Biomarkers in connective tissue disease-associated interstitial lung disease.

181

Biomarkers in Connective Tissue DiseaseAssociated Interstitial Lung Disease Ulrich Costabel, MD1

1 Department of Pneumology and Allergy, Ruhrlandklinik, University

Hospital, University of Duisburg-Essen, Germany Semin Respir Crit Care Med 2014;35:181–200.

Abstract

Keywords

► connective tissue disease ► biomarkers ► interstitial lung disease

Address for correspondence Ulrich Costabel, MD, Department of Pneumology and Allergy, Ruhrlandklinik, University Hospital, University of Duisburg-Essen, Tüschener Weg 40, 45239 Essen, Germany (e-mail: [email protected]).

This article reviews major biomarkers in serum and bronchoalveolar lavage fluid (BALF) with respect to their diagnostic and prognostic value in connective tissue disease– associated interstitial lung disease (CTD-ILD). In some CTD such as systemic sclerosis (SSc), the incidence of ILD is up to two-third of patients, and currently ILD represents the leading cause of death in SSc. Because of the extremely variable incidence and outcome of ILD in CTD, progress in the discovery and validation of biomarkers for diagnosis, prognosis, patients’ subtyping, response to treatment, or as surrogate endpoints in clinical trials is extremely important. In contrast to idiopathic interstitial pneumonias, autoantibodies play a crucial role as biomarkers in CTD-ILD because their presence is strictly linked to the pathogenesis and tissue damage. Patterns of autoantibodies, for instance, anticitrullinated peptide antibodies in rheumatoid arthritis or aminoacyl-tRNA synthetases (ARS) in polymyositis/dermatomyositis, have been found to correlate with the presence and occasionally with the course of ILD in CTD. Besides autoantibodies, an increase in serum or BALF of a biomarker of pulmonary origin may be able to predict or reflect the development of fibrosis, the impairment of lung function, and ideally also the prognosis. Promising biomarkers are lung epithelium-derived proteins such as KL-6 (Krebs von den Lungen-6), SP-D (surfactant protein-D), SP-A (surfactant protein-A), YKL40 (chitinase-3-like protein 1 [CHI3L1] or cytokines such as CCL18 [chemokine (C-C) motif ligand 18]). In the future, genetic/epigenetic markers, such as human leukocyte antigen (HLA) haplotypes, single nucleotide polymorphisms, and micro-RNA, may help to identify subtypes of patients with different needs of management and treatment strategies.

This article reviews the major biomarkers in serum, bronchoalveolar lavage fluid (BALF), and other sources, with diagnostic and prognostic value in interstitial lung disease (ILD) associated with connective tissue disease (CTD). ILD often complicates the course of CTD.1–4 The heterogeneous group of CTDs includes rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), polymyositis/dermatomyositis (PM/DM), primary Sjögren syndrome (SS), mixed CTD (MCTD), and undifferentiated CTD (UCTD).4,5 Although the majority of patients with CTD-ILD experience stable or slowly progressive ILD, a small yet

Issue Theme Pulmonary Complications of Connective Tissue Disease; Guest Editors, Danielle Antin-Ozerkis, MD, and Jeffrey Swigris, DO, MS

significant group exhibits a more severe and progressive course.4 The paradigmatic example of this interstitial lung involvement in CTDs is SSc, where postmortem examination gives evidence that nearly every patient develops pulmonary fibrosis, even though of very different extent. High-resolution computed tomography (HRCT) shows interstitial lung involvement in about two-thirds of the cases.2 Severe pulmonary fibrosis is the leading cause of death in SSc, as demonstrated by Steen and Medsger in the Pittsburgh cohort.6 EUSTAR database recently confirmed these data.7 In PM/DM, ILD is the most common pulmonary manifestation

Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.

DOI http://dx.doi.org/ 10.1055/s-0034-1371527. ISSN 1069-3424.

