of the predicted value; FVC = forced vital capacity; UIP = usual

interstitial pneumonia.

22

2.11.2 Histopathological predictors of mortality Yousem and colleagues were the first to report that among RA-ILD patients, those with a histologic pattern UIP in surgical lung biopsy specimens had the worst prognosis (160). Subsequently, several studies have demonstrated that patients with a histological UIP pattern have a worse prognosis as compared to those with other subtypes (96,161-163).

Contradictory results have, however, also been reported. Yoshinouchi et al. (164) studied 16 patients with RA-ILD (7 UIP, 7 NSIP, 2 UIP/NSIP hybrid pattern) and in contrast to the other studies, survival in the NSIP group seemed worse as more deaths occurred in patients with NSIP, although 2/3 NSIP deaths were from non-respiratory causes. Solomon et al. investigated 48 biopsy-proven RA-ILD cases and found no difference in survival between patients with UIP and NSIP patients (146). In the same study, the NSIP group was further divided into fNSIP and cNSIP. After pooling unclassified ILD, UIP and fNSIP together, these so-called fibrotic ILDs (N=23) had clearly shorter survival times than the “non-fibrotic” (bronchiolitis, DAD, DIP, LIP, cNSIP, OP) patients (N=25) and thus the conclusion was that the presence of any fibrosis on biopsy predicted mortality (146).

A subgroup analysis of the 168 CTD-ILD-patients was performed by Walsh et al on 51 biopsy-proven patients, whose histopathological diagnoses were compared to HRCT data (159). The 51 patients were divided into four groups based on the concordance of the histopathological and radiological diagnoses. It revealed that the patients with discordant UIP had a better prognosis than concordant UIP-patients but worse than that of those with fNSIPs (159).

2.11.3 Pulmonary function tests, 6MWT and prognosis When the fibrotic subtypes of IIPs were examined, it has been demonstrated that pulmonary physiology could be an even stronger predictor of mortality than the histopathologic pattern (165) and that in IPF patients, changes in FVC % predicted and DLCO % predicted have associated with mortality (166,167) especially in patients with a desaturation in 6MWT (166). In RA-ILD studies, the baseline DLCO has been considered as an independent risk factor for death in some univariate/bivariate and multivariate models (95,153,159). Moreover, the change in DLCO has been also identified as a prognostic factor (139,153). Baseline FVC and the change in this parameter have also been shown to be prognostic factors (95,139,153).

Reduced walking distance and oxygen desaturation below 88% during a 6MWT are associated with mortality in IPF (32,168,169), but this has not been examined in patients with RA-ILD.

2.11.4 Patient- and RA-related predictors of mortality Older age (37,146,170) and male sex (95,171) have been detected as risk factors for mortality in several studies. In addition, in one cohort the risk of death was almost doubled in patients with low socio-economic status, although this finding did not quite reach statistical significance (37).

Some factors reflecting the RA severity have also been proposed to associate with worse survival. The severity can be assessed in several different ways, but for example high baseline visual analogue pain scale (VAS), increased ESR, DAS and HAQ-DI have been detected to correlate with worse survival (37,170,171). Furthermore, the presence of RF and high lactate dehydrogenase (LDH) pointed towards a poorer prognosis (154).

23

2.12 THE RISK PREDICTION MODELS IN ILDS

Since the course of the disease is highly variable among ILD patients and no specific biomarker has been found that would predict patient´s survival, several models based on combinations of the above-mentioned separate factors have been developed recently, most of which were developed for IPF, but some of them have been expanded to all ILDs, even though not yet validated in RA-ILD patients (Table 8).

In the Clinical-Radiologic-Physiologic scoring system (CRP) age, smoking history, finger clubbing, arterial blood oxygen during exercise, the percent predicted total lung capacity (TLC), and the extent of profusion of interstitial opacities and evidence of pulmonary hypertension on chest X-ray were used to construct a score (maximum score 100) (172).

The composite physiologic index (CPI), published 2 years after the previous system, displayed some important advantages, since it contained only PFT and gas transfer values but omitted radiological scoring or exercise testing. The formula (CPI= 91 - (0.65 x DLCO% predicted) – (0.53 x FVC % predicted) + (0.34 x forced expiratory volume in 1 second (FEV1) % predicted) was derived by fitting PFT results against disease extent on CT in a regression model and this was shown to correlate better with disease extent than the individual PFT test (173).

The model developed by Goh et al was designed for survival prediction of SSc-ILD patients (174). The model integrated PFT results and HRCT findings, grading the disease extent on HRCT as minimal (defined as clearly <20%) or severe (defined as clearly >20%) and using a FVC threshold of 70% in indeterminate cases to categorize the patients either as having a limited or extensive disease. This kind of integrated staging had a greater prognostic value than either HRCT or FVC thresholds on their own (174).

In the model by du Bois et al. age, respiratory hospitalisation, FVC % predicted, and 24-week change in FVC were combined (175), whereas the Risk Stratification score (ROSE) by Mura et al. was based on combining the Medical Research Council Dyspnoea Score (MRCDS), 6MWT and the CPI (176).

Probably the model that has obtained widest clinical utilisation is the GAP index. This was introduced by Ley et al. in 2012 and it combines gender (G), age (A) and two lung physiology variables (P), i.e. FVC and DLCO, into a multidimensional index and staging system with three stages (I-III) proposing 1-year mortality of 6, 16 and 39%, respectively (177) (Table 9). The GAP model has also been utilized in the prognosis of other chronic ILDs in addition to IPF. The modified model was named as ILD-GAP, with the assumption that patients with chronic hypersensitivity pneumonitis, iNSIP and CTD-ILD enjoyed a better survival than those suffering from IPF (178). The cohort, in which the expanded ILD-GAP model was applied, included the following patients: 307 IPF, 206 chronic hypersensitivity pneumonitis, 45 iNSIP, 173 unclassifiable ILD and 281 CTD-ILD. The number of RA-ILD patients in the CTD-ILD group was not reported and it is unclear which of the prognostic models - GAP or ILD-GAP - would be better suited for RA-ILD, given the high proportion of UIP patients in RA-ILD (96).

24

Table 8. Prediction models in ILD. Adapted and modified from the PhD Thesis of Charlotte

Hyldgaard 2015 (19).

Study (first

author, year)

Name of

the model

Disease The factors that are included

in the model

No. of

patients

Validated

King 2001 CRP IPF Age, smoking, finger clubbing, arterial blood oxygen during exercise, TLC, chest X-ray

238 No

Wells 2003 CPI IPF FVC, FEV1, DLCO 212 Yes

Goh 2008 - SSc-ILD FVC, HRCT 215 Yes

Du Bois 2011 - IPF Age, resp. hosp., FVC, 24-week change in FVC

1099 No

Mura 2012 ROSE IPF MRCDS, 6MWT, CPI 70 No

Ley 2012 GAP IPF Age, FVC, DLCO 228 Yes

Ryerson 2013 ILD-GAP ILD Age, FVC, DLCO 1012 In IPF

CRP = Clinical-Radiologic-Physiologic scoring system; CPI = composite physiologic index; ROSE = Risk

Stratification score; GAP = gender, age, physiologic variables; IPF = idiopathic pulmonary fibrosis; ILD =

interstitial lung disease; SSc = systemic sclerosis; TLC = total lung capacity, FVC = forced vital capacity;

FEV1 forced expiratory volume in 1 second, DLCO = diffusion capacity to carbon monoxide; HRCT = high-

resolution computed tomography; Resp.hosp = respiratory hospitalization; MRCDS = Medical Research

Council Dyspnoea Score; 6MWT = Six-minute walk test.

Table 9. The GAP (gender, age and physiology) index and staging system. Adapted and

modified from the original GAP publication of Ley et al (177). The maximum possible point score

is 8 and the patients are further divided to three stages according to their total scores. The

model-predicted 1-, 2-, and 3-year mortality is shown by stage.

Predictor Details Points

G Gender

Female

Male

0

1

A Age

≤60

61-65

>65

0

1

2

P Physiology

FVC % predicted

DLCO % predicted

>75

50-75

<50

>55

36-55

≤ 35

Cannot perform

0

1

2

0

1

2

3

Total possible points 8

Stage I II III

Points 0-3 4-5 6-8

Mortality years

1

2

3

5.6

10.9

16.3

16.2

29.9

42.1

39.2

62.1

76.8

FVC = forced vital capacity; DLCO = diffusion capacity to carbon monoxide.

25

2.13 COMORBIDITIES

2.13.1 Comorbidities in RA-ILD Comorbidities in RA-ILD have not been previously studied in detail. A Danish cohort of 679 RA-ILD patients reported that the burden of comorbidity assessed by the Charlson Comorbidity Index was higher in the RA-ILD group compared to their RA counterparts without ILD. They also reported that ischemic heart disease, congestive heart failure and diabetes were more frequent in the RA-ILD group, although the difference in ischemic heart disease frequency was rather small and the authors considered that it did not account for the increased mortality observed in the RA-ILD group (179).

2.13.2 Comorbidities in RA Even though studies concerning RA-ILD comorbidities are infrequent, many studies have investigated the co-existing diseases in RA population. An elevated risk has been reported for atherosclerosis, and cardiovascular disease, of which the prevalence has been estimated to be 1.5-2 times higher in RA patients compared to the general population. The risk for myocardial infarction and for stroke is approximately doubled in RA. The prevalence of diabetes seems to be increased, whereas the data are somewhat inconsistent as to whether the prevalence of hypertension is higher in RA than in the general population. Patients with RA are also at an increased risk for cardiac heart failure. Moreover, thyroid dysfunction and depressive symptoms may be as many as 2 to 3 times more common in RA as in the general population (180).

2.14 CAUSES OF DEATH

ILD is the most common pulmonary cause of death, and the second commonest overall cause of death in RA (8,181,182). The causes of deaths of the patients with RA-ILD have not been previously systematically studied, although some data have been published. In the study of Nakamura et al., nine of the 54 biopsy-proven cases had died; in 7 out of the 9 cases, the cause of death was respiratory failure due to disease progression (161). In the study of Koduri et al. in 28 of the 39 deceased RA-ILD patients, the cause of death was attributed to RA-ILD, while the remainder recorded causes of death were bronchopneumonia (n=4), ischemic heart disease (n=3), heart failure (n=2), pulmonary embolism (n=2), cerebrovascular disease (n=2) and miscellaneous reasons (n=5) (37).

2.15 TREATMENT

2.15.1 Whom and how to treat? The management of ILD in patients of RA is challenging due to the lack of randomized controlled trials. Treatment is typically initiated in patients who suffer from respiratory symptoms and show a progressive course of the disease, whereas asymptomatic patients are often simply monitored (119). A 10% decline in FVC in a RA-ILD patient suggests a higher risk of mortality and may help in decisions to treat (153). On the other hand, the treatment is generally focused on controlling the systemic disease even in the cases with a stable lung disease (102). An adaptation of the unclassifiable ILDs categorization by the disease behavior (20) may be useful in deciding the monitoring strategy and treatment choices (Table 10) (22).

Several therapeutic agents have been suggested, but no randomized controlled trials have been performed to guide the clinical practice (103). There is rather limited evidence of

26

specific therapeutic agents; this is mainly based on case reports, case series and retrospective cohorts. Another concern is the possible role of some agents in the progression and/or exacerbations of ILD (17,183).

It remains unclear whether the recent onset ILD or the exacerbation of pre-existing ILD observed during a specific therapy reflects a pulmonary side effect of the drug or whether these events would have occurred regardless of the medication (183). Usually it is advised to perform functional and the radiological evaluation of the lung before starting a new RA treatment (184-186). In Finland, the recommended treatment of newly diagnosed RA is the so-called “FIN-RACo-strategy” (Finnish rheumatoid arthritis combination therapy), which includes MTX, sulfasalazine, hydroxychloroquine plus prednisolone and aims at rapid remission (15). Traditionally, in patients with the development of ILD, the MTX has been discontinued, but recent reviews have recommended that the decision on whether or not to discontinue drugs should be considered on a case-by-case basis and no strict guidelines are given (22,183).

There is evidence that the response to therapy varies in different RA-ILD subtypes, with OP pattern typically showing rapid responses to corticosteroid therapy often with a complete recovery (187) and NSIP pattern having more favourable responses to therapy than the UIP pattern (22,48,119). For example, in the retrospective study of Song et al., 41% of RA-UIP patients were treated with high-dose corticosteroids combined with azathioprine, cyclophosphamide or cyclosporine due to disease progression or poor initial lung function. Fifty percent of the patients improved or had stable lung function but no difference was observed in outcome between the treated and untreated groups (139).

Table 10. Different monitoring and treatment consideration strategies according to disease

behaviour. Original table adapted from the review article of Lake et al. 2014 (22).

Clinical behaviour Treatment and goal Monitoring strategy

Potentially reversible with risk of

irreversible disease (e.g. drug-

related lung disease in RA)

Remove cause, treat to obtain

a response to reverse changes.

Short-term (3-6 months)

observation to confirm disease

regression, or occasionally need

for palliation.

Reversible disease with risk of

progression (e.g. some RA-NSIP,

RA-OP)

Treat to initially achieve

response and then rationalize

longer term therapy.

Short-term observation to confirm

treatment response. Long-term

observation to ensure that gains

are preserved.

Stable with residual disease (e.g.

some RA-NSIP, some RA-UIP)

No treatment if stable, aiming

to maintain status.

Long-term observation to assess

disease course.

Progressive, irreversible disease

with potential for stabilization

(e.g. some RA-NSIP, some RA-

UIP)

Consider treatment trial to

stabilize.

Long-term observation to assess

disease course.

Progressive, irreversible disease

despite therapy (e.g. RA-DAD,

most RA-UIP, some RA-NSIP)

In the absence of

contraindications, consider

treatment trial in selected

patients to slow progression.

Short (DAD) or long-term

observation to assess disease

course, and need for transplant or

effective palliation.

RA = rheumatoid arthritis; NSIP = nonspecific interstitial pneumonia; OP = organizing

pneumonia; UIP = usual interstitial pneumonia; DAD = diffuse alveolar damage.

27

2.15.2 Immunosuppressive agents The treatment of RA-ILD has been typically empirical with corticosteroids being used as first-line agents. Patients who responded to steroids often had immunosuppressive drugs such as azathioprine added to steroids (103). Prolonged durations of even moderate doses of corticosteroids can, however, cause variable adverse effects, for example impairment of muscle strength (188). Moreover, the risk for serious infection was recently determined in 181 RA-ILD patients. The risk was highest in the first year after ILD diagnosis and among patients receiving 10mg or more daily prednisone, with an overall infection rate of 7.4 per 100 person-years which is similar to that of RA patients without ILD (189). The cases with OP and NSIP patterns respond better to corticosteroids but the effect on RA-UIP patients is unclear (48).

Cyclophosphamide treatment was thought to be beneficial in SSc-ILD (190), but a meta-analysis concluded that it did not induce clinically significant improvements of PFT in SSc-ILD patients (191). No randomized controlled trial has been performed to clarify its benefits in RA-ILD (103).

Mycophenolate mofetil (MMF) has been shown to be safe and effective in some patients with CTD-ILDs. In one study of 125 MMF- treated patients with CTD-ILD, including 18 RA-ILD-patients, a slight improvement in FVC was observed in 18 of the total group, with less improvement seen in UIP patterned patients than in the others (192). A prospective study of 10 CTD-ILD-patients, including 3 RA-ILD cases, treated with MMF revealed that all ten patients experienced an improvement in their respiratory symptoms, quality of life and activity levels. Two out of 8 subjects with repeated HRCT exhibited a radiological improvement, 6 stabilized and none worsened, whereas one out of 9 patients showed worsening in PFT, 3 with improvement and 5 stabilized (193).

2.15.3 Synthetic disease modifying antirheumatic drugs (DMARDs) The addition of DMARD (MTX, leflunomide (LEF) or azathioprine in this study) to lowered dose of prednisone was associated with an improvement in baseline FVC in a study of 40 RA-ILD-patients (194). In a subgroup analysis of the above-mentioned study, those with a lower fibrosis score on CT improved and those with a UIP pattern had a higher mean fibrosis score (194).

The treatment of RA-ILD with DMARDs is, however, complicated due to the possibilities of the development of drug-related pneumonitis or worsening of the existing ILD linked in several DMARDs (103). The recommended first-line DMARD for RA is MTX, which has been shown to be associated with the progression of preclinical ILD and an increased risk of pneumonitis in some studies (22,103). Still, some researchers think that it is not conclusively evidenced, that MTX induces / exacerbates the underlying RA-ILD or leads to a greater risk of pulmonary death (103) and a decision on whether or not to avoid the drug needs consideration of both the joint and lung diseases (22).

Leflunomide has also been associated with rapid onset pneumonitis, ILD and nodule development with an almost two-fold risk of ILD compared to those not receiving LEF (195). A case report from Finland described 5 patients with newly developed severe ILDs after combination therapy with LEF and MTX (196).

In some case-reports, positive responses have been described with the use of cyclosporine in RA-ILD patients (197), but in the study of Tokano et al., no persisting response to cyclosporine was found in four steroid-resistant RA-ILD cases, even though positive lasting responses were observed in other CTD-ILDs (198).

2.15.4 Biologic agents A list of biologic therapies for treatment of RA is shown in table 11. Concern about the respiratory safety of anti-TNF agents first appeared after the publication of a few rapid,

28

fatal exacerbations of previously asymptomatic RA-ILD after the introduction of infliximab (199) and subsequently cases of induction or exacerbation of RA-ILD have been repeatedly reported (200,201). However, in contrast, some case-reports have claimed to have detected stabilization or improvement of RA-ILD after the administration of infliximab (202,203). Etanercept has also been linked to exacerbation of pre-existing lung disease in patients with RA (204), but conversely, in a study of 367 patients with RA-ILD treated with either anti-TNF agents (n=299) or traditional RA treatments (n=68), no difference was found in mortality (170). Detorakis et al. examined prospectively 82 RA patients, 42 with and 40 without RA-ILD, treated with anti-TNF agents (68 infliximab, 10 etanercept, 4 adalimumab). Control groups consisted of 44 patients with pre-existing RA-ILD and 44 patients without RA-ILD, treated with non-biologic DMARDs (68 MTX alone, 20 MTX + hydroxychloroquine). There were no episodes of newly emerged ILDs or ILD exacerbation in the anti-TNF- treatment group and moreover, this group displayed an improvement in bronchial wall thickening and air trapping over time (205).

Little information is available regarding the safety and benefits of biological DMARDs other than the TNF-alpha inhibitors in RA-ILD patients, including anakinra, tocilizumab, abatacept and rituximab. Tocilizumab improved RA-ILD in one single case report (206), whereas other reports have addressed ILD occurrence or exacerbation with tocilizumab therapy (207,208). One case series with abatacept claimed that there was stabilization of lung function in RA patients who had developed ILD on anti-TNF agents (209), but another study reported worsening of HRCT findings in a single RA-ILD patient (210). Weinblatt et al. examined the pooled data from eight clinical trials of intravenous abatacept therapy for RA, and discovered a low incidence rate of 0.09 for ILD development. However, the study did not answer the question of abatacept´s safety in RA patients with pre-existing ILD (211). There is no data regarding to non-infective pulmonary complications, nor potential therapeutical / beneficial role in ILD of anakinra.

Rituximab (RTX) is a monoclonal antibody against B-cell marker CD20 (119), often considered as a rescue therapy in RA-ILD, although based on limited evidence (185). Some reports are available regarding the use of RTX in RA-ILD patients. Keir et al. claimed that some of the studied 33 CTD-ILD patients (two with RA-ILD) experienced an improvement in FVC and stability of DLCO in the 6-12 months following RTX treatment, in contrast to the clear decline in both parameters evident prior to rituximab (212). In a 48-week pilot-study of RTX in RA-ILD patients, only one out of 10 patients enjoyed a respiratory improvement, five remained stable, one deteriorated and 3 were unable to complete the study with one of these dying because of pneumonia / acute respiratory distress syndrome (ARDS) (213). Quite recently, experiences over 10 years from a single centre were published demonstrating a progression in 32%, an improvement in 16% and a stable disease in 52% of the 56 RTX-treated RA-ILD patients (214). Of those who deteriorated/died, 79% had severe ILD before RTX treatment, suggesting that the drug had not been contributory to the deterioration (214).

No prospective studies are available identifying predictors of progression of RA-ILD in patients treated with biologic agents and thus, there are no evidence-based guidelines to help clinicians to decide which patients to treat or not to treat with biological therapy. The ongoing clinical trials (uploaded on 13.11.2017) on biologic drugs are listed in table 12. It has been hypothesized that those patients with severe of progressive RA-ILD would probably have a higher risk of developing drug-induced AEs (200). It is crucial to gain a better understanding of factors that predict poor outcomes of biologic therapy. One suggested treatment strategy is shown in figure 6.

29

Table 11. Available biologic therapies for rheumatoid arthritis.

Substance Brand name Main effect Application form

Infliximab Remicade®, Remsima®, Inflectra® TNF inhibition iv

Etanercept Enbrel® TNF inhibition sc

Adalimumab Humira® TNF inhibition sc

Certolizumab Cimzia® TNF inhibition sc

Golimumab Simponi® TNF inhibition sc

Tocilizumab Roactemra® IL-6 inhibition iv

Anakinra Kineret® IL-1 inhibition sc

Rituximab Mabthera®, Ritemvia® B-cell depletion iv

Abatacept Orencia® Inhibition of the

T-cell activation

iv

TNF = Tumor necrosis factor; IL = interleukin; iv = intravenous; sc = subcutaneous.

Figure 6. Suggested treatment options for RA-ILD. Lung transplantation is recommended to be

considered for non-responding progressive RA-ILD patients. Original figure adapted and

modified from the review article of Roblez-Perez and Molina-Molina (185).

ILD = interstitial lung disease; RA = rheumatoid arthritis; RA-ILD = rheumatoid arthritis-

associated interstitial lung disease; UIP = usual interstitial pneumonia; OP = organizing

pneumonia; NSIP = nonspecific interstitial pneumonia.