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

Francesco Bonella, MD1

Biomarkers in CTD-Associated Interstitial Lung Disease and its presence is associated with increased morbidity and mortality. In RA, SLE, and SS, clinically significant ILD is less common and estimated to occur in approximately 10 to 30% of patients.8 Beside these considerations, a consistent proportion of patients with idiopathic ILD presents with positive autoantibodies reflective of an autoimmune process.9 Therefore, it is important to screen routinely ILD patients without clinical evidence of CTD for autoantibodies.1,3,9,10 Considering all the aforementioned aspects, the discovery and validation of biomarkers for the diagnosis, prognosis, patients’ subtyping, response to treatment, or as surrogate endpoints in clinical trials on CTD-ILD patients could be of great clinical importance. Even if a single less invasive, reliable, and cheap biomarker would be optimal, the future will more likely offer a panel of disease-specific biomarkers. One example of that is the multi-biomarker disease activity score for RA,11,12 a quantitative serum-based assay based on 12 biomarkers consistently associated with clinical disease activity levels and damage progression over time as measured by radiography.11 Many attempts have been made to find out a candidate biomarker for CTD-related ILDs, but most data come from retrospective single-center studies. The final step for biomarkers’ validation implicates prospective well-designed multicenter studies in heterogeneous populations. Factors able to influence the levels of these biomarkers, such as covariates and genetic assets, and the dependence on baseline disease severity have to be taken into account as covariates.13 Specific single nucleotide polymorphisms (SNPs), for example, can cause inter-ethnic and inter-individual variability in serum concentrations of biomarkers: well-known examples are angiotensin-converting enzyme II polymorphisms in sarcoidosis14 and Krebs von den Lungen-6 (KL-6) mucin 1 (MUC 1) in fibrotic lung diseases.15–17 Whether microRNAs (miRNAs) may play a clinical role as biomarkers in the future remains to be proven. This review will focus on noninvasive biomarkers. In comparison to BALF or lung function, peripheral blood biomarkers can be easily obtained and measured longitudinally, and thus have the greatest potential to be applied in the clinical routine.

Autoantibodies Autoantibody subsets are associated with different patterns of pulmonary involvement, including ILD.18 It must be taken into account that different techniques for the same antibody test may give different results.19 Immunofluorescence used for antinuclear antibody (ANA) determination can present with three major patterns: homogeneous (associated with ANAs against double-stranded (ds)DNA [SLE] and histones), speckled/peripheral (less specific), and nucleolar (most often associated with limited scleroderma).18 Low ANA titers may be seen in healthy individuals and in disease in remission. ANA titer higher than 1 in 160 is taken as significant in most laboratories.18 By using enzyme immunoassay and enzymelinked immunosorbent assay (ELISA) methods to detect ANAs, it is possible to detect single autoantigens such as dsDNA, Seminars in Respiratory and Critical Care Medicine

Vol. 35

No. 2/2014

Bonella, Costabel Smith antigen, scleroderma (Scl-70) (also termed topoisomerase-1), SSA/Ro, SSB/La, and so on.18 ►Table 1 shows the principal autoantibodies detected in CTD in the clinical routine; antibodies against minor antigens are not reported. Up to 25% of patients with features of CTD do not fulfill American College of Rheumatology (ACR) criteria for specific CTD.20 Patients with symptoms suggestive of CTD but not specific, that present or develop positive autoimmune serology for > 12 months, can be classified as UCTD.20 The majority of patients with these autoimmune undifferentiated features (UCTD features) have nonspecific interstitial pneumonia (NSIP) at surgical lung biopsy.21 Those patients who keep a negative autoimmune serology but still show CTD features should remain unclassified and not included among idiopathic interstitial pneumonias (IIPs).18

Lung Epithelium Specific Biomarkers There are multiple common mechanisms in idiopathic and secondary fibrotic lung diseases. Evidence indicates that repetitive injuries to alveolar epithelial cells (AECs) and airway Clara cells trigger an exaggerated wound healing response resulting in extensive scar formation.22 In many ILD, inflammatory mechanisms exerted by T-lymphocytes and autoantigens can cause AEC injury.23 While AEC type I (AEC I) undergo apoptosis, there is an accumulation of hyperplastic AEC type II (AEC II). Hyperplastic regenerating AEC II produce a vast array of cytokines, growth factors and release surfactant proteins and mucins. Some of them, like KL-6 and surfactant proteins (SP-D and SP-A), have become established biomarkers for several ILDs, in particular idiopathic pulmonary fibrosis (IPF) (►Table 2).