2.15.1 Pulmonary rehabilitation In IPF patients, pulmonary rehabilitation has been shown to improve dyspnea and increase exercise capacity as well as the quality of life – at least in the short term (9). In a recent randomized controlled study, the patients with IPF or asbestosis showed more improvement in the 6MWT, in symptoms and in quality of life measured by different

30

questionnaires, than those with patients with CTD-ILD. However, the CTD-ILD group was rather small (23 patients out of the total 142 ILD patients) and included only 8 RA-ILD patients (215). Thus, the potential of pulmonary rehabilitation in RA-ILD is still undefined and can be limited by the functional impairment due to the joint disease, which may require RA-specific rehabilitation protocols (103).

2.15.2 Lung transplant Patients with progressive disease should be evaluated for LTx (186). There is limited data concerning LTx in CTD-ILD with most of them being studied in patients with SSc-ILD. In a retrospective study of Yazdani et al., ten patients with RA-ILD, 53 with IPF and 17 with SSc-ILD underwent LTx. Groups were matched for age and transplant year and no statistically significant differences were observed between the cumulative survival rates of different disease entities (216). Moreover, the quality of life of RA-ILD patients increased significantly measured by all three different scores in use (216). Another study compared the survival and outcomes after LTx between IPF and non-scleroderma CTD-ILD, including 68 (24.7%) RA-ILD patients, and found no significant differences in survival, acute or chronic rejection, or extrapulmonary organ dysfunction (217). A study with a wide spectrum of different CTD patients, including 36 RA-ILD patients, found that the cumulative survival in patients with CTD-ILD was like that of IPF patients (218). Thus, it seems that LTx would be beneficial in selected patients, but it may be contraindicated because of age, comorbidities or poor functional ability (186).

In many organ transplant centers, the presence of CTD is considered as a contraindication for lung transplant. In Finland, however, these patients have been accepted for transplantation if the CTD is well managed, has been stable for years and there are no other organ manifestations of the CTD that would rule out the surgery (219). The common indications and contraindications for transplantation are applied regardless of the presence or absence of CTD. Of the 282 LTx:s performed in Finland, the reason for transplant was IIP in 97 patients of whom 12 suffered from CTD-ILD and two from RA-ILD (219).

2.15.3 Antifibrotic drugs There is no data concerning antifibrotic agents, such as pirfenidone and nintedanib, for the treatment of RA-ILD. Ongoing clinical trials (uploaded on 13.11.2017) on antifibrotics for RA-ILD are listed in Table 12.

2.15.4 Treatment of RA-ILD exacerbation Clinical data on treatment for non-IPF exacerbation is lacking (133). There are no controlled trials investigating the treatment of AE in IPF or in other ILDs. Thus, the treatment is empirical. Patients with AE-IPF are often treated with corticosteroids, either a pulse dose or lower doses of oral prednisone. Antibiotics are commonly used, since bacterial infection is difficult to exclude (220). In a retrospective analysis of 10 patients (3 RA-ILD, 1 SSc-ILD, 6 iNSIP), nine patients received broad-spectrum antibiotics and high-dose systemic corticosteroid therapy (6 i.v. pulse therapy and three 1mg/kg/d dosage). Six patients needed mechanical ventilation and all of them died. Four patients with idiopathic NSIP survived, when all the CTD-ILD patients died (133).

2.15.5 Other treatments Smoking is a potential risk factor for developing RA-ILD and COPD with or without emphysematous lung damage. It can also affect the severity of joint disease and therefore all patients with RA should be encouraged to stop smoking and provided with the appropriate advice and assistance about cessation of smoking. In the patients in whom the

31

ILD has already developed, smoking cessation is crucial. Annual vaccinations for influenza, as well as pneumococcal vaccination are recommended for RA patients on immunosuppressive therapy as well as in those with a chronic lung disease (9). Some physicians also recommend prophylaxis against Pneumocystis jirovecii for all patients receiving immunosuppressive therapy (98).

2.15.6 Palliative care Cough and dyspnea are common symptoms of ILDs and can cause tremendous suffering and reduce the patient´s quality of life. Opioids may be beneficial and the treatment of possible concomitant gastro-esophageal reflux should be considered (220). Supplemental oxygen therapy may be required in advanced disease, although it is not known, whether oxygen alters the course of the disease (9). Psychological / psychosocial issues need to be addressed and different kinds of support e.g. psychotherapy, counselling or pharmacological therapy, may be beneficial (220).

32

Table

12.

Ongoin

g t

rials

of

bio

logic

and a

ntifibro

tic d

rugs o

n R

A-I

LD

patients

accord

ing t

o C

linic

alT

rials

.gov (

uplo

aded o

n 1

3.1

1.2

017).

* I

nclu

des C

TD

-ILD

patients

who h

ave m

edic

ally indic

ate

d n

eed f

or

change in C

TD

medic

ation a

nd h

ave n

ot

yet

been initia

ted o

f new

thera

py o

r

withdra

wal of th

era

py f

or

CTD

within

6 w

eeks p

rior

to V

isit 1

). P

F =

pro

gre

ssiv

e fib

rosis

; M

MF =

mycophenola

te m

ofe

til;

RTX =

rituxim

ab;

IPAF =

inte

rstitial pneum

onitis

with a

uto

imm

une f

eatu

res;

NSIP

= n

onspecific

inte

rstitial pneum

onia

; Exp =

experi

ment,

Com

p.

= c

om

para

tive g

roup;

FVC

= forc

ed v

ital capacity;

RA-I

LD

= r

heum

ato

id a

rthri

tis-a

ssocia

ted inte

rstitial lu

ng d

isease;

CTD

= c

onnective t

issue d

iseases;

iNSIP

= idio

path

ic

NSIP

.

Nam

e o

f th

e s

tud

y

Cli

nic

alT

ria

ls

Gov i

den

tifi

er

Ph

ase

Dis

ease

Sta

tus

Du

rati

on

(w

eeks)

Esti

mate

d

en

rolm

en

t

In

terven

tion

P

rim

ary

ou

tcom

e

varia

ble

Phase I

I stu

dy o

f

pir

fenid

one in p

atients

with R

A-I

LD

NCT02808871

2

RA-I

LD

Recru

itin

g

52

270

Pirfe

nid

one,

2403m

g/d

ay,

thre

e t

imes /

d

Dis

ease

pro

gre

ssio

n

∆FVC>

10%

Effic

acy a

nd S

afe

ty o

f

Nin

tedanib

in P

atients

with P

rogre

ssiv

e

Fib

rosin

g I

nte

rstitial Lung

Dis

ease (

PF-I

LD

) *

NCT02999178

3

PF-I

LD

Recru

itin

g

52

600

Exp.

Nin

tedanib

Com

p.:

pla

cebo

Annual ra

te o

f

decline in F

VC

Abata

cePt

in R

A-I

LD

(APRIL

)

NCT03084419

2

RA-I

LD

N

ot

yet

recru

itin

g

24

30

I.v.

Abata

cept

appro

xim

ate

ly 1

0m

g/k

g

fort

nig

htly for

the fir

st

4

weeks,

then e

very

4 w

eeks

for

a t

ota

l of 20 w

eeks

Dis

ease

pro

gre

ssio

n

∆FVC>

10%

Evalu

ation o

f Effic

acy a

nd

Safe

ty o

f Rituxim

ab W

ith

Mycophenola

te M

ofe

til in

Patients

With I

nte

rstitial

Lung D

iseases (

EvER-

ILD

)

NCT02990286

3

CTD

-NSIP

,

IPAF-N

SIP

,

iNSIP

Recru

itin

g

26

122

Exp.

MM

F +

RTX

Com

p.:

MM

F+

pla

cebo

Change in F

VC

in

% o

f pre

dic

ted

33

3 Aims of the Study

The aim of this thesis was to investigate a cohort of RA-ILD in patients treated between the year 2000 and the end of 2014 in the Kuopio University Hospital (KUH) pulmonology clinic and to evaluate the course of the disease. The specific aims were:

1. To investigate the numbers and subtypes of the patients with RA-ILD treated in KUH during the years 2000-2014, to evaluate the course of the disease, medication, pulmonary function test results, survival, comorbidities and causes of death and to compare these parameters between UIP and non-UIP cases.

2. To determine the applicability of CPI, GAP and ILD-GAP scores for predicting the prognosis of the patients with RA-ILD and to examine the association between individual PFT and demographic factors with the survival of the patients.

3. To evaluate the HRCT findings in patients with RA-ILD and to compare the presence and extent of different radiologic findings in different RA-ILD subtypes, as well as to identify associations between radiological findings and clinical factors, survival and pulmonary function tests.

34

4 Material and Methods

4.1 DATA SOURCES AND PATIENT SELECTION

The study cohort consisted of patients treated in the KUH pulmonology in-patient or out-patient clinic between 1.1.2000 and 31.12.2014. The patients were identified from the database of KUH using two International Classification of Diseases (ICD-10) codes, namely J84.X and M05.X/M06.X. From these patients, we only included those subjects that had been examined or treated in the pulmonology in-patient or out-patient clinic between 1.1.2000 and 31.12.2014 for any respiratory symptoms or any suspected pulmonary disease, thus omitting those RA patients with no symptoms or chest X-ray abnormalities. For the third study, another search was performed using the code J99.0*M05.1, but only one extra UIP patient fulfilling the study inclusion criteria was detected. The two first searches resulted in the identification of 1047 patients, and their patient records were evaluated to identify those patients suffering from clinically relevant RA-ILD (Figure 7).

At baseline, the patients with ILD but without RA (i.e. patients with IIP, other CTDs or allergic alveolitis) and those with RA, whose visits to pulmonology clinic were because of some other lung diseases (such as asthma, COPD, obstructive sleep apnea) were excluded. We also excluded suspected but not confirmed RA-ILD patients, for whom HRCT, or some other comparable radiological examination capable of achieving a reliable analysis of the lung parenchyma were not available, as were those patients whose RA diagnosis was not certain according to the 1987 classification criteria (221), or who developed later mixed CTD- like symptoms.

Another 38 patients were excluded subsequently after the evaluation by the radiologist and/or after a multidisciplinary discussion due to the very minor signs or nonspecific features for ILD, leaving a total of 59 RA-ILD (60 in study no. III) patients to be studied in detail and classified.

Figure 7. The study protocol and the final re-categorization of the patients with RA-ILD in the first two

studies. In the third study, one additional UIP patient was found. *additional 2 DAD findings included in OP

group (n=1) and UIP group (n=1).

RA = rheumatoid arthritis, ILD = interstitial lung disease, HRCT = high-resolution computed tomography,

MDD = multidisciplinary discussion, UIP = usual interstitial pneumonia, NSIP = nonspecific interstitial

pneumonia, OP = organizing pneumonia, DAD = diffuse alveolar damage.

35

4.2 GATHERING OF DEMOGRAPHIC INFORMATION (I, II, III)

Clinical information was inclusively gathered from the patient records of KUH, primary health care centers and other hospitals using a specially designed form (Table 13). The gathered laboratory test results included RF and anti-nuclear antibody (ANA) titer, as well as ACPAs and arterial blood examples. ACPAs were not available for half of the patients. The results of PFT were gathered at baseline and, when available, during the follow-up at 6 months, 1 year, 2 year and subsequently annually, including also the most recent available results. The reference values of Viljanen were used when assessing PFT results (222). Any medication in use prior to ILD diagnosis was recorded, as was the lifelong medication used for RA. In addition, possible palliative therapy, e.g. opioids, for RA-ILD was recorded. Histological data (BAL, TBB, SLB, autopsy samples) also was collated, when available. The numbers of hospitalizations due to either respiratory problems (including infections, suspected drug reactions and suspected acute exacerbations) or cardiac problems like unstable angina pectoris, myocardial infarctions, arrhythmias and cardiac failures were collected.

Table 13. Detailed list of demographic and other data that was gathered from the patient

records of KUH, primary health care centers and other hospitals.

RA = rheumatoid arthritis; ILD = interstitial lung disease; RF = rheumatoid factor; ANA antinuclear

antibodies; ACPAs = anticitrullinated protein antibodies; DLCO = diffusion capacity to carbon monoxide;

FVC = forced vital capacity; FEV1 = forced expiratory volume in 1 second; BAL = bronchoalveolar lavage;

TBB = transbronchial biopsy; SLB = surgical lung biopsy.

Gathered data Details

Date of birth

Sex

Occupation

Family history of pulmonary fibrosis

Smoking Duration, amount, pack-years, passive exposure

Exposure to asbestos

Radiation therapy of the thorax region

Duration of RA

Date of RA diagnosis

RA-related surgery

Date of the first visit due to ILD

Comorbidities

Use of oxygen

Rehabilitation due to ILD

Symptoms at baseline Cough, dyspnea at rest/exercise, hemoptysis, pain, fever

Respiratory status findings at baseline Inspiratory crackles, finger clubbing, dyspnea at rest

Baseline laboratory test RF, ANA titer, ACPAs, arterial blood examples

Death certificate data Primary and immediate causes of death, place of death

Pulmonary function test results DLCO and spirometry (FVC, FEV1, FEV1/FVC)

Medication Any medication prior to ILD diagnosis, lifelong RA

medication, opioids in palliative purposes

Histological data BAL, TBB, SLB, autopsy samples

Hospitalizations due to cardiac and

respiratory reasons

36

4.3 RADIOLOGICAL EVALUATION

4.3.1 Re-classification of HRCTs (I, II, III) An experienced radiologist evaluated baseline HRCTs blinded to the demographic data and without consideration of the reports accompanying the original CT results. In study III the re-classification was performed independently by two radiologists. Radiological ILD re-categorization was conducted according to the 2013 IIP classification (20) as UIP, NSIP, OP, DAD and “unclassified” subgroups. The radiological RA-UIP criteria were applied from those of IPF (32). Mainly patients with a definite UIP pattern were included in the UIP group, but three patients who displayed a slightly upper (n=2) or mid-lung (n=1) predominated distribution, were included after a multidisciplinary discussion. Patients with possible UIP, i.e. a subpleural and basal predominated reticular abnormality without honeycombing, were not included in the UIP group. RA-NSIP was defined as the predominance of GGO, possible visible subpleural sparing and possible fine reticulation with minor or no honeycombing. RA-OP was defined as single or multiple patchy consolidations. The “unclassified” subgroup consisted of those patients that did not fit the definition of any specific subtype.

In addition to the baseline CT, the most recent HRCT was also evaluated in a similar manner from 33 patients who had a follow-up CT available. In those patients, the final subgroup was determined based on the analysis of both CTs.

4.3.2 Further interpretation of the CTs and the scoring system (study III) In addition to the radiological subgrouping performed by the two radiologists, the radiological findings were further assessed in detail in study III by the first radiologist, using a form designed for the study. The presence and the extent of the following findings were evaluated separately: GGO, reticulation, honeycombing, emphysema, consolidation, crazy-paving appearance, bronchiectasis, traction bronchiectasis, nodules, thickening of the bronchovascular bundle, cysts, mosaic attenuation, air trapping (when applicable), rounded atelectasis, architectural distortion, pleural plaques, pleural effusion and tumours. The definitions of these findings used in this study are those issued by the Fleischner Society (223). The most prominent observation was designated in each HRCT.

Both lungs were divided into three zones. The upper zones were at or superior to the aortic arch, the middle zones were between the aortic arch and pulmonary veins and the lower zones were at or below the pulmonary veins. The extents of GGO, reticulation and honeycombing were semi-quantitatively graded on a scale from 0 to 4 as follows: 0 = finding absent, 1 = minor peripheral scattered changes, 2 = uniform peripheral or minor central changes, 3 = substantial peripheral changes that penetrated deeply into the lung parenchyma, 4 = very abundant peripheral and central changes. The total score of these three findings was obtained by summing the grades for all six zones i.e. the maximum score was 24.

Emphysema, traction bronchiectasis, architectural distortion and pleural plaques were scored similarly, adding up the given grades in six zones, but now scored with a three-point scale (0-3; 0 = absent, 1 = single scattered changes, 2 = larger single changes or several minor changes, 3 = uniform or substantial changes) resulting in a score ranging from 0-18.

4.4 STAGING SYSTEMS (II)

CPI was calculated using the formula (173): CPI= 91 – (0.65 x DLCO % predicted) – (0.53 x FVC % predicted) + (0.34 x FEV1 % predicted). Requisite data was available from 51 patients, from whom the GAP / ILD-GAP scores were calculated by gender, age, FVC % predicted and DLCO % predicted following the division of patients into GAP / ILD-GAP

37

stages I and II as previously described (177,178). There were no stage III (or IV in ILD-GAP) patients in our study material (Figure 8).

Figure 8. Flowchart of a patient´s enrollment into the study showing the subdivision into the different

GAP/ILD-GAP groups (Study II).

RA-ILD = rheumatoid arthritis-associated interstitial lung disease; GAP = gender, age, physiologic

variables.

4.5 STATISTICAL ANALYSIS

The different statistical tests that were used in the study are listed in Table 14. In studies I and II, the distribution of the continuous variables was verified with Shapiro-Wilk test. If the distribution was normally divided, the comparison was made using an independent T-test; otherwise Mann-Whitney U-test was applied. The chi-squared test or Fisher test, when appropriate, was used for comparison of the categorical variables. Gender, amounts of different RA-ILD subtypes, smoking habits, laboratory results, use of medications, symptoms, inspiratory crackles, comorbidities, use of oxygen, numbers of observed deaths and the presence of different radiological findings were calculated as percentages. Age at the time of RA-ILD, at diagnosis or at death, RA duration, PFT results, CPI score, hospitalizations and the extents of different radiological findings were expressed as mean ± SD.

Survival analysis was done using the Kaplan-Meier method and survival curves were compared using the log-rank test. Survival time was calculated from the first visit to the pulmonology clinic due to ILD to the date of death or November 4, 2015 when the vital status was ascertained. Survival results are expressed as median (95% confidence interval).

In the second study, the observed 1-, 2-, and 3-year mortality rates were calculated and these were supplemented with an estimate of the confidence interval by using the Wilson score. Next, the observed mortality and the risk of death predicted by the GAP / ILD-GAP models were compared using Hosmer-Lemeshow goodness-of-fit test. Finally, Cox regression analysis was used to identify factors that predicted mortality.

In the third study, the associations between different radiological findings and survival were estimated using the Kaplan-Meier method and the univariate Cox regression analysis. The correlations between radiological finding scores and PFT as well as with other clinical factors were estimated using the Spearman rank correlation coefficient. Agreement between the radiologist´s re-categorization was expressed as a kappa value (κ). Values of κ 0.41 – 0.60 were considered as moderate and κ values 0.61 – 0.80 as good agreement.

38

We considered a p-value <0.05 as statistically significant. All data was analyzed using IBM Statistics SPSS software, version 21.0.

Table 14. Summary of the statistical methods used in studies I, II and III

Statistical test Use of the test Study in

which used Chi-Square test Comparison of categorical variables I, II, III

Fisher test Comparison of categorical variables I, II, III

Shapiro-Wilk test The distribution of the continuous variables I, II

Independent T-test Comparison of normally distributed

continuous variables

I, II, III

Mann-Whitney U-test Comparison of continuous variables, not

normally distributed

I, II

Kaplan-Meier method, log

rank test

Mean survivals, survival comparison I, II, III

Cox´s regression analysis Prognostic factors for mortality II, III

Wilson score Confidence interval estimation for the

observed mortality

II

Spearman rank correlation

coefficient

Correlations between the extents of different

radiological findings and PFT/clinical data

III

Hosmer-Lemeshow

goodness-of-fit test

Suitability of GAP/ILD-GAP models for

predicting RA-ILD mortality

II

Cohen´s kappa Agreement between the radiologists´ re-

categorization

III

4.6 ETHICAL CONSIDERATIONS

In this retrospective study, most of the patients were deceased and no consents to participate were gathered due to the register-based nature of research in accordance with the Finnish legislation. The study protocol was approved by the Ethical Committee of Kuopio University Hospital (statement 17/2013). Organizational permission of Kuopio University Hospital was obtained as well as permissions from the Finnish National Institute for Health and Welfare (THL/1052/5.05.01/2013) and Statistics Finland (TK-53-911-13), which enabled data collection from other hospitals, primary health care centers and death certificates. This study was conducted in compliance with the Declaration of Helsinki.

39

5 Results

5.1 PATIENT CHARACTERISTICS

5.1.1 Demographics

Fourteen patients were diagnosed by the end of year 2000, 19 between the years 2001 and 2007, and 27 between the years 2008-2014. The highest amounts of new diagnoses were seen in the years 2012 and 2014, with 6 and 7 new RA-ILD diagnoses, respectively.

Of the 60 HRCT-confirmed RA-ILD patients, 34 (56.7%) were male and 35 (59.3%) were current or former smokers. The mean age at diagnosis was 66 ± 11.2 years, ranging from 32 to 87 years. The mean follow-up time was 4.2 ± 5.2 years and in eight patients (13.6%) ILD diagnosis was made before RA diagnosis. In the cases where ILD followed the RA diagnosis, the time interval between the two diagnoses was ≤ 1 year in 13%, ≤ 3 years in 27% and ≤ 5 years in 40%, when the longest time interval between RA and ILD was 52 years. RF was positive in 84.5%, ANA in 19.6% and ACPAs were present in 68% of the patients from whom the data was available. The majority, i.e. 61.5% of the patients suffered from cough and almost as many (60.3%) from dyspnea.

5.1.2 Medication for RA Seventy-five percent of patients were receiving some medication for RA at the time of RA-ILD diagnosis and in 11 of them, the medication was changed or discontinued after the ILD diagnosis. In all of them, however, the ILD continued to progress. At any time, almost all (54/90%) had received glucocorticoids, over half (35/58.3%) MTX and 14/23.3% had received biologic drugs.

5.1.3 PFT Baseline spirometry was missing from five, and baseline DLCO from eight patients. Thirty-one patients (56.4%) had normal FVC at baseline. Twenty-five (48.1%) had a normal baseline DLCO. In 18 patients (34.6%), both the baseline DLCO and FVC were normal.

5.1.4 Radiological subtypes The re-categorization was based on both the baseline and, if available, on the follow-up HRCT, as well as on the rarely available histological samples. From the 60 individuals with RA-ILD, 36 (60%) revealed the UIP pattern, 8 (13%) NSIP, 7 (12%) OP and 8 (13%) unclassified pattern in their HRCTs (Figure 9). One case with DAD was observed, with a previously normal HRCT and then a rapidly progressing dyspnoea, severe hypoxemia as well as newly developed bilateral GGO changes in the HRCT assessment. In the follow-up, additional two DAD patterns were observed in patients with OP and UIP diagnoses prior to DAD.

5.1.5 GAP and ILD-GAP (II) Thirty-nine (76.5%) patients, from whom GAP/ILD-GAP scores could be calculated, belonged to stage I with the remaining categorized into stage II group. There were no stage III patients. Stage I patients were younger (p=0.024) and more likely to have never smoked (p=0.033) than the stage II patients. Baseline FVC, FEV 1 and DLCO were better preserved in stage I patients. RA-UIP patients were divided equally between both stages.

40

Figure 9. Final diagnoses after the re-classification of the HRCTs, with the consideration of the

histological and clinical data.

UIP = usual interstitial pneumonia; NSIP = nonspecific interstitial pneumonia; OP = organizing

pneumonia; DAD =diffuse alveolar damage.

5.1.6 Comparison of the demographics in UIP and non-UIP patients (I) Dyspnea (p= 0.022) and inspiratory crackles (p=0.007) were more often present with the RA-UIP patients compared to non-UIP individuals. No differences were observed between subgroups with respect to age, smoking, baseline PFT or RA, serology. No statistically significant differences were found either in the use of MTX or biologic drugs.

5.1.7 Comparisons within RA-UIP subgroup Among the RA-UIP patients, more males were former or current smokers, when only two (11%) were lifelong non-smokers, compared to 13 (81.3%) female non-smokers (p<0.001) (Table 9). All RA-UIP male were RF positive compared to 67% of the females (p=0.009). The male RA-UIP individuals had poorer baseline DLCO (p<0.001), FEV1 (p=0.006), CPI-points (p=0.005) and baseline GAP score (p=0.018) than the female counterparts (Table 15).

When the UIP group of 36 patients was divided into subgroups of slowly (patient alive > 5 years after the diagnosis) and rapidly (patient dying <5 years after the diagnosis) progressing cases, the baseline CPI score was higher in the rapid group (p=0.037) and the mean number of hospitalizations due to cardiac illness was higher in the slow group (p= 0.043). The median survival was shorter (16 months vs. 152 months, p<0.001) and the number of deaths higher in the rapid group (p=0.024) (Table 15).

41

Table

15.

The d

iffe

rences o

f clinic

al chara

cte

ristics b

etw

een g

enders

and r

apid

ly /

slo

wly

pro

gre

ssed R

A-U

IP c

ases.

R

A-U

IP

(n

=3

6)

MA

LE

(n

=2

0/

55

.6%

)

FEM

ALE

(n

=1

6/

44

.4%

)

P-v

alu

e

RA

PID

(=

0-5

Y)

(n

=1

2/

40

%)

SLO

W (

>5

Y)

(n

=1

8/

60

%)

P-v

alu

e

Age a

t dg

66.0

± 1

2.1

63.8

± 1

2.4

68.8

± 1

1.5

0.2

28

70.6

± 1

0.9

62.5

± 1

2.2

0.0

67

Age a

t death

74.1

± 9

.9

70.1

± 9

.1

78.0

± 9

.8

0.0

79

72.7

± 1

0.4

74.6

± 9

.5

0.6

52

Num

ber

of death

s

24 (

66.7

) 13 (

65.0

) 11 (

68.8

) 1.0

00

F

12 (

100.0

) 11 (

61.1

) 0.0

24

F

Sm

okin

g

N

on-s

mokers

Ex-s

mokers

C

urr

ent

sm

okers

15 (

42.9

)

14 (

40.0

)

6 (

17.1

)

2 (

10.5

)

12 (

63.2

)

5 (

26.3

)

13 (

81.3

)

2 (

12.5

)

1 (

6.3

)

<0.0

01

F

5 (

41.7

)

4 (

33.3

)

3 (

25.0

)

8 (

47.1

)

8 (

47.1

)

1 (

5.9

)

0.7

74

F

Sero

logy

RF p

ositiv

ity

AN

A p

ositiv

ity

30 (

85.7

)

6 (

23.1

)

20 (

100.0

)

4 (

28.6

)

10 (

66.7

)

2 (

16.7

)

0.0

09

F

0.6

52

F

11 (

91.7

)

2 (

25.0

)

14 (

77.8

)

2 (

14.3

)

0.6

22

F

0.6

02

F

GAP p

oin

ts

2.2

± 1

.3

2.8

± 1

.4

1.7

± 0

.9

0.0

18

2.6

± 1

.2

2.1

± 1

.3

0.3

56

CPI

poin

ts

27.5

± 1

6.0

35.0

± 1

7.2

19.5

± 1

0.1

0.0

05

38.4

± 1

3.1

23.6

± 1

6.8

0.0

37

RA d

ura

tion,

years

15.9

± 1

1.9

16.2

± 1

4.1

15.6

± 8

.5

0.8

85

15.9

± 1

5.7

17.5

± 1

0.0

0.7

38

Lung f

unctions

D

LCO

% p

red

FVC

% p

red

FEV1 %

pre

d

71.7

± 2

0.6

82.7

± 1

6.8

81.0

± 1

7.4

60.3

± 1

9.4

77.8

± 1

7.8

74.0

± 1

5.2

84.5

± 1

3.1

88.8

± 1

3.6

89.8

± 1

6.3

<0.0

01

0.0

56

0.0

06

60.6

± 1

9.1

75.0

± 2

1.1

81.4

± 2

0.3

77.5

± 2

1.9

84.3

± 1

4.8

81.3

± 1

6.3

0.0

73

0.1

81

0.9

92

MTX e

ver

18 (

50.0

) 9 (

47.4

) 9 (

56.3

) 0.7

38

F

6 (

50.0

) 8 (

44.4

) 0.7

65

Bio

logic

al ever

7 (

19.4

) 3 (

15.8

) 4 (

25.0

) 0.6

75

F

3 (

25.0

) 2 (

11.1

) 0.3

64

F

Pre

dnis

olo

ne e

ver

32 (

88.9

) 17 (

89.5

) 15 (

93.8

) 0.6

13

F

12 (

100.0

) 15 (

83.3

) 0.2

55

F

Dyspnoea

25 (

71.4

) 16 (

84.2

) 9 (

56.3

) 0.0

68

6 (

54.5

) 14 (

77.8

) 0.2

37

F

Cough

18 (

62.1

) 10 (

66.7

) 8 (

57.1

) 0.5

97

8 (

72.7

) 6 (

46.2

) 0.2

40

F

Cra

ckle

s

30 (

83.3

) 15 (

75.0

) 15 (

93.8

) 0.1

96

F

12 (

100.0

) 15 (

83.3

) 0.2

55

F

Hospitalization d

ue t

o

respir

ato

ry illness

1.9

± 2

.6

2.3

± 3

.2

1.4

± 1

.6

0.3

17

2.5

± 2

.5

1.9

± 2

.8

0.5

85

Hospitalization d

ue t

o

card

iac illness

0.7

± 1

.3

0.8

± 1

.5

0.6

± 1

.0

0.7

04

0.2

5 ±

0.6

1.1

± 1

.5

0.0

43

Media

n s

urv

ival

88.0

(41.1

– 1

34.9

) 64.0

(6.8

– 1

21.2

) 92.0

(0.0

– 1

85.2

) 0.6

44

16.0

(4.1

– 2

7.9

) 152.0

(87.7

–

216.3

)

<0.0

01

F=

Fis

her

test.

In 6

patients

, th

e follow

-up t

ime w

as t

oo s

hort

to b

e a

ble

to c

ate

gori

ze e

ither

as s

low

or

rapid

. The follow

ing d

ata

was m

issin

g:

sm

okin

g s

tatu

s,

RF,

and info

rmation o

f dyspnoea fro

m 1

patient,

data

about

AN

A fro

m 1

0 p

atients

, in

form

ation o

f cough fro

m 7

patients

. RF =

rheum

ato

id facto

r; A

NA =

antinucle

ar

antibodie

s;

RA =

rheum

ato

id a

rthritis;

DLCO

= d

iffu

sio

n c

apacity t

o c

arb

on m

onoxid

e;

FVC =

forc

ed v

ital capacity;

FEV1 F

orc

ed e

xpir

ato

ry v

olu

me in o

ne s

econd;

GAP =

gender,

age,

physio

logy;

CPI

= c

om

posite p

hysio

logic

index;

RA =

rheum

ato

id a

rthri

tis;

MTX =

meth

otr

exate

; U

IP =

usual in

ters

titial pneum

onia

.

42

5.2 RADIOLOGICAL FINDINGS

5.2.1 Disease progression In addition to baseline imaging, an additional HRCT was available for 33 patients (17 UIP, 4 OP, 7 NSIP, 4 unclassified, 1 DAD) (unpublished data). The second HRCT of 17 RA-UIP-patients showed clear signs of a progression in 11 cases, a mild progression in two cases and unchanged imaging in two cases (time between scans ranging from 19 to 77 months). In two cases, the possible progression could not be evaluated due to the poor quality of the second scan. In the 7 RA-NSIP patients, two clear progressions and one milder progression were observed, whereas the changes had diminished in three cases. One RA-NSIP exhibited new changes in the second imaging as the first scan had revealed no signs of any kind of ILD. In the RA-OP subgroup, two patients healed completely, one remained unchanged between scans and one developed DAD-like changes. Two of the unclassified ILD cases displayed a mild progression, remaining still as unclassifiable, and two remained unchanged. Nine patients, who could not be specifically categorized based on the first scan, developed more specific ILD pattern in their second scan, resulting in the appearance of an RA-UIP pattern in 7 cases and an RA-NSIP pattern in two cases.

5.2.2 Inter-observer agreement (III) When categorized into five subgroups (UIP, NSIP, OP, DAD, unclassified), the overall agreement between the radiologists was moderate (κ = 0.492). When categorized only into two groups i.e. “definite UIPs” vs. “others”, the inter-agreement rose slightly (κ = 0.592). When “definite UIPs” and the unclassified subgroup likely representing possible UIPs were pooled as one category, the agreement improved to good (κ= 0.629).

5.2.3 The HRCT findings in different subtypes (III) Reticulation (93.1%) and GGO (72.4%) were the most common findings and observed in every subgroup to some extent. Reticulation was more abundant in UIP vs. OP (p<0.001), UIP vs. unclassified (p=0.041), NSIP vs. OP (p=0.020) and unclassified vs. OP (p=0.001), but similar in extent in UIP and NSIP patients. GGO was more extensive in the NSIP group vs. the unclassified subgroup (p=0.017). Honeycombing and architectural distortion were most often seen in patients with UIP and the extent of those findings was also significantly higher compared to all other subgroups (p<0.001). Emphysema (29.3%), bronchiectasis (24.5%) and pleural plaques (32.6%) were observed in approximately every third patient, without any statistically significant differences between subgroups with respect to the prevalence of the findings, although emphysema was more extensive in the UIP subgroup vs. RA-OP patients.

5.2.4 Original radiological reports Original reports were available from 59 patients, with 1 report missing from a patient that was re-classified as OP. A large proportion of the reports were non-specific descriptive reports, with the modern IIP classification being most often used in patients that were re-classified as NSIP or OP, whereas the UIP pattern was less mentioned (Table 17). More recent reports, i.e. those after the year 2011, were more specific than their older counterparts. The raw data of the original reports is shown in Table 16.

43

Table 16. Raw data of individual patients´ original radiological reports with selected details.

Re-

categorized

RA-ILD

subtypes

Years of

the

baseline

/ latest

CTs

Original

radiological

report

Selected details of the original reports

UIP 2002/- UIP ”lung fibrosis with basal predominance, interlobular

septa thickening and comb formation. Consistent

with IPF”

UIP 1999/2003 UIP ”peripheral fibrotic changes with basal predominance,

reticulation and honeycombing, could be IPF,

inconsistent with allergic alveolitis or asbestosis”

UIP 2003/- descriptive ”subpleural, peripheral fibrosis, basal and posterior

predominance, few traction bronchiectasis, few

honeycombs. Consistent with rheumatoid lung”

UIP 1997/1998 descriptive “pleural plaques, peripheral basal fibrosis, impression

of honeycombing, some traction bronchiectasis.

Etiology could be asbestos but the role of MTX cannot

be excluded”

UIP 2000/2000 descriptive “extremely extensive fibrosis with honeycombing”

UIP 2006/2015 descriptive “advanced fibrosis with honeycombing”

UIP 2004/- descriptive ”fibrotic changes with basal predominance, traction

bronchiectasis and slight honeycombing. Could be

idiopathic or RA-related fibrosis”

UIP 2002/- descriptive “basal and peripheral reticulation and honeycombing,

consistent with lung fibrosis”

UIP 2012/- UIP “most probably RA-related UIP-changes”

UIP 1996/2004 descriptive ”progression. In both sides, clear fibrotic changes,

which are most extensive in right middle lobe and

less so in lower lobes, which speaks against RA-

related fibrosis”

UIP 2005/2013 UIP “most probably RA-related UIP-changes”

UIP 2008/- descriptive ”fibrosis advanced to honeycombing stage”

UIP 2004/2012 descriptive ”abundant fibrosis, clear progression”

UIP 2008/2011 descriptive ”apparently RA-related fibrosis, advanced to

honeycombing stage”

UIP 2004/2013 UIP ”radiological UIP pattern, could be RA-related”

UIP 2009/- descriptive ”symmetrical peripheral fibrosis, advanced to

honeycombing stage. Methotrexate reaction usually

has more acute nature with GGO”

UIP 2006/2007 UIP “rapidly progressive fibrosis, most likely IPF or a drug

reaction”

UIP 2011/- UIP/NSIP “distribution of the changes and the existing

honeycombing are consistent with UIP, but in places

there´s an impression of subpleural sparing and

GGO, could be UIP or NSIP, possibly related to RA or

drugs”

UIP 2009/- descriptive “old fibrosis, partly in honeycombing stage”

UIP 2012/2013 UIP ”subpleural, basal, honeycombing, consistent with

UIP. Could be related to RA. NSIP also possible the

pattern of which mostly suggests a drug reaction”

UIP 2010/- descriptive “extensive honeycombing as a sign of mature

fibrosis, no parts of the lungs spared”

UIP 2005/- descriptive “very extensive honeycombing referring to fibrosis”

UIP 2006/- descriptive “honeycombing-staged fibrosis in the basal parts.

Quite extensive fibrotic changes that could be RA-

related”

44

UIP 2000/2007 descriptive “bilateral peripheral extensive fibrotic changes, basal

predominance, honeycombing, GGO both sides as a

sign of disease activity”

UIP 2010/- UIP “very severe lung fibrosis, reticulation and

honeycombing, probably related to RA. Not quite

typical UIP, even though these naturally cannot be

differentiated radiologically”

UIP 2007/- descriptive “basal predominance, fibrotic changes with

honeycombing, these non-specific changes can be

related to use of sulfasalazine or RA”

UIP 2007/2013 UIP “consistent with UIP pattern, even though unchanged

compared to older scans”

UIP 2014/- descriptive “bilateral, basal honeycombing”

UIP 2010/2014 UIP / fNSIP “upper-lobe predominated UIP-like fibrosis with

reticulation and scarce honeycombing. Possible UIP

or fNSIP”

UIP 2000/- descriptive “bilateral basal peripheral honeycombing and traction

bronchiectasis”

UIP 1995/- descriptive “extensive honeycomb fibrosis in left lower lobe”

UIP 2014/- UIP “radiological UIP pattern most likely associated with

RA”

UIP 1993/- descriptive “basal, peripheral fibrosis, partly in honeycombing

stage. Could be RA-related”

UIP 2009/2012 UIP “bilateral basal extensive honeycombing, UIP-like

fibrosis”

UIP 2006/2015 descriptive ”lung fibrosis, with subpleural honeycombing and

scarring”

UIP 2004/- descriptive ”fibrotic honeycomb formation”

NSIP 2012/- descriptive ”left: mild fibrotic changes. In the right side slightly

more extensive fibrosis, with minor traction

bronchiectasis, reticulation and GGO”

NSIP 2008/2013 descriptive “bilateral middle and lower-lobe predominated

interlobular septa thickening and bronchiectasis

consistent with fibrosis, which might be RA-related”

NSIP 2008/2015 NSIP “fibrotic, primarily NSIP-consistent changes, could be

RA-ILD or a drug reaction”

NSIP 2005/2012 NSIP “basal reticular abnormalities, no honeycombing.

Could be e.g. RA-associated NSIP”

NSIP 2007/2009 UIP/fNSIP “Not IPF-like UIP. Rather RA-related UIP or fNSIP

based on slow progression” “no honeycombing”

NSIP 2006/2012 NSIP “the distribution of the changes and the lack of

honeycombing speaks for NSIP”

NSIP 2006/2007 NSIP “interlobular septa thickening, GGO, no

honeycombing. NSIP pattern, probably RA-related”

NSIP 2014/2014 NSIP “GGO, slight reticulation, a few posterior honeycomb

cysts. Not typical for asbestosis, rather RA-NSIP”

OP 2005/2009 Original report not found

OP 2012/- COP ”several patchy subpleural consolidations, primarily

consistent with COP”

OP 2007/- descriptive ”two separate pneumonis-like consolidations”

OP 2011/2012 NSIP/COP/IPF ””extensive GGO, consolidation in the left side, small

area with local honeycombing. Differential diagnosis

contains NSIP, COP and apparently also IPF”

OP 2013/2013 COP ”multifocal consolidations consistent with COP”

OP 2014/- COP ”multifocal consolidations, primarily COP, although

vasculitis also possible”

OP 2014/2015 COP ”single peripheral consolidation, malignancy possible,

or COP”

45

Unclass. 2003/- UIP ” interstitial intralobular fibrosis in basal parts. Could

be related to rheumatoid lung, but the lack of noduli

makes it slightly unlikely. Overall, the findings are

very close to those of IPF”

Unclass. 1998/- descriptive “subpleural fibrotic changes especially in basal parts,

reticulation, interlobular septa thickening,

honeycombing and traction bronchiectasis. Asbestos

cannot be excluded, but also RA and drug reaction is

possible”

Unclass. 2002/- descriptive “clear fibrosis in basal areas, peripheral, minor

subpleural fibrotic changes also in upper lobes,

traction bronchiectasis, incipient honeycomb

formation. Can be caused by CTD”

Unclass. 2012/2013 possible UIP / RB-ILD

”early fibrosis, peripheral reticulation, small

centrilobular nodules, local few honeycomb cysts,

could be UIP or RB-ILD”

Unclass. 2007/2009 descriptive ”small basal and peripheral fibrotic changes that

could represent idiopathic pulmonary fibrosis due to

RA or drug hypersensitivity”

Unclass. 1997/2005 descriptive ”TB-related scarring in right upper lobe,

bronchiectasis both sides, not proper lung fibrosis nor

GGO as a sign of an active process”

Unclass. 2008/- descriptive ”minor interlobular septa thickening, might be

incipient fibrosis, very unspecific finding”

Unclass. 2013/2015 possible UIP ”reticular abnormalities with basal predominance,

traction bronchiectasis, no clear honeycombing”

RA-ILD = rheumatoid arthritis-associated interstitial lung disease; UIP = usual interstitial pneumonia;

NSIP = nonspecific interstitial pneumonia; OP = organizing pneumonia; Unclass. = unclassified; fNSIP =

fibrotic nonspecific interstitial pneumonia; COP = cryptogenic organizing pneumonia; RB-ILD =respiratory

bronchiolitis- interstitial lung disease; RA = rheumatoid arthritis; MTX =methotrexate; GGO = ground-

glass opacities; CTD = connective tissue diseases; IPF = idiopathic pulmonary fibrosis; TB = tuberculosis.

Table 17. Summary of the contents of the original radiological reports in different subtypes.

RA-ILD

subtype in re-

categorization

Original

radiological

reports

available n (%)

Contents of the original reports n (%)

IIP classification used Descriptive report

UIP n=36 36 (100) 13 (25.0) UIP (n=11) UIP/fNSIP (n=2)

23 (63.9)

NSIP n=8 8 (100.0) 6 (75.0) NSIP (n=5) UIP/NSIP (n=1)

2 (25.0)

OP n=7 6 (85.7) 5 (71.4)

COP (n=4) COP/NSIP/UIP (n=1)

1 (14.3)

Unclassified n=8 8 (100.0) 3 (37.5)

UIP (n=1) possible UIP (n=1) possible UIP / RB-ILD (n=1)

5 (62.5)

RA-ILD = rheumatoid arthritis-associated interstitial lung disease; IIP = idiopathic interstitial pneumonias;

UIP = usual interstitial pneumonia; NSIP = nonspecific interstitial pneumonia; OP = organizing

pneumonia; fNSIP = fibrotic nonspecific interstitial pneumonia; COP = cryptogenic organizing pneumonia;

RB-ILD =respiratory bronchiolitis- interstitial lung disease.

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5.3 HISTOLOGICAL DATA AND BAL

Seven out of nine available TBB samples were non-diagnostic, while two showed a suspected OP of which both were suitable with OP also radiologically. One CT-guided transthoracal needle biopsy was performed in which the histopathologic diagnosis was OP. One patient had undergone a VATS biopsy. This patient died within a week from the biopsy which revealed a DAD diagnosis.

Altogether 10 autopsies were performed, of which six were clinical autopsies and four forensic autopsies. Histological analyses of the autopsies were available in four cases, two of which revealed histopathological UIP- patterns, one OP-pattern and one nonspecific description of lung fibrosis.

One RA-UIP patient underwent LTx but did not survive. The pathological examination of the original lungs revealed a severe and extensive UIP- pattern.

BAL samples were gathered from 22 patients with the total instilled volume of saline mentioned in 5 cases, ranging from 50 to 300 ml. The differential cell count was available in 16 cases. The mean value of macrophages was 63.7 ± 26.6, that of lymphocytes 16.6 ± 13.4, of neutrophils 16.5 ± 18.4 and of eosinophils 3.5 ± 7.9 (Table 14). The mean percentage of macrophages was significantly higher in UIP-patients compared to BAL samples of OP individuals (p=0.002). The mean percentages of neutrophils differed significantly between UIP vs. OP subtypes and NSIP vs. OP subtypes (Table 18).

Table 18. The mean percentages of cell counts in the 16 BAL samples from which the

differential cell count was available.

Cell type (mean ± SD)

RA-ILD (n=16)

RA-UIP (n=8)

RA-NSIP (n=3)

RA-OP (n=4)

Unclassified (n=1)

Macrophages 63.7 ± 26.6 79.9 ± 18.5* 52.7 ± 33.6 36.75 ± 13.0 75.0

Lymphocytes 16.3 ± 13.4 12.4 ± 11.4 20.3 ± 21.5 20.25 ± 14.0 20.0

Neutrophils 16.5 ± 18.4 5.1 ± 8.6* 17.0 ± 11.5¥ 42.0 ± 12.8 4.0

Eosinophils 3.5 ± 7.9 2.6 ± 4.8 10.0 ± 17.3 1.0 ± 0.8 1.0

p<0.05: * UIP vs. OP, ¥ NSIP vs. OP

BAL = bronchoalveolar lavage; RA-ILD = rheumatoid arthritis-associated interstitial lung

disease; UIP = usual interstitial pneumonia; NSIP = nonspecific interstitial pneumonia; OP =

organizing pneumonia; SD = standard deviation.

5.4 COMORBIDITIES (I)

The most common comorbidities were hypertension (30/50.8%), coronary artery disease (CAD) (21/35.6%), chronic obstructive pulmonary disease (COPD) (17/28.8%), cardiac insufficiency (16/27.1%), diabetes (13/22.0%) and asthma (12/20.3%). Gastroesophageal reflux (GER) was reported in six (10.2%) and hypothyroidism in three (5.1%) patients. There were two lung cancers (3.4%) and nine (15.3%) other cancers, including basal cell carcinoma (n=2), diffuse large B cell lymphoma (n=2), urinary bladder carcinoma (n=1), colon adenocarcinoma (n=1), squamous cell carcinoma in upper lip (n=1) and in tongue (n=1) and one ventricle carcinoma. Six (10.2%) patients suffered from tuberculosis (five in lungs and one intestinal) and 7 (11.9%) from depression. Obstructive sleep apnea (2/3.4%) was infrequent in our cohort. No statistically significant differences in the comorbidities were found between the UIP and non-UIP groups, although COPD was more common in the UIP group (p= 0.088). Asthma was more common in women (p= 0.016) and COPD in men (p<

47

0.001). Comorbidities were divided equally in non-smokers and ever-smokers, except for COPD (p<0.001).

5.5 CAUSES OF DEATHS (I)

According to the death certificates of the 33 deceased patients in study I, RA-ILD was the most common primary cause of death in 13 cases and reported as commonly in men and women (8 vs. 5, p=1.000), in non-smokers and ever-smokers (6 vs. 7, p= 0.522) and in UIP and non-UIP individuals (10 vs. 3, p=0.701) (Figure 10). CAD was the second most common primary cause of death in seven cases, equally in UIP and non-UIP patients (p=0.161). RA was the primary cause of death in five cases. The other reported primary causes of death were Alzheimer´s disease, universal atherosclerotic disease with acute lower limb ischemia, acute pancreatitis, intestinal tuberculosis, COPD, massive bleeding due to pelvic fracture, lung cancer and suspected viral infection in the central nervous system - one case of each disease.

Pneumonia and CAD were equally common as the immediate cause of death (both 10/30.3%; 6 UIP, 4 non-UIP) and RA-ILD (5/15.2%; 4 UIP, 1 non-UIP) was also prevalent (Figure 10). The following immediate causes of deaths were reported each in single cases: lung cancer, RA, diabetes, RA associated secondary amyloidosis with renal failure, acute pancreatitis, intestinal tuberculosis and gastroenteritis.

Figure 10. The most common primary and immediate causes of deaths in 59 patients with RA-

ILD. RA = rheumatoid arthritis; ILD = interstitial lung disease; CAD = coronary artery disease.

5.6 CORRELATIONS BETWEEN CLINICAL DATA, PFT AND RADIOLOGY

(III)

The strongest negative correlation (r= -0.430, p=0.001) was seen between the extent of emphysema and DLCO, which also correlated with the extent of architectural distortion (r= -0.235, p=0.033). A negative correlation between GGO extent and the duration of RA was observed (r= -0.308, p=0.023). The extents of honeycombing (r=0.266, p=0.046), traction

48

bronchiectasis (r=0.333, p=0.012) and architectural distortion (r=0.353, p=0.007) correlated with hospitalizations due to respiratory reasons.

5.7 THE COURSE OF THE DISEASE

5.7.1 Differences between RA-UIP and non-UIP patients (I) The patients with the definite UIP pattern needed more long-term oxygen therapy than their non-UIP counterparts (p=0.016). In addition, their DLCO result declined more during the disease course (p=0.021), and their main number of hospitalizations due to respiratory causes was higher than in the non-UIP group (p=0.004) a phenomenon which was not present with hospitalizations due to cardiac reasons (Table 19). Table 19. Factors associating with the differential course of the disease in the patients with rheumatoid

arthritis associated usual interstitial pneumonia (RA-UIP) and non-UIP patterns (RA-non-UIP).

RA-ILD

(n=59)

RA-UIP

(n=35/59.3%)

RA-non-UIP

(n=24/40.7%)

P-

value

Oxygen therapy, n (%) 8 (13.6) 8 (22.9) 0 (0) 0.016

Hospitalization due to respiratory

illness (mean ± SD)

1.29 ± 2.2 1.9 ± 2.6 0.5 ± 0.9 0.004

Hospitalization due to cardiac illness 0.6 ± 1.2 0.7 ± 1.3 0.4 ± 1.2 0.100

Latest available FVC % pred 82 ± 21.2 78 ± 22.9 87 ± 17.2 0.091

Latest available DLCO % pred 61 ± 21.3 56 ± 20.6 69 ± 20.2 0.021

RA = rheumatoid arthritis, ILD = interstitial lung disease; UIP = usual interstitial pneumonia; FVC =forced

vital capacity; DLCO = diffusion capacity to carbon monoxide; SD = standard deviation.

5.7.2 Survival (I, II) Overall, 34 (56.7%) of the 60 patients had died with the clear majority (87.9%) of the patients dying in hospital or in other health care centers, whereas only 4 patients died at home or outdoors. The average age of death was 75.0 ± 9.1 years, ranging from 54.8 to 91.7 years. The RA-UIP patients died slightly younger than the non-UIP- patients (73.6 ± 9.8 vs. 78.2 ± 6.5, p=0.187).

The survival analyses in the first two studies were performed after the exclusion of the RA-DAD patient, thus the total number of patients was 58, and the number of the deceased was 33. More patients had died in the UIP group versus non-UIP patients (p= 0.046). The median survival in the whole group was 107.0 months with no statistically significant differences between UIP vs. non-UIP patients, male vs. female or between non-smokers vs. the combined group of current and former smokers (Table 20). The median survivals were 152 months and 61 months (p=0.017) in the GAP / ILD GAP stages I and II, respectively (Figure 11).

In the non-UIP group, there was a trend towards a longer survival in female vs. male (p=0.093) patients and non-smokers vs. ever-smokers (p=0.218), whereas no such trend was observed in the UIP-group.

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Table 20. Survival of the patients (months) in different subgroups.

Median survival,

months

95% confidence

interval

P-value

Overall 107.0 73.1 – 140.9

UIP 92.0 62.8 – 121.2 0.417

non-UIP 137.0 31.0 – 243.0

Male 87.0 46.0 – 128.0 0.305

Female 152.0 87.7 – 216.3

Non-smokers 152.0 94.3 – 209.7 0.525

Ever-smokers 88.0 29.4 – 146.6

GAP/ILD-GAP stage I 152.0 93.0 – 211.0 0.017

GAP/ILD GAP stage II 61.0 25.2 – 96.8

UIP = usual interstitial pneumonia; GAP = gender, age, physiologic variables- model.

Figure 11. Comparison of the survival curves of the patients with rheumatoid arthritis-

associated ILD categorized into either GAP / ILD-GAP stage I or II. The survival was significantly

worse in GAP / ILD-GAP stage II (p=0.017, Log Rank).

GAP = gender, age, physiologic variables- model; ILD = interstitial lung disease.

50

5.7.3 Predictors of mortality (II, III) All tested risk predicting models, i.e. GAP, ILD-GAP and CPI, were significant predictors of mortality in the Cox univariate model, as were the age at diagnosis, baseline DLCO and hospitalization due to respiratory reasons. In addition, several radiological features, i.e. the extents of reticulation, traction bronchiectasis and architectural distortion, were associated with decreased survival. For every increased GGO score point the mortality risk increased by 8 %, nearly reaching statistical significance (p=0.051) (Table 21).

After adjusting for age, CPI score and baseline DLCO remained as significant predictors of mortality, whereas respiratory hospitalization and GAP/ILD-GAP lost their statistical significance.

The median survival of four patients with pleural fluid was 10 months compared to 107 months in those without pleural effusions (p<0.001). Neither the presence of GGO, honeycombing nor reticulation associated statistically significantly with survival when assessed by either the presence or absence of these features. Smoking, FVC, male sex, UIP pattern or the use of methotrexate did not affect survival in a statistically significantly manner.

Table 21. Prognostic factors for survival in patients with RA-ILD using a univariate Cox model.

Hazard ratio 95% CI P-value

Age at diagnosis 1.06 1.02 – 1.10 0.002

DLCO % pred 0.98 0.96 – 1.00 0.014

Resp.hospitalization 1.12 1.01 – 1.26 0.039

Card. hosp. 1.13 0.87 – 1.46 NS

CPI-points 1.03 1.01 – 1.06 0.015

GAP score 1.56 1.15 – 2.11 0.004

ILD-GAP score 1.51 1.05 – 2.18 0.026

Extent of GGO 1.079 1.000 – 1.166 0.051

Extent of reticulation 1.144 1.005 – 1.302 0.041

Extent of traction bronchiectasis 1.184 1.016 – 1.379 0.030

Extent of architectural distortion 1.094 1 003 – 1.194 0.044

DLCO = diffusion capacity to carbon monoxide; Resp.hospitalization = hospitalization for

respiratory reasons; Card. hosp. = hospitalization for cardiac reasons; CPI = composite

physiologic index; GAP =gender, age, physiologic variables; GGO = ground-glass opacity; CI =

confidence interval.

5.8 VALIDATION OF THE GAP AND ILD-GAP MODELS (II)

Both GAP and ILD-GAP models predicted the mortality accurately, since both prediction models fitted the Wilson score confidence interval and no apparent differences were seen between the observed cumulative mortality and the predicted risk of mortality (Table 22).

The observed mortality and the risk of death predicted by these models were also compared using the Hosmer-Lemeshow goodness-of-fit test. All the p-values were >0.05, meaning that there were no statistically significantly differences between estimated and observed mortality (Figure 12). ILD-GAP was more accurate in its prediction of 1-year cumulative mortality in both stages, whereas the GAP model was slightly more accurate at 2- and 3-year mortality prediction.

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Table 22. Predicted and observed cumulative mortality of the patients with RA-ILD.

GAP / ILD-GAP

stage

Observed (95% CI

calculated by Wilson score)

Predicted by GAP index

and staging system

Predicted

by ILD-GAP

1-Y mortality

Stage I

Stage II

0.0 (0.0 – 9-4)

8.3 (1.5 – 35.4)

5.6

16.2

3.1

8.8

2-Y mortality

Stage I

Stage II

14.3 (6.3 – 29.4)

9.1 (1.6 – 37.7)

10.9

29.9

6.6

18.0

3-Y mortality

Stage I

Stage II

17.6 (8.3 – 33.5)

27.3 (9.7 – 56.6)

16.3

42.1

10.2

26.9

GAP = gender, age, physiologic variables.

Figure 12. The Hosmer-Lemeshow statistic test shows that predicted and observed risks do not

differ significantly (p>0.05). The x-axis shows the 1-y, 2-y and 3-y risk of mortality as

predicted by the GAP and ILD-GAP staging system and the y-axis shows the observed risk. In

every figure, stage I is on the left side and stage II on the right side. The vertical lines

represent the confidence interval of the observed mortality rate.

GAP = gender, age, physiologic variables.

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6 Discussion

The development of modern RA therapies has resulted in a decline in RA-related death, but the prevalence, burden and mortality of RA-ILD are all increasing (10,224). The increased prevalence could partly reflect an increased detection of this ILD (60) and another explanation is the increased survival of patients with RA, since advanced age is risk factor for the development of RA-ILD (4,37,73). In Denmark, the number of prevalent RA patients more than doubled during the years 2004-2016 while the incidence remained stable, which reflects the increased survival among patients with RA (179). At the same time with the increased survival of RA, the prognosis of RA-ILD has been reported to be poor (37) with RA-ILD being responsible for 7% of the deaths in RA patients (10).

The prevalence or incidence of RA-ILD in Finland has not been studied. Hakala et al. reported the RA-ILD incidence in Finland to be roughly one case per 3500 patient years, but only included those that were hospitalized and moreover included those with a suspected drug-induced lung disease (141). We detected 60 clinically relevant RA-ILD patients, which can be considered as representative sample size since KUH is responsible for the specialist medical care of the 248 000 citizens in its catchment area and the prevalence of RA in Finland is approximately 0.8% (2). A slight trend towards an increased incidence might be present in our cohort, since in years 2012 and 2014 6-7 new patients were found compared to 0-4 new patients detected in each of the previous years, and in the last 7 years of data collection, the total number of new patients amounted to 27, compared to 19 new patients between years 2001-2007. One should bear in mind the variable ICD-coding used and the fact that patients without HRCT were excluded from the cohort. Thus, this can only be considered as a directional result.

This study represents real-life data from clinically significant RA-ILD in Finnish patients in whom we conducted a retrospective study by gathering and re-evaluating the demographic and clinical data extremely thoroughly. We have shown that there is variability in the course of the disease depending on the presence or absence of definite UIP pattern in HRCT. The patients with the UIP pattern more often 1) needed oxygen therapy, 2) were admitted to hospital care due to respiratory reasons and 3) suffered from an accelerated PFT decline in comparison with those with the non-UIP subtype. We applied the GAP and ILD/GAP scores in RA-ILD patients and, as far as we are aware, we are the first group to demonstrate the suitability of these risk prediction models in RA-ILD. We have also revealed several radiological and other findings associated with reduced survival.

6.1 GENERAL DISCUSSION OF THE STUDY DESIGN

6.1.1 Search for the patients and sample size Identifying the RA-ILD patients from hospital registers was challenging. The coding of the diagnoses has varied over the years and no standardized policy in the use of ICD-10 codes has been applied in clinical practice. Therefore, we decided to use a common pulmonary fibrosis code J84.X, even though it resulted in mainly finding IPF patients. Another search was conducted using common RA diagnoses M05.X and M06.X with the additional criterion that the patient had been examined / treated in the KUH pulmonology clinic. The inclusiveness of the searches was further ascertained with a third search using a code J99.0*M05.1. A similar search strategy with pulmonary fibrosis and RA codes has been used by other study groups also for the identification of suspected ILD patients (10,179). Another frequent method is to gather all RA patients from the studied area/hospital using different

53

registers and then evaluate the SLBs or HRCTs in these subjects to identify those with ILD (153,225), but often the exact data of how patients were detected is not provided. Our first search with the above-mentioned ICD-codes encompassed the years 2002-2012, resulting in the identification of approximately 50 RA-ILD patients. At that time, we considered broadening the searches to other Finnish hospitals but that would have delayed the research for several months or even years, as no appropriate registers of RA-ILD patients existed and new investigators would have needed to be recruited. Therefore, we decided to extend the search years instead. In 2015, when the patient search was underway, the current study population of 60 patients was similar in size with the majority of other RA-ILD publications, except for one or two UK/USA studies, where larger cohorts are possible due to their larger populations.

Overall, medical records of over thousand patients had to be reviewed to achieve this study population of 60 RA-ILD patients, which is similar in size as most of the published reports (80,89,161), except for a few multicenter studies (73,225). It was our intention to investigate clinically relevant RA-ILD patients, and thus those patients with only minimal changes in their HRCTs were excluded. It is also probable that all RA-ILD patients have not been diagnosed with ILD.

6.1.2 Data gathering and missing data One strength in our cohort is that it is very well characterized since we gathered the data highly inclusively. In other investigations the gathered data has varied, especially the symptoms have often not been reported (73,179,225). Some studies lack RA serology (95), some PFT and smoking data (179) and some report only the percentage of current smokers (161). It is rare that all the above-mentioned data as well as comorbidities and causes of deaths have been evaluated from the same cohort and moreover our study is the first where hospitalizations and the use of oxygen have been investigated in RA-ILD patients.

In a retrospective study protocol, there are always problems with missing data. To minimize this error, we have gathered the demographic data in a detailed manner using a specially designed form and gathered the data not only from KUH databases, but also from other hospitals and primary health care centres in which the patients had been treated. We believe that this approach has reduced the missing data to an absolute minimum. The smoking data was lacking from one patient (1.7%), RF from two (3.3%), baseline spirometry from five (8.3%) and baseline DLCO results from eight (13.3%) patients. Other retrospective studies have confronted similar problems with missing data. For example, in a study of 77 RA-ILD patients the RF data was missing from 1.3%, smoking data from 11.7% and ACPA data from 44.2% (80). It is also worth remembering that at least in a small country like Finland with a population of 5.5 million, it would take a very long time to gather a similar size RA-ILD cohort using a prospective study protocol.

6.1.3 Implication of the RA medication In a retrospective study, the patients have received highly variable treatments for RA and/or ILD without being followed using a standardized protocol, making it impossible to evaluate the effects of any specific treatment. We collected and reported, however, the medication used at the time of ILD diagnosis and the lifetime usage of biologic drugs, MTX and corticosteroids. Similar tactics have also been exploited in other reports (37,95,225) with medication history being obtained from a medical record charts similarly as in our study, while some reports have left RA medication unreported (39,73).

6.1.4 Diagnostics Since histological data was limited, the re-categorization into different RA-ILD subtypes was performed radiologically, which is a common policy in ILD studies (90,100,194). This re-categorization can be considered as reasonably reliable, since a definite UIP pattern in HRCT has been proven to be a sensitive and specific method to detect the histopathologic

54

UIP in both IPF and RA-ILD. Assayag et al investigated 69 biopsy-proven RA-ILD patients from three tertiary care centres who also had undergone a CT scan within 12 months of their SLB (113). They observed that a definite UIP pattern on a CT was highly specific (96%; 95%CI 81-100%) with a negative predictive value of 53%, and rather sensitive (45%; 95% CI 30-61%) with a positive predictive value of 95% (113). Similar results have also been reported from IPF studies, with a definite UIP pattern in CT showing specificity of 90-95% and sensitivity of 79 – 85% in depicting a histopathologic UIP pattern (112,114). Therefore, we are confident that the UIP subgroup in this study reliably represents true RA-UIP patients. It is, however, possible that some patients re-categorized into the NSIP or unclassified subgroups may be suffering from histopathological UIP. Another strength that increases the reliability of our re-categorization is the fact that a large proportion of the cases / HRCT scans were evaluated in a MDD.

6.1.5 Reliability of the radiological re-categorization The inter-observer agreement of our study (III) was in line with a previous report from Assayag et al (113), in which the agreement of UIP using strict criteria (definite UIP vs. possible UIP + inconsistent with UIP) was good (κ = 0.67) and moderate (κ = 0.52) when using the broader criteria (definite + possible UIP vs. inconsistent).

6.2 CLINICAL FEATURES OF THE COHORT

6.2.1 Subject characteristics and PFT The mean age of the patients and the amount of cases in which ILD preceded RA were similar as described in a recent multicentre UK study (73). In our study, there was almost equal numbers of both genders. Since RA is twice as common in females (226), our gender distribution supports previous findings that male sex is a risk factor for ILD development (4,7). The PFTs, especially FVC, were rather well preserved in our cohort, which indicates that the patients had been diagnosed earlier than in many other studies. For example, FVC was normal in 55.6% of our patients, and the mean baseline value was as high as 84.8%, whereas others have reported mean FVC values in a range 69-75% (139,153). This may be partly explained also by our rather large proportion of never-smokers (42.9%) e.g. compared to 36% in the study of Solomon et al (153). In our cohort, dyspnoea was more common and cough as common, as in the biopsy-proven group of 54 RA-ILD cases of Nakamura et al (161). The difference in the numbers of patients suffering from dyspnoea may be explained by the larger proportion of UIP cases in our cohort (59% vs. 28%), although inspiratory crackles, more often present in RA-UIP cases in our cohort, were as common in both studies (161).

6.2.2 Radiological features and their correlation to RA duration (III) The proportion of different radiological subtypes after the re-categorization was in line with the previous literature (148,227), with UIP being the most common subtype. Our most commonly observed radiological findings i.e. reticulation (93.1%) and GGO (72.4%) were also in line with previous investigations, since Tanaka et al. reported 90% of 63 RA-ILD patients having GGO and 98% having reticulation (31). In the same study, also the frequencies of honeycombing (60%), emphysema (24%) and traction bronchiectasis (75%) were very similar as encountered in our works (53%, 29% and 60%, respectively), but nodules were much more common in their study (49% vs. 4%), the reason for this discrepancy is unclear (31). Another study with 29 RA-ILD patients reported the most common radiological observations as being reticulation (72%) and GGO (66%) (29). In that study, of the 14/19 patients with likely definite and possible UIPs with reticulation with or without honeycombing underwent a follow-up CT, in which progression of the disease was detected in 79% of the patients (29). In our study, 13/17 RA-UIP patients showed

55

progression of the disease. Moreover, nine patients that initially could not be categorized to any specific subgroup later developed more distinct features and 7 of them fulfilled definite UIP criteria based on the follow-up scan. This gives the impression that if RA-ILD patients were followed longer and if HRCT was repeated, then a more accurate diagnosis could probably be made.

In the study of Kim et al, the RA duration was longer in the RA-UIP than in the non-UIP patients (95). A similar result has been observed by others, with those patients with a predominantly reticular pattern on HRCT having a longer duration of RA than those with predominantly ground-glass pattern (94). In our study, GGO was negatively correlated with the duration of RA, which could indicate that GGO is an early phenomenon in RA-ILD, thus being in line with the above-mentioned investigations. Conflicting reports have, however, been published. In one study, GGO was as prevalent in early as in longstanding RA (43) and thus, the timeframe of GGO development remains unclear and might vary from patient to patient.

6.2.3 BAL results In our retrospective study, BAL samples were taken using variable techniques and only 16 out of 22 samples were representative. The total amount of saline was mentioned in 5 cases, varying between 50 to 300 ml given in 2-6 doses. It was impossible to evaluate the impacts of exogenous factors of e.g. smoking, infections, drugs on the BAL results. Ten out of 16 BAL samples with differential cell counts were abnormal, which is in line with several previous studies (7,104,105). Some differences were observed between RA-ILD subtypes, but the number of samples was so limited that it is hard to draw any definitive conclusions. BAL techniques vary in different countries and different hospitals and the indications when BAL is performed are variable. In RA-ILD, BAL should perhaps have a greater role than in other ILDs, since the patients are receiving immunosuppressive medication and thus at a higher risk of developing opportunistic infections and experiencing drug reactions. The differential diagnostics of these illnesses can be challenging and evaluation of BAL can be helpful to some extent. The ATS Guideline of BAL recommends BAL being performed in cases with non-diagnostic HRCT, using a standardized technique and always including a differential cell count (107). As noted in our study, this has not been a common policy in clinical practice.

6.2.4 Original radiological reports There is no formal recommendation or a guideline about the use of the IIP classification in CTD-ILD patients. The classification has been gradually introduced into use quite recently, especially in the last 5-7 years. In the 2002 ATS/ERS international multidisciplinary consensus classification of IIPs, it was stated that in the case of a suspected diffuse lung disease, the presence or absence of typical UIP pattern should be determined (18). However, as our data shows, the UIP pattern was not mentioned in a routine manner in the radiological reports of RA-ILD patients and actually, the process of adopting the IIP classification into use has been rather slow also in patients with IIPs. Interestingly a high proportion of the NSIP patients had NSIP mentioned already in their original reports which could be due to the fact that previously mainly the NSIP pattern has been associated with CTD-ILDs, whereas UIP mostly was perceived as an IPF-related pattern. Gradually, an increasing number of studies has revealed the high proportion of UIP patients in RA. In our cohort, it seemed that by the year 2011, the UIP/IIP definitions were being better adopted also in the non-idiopathic ILDs and the reports more often contained a specific classification.

6.2.5 Disease course in UIP and non-UIP patients (I) Differences in the course of the disease in distinct RA-ILD subtypes have not been studied extensively, apart from the differences in survival. In our study, the lung disease was more

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progressive in the UIP subgroup based on the number of deaths, greater need for oxygen therapy, hospitalization due to respiratory reasons and the decline of PFT. The last of those findings was confirmed in a recent study, in which the PFTs of 167 RA-ILD patients were evaluated at baseline and then annually, when available, up to 10 years after ILD diagnosis. It was found that the UIP pattern was a risk factor for DLCO progression (140). Moreover, the need for supplemental oxygen was more common to some extent among patients with UIP compared to NSIP patients, similarly as observed in our study, although this difference did not reach statistical significance (140). In longitudinal analyses, significant differences between groups of IPF and CTD-UIP were not detected in changes of FVC% or DLCO%, but nonetheless those subjects with IPF had a poorer survival (228).

6.3 COMORBIDITIES AND CAUSES OF DEATHS (I)

The most common comorbidities in our study were hypertension and CAD, which was much more common (36%) in our cohort than in the Danish cohort (13%) of 679 RA-ILD patients (179). We also had a double amount (22% vs. 10%) of diabetics and a three-fold higher amount (27% vs. 9%) of patients with heart failure (179). This could reflect the unfavourable genetic background in eastern Finland. Indeed, an IPF cohort of KUH region revealed very similar comorbidity rates as encountered in our study: CAD 49%, diabetes 27%, heart failure 27%, hypertension 46% (vs. 51% in our study) (229).

COPD was observed in almost 30% of the patients, which is in line with a recent study revealing a 48% prevalence of emphysema (230). Interestingly, COPD was more prevalent in UIP individuals, even though smoking was similar in UIP and non-UIP groups.

There is some evidence for an association between ILD and lung cancer. One study compared 18 RA-ILD patients with 18 matched IPF patients and observed more patients dying from lung cancer in RA-ILD (147). In our study, lung cancer was present in only 2 patients (3.4%), whereas in the IPF cohort from the same district, a higher proportion i.e. 6.8% was observed, even though the amount of non-smokers was almost identical (our 39.7% vs. their 35.2%) in both studies (229).

Earlier, some studies have addressed causes of death in RA-ILD patients and reported results similar to ours. Hakala et al. claimed that 80% of the patients died because of progression of the lung disease (141). In another RA-UIP cohort of 10 patients, there were 5 deaths and all of them were attributable to respiratory diseases with three steady progressions of ILD, one pneumonia and one acute exacerbation (96). Moreover, Tsuchiya et al. reported that in their cohort of 144 RA-ILD patients, there were 71 deaths of which most (58/81.7%) were due to respiratory reasons. The reported respiratory complications included 19 UIP exacerbations, 9 pneumonias, 4 other pulmonary infections, 13 ILD progressions, 6 lung cancers, 3 bronchiectasis exacerbations, 2 pneumothoraxes and 2 pneumonitis (drug- or radiation- induced) (148). However, it is somewhat unclear how exacerbations were distinguished from different respiratory infections. Our results concerning causes of deaths are in line with the previous reports, as in our cohort also the patients mostly died because of the ILD. This was especially the case with the RA-UIP patients, with more people in the non-UIP group having CAD as the primary cause of death, even though this finding did not reach statistical significance.

Other reports have not separated underlying and immediate causes of deaths and thus we are providing some novel data about this topic. It is possible that some of the patients whose immediate cause of death was coded as pneumonia actually suffered from AE, but this is impossible to ascertain in a retrospective study protocol. This hypothesis is perhaps supported by our novel finding of the correlation between the hospitalizations due to respiratory reasons and the extents of honeycombing and architectural distortion, i.e. features most typical in UIP in which the AEs are most common (133) and in which group most deaths occurred.

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6.4 SURVIVAL (I)

Previous publications have reported variable results concerning the survival of RA-ILD patients. Some have reported survival as being as poor as in IPF i.e. 2-3 years (4,37,146), while other have demonstrated survival times of up to 6-8 years (143,148) in line with the present study. One possible reason for the longer survival is the fact that in this study we included also patients with the OP pattern. The studies investigating mortality of RA-ILD have often consisted only of UIP and NSIP, but not of other types of ILDs. Another possible reason is the large proportion of patients with well-preserved PFT. Furthermore, almost 24% of the patients had received treatment with biological drugs, which may be speculated to have influenced their survival.

In our study, the difference in median survival between UIP and non-UIP patients did not reach statistical significance, even though the difference was almost four years (92 vs 137 months). This could be a consequence of our rather small study population. Among the UIP patients, there were eight patients that have stayed alive for over 10 years, three for over 15 years and two with an extremely indolent course of disease who have lived for over 20 years. All the above-mentioned patients had a definite UIP pattern in HRCT and no explanatory reason for their long survival could be detected. In a previous study of biopsy-proven 48 RA-ILD patients, no differences in survival for patients with UIP, fNSIP or unclassifiable fibrosing ILD were observed, but when these were pooled into one “fibrotic” category and compared to a “non-fibrotic” group consisting of cNSIP, DAD, DIP, LIP and OP patients, the fibrotic ILDs had significantly worse survival (146).

6.5 PREDICTORS OF MORTALITY (II, III)

6.5.1 Pulmonary function tests and CPI Previously, several studies have highlighted the importance of pulmonary physiology when evaluating the risk of death. In fibrotic IIPs, for example, the pulmonary physiology appeared as an even stronger predictor of survival than the histopathologic pattern (165). In our study, the baseline DLCO, but not FVC, was an independent risk factor for mortality in the univariate analysis and retained its significance after adjusting for age. This could be explained by the relatively high mean baseline FVC and/or by the small patient cohort. Not all studies have, however, been unanimous when investigating the role of FVC in predicting mortality. In the study of 84 RA-ILD patients conducted by Kim et al., FVC did not act as an independent predictor of death, despite the lower mean FVC values than in our study (95) whereas others have demonstrated that a lower baseline FVC value and the FVC decline over time were both associated with an increased hazard of death (139,153).

Various studies have identified the association of DLCO with survival either in univariate (95,146), or multivariate (95) models, a finding which we confirmed here. Some investigators have also used longitudinal methods and substantiated that a decline of 10% or more in DLCO as being a significant predictor of mortality in RA-ILD (153) or RA-UIP cohorts (139), as well as a predictor of progressive disease (140). Unfortunately, it was not possible to conduct multivariate models with our small cohort and the missing follow-up data prevented longitudinal investigations of PFT.

The CPI score has been investigated by other groups. In line with the results of our study, Solomon et al revealed CPI to be a significant predictor of mortality in a univariate model, but not in the multivariate model which controlled for age, gender, smoking, baseline FVC and HRCT pattern (153).

6.5.2 Clinical factors Previously male sex has been associated with worse survival. Solomon et al. investigated 137 RA-ILD patients and observed a hazard ratio for mortality of 0.58 in females (153). In

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another retrospective study of 82 patients with RA-ILD, female sex was associated with better survival in both bivariate and multivariate models (95). Male sex, contrary to the above-mentioned reports, was not a statistically significantly associated with mortality in our study. Nonetheless, our survival analyses did reveal a tendency towards a better survival in non-UIP females. The mean amount of hospitalizations due to respiratory reasons was an independent predictor of mortality in our univariate analysis, which seems to be a novel finding as we have been unable to find any other report investigating this parameter in RA-ILD patients. However, a similar result has been observed previously in an IPF study, in which a 24-week history of respiratory hospitalization was associated with a more than fourfold increase in the risk of death (175). The RF positivity was not a significant prognostic factor in our study nor was it in a Danish population-based cohort study of 679 RA-ILD patients (179), but in contrast, in a very recent study, a high titer of RF was associated with poor survival (80).

6.5.3 Radiological factors associating with decreased survival Our study revealed that the extents of reticulation, traction bronchiectasis and architectural distortion were associated with decreased survival, the last of these, as far as we are aware, is a novel finding. We used a semi-quantitative method to evaluate the extents of different findings. A similar method has been previously used in one study of RA-ILD, which we believe is also the only previous RA-ILD study which has investigated the association between different radiological details and mortality (95). In that other study, the extents of GGO, reticulation, traction bronchiectasis and honeycombing were graded as absent, mild, moderate or severe similarly as conducted in our study. They observed that the presence of reticulation, traction bronchiectasis and honeycombing, as well as the extents of honeycombing and traction bronchiectasis were independently associated with worse survival (95). Thus, the results of both studies are rather similar, although they did not investigate the role of architectural distortion as a predictor of mortality. Another study of 168 CTD-ILD patients (including 39 RA-ILD) also reported that the severity of traction bronchiectasis, graded on a scale 0-3, and the extensiveness of honeycombing were associated with an increased death hazard (159). The fact that their study population was mostly constituted of patients with other than RA-related ILDs complicates the comparison of the results. In addition, the method was different, since they estimated extents of all other findings other than traction bronchiectasis to the nearest 5% (159).

Some studies have explored the association between CT findings and survival in the patients with IIP. In the study of Edey et al., the extent of traction bronchiectasis was graded on a scale 0-3 when other findings were estimated to the nearest 5% and then the average scores of 6 levels of both lungs were used to calculate a global disease score (231). These investigators observed somewhat similar results as us, since the extents of reticulation and traction bronchiectasis were associated with worse survival. In addition, the overall extent of any lung abnormalities and honeycombing were also related to poor prognosis (231). Another study of 98 biopsy-proofed IPF patients reported that traction bronchiectasis and fibrosis scores were significant predictors of outcome (232).

6.6 VALIDATION OF THE GAP AND ILD-GAP MODELS (II)

In our study, both GAP and ILD-GAP could provide relatively accurate estimations of mortality in stage I and II patients, whereas stage III patients were not present in our study for some unknown reason. In a previously published Danish ILD cohort, 32% of the 115 IPF patients belonged to stage I, 48% to stage II and 20% to stage III (157). Other investigators have reported GAP stage III patients to account for approximately 14-22% of the studied IPF cohorts (233,234).

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Interestingly, the ILD-GAP index was more accurate at predicting 1-year mortality, whereas in the 2-year and 3-year prediction, the GAP index was slightly more accurate. Our study was the first one to investigate these risk prediction models in a RA-ILD cohort, although previous studies have been conducted on IPF and SSc-ILD patients. In Korean IPF patients, GAP produced accurate 1-year, but not 3-year, mortality estimates (234). In another cohort of IPF patients, the GAP staging was found to be useful for evaluating the IPF severity, revealing statistically significant differences in survival in different GAP stages (233). The GAP index, however, displayed poor applicability for the predicted 1-year mortality in SSc-ILD patients (235).

After the publication of our results (236), two studies have investigated the applicability of the GAP model in RA-ILD patients. The first report investigated 309 RA-ILD patients and stated that the discrimination of the model was similar to that previously reported in IPF patients and that the addition of other variables, for example a definite UIP pattern, did not improve the discrimination of the model (225). They also reported that GAP Index and a staging system had satisfactory capabilities in predicting mortality at 1, 2 and 3 years (225). In another study of 181 RA-ILD patients, the GAP model demonstrated good calibration and discrimination in both sexes and all types of ILD, but the ILD-GAP did not perform as well as the GAP model (237). We observed that the 2-year mortality in stage I patients was much higher than predicted by the ILD-GAP model, which also underestimated the 3-year mortality of stage I patients.

It remains unclear which of the risk prediction models is better suited for patients with RA-ILD. The ILD-GAP was originally developed in a study protocol including all kinds of ILDs without considering the variable prognosis and courses of diseases in different CTD-ILDs. It has been pointed out that patients with other CTD-ILDs enjoy a better survival than those with RA-ILD (110,162). At least partly, this could be a consequence of the higher proportion of UIP patients in RA-ILD (96). Therefore, it can be debated whether the ILD-GAP is truly valid for all CTD-ILDs.

It is also worth pondering whether the accuracy of GAP/ILD-GAP models would improve with additional variables, such as smoking or symptoms. Originally, when the GAP model was being designed, the researchers considered several commonly available predictor variables, such as body mass index, smoking status and the use of long-term oxygen and the best combination of variables was screened using complex and sophisticated statistical methods (177). Oxygen use was removed due to its different effects in the derivation and validation cohorts. Dyspnoea was omitted because it was not available in the validation cohort (177). Very recently, it was shown that combining position emission tomography data with GAP data was able to improve the models´ ability to predict mortality (238). Future research might well devise improved versions of the prediction models, but overall for any staging system, it is important to keep it simple and repeatable in order to make possible its use in daily practice.

6.7 FUTURE PERSPECTIVES

Historically, when compared with the remarkable advances in clarifying the articular aspects of RA, RA-ILD has remained poorly understood, under-recognized, undertreated, even its very existence doubted. Gradually, RA-ILD research has attracted more interest. With the help of modern imaging possibilities and less risky biopsy procedures, it is now possible to increase our knowledge of this illness. Accurate biomarkers could help to recognize those patients who are at high risk of rapidly progressing disease and those who remain stable, which might allow clinicians to target interventions to patients at the highest risk. Moreover, disease monitoring could be planned more personally if it were possible to identify different courses of diseases already during their early phases. Patients with a potentially lethal disease deserve proper counselling; this is easier to accomplish if we can

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identify those at the highest risk of disease progression or death. Risk prediction models, such as GAP, could offer a framework for discussing prognosis and hopefully their use will increase in clinical practise. Another important and under-used utilization of GAP is in the decision-making of when to refer a patient for LTx. For example, if the 1-, 2- or 3-year risk for mortality predicted by GAP surpasses the published risks for mortality after LTx, the patient should be screened and listed for transplantation, if appropriate. In some countries, risk estimation with GAP is already required in IPF patients that are referred to LTx.

Key areas in future RA-ILD research include also other treatment strategies. If we are to discover new treatment options or to ascertain the safety profile of currently available biologic or other drugs, it is crucial to conduct well-designed clinical trials. GAP or other risk prediction models would probably also be useful in various areas of research. If the patients could be categorized into different groups by their predicted risk of death, this would enable the evaluation of identifying which patients would obtain the greatest benefit from the investigated drug. Results of the ongoing clinical trials on antifibrotics are eagerly awaited and perhaps in the future these will become available for RA-ILD or RA-UIP patients.

The diagnosis, not to mention treatment, of RA-ILD/CTD-ILD is not straightforward. The disease is so rare, that national/international collaboration, such as national register or biobank, should be considered since this would make possible examining larger study populations and samples. ILD research continues actively in KUH in collaboration with other hospitals. Cohorts of asbestosis and IPF have already been gathered from KUH databases using the same data collection form as used here, making comparative studies possible in the future.

This thesis has highlighted the clinical importance of RA-ILD. We found rather many RA-ILD patients in KUH region and our coarse estimations suggested that the incidence is rising also in this region, as other reports have indicated is the case elsewhere. These patients deserve to be well diagnosed and assessed as candidates for modern treatment protocols. The recognition of RA-ILD is important in every day clinical practice as a part of ILD differential diagnostics, since ILD can be the first manifestation of RA and furthermore, since most RA-ILD patients reveal a UIP pattern similarly as IPF.

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7 Conclusions

1. During 1.1.2000-31.12.2014, a total of 60 clinically relevant RA-ILD patients were treated in the KUH pulmonology clinic. Of those, 60% revealed a UIP pattern, followed by 13.3% NSIP, 11.7% OP, 1 DAD with the rest having an unclassifiable subtype. The RA-UIP patients followed a distinctive and more progressive course of disease based on the higher number of deaths, greater use of oxygen therapy, more extensive decline in PFT and the increased number of hospitalizations. Although different comorbidities were frequent, the RA-ILD patients mostly died because of the ILD itself.

2. Both GAP and ILD-GAP can provide relatively good estimates of mortality in RA-ILD patients, even though it remains unclear which of these models would be better suited for these patients. In addition, CPI and baseline DLCO are associated with shortened remaining lifetime.

3. Reticulation and GGO are the most common radiological findings in RA-ILD

patients, and can be present in every subtype. Rather than the presence of different findings, it is their extent that is clinically important; this can be estimated using a semiquantitative method. The extents of reticulation, traction bronchiectasis and architectural distortion are associated with decreased survival. The two last parameters also correlate with the number of hospitalizations, as does the extent of honeycombing. HRCT findings can be useful when evaluating the risk of death and the course of the disease.

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ORIGINAL PUBLICATIONS (I-III)

I

Variable course of disease of rheumatoid arthritis-associated usual interstitial pneumonia

compared to other subtypes.

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

BMC Pulm Med 16:107-016-0269-2, 2016.

Reprinted with the kind permission of BMC Pulmonary Medicine.

The original article is an open access article distributed under the terms of Creative

Commons Attribution License which permits unrestricted use, distribution, and

reproduction in any medium, provided the original work is properly cited.

RESEARCH ARTICLE Open Access

Variable course of disease of rheumatoidarthritis-associated usual interstitialpneumonia compared to other subtypesHanna M. Nurmi1,2*, Minna K. Purokivi1, Miia S. Kärkkäinen2,4, Hannu-Pekka Kettunen5, Tuomas A. Selander6

and Riitta L. Kaarteenaho1,2,3

Abstract

Background: In rheumatoid arthritis-associated interstitial lung disease (RA-ILD), occurring in 10 % of patients withpatients with RA, usual interstitial pattern (UIP) has shown to associate with poor prognosis but more detailed dataabout the course of the disease in different subtypes is limited. Our aim was to compare the disease course ofpatients with RA-ILD categorized into either UIP or other types of ILDs.

Methods: Clinical and radiological information of 59 patients with RA-ILD were re-assessed and re-classified intoUIP or non-UIP groups, followed by a between-group comparison of demographic data, lung function, survival,cause of death and comorbidities.

Results: The majority of patients (n = 35/59.3 %) showed a radiological UIP-like pattern in high resolutioncomputed tomography. The median survival was 92 months (95 % CI 62.8–121.2) in the UIP-group and 137 months(95 % CI 31.0–243.0) in the non-UIP-group (p = 0.417). Differences in course of disease were found in the number ofhospitalizations for respiratory reasons (mean 1.9 ± 2.6 in UIP vs. 0.5 ± 0.9 in non-UIP group, p = 0.004), the use of oxygentherapy (8/22.9 % UIP patients vs. 0 non-UIP patients, p = 0.016), number of deaths (23/65.7 % vs. 10/41.7 %, p = 0.046)and decline in diffusion capacity (56 ± 20.6 vs. 69 ± 20.2, p = 0.021). Dyspnea and inspiratory crackles were detected moreoften in the UIP group. RA-ILD was the most common primary cause of death (39.4 % of cases). Hypertension, coronaryartery disease, chronic obstructive pulmonary disease, heart insufficiency, diabetes and asthma were commoncomorbidities. ILD preceded RA diagnosis in 13.6 % of patients.

Conclusions: The course of the disease in RA-UIP patients is different from the other RA-ILD subtypes. Severalcomorbidities associated commonly with RA-ILD, although ILD was the predominant primary cause of death.

Keywords: High-resolution computed tomography, Cause of death, Comorbidity

BackgroundInterstitial lung disease (ILD) is a rather common extra-articular manifestation of rheumatoid arthritis (RA) anda major cause of morbidity and mortality in RA patients[1, 2]. Approximately 10 % of patients with RA may de-velop clinically evident ILD with respiratory symptomsand/or a decline in pulmonary function tests [3]. In

asymptomatic RA patients, high-resolution computedtomography (HRCT) scans commonly reveal evidenceof interstitial lung involvement, and a large proportionof those with subclinical disease deteriorate with time[4, 5]. However, the clinical course of RA-ILD is highlyheterogenic, as some patients remain stable for years,even decades, while others develop an insidious pro-gressive disease [6].While the overall mortality in RA has declined, the

numbers of deaths due to RA-ILD have increased [7], al-though the results of studies investigating survival havebeen variable. Some studies have reported survival of3 years, similar to that of idiopathic pulmonary fibrosis

* Correspondence: [email protected] of Medicine and Clinical Research, Division of Respiratory Medicine,Kuopio University Hospital, POB 100, 70029 KYS Kuopio, Finland2Division of Respiratory Medicine, Institute of Clinical Medicine, School ofMedicine, Faculty of Health Sciences, University of Eastern Finland, POB 1627,70211 Kuopio, FinlandFull list of author information is available at the end of the article

© 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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(IPF) [8, 9], whereas in others the prognosis of RA-ILDhas been significantly better, with median survival of ap-proximately 6–8 years [10, 11].Since it lacks its own distinctive classification, the

subtypes of RA-ILD have been categorized accordingto the subdivisions of the idiopathic interstitial pneu-monias (IIP) [12]. Unlike the situation in other con-nective tissue diseases (CTD), the most commonradiologic and histopathologic pattern of RA-ILD isusual interstitial pneumonia (UIP), whereas nonspe-cific interstitial pneumonia (NSIP) and other subtypesalso exist to a lesser extent [13]. The clinical signifi-cance of these different histological and radiologicalpatterns has become nowadays more important sincethe RA-ILD patient with the UIP pattern (RA-UIP)seems to have a significantly worse prognosis and re-duced survival compared to other types such as NSIPand organizing pneumonia (OP) [11, 14–16]. Otherdifferences in the course of the disease in distinct RA-ILD subtypes, in addition to the difference in survival,have not been widely studied so far.Recently the significance of radiologic and histo-

pathological subtyping of RA-ILD was highlighted asone important area for future investigation [17]. Littleis known about concomitant diseases or causes ofdeath of RA-ILD patients. The few studies that haveaddressed cause of death in these patients, have beenunanimous that the majority of deaths are due to re-spiratory disease either after an exacerbation, infectionor simply due to the steady progression of the ILD[11, 13, 18].The aims of this study were to investigate the numbers

and subtypes of the patients with RA-ILD treated inKuopio University Hospital (KUH), in Eastern Finland,during 2000–2015. The course of the disease, survival,co-morbidities and cause of death were evaluated andcompared between UIP and non-UIP cases.

MethodsSearch and evaluation of dataThe subjects for the study were identified from the data-base of KUH using two International Classification ofDiseases (ICD-10) codes, namely J84.X and M05.X/M06.X. (Fig. 1). From these patients we only includedthe subjects that had been examined or treated in thepulmonology in-patient or out-patient clinic between1.1.2000 and 31.12.2014 for any respiratory symptoms orany suspected pulmonary disease, thus omitting thoseRA patients with no symptoms or chest X-rayabnormalities.A total of 1047 patients were identified and their pa-

tient records were evaluated. At baseline, the patientswith ILD but without RA (i.e. patients with IIP, otherconnective tissue disorders (CTD) or allergic alveolitis)and those with RA, whose visits to pulmonology clinicwere because of some other lung diseases (such asasthma, chronic obstructive pulmonary disease (COPD),obstructive sleep apnea) were excluded. We also ex-cluded suspected but not confirmed RA-ILD patients,for whom HRCT, or other comparable radiologicalexamination capable of allowing reliable analysis of thelung parenchyma were not available, as were those pa-tients whose RA diagnosis was not certain according tothe 1987 classification criteria [19], or who developedlater mixed CTD- like symptoms.Another 38 patients were excluded subsequently after

the evaluation by the radiologist and/or after a multidis-ciplinary discussion due to the very minor signs or non-specific features for ILD, leaving a total of 59 RA-ILDpatients to be studied in detail and classified.Clinical information was gathered from the patient re-

cords of KUH, primary health care centers and otherhospitals using a specially designed form. Demographicdata included date of birth, sex, occupation, smokinghabits, exposure to asbestos, radiation therapy of the

J84.X / M05.X + M06.X + a visit to the

pulmonology clinic

n=1047

No RA, No ILD, No HRCT

-> excluded n=950

Suspected RA-ILD n=97

RA-ILD n=59

35 RA-UIP

8 RA-NSIP

7 RA-OP

1 RA-DAD*

8 unclassified

MDD/pulmonary radiologist evaluation

-> excluded n=38

Fig. 1 The study protocol and the final categorization of the patients with RA-ILD. *additional 2 DAD findings included in OP group (n = 1) andUIP group (n = 1)

Nurmi et al. BMC Pulmonary Medicine (2016) 16:107 Page 2 of 10

thorax region, date of RA diagnosis, date of the first visitto pulmonology clinic due to ILD, comorbidities, deathcertificates, use of long term oxygen therapy, symptomsand respiratory status findings at baseline, laboratory testresults including rheumatoid factor (RF) and antinuclearantibody (ANA) titer and surgery due to RA. Antibodiesagainst cyclic citrullinated peptide were not available forhalf of the patients. The results of lung function tests,such as spirometry including forced vital capacity (FVC),forced expiratory volume (FEV1) and diffusion capacityto carbon monoxide (DLCO), were gathered at baselineand, when available, during the follow-up at 6 months,1 year, 2 year and so on annually, including also themost recent available results. Any medication in useprior to ILD diagnosis and also lifelong medication usedfor RA were recorded. Histological data also was col-lated. The numbers of hospitalizations due to either re-spiratory problems (including infections, suspected drugreactions and suspected acute exacerbations) or cardiacproblems like unstable angina pectoris, myocardial in-farctions, arrhythmias and cardiac failures were col-lected. Data from death certificates was also collected.An experienced radiologist evaluated baseline HRCTs

from these 59 patients. Radiological ILD categorizationwas conducted according to the 2013 IIP classification[12]. The radiological RA-UIP criteria were applied fromthose of IPF [20]. Mainly patients with a definite UIPpattern were included in the UIP group (32 out of 35,91.4 %). Three patients who displayed a slightly upper(n = 2) or mid-lung (n = 1) predominated distribution,were included after a multidisciplinary discussion.Patients with possible UIP, i.e. a subpleural and basalpredominated reticular abnormality without honey-combing, are not included in the UIP group. Whenavailable, an additional HRCT during the follow-up wasalso evaluated to reveal the progression of the lungdisease.The study protocol was approved by the Ethical Com-

mittee of Kuopio University Hospital (statement 17/2013).

Statistical analysisThe distribution of the continuous variables was verifiedwith Shapiro-Wilk test. If distribution was normally di-vided, the comparison was made using an independentT-test, otherwise Mann–Whitney U-test was applied.The chi-squared test or Fisher test, when appropriate,was used for categorical variables. Sex, smoking habits,laboratory results and the numbers of deaths are calcu-lated as percentages. Age at the time of RA-ILD diagno-sis and lung function results are expressed as mean ±SD. The mean values of the first and most recent avail-able FVCs and DLCOs were calculated in both UIP- andnon-UIP groups to determine whether there had been

any change in lung function. The mean values of bothgroups were compared using the independent T-test toevaluate possible differences in lung function tests at thetime of RA-ILD diagnosis and also the difference in lungfunction development. In survival analyses, we excludedthe patient who did not have an underlying ILD preced-ing acute DAD changes. Survival analysis was doneusing the Kaplan-Meier method and survival curveswere compared using the log-rank test. Survival timewas calculated from the first visit to the pulmonologyclinic due to ILD to the date of death or November 4,2015 when the vital status was ascertained. Survival re-sults are expressed as median (95 % confidence interval).We considered a p-value <0.05 as statistically signifi-

cant. All data was analyzed using IBM Statistics SPSSsoftware, version 21.0.

ResultsRadiologic findings and demographicsThirty-three (59.5 %) of the patients were male. Most ofthe patients (n = 35/60.3 %) were current or formersmokers (Table 1). Five (15.6 %) male and 18 (69.2 %) fe-male patients were never-smokers (p < 0.001). The meanage at diagnosis was 66 ± 11.1 years (range 32–87) differ-ing non-significantly in subgroups (UIP vs. non-UIP,non-smokers vs. ever-smokers, male vs. female). RF waspositive in 84.2 %, ANA in 17.8 % and antibodies againstcyclic citrullinated peptide (CCP) in 60.8 % of thepatients.The majority (35/59.3 %) of the patients showed a

radiological UIP-pattern in HRCT and the remainderwere NSIP (8/13.6 %), OP (7/11.9 %) and 8 patientswhose radiological features remained nonspecific,which we termed as unclassified (13.6 %). A diffusealveolar damage (DAD) pattern was detected in onepatient without an underlying ILD, thus likely repre-senting RA-DAD. Additional two DAD patterns wereseen in patients with OP and UIP diagnoses prior toDAD.No statistically significant differences were ob-

served between groups with respect to age, smoking,baseline lung functions or RA serology. Thirty-five(61.4 %) patients suffered from dyspnea and 31(60.8 %) from cough. Cough was equally common inboth groups, but dyspnea occurred more often in theUIP group (p = 0.022). Inspiratory crackles were more com-mon in UIP than in non-UIP patients (p = 0.007) (Table 1).

Medication for RA and RA-ILDSeventy-five percent of patients were receiving somemedication for RA at the time of RA-ILD diagnosis(Tables 1 and 2). In 11 cases the RA medication hadbeen markedly changed due to ILD diagnosis. In mostcases (9 out of 11), the change was a discontinuation of


methotrexate after the diagnosis of ILD. In two patients,either leflunomide or sulfasalazine was discontinued. Inall 11 cases (9 UIP, 2 NSIP), ILD continued to progressdespite the changes to their RA medication. There wereno differences between RA-UIP and RA-non-UIP groupsin their use of methotrexate or biological drugs (Table 1).Almost all patients (n = 54/91.5 %) had received gluco-corticoids at some point.Most i.e. 6/7 (85.7 %) RA-OP patients received gluco-

corticoid treatment for their lung disease and the sev-enth patient recovered without extra treatment. Of thesix steroid-treated RA-OP patients, 5 recovered com-pletely but one did not exhibit a clear beneficial responseto treatment. Five of the eight (62.5 %) RA-NSIP pa-tients were treated with high doses of prednisolone twoof them enjoying at least a partial response. Two NSIP

patients received cyclophosphamide treatment, but bothdeteriorated despite the treatment. In five RA-UIP pa-tients, high-dose cyclophosphamide plus high-dose ster-oid treatment was provided but without any positiveresponses.

SurvivalThirty-three (55.9 %) patients died with median survivalof 92.0 months in the UIP and 137.0 months in the non-UIP groups (p = 0.417, Table 3). Of the deceased pa-tients, the one with RA-DAD was excluded from thesurvival analysis. The number of deceased patients wassignificantly higher in the UIP group, i.e. 23/35 patientswith UIP (65.7 %) had died compared with 9/24 (37.5 %)patients with non-UIP (p = 0.046, Table 4). Although themedian survival in the whole group was longer in

Table 1 Clinical characteristics of the patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD), which havebeen classified according to the presence or absence of usual interstitial pneumonia (UIP) pattern in high resolution computedtomography (HRCT)

Characteristics RA-ILD RA-UIP RA-non-UIP P-value

(n = 59) (n = 35, 59.3 %) (n = 24, 40.7 %) (UIP vs. non-UIP)

Gender

Male 33 (55.9) 19 (54.3) 14 (58.3) 0.758

Female 26 (44.1) 16 (45.7) 10 (41.7)

Smokinga

Never 23 (39.7) 14 (41.2) 9 (37.5) 0.778

Ex-smoker 26 (44.8) 14 (41.2) 12 (50.0)

Current smoker 9 (15.5) 6 (17.6) 3 (12.5)

Age (y) 66 ± 11.1 66 ± 11.9 67 ± 10.0 0.597

Serology

Positive RFb 48 (84.2) 29 (85.3) 19 (82.6) 1.000

Pos. ANAc 8 (17.8) 5 (20.0) 3 (15.0) 0.716

Pos. anti-CCP antibodyd 17 (60.8) 10 (71.4) 7 (63.6) 0.504

Dyspneab 35 (61.4) 25 (73.5) 10 (43.5) 0.022

Coughe 31 (60.8) 17 (60.7) 14 (60.9) 0.991

Inspiratory crackles 41 (69.5) 29 (82.9) 12 (50.0) 0.007

FVC % pred 85 ± 17.0 82 ± 17.1 89 ± 16.5 0.164

DLCO % pred 71 ± 18.1 72 ± 20.7 70 ± 13.3 0.635

Medications

Steroids, ever 54 (91.5) 32 (91.4) 22 (91.7) 1.000

MTX, ever 35 (59.3) 18 (51.4) 17 (70.8) 0.136

MTX, when ILD diagnosed 15 (25.4) 6 (17.1) 9 (37.5) 0.078

Biological drugs, ever 14 (23.7) 7 (20.0) 7 (29.2) 0.416

Data presented as n (percentage) or mean ± SD. P-values calculated using Fisher test, χ2- test or independent T-testRA-UIP usual interstitial pneumonia (UIP) pattern in patients with rheumatoid arthritis (RA). RA-non-UIP Rheumatoid arthritis patients with other than UIP-patterninterstitial lung disease (ILD). FVC forced vital capacity. DLCO diffusing capacity of the lung for carbon monoxide. % pred: percentage of the predicted value. RF:rheumatoid factor. ANA: anti-nuclear antibodies. MTX: methotrexate. CCP: cyclic citrullinated peptideadata missing from 1 RA-UIP patientbdata missing from 2 patients (1 RA-UIP, 1 RA-non-UIP)cdata missing from 14 patients (10 RA-UIP, 4 RA-non-UIP)edata missing from 34 patients (21 RA-UIP, 13 RA-non-UIP)fdata missing from 8 patients (7 RA-UIP, 1 RA-non-UIP)


women (152 months) than in men (87 months) this dif-ference was not statistically significant (p = 0.305). Sur-vival between non-smokers and current/former smokerswas also similar in the whole ILD group (p = 0.525).Female and non-smoker individuals had a tendency to-wards longer survival than men and smokers in the non-UIP group, but not in the UIP-group (Table 3, Fig. 2a-d).

Causes of deathThe average age at death was 75.0 ± 9.1 years, rangingfrom 54.8 to 91.7 years. The UIP patients died slightly

younger than their non-UIP counterparts (73.6 ± 9.8 vs.78.2 ± 6.5, p = 0.187).According to the death certificates of the 33 deceased

patients, RA-ILD was the most common primary causeof death; 13/39.4 % cases (10 UIP, 3 non-UIP; p = 0.701),(Fig. 3). RA-ILD was primary cause of death equally inmen and women (8 vs. 5, p = 1.000) and in non-smokersand ever-smokers (6 vs. 7, p = 0.522). Coronary arterydisease (CAD) was the second most common primarycause of death in 7 individuals (21.2 %; 3 UIP, 4 non-UIP, p = 0.161). RA was the primary cause of death in 5

Table 2 The medications of the patients with RA-ILD

Medicine Ever used for RA or ILD N (%) Used at the time of ILD diagnosis N (%) Discontinued due to ILD diagnosis N (%)

Prednisolone 54 (91.5) 10 (16.9) 0 (0.0)

Azathioprine 42 (71.2) 8 (13.6) 0 (0.0)

Methotrexate 35 (59.3) 15 (25.4) 9 out of 15 (60.0)

Hydroxychloroquine 47 (79.7) 16 (27.1) 0 (0.0)

Sulfasalazine 45 (76.3) 16 (27.1) 2 out of 16 (12.5)

Leflunomide 12 (20.3) 2 (3.4) 2 out of 2 (100.0)

Penicillamine 5 (8.5)

Mycophenolate Mofetil 7 (11.9)

Sodium aurothiomalate 32 (54.2) 7 (11.9) 0 (0.0)

Cyclosporin 15 (25.4)

Cyclophosphamide 13 (22.0)

Chlorambucil 5 (8.5)

Podophyllotoxin 24 (40.7) 7 (11.9) 0 (0.0)

Etanercept 6 (10.2)

Infliximab 2 (3.4)

Golimumab 0 (0.0)

Adalimumab 5 (8.5)

Abatacept 1 (1.7)

Rituximab 11 (18.6) 1 (1.7) 0 (0.0)

Tocilizumab 1 (1.7)

The first column shows the number of patients receiving each medication at any point and of any duration during their lives. The second column shows thenumber of patients receiving any particular medication at the time of the RA-ILD diagnosis

Table 3 Survival of the patients (months) according to gender and smoking in subgroups

RA-ILD (n = 59) RA-UIP (n = 35, 59.3 %) RA-non-UIP (n = 24, 40.7 %) P-value (UIP vs. non-UIP)

Overall 107.0 (73.1–140.9) 92.0 (62.8–121.2) 137.0 (31.0–243.0) 0.417

Gender

Male 87.0 (46.0–128.0) 88.0 (31.0–145.0) 87.0 (33.0–141.0) 0.976

Female 152.0 (87.7–216.3) 92.0 (0.0–185.2) a 0.123

(p = 0.305) (p = 0.777) (p = 0.093)

Smoking

Non-smokers 152.0 (94.3–209.7) 92.0 (0.0–205.4) a 0.174

Ever-smokers 88.0 (29.4–146.6) 88.0 (30.0–146.0) 137.0 (43.6–230.4) 0.754

(p = 0.525) (p = 0.921) (p = 0.218)

Data are presented as median (95 % CI). The RA-DAD patient is excluded from the survival analysesaMedian survival cannot be calculated since only one death has occurred in this group


Table 4 Factors associating with the differential course of disease in the patients with rheumatoid arthritis associated usualinterstitial pattern (RA-UIP) and non-UIP patterns (RA-non-UIP)

Factor RA-ILD RA-UIP RA-non-UIP P-value

(n = 59) (n = 35, 59.3 %) (n = 24, 40.7 %)

Oxygen therapy 8 (13.6) 8 (22.9) 0 (0) 0.016

Hospitalization due to respiratory illness 1.29 ± 2.2 (0–11) 1.9 ± 2.6 (0–11) 0.5 ± 0.9 (0–4) 0.004

Hospitalization due to cardiac illness 0.6 ± 1.2 (0–5) 0.7 ± 1.3 (0–5) 0.4 ± 1.2 (0–4) 0.100

Latest FVC % pred 82 ± 21.2 78 ± 22.9 87 ± 17.2 0.091

(Baseline FVC %) 85 ± 17.0 82 ± 17.1 89 ± 16.5

Latest DLCO % pred 61 ± 21.3 56 ± 20.6 69 ± 20.2 0.021

(Baseline DLCO %) 71 ± 18.1 72 ± 20.7 70 ± 13.3

Number of deaths 33 (55.9) 23 (65.7) 9 (37.5)a 0.046

Data are presented as percentage or mean ± SD and also (range) in hospitalizationHospitalization comparison performed using Mann–Whitney U-test and the lung function comparison using an independent sample T-testaOne RA-DAD-patient is excluded from this group, P-value calculation and survival analyses

Fig. 2 a-d. Shorter survival (Kaplan-Meier, log-rank) of men was observed in the non-UIP group, but the difference was not quite statisticallysignificant (p = 0.093). Survival differences between genders in UIP group were not found (p = 0.777). In the non-UIP group, the non-smokingpatients seemed to survive for longer than ever-smokers i.e. current smokers and ex-smokers, but the difference did not reach statistical significance(p = 0.218). In the UIP group, no differences were found in survival between non-smokers and ever-smokers (p = 0.921)


cases (15.2 %). In the other cases, the primary causes ofdeath were Alzheimer’s disease, universal atheroscleroticdisease with acute ischemia in legs, acute pancreatitis,intestinal tuberculosis, chronic obstructive pulmonarydisease (COPD), massive bleeding due to pelvic fracture,lung cancer and suspected viral infection in the centralnervous system – each one case.Pneumonia and CAD were equally common as the im-

mediate cause of death (both 10/30.3 %; 6 UIP, 4 non-UIP) and RA-ILD (5/15.2 %; 4 UIP, 1 non-UIP) was alsoprevalent. Lung cancer, RA, diabetes, RA associated sec-ondary amyloidosis with renal failure, acute pancreatitis,diabetes, intestinal tuberculosis and gastroenteritis rep-resented immediate causes of death of single cases.

ComorbiditiesThe most common comorbidities were hypertension(30/50.8 %), CAD (21/35.6 %), COPD (17/28.8 %), heart

insufficiency (16/27.1 %), diabetes (13/22.0 %) andasthma (12/20.3 %) (Fig. 4). Gastroesophageal reflux(GER) occurred in 6 (10.2 %) and hypothyroidism in 3(5.1 %) patients. There were two lung cancers (3.4 %)and 9 (15.3 %) other cancers including basal cell car-cinoma (n = 2), diffuse large B cell lymphoma (n = 2),urinary bladder carcinoma (n = 1), colon adenocarcinoma(n = 1), squamous cell carcinoma in upper lip (n = 1) and intongue (n = 1) and carcinoma in ventricle (n = 1). Most ofthe cancers were not primary causes of death. Six (10.2 %)patients suffered from tuberculosis (five lung and oneintestinal). No statistically significant differences inthe comorbidities were found between UIP and non-UIP groups, although COPD was more common in theUIP group (p = 0.088). Asthma was more common inwomen (p = 0.016) and COPD in men (p < 0.001).Comorbidities divided equally between non-smokersand ever-smokers, except for COPD (p < 0.001).

0 5 10 15 20 25 30 35 40 45 50

other

other cancer

lung cancer

COPD

RA

CAD

RA-ILD

%

Primary causes of death

UIP non-UIP

Fig. 3 ILD was the major cause of death in the UIP group (10/43.5 %), whereas that of the non-UIP group was cardiovascular disease (4/40.0 %).None of the differences reached statistical significance. CAD : coronary artery disease, COPD: chronic obstructive pulmonary disease, RA:rheumatoid arthritis

0 10 20 30 40 50 60

Lung cancer

Other cancer

GER

Asthma

Heart failure

Diabetes

COPD

CAD

Hypertension

%

Comorbidites

UIP non-UIP

Fig. 4 The most common comorbidities were hypertension, coronary artery disease (CAD), COPD, diabetes and heart failure, although asthmawas also relatively common. COPD occurred more often in patients with UIP (13/37.1 % UIP vs. 4/16.7 % non-UIP, p = 0.088). CAD: coronary arterydisease, COPD: chronic obstructive pulmonary disease, GER: gastroesophageal reflux


Timing of diagnosisIn eight patients (13.6 %), ILD preceded RA diagnosis.In three of these cases (2 UIP, 1 OP) the RA diagnosiswas made within one year after the ILD diagnosis, but infive cases (3 UIP, 1 OP, 1 unclassified) joint symptomsand RA diagnosis appeared over one year after the ILDdiagnosis (range 2.17–9.58 years). In two cases (3.4 %)RA and ILD were diagnosed simultaneously. The RAdiagnosis date was missing in one case. ILD followed thediagnosis of RA in 48 patients after a variable period oftime i.e. 6/12.5 % within a year, 13/27.1 % within 3 yearsand 19/39.6 % within 5 years. The longest time intervalbetween RA and ILD was 52.1 years.

Course of diseaseSeveral factors were indicative of ILD progression i.e.oxygen treatment, hospitalizations and decline of dif-fusion capacity to carbon monoxide (DLCO) (Table 4).All patients (n = 8) using oxygen therapy belonged tothe UIP group (p = 0.016). The number of hospitaliza-tions due to respiratory causes was significantly higherin UIP compared to non-UIP (p = 0.004). The latestavailable DLCO results were significantly lower in UIP(p = 0.021). Forced vital capacity (% predicted) (FVC %)showed a trend towards a greater decline in the UIP group,(p = 0.091).

DiscussionThis study revealed that the course of disease in the pa-tients with RA-ILD was variable in subtypes categorizedaccording to either the presence or absence of the UIP-pattern in HRCT. The patients with RA-UIP used oxy-gen, suffered from hospitalizations due to respiratoryreasons and suffered an accelerated decline of lung func-tion more often than those with non-UIP subtype.Moreover, several comorbidities were very common, andin addition to RA-ILD, CAD was a common primarycause of death.The distribution of genders was almost equal support-

ing previous findings that male sex is a risk factor forILD [5, 8, 21], minding that RA is twice as common infemales [22]. The proportion of patients with UIP(59.3 %) and the amount of cases (13.7 %) in which ILDpreceded articular disease were similar as described re-cently [21]. Dyspnea and inspiratory crackles were morecommon in the patients with UIP, in agreement withprevious results [23]. The lung disease was more pro-gressive in the UIP group based on the number ofdeaths, use of oxygen, hospitalization due respiratoryreasons and decline of pulmonary function, especiallyDLCO. Some of the hospitalizations may have been at-tributable to acute exacerbations, known to occur mostlyin UIP patterned RA-ILD [24]. In summary, our findings

support previous studies suggesting that RA-UIP followsa distinctive pathological course [13, 25].ILD was the primary cause of death in the majority of

subjects, especially in the UIP group, although this didnot reach statistical significance in our small studypopulation. A previous study also indicated that RA-ILDpatients were most likely to die of ILD or RA itself [7].A recent Finnish study revealed that CAD was respon-sible for 43 % of deaths of RA patients [26] whereas inKorea, malignancies were the major cause of death inthese patients [27]. The high percentage (39.4 %) of ILDas a primary cause of death indicates that even thoughseveral comorbidities often coexist, ILD remains theleading cause of death. The immediate causes of deathsdid not exhibit any significant differences between theUIP and non-UIP groups.CAD was a major comorbidity in RA-ILD. Previously,

the risk of CAD and hypertension has been shown to in-crease in RA already at disease onset [28]. One novelfinding was that asthma was more common in females,although an association between asthma and RA hasbeen previously detected [29]. COPD was observed inalmost 30 % of patients, in line with a recent study re-vealing a 48 % prevalence of emphysema [30]. COPDwas more common in men, although this may be at-tributable to different smoking habits between thegenders. COPD was also more prevalent in UIP pa-tients even though smoking was similar in bothgroups. GER, previously claimed to be associated withIPF [31], or hypothyroidism thought to be more com-mon in RA [32], were not prevalent in our study.Previously published studies of survival of the patients

with RA-ILD have revealed variable results. Some havereported survival as being as poor as in IPF i.e. approxi-mately 3 years [8, 33, 34] but others have revealed longersurvival times i.e. 7–8 years [10, 11], durations in linewith the present study. Furthermore, the lifespan of RA-UIP has been shown to be shorter than that of the othersubtypes [14]. The median survival in our study wasshorter in patients with UIP than in their non-UIP coun-terparts (92 vs 137 months) but this result did not reachstatistical significance. Male gender has been recognizedas a risk factor for RA-ILD mortality in previous studies[35]. In our study, survival analyses revealed a tendencythat non-UIP, but not UIP, females and non-smokers,lived longer.Identifying the RA-ILD patients from hospital registers

was challenging since two different diagnosis codes wereneeded and, moreover, medical records of hundreds ofpatients had to be reviewed before we could gather thisstudy population, which is similar in size as the majorityof published reports, except for a few multicenter studies[21]. In fact, this sample size can be considered as repre-sentative since approximately 248,400 people live in the


KUH region. In addition, we intentionally excluded thepatients with only minor changes in HRCT since ourpurpose was to study the verifiably clinically relevantRA-ILD. The retrospective protocol of the data collec-tion may have caused some inaccuracies and missingdata. Categorization into either UIP or non-UIP groupswas based on radiological evaluation, since histologicaldata was limited. The radiological categorization cannonetheless be considered as reasonably reliable, since adefinite UIP pattern in a HRCT scan has been demon-strated to be a sensitive and specific way of detecting thehistopathologic UIP pattern in both IPF and RA-ILD[36–38]. Therefore we are confident that the UIP groupreliably consists of true RA-UIP patients, although it ispossible that some of the patients in the NSIP or unclas-sified group may be suffering from histological UIP. Oneobvious limitation of this study is the fact that the re-categorization of the patients was performed by oneradiologist. However, a large proportion of the HRCTscans were evaluated in a multidisciplinary discussion. Inthis study, due to its retrospective nature, it was not pos-sible to evaluate thoroughly the effects of therapeutic in-terventions since the patients had received highlyvariable treatments for RA and ILD without beingfollowed with a standardized protocol as was also thecase in a previously published investigation [39].

ConclusionsIn summary, we detected several differences in diseasecourse between RA-UIP and RA-non-UIP confirmingthe existing impression, that the UIP patterned ILD ismore severe than the other subtypes of RA-ILD. Inaddition, even though several comorbidities often coexistwith RA-ILD, the ILD itself seems to cause the majorityof the deaths in these patients.

AbbreviationsANA, antinuclear antibodies; CAD, coronary artery disease; CCP, cycliccitrullinated peptide; CI, confidence interval; COPD, chronic obstructivepulmonary disease; CTD, connective tissue diseases; DAD, diffuse alveolardamage; DLCO, diffusion capacity to carbon monoxide; FVC, forced vitalcapacity; GER, gastro-esophageal reflux; HRCT, high-resolution computedtomography; IIP, idiopathic interstitial pneumonias; ILD, interstitial lungdisease; IPF, idiopathic pulmonary fibrosis; KUH, Kuopio University Hospital;MDD, multidisciplinary discussion; NSIP, nonspecific interstitial pneumonia;OP, organizing pneumonia; RA, rheumatoid arthritis; RA-DAD, rheumatoidarthritis-associated diffuse alveolar damage; RA-ILD, rheumatoid arthritis-associated interstitial pneumonia; RA-NSIP, rheumatoid arthritis-associatednonspecific interstitial pneumonia; RA-OP, rheumatoid arthritis-associatedorganizing pneumonia; RA-UIP, rheumatoid arthritis-associated usual interstitialpneumonia; RF, rheumatoid factor; SD, standard deviation; UIP, usual interstitialpneumonia

AcknowledgementsThe authors wish to thank Ewen MacDonald for providing assistance withthe language.

FundingThe study was supported by the Finnish Anti-Tuberculosis Association, theJalmari and Rauha Ahokas Foundation, the Väinö and Laina Kivi Foundation,

The Research Foundation of the Pulmonary Diseases, The Kuopio regionRespiratory Foundation and a state subsidy to the Kuopio University Hospital.

Availability of data and materialsWe cannot share our original data. It has been gathered in a detailedmanner and minding that our population is relatively small in this Eastern-Finland hospital, we could not ascertain individuals’ anonymity.

Authors’ contributionsHN collected the study material, analyzed the data and prepared the draft ofthe manuscript and takes responsibility for the integrity of the data andaccuracy of the data analysis. MP contributed to the study design, analysesof data and planning of the data collection form. MK participated inplanning of the data collection form. H-PK performed the radiologicalanalyses and planned radiological data collection form. TS was responsiblefor the statistical analyses. RK designed and managed the study, planned thedata collection form and interpreted data. All authors participated in manuscriptpreparation. All authors read and approved the final manuscript.

Competing interestsHanna Nurmi: Consulting fees from Boehringer-Ingelheim and Roche Oy.Congress travel grants from Boehringer-Ingelheim, Lilly Oncology, Novartis,Orion Pharma and GlaxoSmithKline.Minna Purokivi: Personal fees from Boehringer-Ingelheim, Chiesi, Intermune,Orion Pharma, Roche and Takeda Leiras. Congress travel grants fromBoehringer-Ingelheim and Takeda Leiras Miia Kärkkäinen: Consulting fee fromBoehringer-Ingelheim. Congress travel grants from Intermune, Boehringer-Ingelheim and Roche.Hannu-Pekka Kettunen: Consulting fees from Siemens and Roche.Riitta Kaarteenaho: Congress travel grants from Intermune, Boehringer-Ingelheim, Orion Pharma and Roche.Tuomas Selander: No conflicts of interests.

Ethics approval and consent to participateThe study protocol was approved by the Ethical Committee of KuopioUniversity Hospital (statement 17/2013). In this retrospective study, themajority of the patients are deceased and no consents for publications weregathered.

Author details1Center of Medicine and Clinical Research, Division of Respiratory Medicine,Kuopio University Hospital, POB 100, 70029 KYS Kuopio, Finland. 2Division ofRespiratory Medicine, Institute of Clinical Medicine, School of Medicine,Faculty of Health Sciences, University of Eastern Finland, POB 1627, 70211Kuopio, Finland. 3Respiratory Medicine, Internal Medicine Research Unit,Medical Research Center Oulu, Oulu University Hospital and University ofOulu, POB 20, 90029 Oulu, Finland. 4Harjula Hospital, the Municipal Hospitalof Kuopio, Niuvantie 4, 70101 Kuopio, Finland. 5Diagnostic Imaging Center,Division of Radiology, Kuopio University Hospital, POB 100, 70029 Kuopio,Finland. 6Science Services Center, Kuopio University Hospital, POB 100, 70029Kuopio, Finland.

Received: 19 May 2016 Accepted: 19 July 2016

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II

Are risk predicting models useful for estimating survival of patients with rheumatoid

arthritis-associated interstitial lung disease?

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

BMC Pulm Med 17:16-016-0358-2, 2017.

Reprinted with the kind permission of BMC Pulmonary Medicine.

The original article is an open access article distributed under the terms of Creative

Commons Attribution License which permits unrestricted use, distribution, and

reproduction in any medium, provided the original work is properly cited.

RESEARCH ARTICLE Open Access

Are risk predicting models useful forestimating survival of patients withrheumatoid arthritis-associated interstitiallung disease?Hanna M. Nurmi1,2*, Minna K. Purokivi1, Miia S. Kärkkäinen2, Hannu-Pekka Kettunen4, Tuomas A. Selander5

and Riitta L. Kaarteenaho1,2,3

Abstract

Background: Risk predicting models have been applied in idiopathic pulmonary fibrosis (IPF), but still not validatedin patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD). The purpose of this study was totest the suitability of three prediction models as well as individual lung function and demographic factors forevaluating the prognosis of RA-ILD patients.

Methods: Clinical and radiological data of 59 RA-ILD patients was re-assessed. GAP (gender, age, physiologic variables)and the modified interstitial lung disease (ILD)-GAP as well as the composite physiologic indexes (CPI) were tested forpredicting mortality using the goodness-of-fit test and Cox model. Potential predictors of mortality were also soughtfrom single lung function parameters and clinical characteristics.

Results: The median survival was 152 and 61 months in GAP / ILD-GAP stages I and II (p = 0.017). Both GAP and ILD-GAPmodels accurately estimated 1-year, 2-year and 3-year mortality. CPI (p = 0.025), GAP (p = 0.008) and ILD-GAP (p = 0.028)scores, age (p = 0.002), baseline diffusion capacity to carbon monoxide (DLCO) (p = 0.014) and hospitalization due torespiratory reasons (p = 0.039), were significant predictors of mortality in the univariate analysis, whereas forced vitalcapacity (FVC) was not predictive. CPI score (HR 1.03, p = 0.018) and baseline DLCO (HR 0.97, p= 0.011) remainedsignificant predictors of mortality after adjusting for age.

Conclusions: GAP and ILD-GAP are applicable for evaluating the risk of death of patients with RA-ILD in a similar manneras in those with IPF. Baseline DLCO and CPI score also predicted survival.

Keywords: Mortality, Rheumatoid arthritis, Interstitial lung disease, RA-ILD, GAP, ILD-GAP, Composite physiologic index

BackgroundThe course of disease in interstitial lung diseases (ILD), in-cluding rheumatoid arthritis-associated interstitial lungdisease (RA-ILD), is known to be highly variable. Predict-ing the survival of an individual patient with ILD ischallenging [1]. Several factors have, however, been pro-posed to predict disease progression and survival i.e.

physiological, radiological and histopathological character-istics, as well as demographic variables such as age andgender [2]. Some factors reflecting the severity of therheumatoid arthritis (RA) have also been associated withworse survival, e.g. baseline pain [3], disease activity score[4] and health-assessment questionnaire score [3, 5].There are now several indexes which combine single

factors into a multifaceted scoring system and these haveproved beneficial in estimating prognosis. These modelshave, however, focused mainly on idiopathic pulmonaryfibrosis (IPF) and some of the earliest models were ra-ther cumbersome and therefore never achieved anywidespread clinical acceptance [6]. A composite

* Correspondence: [email protected] of Medicine and Clinical Research, Division of Respiratory Medicine,Kuopio University Hospital, POB 10070029 Kuopio, Finland2Division of Respiratory Medicine, Institute of Clinical Medicine, School ofMedicine, Faculty of Health Sciences, University of Eastern Finland, POB162770211 Kuopio, FinlandFull list of author information is available at the end of the article

© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Nurmi et al. BMC Pulmonary Medicine (2017) 17:16 DOI 10.1186/s12890-016-0358-2

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physiologic index (CPI) displayed some important ad-vantages over the older models, since it contained onlypulmonary function test (PFT) and gas transfer valuesbut omitted radiological scoring or exercise testing [7].The subsequently developed GAP model combines gen-der (G), age (A) and two lung physiology variables (P),i.e. forced vital capacity (FVC) and diffusion capacity tocarbon monoxide (DLCO), into a multidimensionalindex and staging system with three stages (I-III) pro-posing 1-year mortality of 6, 16 and 39% [8]. This GAPmodel has also been utilized in the prognosis of otherchronic ILDs in addition to IPF. The modified modelwas named as ILD-GAP, with the assumption that pa-tients with connective tissue disease-related ILDs (CTD-ILD) enjoyed a better survival than those suffering fromIPF [9]. The survival of patients with RA-ILD has beenshown to be as poor as in IPF patients [10], at least inthose cases with usual interstitial pneumonia (UIP)which is the most common subtype in RA-ILD and un-like the situation in the other CTD-ILDs [11]. Thus,since it is mainly UIP-typed, RA-ILD follows a distinct-ive disease course from the other CTD-ILDs and it re-mains unclear which of the prognostic indexes, GAP orILD-GAP, would be better suited for RA-ILD. There aresome reports of the benefits of using the CPI score,GAP and ILD-GAP staging systems in patients with IPFand systemic sclerosis-associated ILD [12–14]. However,as far as we are aware, neither CPI nor GAP/ILD-GAPhave been previously investigated in patients with RA-ILD, if one excludes the subjects in the original ILD-GAP publication, which did include some RA-ILD

patients in their CTD-ILD/idiopathic nonspecific inter-stitial pneumonia (iNSIP) group of 326 patients.The aims of this study were to investigate the applic-

ability of CPI, GAP and ILD-GAP scores for predictingthe prognosis of the patients with RA-ILD treated inKuopio University Hospital (KUH), in Eastern Finland,during the years 2000–2014. In addition, we examinedthe association between individual PFT and demographicfactors with the survival of the patients.

MethodsData sources and searchThe study cohort consists of patients treated in theKUH pulmonology in-patient or out-patient clinic be-tween 1.1.2000 and 31.12.2014. The patients wereidentified from the database of KUH using two Inter-national Classification of Diseases (ICD-10) codes,namely J84.X and M05.X/M06.X (Fig. 1). Thesesearches resulted in identification of 1047 patients,and their patient records were evaluated in order toidentify those patients suffering from clinically rele-vant RA-ILD. The search process and clinical charac-teristics of the patients are thoroughly described inour previous study [15]. Shortly, all patients without acertain diagnosis of RA or without HRCT confirmedILD were excluded, as were those with mixed CTD-like symptoms. Atypical cases were debated by amultidisciplinary discussion. Finally, 59 radiologicallydiagnosed RA-ILD patients were identified to be stud-ied in detail and classified adopting the year 2013 IIPclassification [16]. The radiological RA-UIP criteria

Fig. 1 Study protocol. Flowchart of patient enrollment into the study showing the subdivision into the different GAP / ILD-GAP groups. ILD = interstitiallung disease; RA = rheumatoid arthritis; HRCT = high-resolution computed tomography; RA-ILD = rheumatoid arthritis-associated interstitial lung disease;UIP = usual interstitial pneumonia; NSIP = nonspecific interstitial pneumonia; OP = organizing pneumonia; DAD = diffuse alveolar damage;MDD =multidisciplinary discussion; GAP = gender, age, physiologic variables


that were applied were those for the diagnosis of IPF[17] when 32 (54.2%) of the patients had a radio-logical definite UIP pattern [15]. After a multidiscip-linary discussion, two additional patients with aslightly upper- or mid-lung predominated distributionwhere included in the RA-UIP group (35/59.3%),whereas patients with a possible UIP pattern are notincluded in the UIP group but instead categorized inthe unclassified group. In addition to RA-UIP pa-tients, there were eight RA-NSIP (13.6%), seven RA-OP (11.9%), one RA-DAD (1.7%) and eight unclassi-fied patients (13.6%) as previously described [15].

Gathering of demographic informationClinical information was gathered from the patientrecords of KUH, primary health care centers and otherhospitals using a specially designed form. Demographicdata and the lifelong medication history for RA weregathered comprehensively. The number of hospitaliza-tions was also obtained and further categorized intoeither mainly respiratory (i.e. infections, suspected drugreactions and suspected acute exacerbations of ILD) orcardiac problems as presented previously [15]. Theresults of PFT, such as spirometry including FVC andforced expiratory volume (FEV1), as well as DLCO weregathered at baseline and, when available, during thefollow-up annually, including also the most recent avail-able results. The reference values of Viljanen were usedwhen assessing PFT results [18].

Staging systemsComposite physiologic index (CPI) was calculated usingthe formula [7]: CPI = 91 – (0.65 × DLCO % predicted)– (0.53 × FVC % predicted) + (0.34 × FEV1 % predicted).GAP / ILD-GAP score was calculated by gender, age,FVC % predicted and DLCO % predicted and patientsdivided to GAP / ILD-GAP stages I and II as previouslydescribed [8, 9]. There were no stage III (or IV in ILD-GAP) patients in our study material.

Statistical analysisThe distribution of the continuous variables was verifiedwith the Shapiro-Wilk test. If there was a normal distri-bution, the independent T-test was used to comparecontinuous variables, otherwise the Mann-Whitney U-test was used. The chi-squared test or Fisher test, whenappropriate, was used for comparison of categorical vari-ables. Gender, smoking habits, laboratory results, use ofmedications, comorbidities, use of oxygen and the num-bers of observed deaths were calculated as percentages.Age at the time of RA-ILD diagnosis or death, lungfunction results and hospitalizations were expressed asmean ± SD. Survival curves were estimated using theKaplan-Meier method and differences in survival time

between GAP / ILD-GAP stages I and II were calculatedby the log-rank test. Survival results are expressed asmedian (95% confidence interval). The observed 1-, 2-,and 3-year mortality rates were calculated and thesewere supplemented with an estimate of the confidenceinterval by using the Wilson score. Next, the observedmortality and the risk of death predicted by the GAP /ILD-GAP model were compared using Hosmer-Lemeshow goodness-of fit-test. Finally, Cox regressionanalysis was used to identify factors that predictedmortality.P-values <0.05 were considered significant. All data

was analyzed using IBM Statistics SPSS software,version 21.0.

ResultsPatient characteristics, lung functions and CPI scoreThe mean RA duration at the point when ILD was diag-nosed was 15.6 ± 12.2 years, ranging from 0 to 52 years.The female–male ratio was 1:1.27. A substantial number(39.7%) of the patients had never smoked. The meanCPI score of all RA-ILD patients was 27.2 ± 14.4 (range2.4–61.3) (Table 1).The detailed data of the lung function test results is

shown in Table 1. Over half (30/55.6%) of the patientshad a normal FVC at the time of RA-ILD diagnosis.Twenty-five (49%) of the patients had a normal baselineDLCO and furthermore, in 17 patients (33.3%) bothFVC and DLCO were normal (Table 1). The clearest de-cline of all PFT was observed in DLCO, the final meanwas 61.1 ± 21.4 (range 13–105).

Table 1 Pulmonary function test results of the patients withRA-ILD

Variable Baseline results

FVC

Normal (>80%) 30 (55.6)

Declined (50–80%) 23 (42.6)

Severely declined (<50%) 1 (1.9)

Normal FEV1 (>80%) 29 (53.7)

Normal FEV1/FVC (>88%) 44 (81.5)

Normal DLCO (>74%) 25 (49.0)

Normal FVC + Normal DLCO 17 (33.3)

Mean FVC 84.76 ± 16.9

Mean FEV1 81.76 ± 16.3

Mean FEV- % 97.59 ± 12.4

Mean DLCO 71.12 ± 18.1

CPI score 27.2 ± 14.4

Data shown as number (%), or mean ± SD. FVC, FEV1 and FEV1/FVC results aremissing from five patients. DLCO results are missing from eight patients. BothFVC and DLCO results were available for 51 patients


GAP and ILD-GAPThere was all the necessary data available from 51patients to allow the calculation of GAP and ILD-GAP scores. The majority of the subjects i.e. 76.5%(n = 39) belonged to stage I with the remaining 23.5%categorized into the stage II group. There were nopatients in stage III. The same patients who werecategorized as GAP I constituted the ILD-GAP Igroup and the patients in GAP II group, were also the pa-tients with ILD-GAP II (Fig. 1). GAP / ILD-GAP I and IIdiffered significantly with respect to several clinicalfindings and lung function e.g. age (p = 0.024), gender(p < 0.001), smoking status (p = 0.033), baseline FVC(p < 0.001), FEV1 (p = 0.013) and DLCO (p < 0.001)(Table 2). The use of methotrexate was also more

common in stage I patients than in their stage IIcounterparts (64.1% vs. 33.3%), although this findingdid not reach statistical significance (p = 0.060). Nostatistically significant differences were observed inRA serology or comorbidities. The mean CPI scorewas 22.4 ± 12.2 in GAP / ILD-GAP I and 42.8 ± 9.3 instage II (p < 0.001). Patients with the UIP pattern inHRCT (RA-UIP) divided almost equally in both stages(64% in stage I, 50% in stage II, p = 0.502).

The follow-up outcomesNo statistically significant differences were observedbetween GAP / ILD-GAP I and II with regard to hos-pital admissions either due to respiratory or cardio-logic reasons (Table 3). The use of oxygen was alsosimilar in both groups (p = 1.000). Eighteen patients(46.2%) died due to any cause in the GAP / ILD-GAPstage I whereas there were 9 deceased patients(75.0%) in the stage II group (p = 0.080). The ob-served cumulative mortality rates at 1, 2 and 3 yearswere 7.0, 16.7 and 22.6%, respectively. The observed1-year, 2-year or 3-year mortality did not differ sig-nificantly according to GAP / ILD-GAP stage.

Survival and validation of the GAP and ILD-GAP modelsThe median survival was 152 months in stage I but only61 months in stage II (p = 0.017) (Fig. 2). There were noapparent differences in the observed and predicted riskof death (Table 4). Both prediction models fitted theWilson score confidence interval of the observedmortality.The observed mortality and the risk of death predicted

by these models were compared using the Hosmer-Lemeshow goodness-of-fit test (Figs. 3 and 4). Both GAPand ILD-GAP indexes predicted 1-year, 2-year and 3-year mortality accurately (all p-values were > 0.05). TheILD-GAP index was more accurate at predicting 1-yearmortality (p = 0.552) than the GAP index (p = 0.254).However, the GAP index was slightly more accurate atpredicting 2-year (p = 0.261) and 3-year (p = 0.595)mortality than the ILD-GAP index (2-year p = 0.139,3-year p = 0.357).

Predictors of mortalityGAP and ILD-GAP indexes, as well as the CPI scorewere all significant predictors of mortality when assessedwith the univariate Cox model. The hazard ratio (HR) ofGAP was 1.56 (95% CI: 1.15–2.11; p = 0.004), that ofILD-GAP 1.51 (95% CI: 1.05–2.18; p = 0.026) and of CPI1.03 (95% CI 1.01–1.06; p = 0.015) (Table 5).Age at diagnosis (HR 1.06, 95% CI 1.02–1.10, p = 0.002),

baseline DLCO (HR 0.98, 95% CI 0.96–1.00, p = 0.014)and hospitalization due to respiratory reasons (HR 1.12,1.01–1.26, p = 0.039) were also significant predictors of

Table 2 Baseline characteristics of the patients with RA-ILD

GAP / ILD-GAP stage I(n = 39/76.5%)

GAP/ILD-GAP stage II(n = 12/23.5%)

P-value

Age (y) 63.4 ± 11.6 71.5 ± 5.5 0.024

Age at death (y) 72.6 ± 9.9 76.6 ± 5.6 0.266

Male sex 16 (41.0) 12 (100.0) <0.001

UIP pattern 25 (64.1) 6 (50.0) 0.502

Smoking*

Never 19 (48.7) 1 (9.1) 0.033a

Ex-smoker 15 (38.5) 7 (63.6)

Current smoker 5 (12.8) 3 (27.3)

Serology

Positive RF** 29 (78.4) 11 (91.7) 0.420a

PositiveANA***

4 (14.3) 2 (22.2) 0.620a

Medications

Steroids 36 (92.3) 10 (83.3) 0.580a

MTX 25 (64.1) 4 (33.3) 0.060

Biologicaldrugs

11 (28.2) 1 (8.3) 0.250a

Lung functions

FVC % pred 89.8 ± 15.8 72.6 ± 8.5 <0.001

FEV1 % pred 85.1 ± 16.3 72.3 ± 8.9 0.013

DLCO % pred 76.8 ± 15.6 52.8 ± 12.7 <0.001

RA duration (y) 15.7 ± 10.6 14.8 ± 14.4 0.808

CPI points 22.4 ± 12.2 42.8 ± 9.3 <0.001

For eight patients there was no lung function data and therefore the GAP /ILD-GAP score could not be calculatedRF rheumatoid factor, ANA antinuclear antibodies, MTX methotrexate, FVCforced vital capacity, DLCO diffusing capacity of the lung for carbonmonoxide, % pred percentage of the predicted value, CPI compositephysiologic index*Data missing from one stage II patient**Data missing from two stage I patients with positive anti-cyclic citrullinatedpeptide antibodies***Data missing from 14 patients (11 stage I, 3 stage II)aFisher test


mortality in the univariate model, but neither FVC norhospitalization due to cardiologic reasons was predictive.The UIP pattern was not an independent risk factor in thiscohort, neither was smoking nor male gender. The use ofeither methotrexate or oxygen did not reach statistical sig-nificance as risk factors for death (Table 5).

Age adjusted predictors of mortalityAfter adjusting for age, CPI score and baseline DLCOremained as significant predictors of mortality. Forevery increased CPI point, the mortality risk increasedby 3% (HR 1.03, 95% CI 1.01–1.06, p = 0.014) and forevery increased DLCO level, the risk of death dimin-ished by 3% (HR 0.97, 95% CI 0.95–0.99, p = 0.011).

The rest of the factors that were detected in the uni-variate Cox model lost their statistical significanceafter adjustment for age (Table 6).

DiscussionIn this present study, we applied the GAP and theILD-GAP scores in a cohort consisting of 59 patientswith RA-ILD subdivided into GAP / ILD-GAP stagesI and II. Both GAP systems showed significant differ-ences in age, gender, FVC, FEV1, DLCO and CPI-score, which is understandable since GAP / ILD-GAPare mainly composed of the above-mentioned compo-nents. The median survival of the patients categorizedinto GAP / ILD-GAP II groups was significantlyshorter than those in the GAP / ILD-GAP I group.The CPI score was an independent predictor of mor-tality similarly as GAP / ILD-GAP scores, age, base-line DLCO and hospitalization due respiratoryreasons. However, after adjustment for age, only theCPI score and DLCO remained as statistically signifi-cant predictors. In addition to the Cox model, theapplicability of GAP and ILD-GAP was tested using

Table 3 Course of disease and survival of the patients with RA-ILD

GAP / ILD-GAP stage I (n = 39/76.5%) GAP / ILD-GAP stage II (n = 12/23.5%) P-value

Number of deaths 18 (46.2) 9 (75.0) 0.080

Hospitalization due to respiratory illness 1.0 ± 1.4 (0–5) 1.6 ± 3.1 (0–11) 0.343

Hospitalization due to cardiac illness 0.5 ± 1.0 (0–5) 1.0 ± 1.8 (0–4) 0.366

Use of Oxygen 6 (15.4) 1 (8.3) 1.000a

Median survival 152.0 (93.0–211.0) 61.0 (25.2–96.8) 0.017

Observed 1-y deaths* 0 (0.0) 1 (8.3) 0.245

Observed 2-y deaths** 5 (14.3) 1 (9.1) 1.000

Observed 3-y deaths*** 6 (17.6) 3 (27.3) 0.666

Categorical variables are compared using the Fisher test when marked a, otherwise χ2-test. Hospitalizations are compared using the Mann-Whitney U-test*Data missing from two stage I patients**Data missing from four stage I patients and one Stage II patient*** Data missing from five Stage I patients and one Stage II patient

Fig. 2 Comparison of the survival curves of the RA-ILD patientscategorized into either GAP / ILD-GAP stage I or II. The survival wassignificantly worse in GAP / ILD-GAP stage II (p = 0.017, Log Rank)

Table 4 Predicted and observed cumulative mortality of thepatients with RA-ILD

GAP/ILD-GAPstage

Observed Predicted by GAP indexand staging system

Predictedby ILD-GAP

1-Y mortality

Stage I 0.0 (0.0–9.4) 5.6 3.1

Stage II 8.3 (1.5–35.4) 16.2 8.8

2-Y mortality

Stage I 14.3 (6.3–29.4) 10.9 6.6

Stage II 9.1 (1.6–37.7) 29.9 18.0

3-Y mortality

Stage I 17.6 (8.3–33.5) 16.3 10.2

Stage II 27.3 (9.7–56.6) 42.1 26.9

% (95% CI calculated by Wilson score)


two different statistical methods. Both the GAP andthe ILD-GAP methods provided relatively good esti-mates of mortality. Interestingly, the GAP index wasmore accurate at predicting 2-year and 3-year mortal-ity, whereas ILD-GAP predicted 1-year mortality moreprecisely.To our knowledge, only a few previous studies have

investigated GAP or ILD-GAP scores in patients withCTD-ILD but some analyses of IPF have been published.In Korean IPF patients, the GAP score produced accur-ate 1-year, but not 3-year, mortality estimates [13]. Inanother study of IPF patients, the GAP staging wasfound to be useful for evaluating the IPF severity, reveal-ing statistically significant differences in survival in dif-ferent GAP stages [12]. On the other hand, the ILD-GAP index displayed poor applicability for the predicted1-year mortality in systemic sclerosis-associated ILDpatients [14].In this study, the observed 1-year mortality was 0 in

stage I and 8.3% in stage II patients. Predicted 1-year

mortality using the ILD-GAP was 3.1 and 8.8% in stagesI and II, respectively. Thus, the accuracy of ILD-GAPwas good at predicting 1-year mortality but the observed2-year mortality in stage I patients was much higherthan predicted by the ILD-GAP model i.e. the GAPmodel was more accurate at that time point. The ILD-GAP prediction also underestimated the 3-year mortalityof stage I patients, which was observed to be 17.6 andtherefore was even slightly higher than the value pre-dicted by GAP. Both of the indexes, however, fittedwithin the confidence interval of the observed mortality.Since the accuracy of GAP and ILD-GAP in predictingannual mortality in our study was variable at differentpoints, it remains unclear whether the GAP or ILD-GAPindex is better suited in predicting mortality of patientswith RA-ILD. The ILD-GAP was originally developed ina study protocol including all kinds of ILDs without tak-ing into account the fact that the prognosis and courseof disease is variable in the different types CTD-ILDs[19, 20]. In some earlier studies, the survival of RA-ILD

Fig. 3 The Hosmer-Lemeshow statistic tests show that the predicted and observed risks do not differ significantly (p > 0.05). The x-axis shows the1-y, 2-y and 3-y risk of mortality as predicted by the GAP staging system and the y-axis shows the observed risk. In every figure, stage I is on theleft side and stage II on the right side. The vertical lines represent the confidence interval of the observed mortality rate

Fig. 4 The Hosmer-Lemeshow statistic tests show that the predicted and observed risks do not differ significantly (p > 0.05). The x-axis shows the1-y, 2-y and 3-y risk of mortality as predicted by the ILD-GAP staging system and the y-axis shows the observed risk. In every figure, stage I is onthe left side and stage II on the right side. The vertical lines represent the confidence interval of the observed mortality rate


patients has been reported as being as poor as in IPF[3, 21], whereas that of other types of CTD-ILD hasappeared to be better [10, 19, 22]. Furthermore, vari-ous radiological or histological patterns in certainCTD may behave differently, e.g. patients with RA-UIP have been shown to have a shorter survival thanthose with other CTD-ILDs [23, 24]. Therefore, itcan be debated whether the ILD-GAP, which ismerely a simple subtraction from the GAP score as-suming a better survival in CTD-ILDs, is valid in allCTD-ILDs.The significance of PFT has been widely recognized

when evaluating ILD severity and the risk of death. In fi-brotic subtypes of IIPs, it has been postulated that pul-monary physiology is an even stronger predictor ofsurvival than the histopathologic pattern [25] and that inpatients with IPF, changes in FVC % predicted andDLCO % predicted have been shown to associate withmortality [26, 27]. Moreover, a prospective follow-upstudy of 29 RA-ILD patients demonstrated that in over30% of cases, a degree of radiological progression wasobserved, and this progression was strongly associatedwith a reduced DLCO [28].

In a recent retrospective study of 48 biopsy-confirmedRA-ILD patients, the baseline DLCO was detected as animportant risk factor for death in a univariate modelsimilarly as found here [29]. In that particular study,however, DLCO lost its statistical significance in themultivariate model, when only age and the presence offibrosis remained significant [29]. Another study of 82RA-ILD patients diagnosed without biopsy found thatbaseline DLCO was associated with survival in the bi-variate analysis, and DLCO remained statistically signifi-cant also in the multivariate analysis [30]. In a veryrecent study, a relatively large cohort of 137 RA-ILD pa-tients was retrospectively evaluated, with univariate,multivariate and also longitudinal methods being used toanalyze the predictors of mortality [31]. In that study abaseline DLCO value of 10% lower than the mean valueand DLCO decline of 10% or more at any time afterbaseline were identified as significant predictors of mor-tality [31]. Furthermore, in the study of Song et al. [32]which examined 84 RA-UIP patients, the hazard ratio ofbaseline DLCO did not reach statistical significance, butthe change of DLCO was significant in both univariateand multivariate models. Unfortunately, we were notable to investigate the change in DLCO over time be-cause of missing follow-up data due to the retrospectivenature of our study protocol. In addition, multivariatemodels could not be applied because of the small num-ber of patients in our study. However, we observed thatthe significant positive result of DLCO in univariate ana-lysis remained after adjusting for age. Overall, the resultsof DLCO in our study support the previous findings ofthe suitability of DLCO in the disease severity evaluationof RA-ILD.Baseline FVC was not found to be an independent

predictor of mortality in our study, a finding which is atodds with some previous studies. A recent study showedthat the lower baseline FVC (10% or more under meanvalue) and a 10% decline in FVC were both associatedwith an increased death hazard in various multivariatemodels [31]. Furthermore, another investigation demon-strated that the baseline FVC, as well as the FVC changeover time, were significant predictors of mortality in pa-tients with RA-UIP [32]. There may be two possible ex-planations why the significance of FVC in our studydiffers from these other publications. Firstly, in ourstudy, the mean baseline FVC was relatively high, i.e.84.8, being within the normal limits in the majority ofthe patients whereas the corresponding value in thestudy of Solomon et al. was 69.3, and that from Song etal. was 75.1 [31, 32]. Our finding refers that the patientshad been diagnosed earlier with more preserved lungfunctions. Secondly, our study includes 59 patients, thusbeing relatively small, compared to those other studiesof 84 and 137 patients. On the other hand, the results of

Table 5 Prognostic factors for survival in patients with RA-ILDusing a univariate Cox model

Hazard ratio 95% CI P- value

Age at diagnosis 1.06 1.02–1.10 0.002

Male sex 1.49 0.73–3.05 NS

Smoking 0.83 0.41–1.67 NS

FVC % pred 0.98 0.96–1.01 NS

DLCO % pred 0.98 0.96–1.00 0.014

RA duration 0.99 0.96–1.03 NS

UIP pattern in HRCT 0.77 0.36–1.64 NS

Positive RF 0.69 0.24–1.98 NS

MTX 1.20 0.59–2.42 NS

Use of oxygen 1.74 0.74–4.09 NS

Resp. hospitalization 1.12 1.01–1.26 0.039

Card. hospitalization 1.13 0.87–1.46 NS

CPI- points 1.03 1.01–1.06 0.015

GAP score 1.56 1.15–2.11 0.004

ILD-GAP score 1.51 1.05–2.18 0.026

Table 6 Prognostic factors for survival after adjustment for age

Hazard ratio 95% CI P- value

DLCO % pred 0.97 0.95–0.99 0.011

Resp. hospitalization 1.11 0.99–1.26 0.084

CPI- points 1.03 1.01–1.06 0.014

GAP score 1.37 0.96–1.94 0.083

ILD-GAP score 1.32 0.90–1.95 0.158


the study of Kim et al., which included 84 patients withRA-ILD who had lower mean baseline of FVC valuesthan in our study (66 ± 25 in RA-UIP, 70 ± 20 in non-UIP) did not actually find FVC to be a predictor ofdeath, i.e. similar to our results [23]. Even though FVCalone was not a strong predictor of mortality in ourstudy, it is one factor included in CPI and GAP / ILD-GAP scores, all of which showed significant positive re-sults in our univariate analyses. Our finding supportsthat the use of multifaceted scoring systems for evaluat-ing the prognosis of the patients with RA-ILD may bebeneficial.

ConclusionsIn conclusion, GAP, ILD-GAP and CPI were all func-tional when predicting survival of patients with RA-ILD.In addition, baseline DLCO was associated with lengthof remaining lifetime. In clinical practice, reliablemethods are needed for evaluating the progression ofthe disease and predicting an individual’s life expectancyand predictive scoring systems could be helpful in every-day work and in patient counselling. Hopefully in the fu-ture, more disease-specific methods can be developedand validated, although this would require additionalmulticenter studies.

AbbreviationsANA: Antinuclear antibodies; CI: Confidence interval; CPI: Compositephysiologic index; CTD: Connective tissue diseases; DAD: Diffuse alveolardamage; DLCO: Diffusion capacity to carbon monoxide; FEV1: Forcedexpiratory volume; FVC: Forced vital capacity; GAP: Gender, age andphysiological variables; HR: Hazard ratio; HRCT: High-resolution computedtomography; IIP: Idiopathic interstitial pneumonias; ILD: Interstitial lungdisease; ILD-GAP: Interstitial lung disease – gender, age, physiology;iNSIP: Idiopathic nonspecific interstitial pneumonia; IPF: Idiopathic pulmonaryfibrosis; KUH: Kuopio University Hospital; MDD: Multidisciplinary discussion;NSIP: Nonspecific interstitial pneumonia; OP: Organizing pneumonia;PFT: Pulmonary function test; RA: Rheumatoid arthritis; RA-ILD: Rheumatoidarthritis-associated interstitial pneumonia; RA-UIP: Rheumatoidarthritis-associated usual interstitial pneumonia; RF: Rheumatoid factor;SD: Standard deviation; UIP: Usual interstitial pneumonia

AcknowledgementsThe authors wish to thank Ewen MacDonald for providing assistance withthe language, Tiina Laitinen for assistance in the search of missing PFT dataand Juuso Tamminen for helping editing Fig. 1.

FundingThe study was supported by the Foundation of the Finnish Anti-TuberculosisAssociation, the Jalmari and Rauha Ahokas Foundation, the Väinö and LainaKivi Foundation, The Research Foundation of the Pulmonary Diseases, TheKuopio region Respiratory Foundation and a state subsidy of the KuopioUniversity Hospital.

Availability of data and materialsWe cannot share our original data. It has been gathered in a detailed manner andminding that our population is relatively small in this Eastern-Finland hospital, wecould not guarantee anonymity of the individual patients.

Authors’ contributionsH.N. collected study material, analyzed data and prepared the draft of themanuscript and takes responsibility for the integrity of the data and accuracyof the data analysis. M.P. contributed to the study and design, analyses of

data and planning of the data collection form. M.K. participated in thedesign of the data collection form. H-P.K. performed the radiological analysesand designed the radiological data collection form. T.S. was responsible forthe statistical analyses and prepared the Hosmer-Lemeshow calculations andpictures. R.K. designed and managed the study, planned the data collectionform and interpreted the data. All authors participated in the preparation ofthe manuscript. All authors have read and approved the final manuscript.

Competing interestH.N. has received consulting fees from Boehringer-Ingelheim and Roche Oyand congress travel grants from Boehringer-Ingelheim, Lilly Oncology, Novartis,Orion Pharma and GlaxoSmithKline. M.P. has received congress travel grantsfrom Boehringer-Ingelheim, Roche and Takeda Leiras and personal fees fromBoehringer-Ingelheim, Chiesi, Intermune, Orion Pharma, and Takeda Leiras. M.Khas received a consulting fee from Boehringer-Ingelheim and congress travelgrants from Intermune, Boehringer-Ingelheim, Orion Pharma and Roche. H-P.Khas received consulting fees from Siemens and Roche. R.K has receivedcongress travel grants from Intermune, Boehringer-Ingelheim, Orion Pharmaand Roche. T.S has no conflicts of interests.

Consent for publicationNot applicable.

Ethical approval and consent to participateThe study protocol was approved by the Ethical Committee of KuopioUniversity Hospital (statement 17/2013). In this retrospective study, themajority of the patients are deceased and no consents to participate weregathered due to register-based nature of research in accordance with theFinnish legislation. The Research Ethics Committee of the Northern SavoHospital District delivered a favourable statement (17/2013). Organizationalpermission of Kuopio University Hospital was retrieved as well as permissionsfrom the Finnish National Institute for Health and Welfare (THL/1052/5.05.01/2013) and Statistics Finland (TK-53-911-13), which enabled data collectionfrom other hospitals, primary health care centers and death certificates.

Author details1Center of Medicine and Clinical Research, Division of Respiratory Medicine,Kuopio University Hospital, POB 10070029 Kuopio, Finland. 2Division ofRespiratory Medicine, Institute of Clinical Medicine, School of Medicine,Faculty of Health Sciences, University of Eastern Finland, POB 162770211Kuopio, Finland. 3Respiratory Medicine, Internal Medicine Research Unit,Medical Research Center Oulu, Oulu University Hospital and University ofOulu, POB 2090029 Oulu, Finland. 4Diagnostic Imaging Center, Division ofRadiology, Kuopio University Hospital, POB 10070029 Kuopio, Finland.5Science Services Center, Kuopio University Hospital, POB 10070029 Kuopio,Finland.

Received: 24 September 2016 Accepted: 22 December 2016

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http://dx.doi.org/10.1186/s12890-016-0269-2

III

Several high-resolution computed tomography findings associate with survival and clinical

features in rheumatoid arthritis-associated interstitial lung disease.

Nurmi H, Kettunen H-P, Suoranta S-K, Purokivi M, Kärkkäinen M, Selander T, Kaarteenaho R.

Resp Med 2018;134:24-30

Reprinted with the kind permission of Respiratory Medicine.

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



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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