Biomarkers from Other Cellular Sources Multiple mechanisms converge to an overproduction of transforming growth factor-β (TGF-β) and consequent accumulation of fibroblasts and deposition of extracellular matrix (ECM).24–26 Activated macrophages, T cells, endothelial cells, and fibrocytes, as well as the ECM itself are important sources of circulating biomarkers (►Table 2).13,22,27 In general, an increase in the serum concentration of a biomarker of pulmonary origin can be due to elevated pulmonary production, an increased spillover to the systemic circulation due to leakage of the alveolo-capillary membrane and/or a decrease in extrapulmonary degradation; an extrapulmonary production of some of these biomarkers is also possible.22,28

Systemic Sclerosis—ILD ILD is identified more often in SSc than in any other CTD; evidence of radiographic findings of ILD occurs up to twothirds of patients with SSc. The most prevalent histologic pattern identified in SSc is fibrotic NSIP followed by the usual interstitial pneumonia (UIP) lung injury pattern.1 During the past decade, research aimed to identify biomarkers for predicting the disease course in SSc-ILD. The


182

Biomarkers in CTD-Associated Interstitial Lung Disease

Bonella, Costabel

183

Table 1 Specific nuclear antigen and non-antinuclear autoantibodies in connective tissue disease and their relation with the presence of ILD SSc

RA

PM/DM

MCTD

pSS

SLE

UCTD

þ

þ

þ

þ

Specific nuclear antigen antibodies dsDNAa Histones (AHA)

þ (ILD)

b

Smc þ (PH)

U1-RNPc U2-RNP

U11-RNPc

þ (ILD)

c

þ (ILD)

rRNP

þ

c

Ro52 (TRIM21)

c

SSB (La)c d

þ

þ

þ

þ (ILD)

þ

þ (ILD)

þ (ILD)

þ (ILD)

þ

þ

þ

þ

þ

þ

þ (PH)

þ

þ þ

þ

þ

þ

þ (ILD)

c

þ (PH, ILD)

Th/Tod

þ (ILD, PH)

RNA-pol-I

RNA-pol-III

þ þ

þ

þ

d

þ

RNA-pol-IId

þ

d

þ (ILD)

Anti-tRNA synthetases Jo-1c

þ

þ

þ (ILD)

EJe

þ (ILD)

e

þ (ILD)

PL-7c PL-12 KS

þ

þ (ILD )

ACA/CENP (A-E)

OJ

þ

þ (ILD)

f

c

Scl-70

þ (ILD) þ (ILD)

c

þ (ILD)

e

þ

ZOe Ha

þ

e

Mi-2 (Helicase) SRP

þ

þ þ

SSA (Ro60)

Ki-SL

þ (ILD)

e

RNPe

Ku

þ þ

þ (ILD, PH)

U3-RNPd U12-RNP

þ

þ

c

þ þ

þ

c

þ

c

þ (ILDf )

CADM140/MDA5e p155/140 (anti-TIF1-γ) MJ/NXP2

þ

d

þ

e

þ

SAE (anti-SUMO protein) PM-Scl

c

þ

þ

Non-ANA autoantibodies RF

þ

Anti-CCP (CCP1–3)

þ (ILD)

Hsp90

þ (ILD)

þ

(Continued) Seminars in Respiratory and Critical Care Medicine

Vol. 35

No. 2/2014


ssDNA

b


Bonella, Costabel

Table 1 (Continued) SSc

RA

þ (ILD)

þ

Anti-Hsp47 AECA

PM/DM

MCTD

pSS

þ (ILD)

þ

SLE

UCTD

þ

Abbreviations: ACA, anticentromere antibody; ACPA, anti-citrullinated peptide antibody; AECA, antiendothelial cells antibodies; AIP, acute interstitial pneumonia; ANA, antinuclear autoantibodies; ANCA, antineutrophil cytoplasmic antibodies; CCP, cyclic citrullinated peptide; CENP, centromereassociated protein; CTD, connective tissue disease; dsDNA, double-stranded DNA; ILD, interstitial lung disease; HMGCR, 3-hydroxy-3-methylglutarylcoenzyme A reductase; IPF, idiopathic pulmonary fibrosis; MCTD, mixed connective tissue disease; PH, pulmonary hypertension; NXP2, nuclear matrix protein NXP2; PM/DM, polymyositis/dermatomyositis; pSS, primary Sjögren syndrome; RA, rheumatoid arthritis; RF, rheumatoid factor; RNA-pol, RNA polymerase; RNP, ribonucleoprotein; rRNP, ribosomal ribonucleoprotein; SAE, anti-small ubiquitin-like modifier activating enzyme; SLE, systemic lupus erythematosus; Sm, Smith antigen; SRP, signal recognition particle; SSc, systemic sclerosis; ssDNA, single-stranded DNA; UCTD, undifferentiated connective tissue disease. Source: Modified from Papiris et al.18 Notes: Antibodies with rare incidence (< 5%) have been excluded. Association with ILD or PH is reported. a Peripheral pattern at immunofluorescence (IF). b Homogeneous pattern at IF. c Speckled pattern at IF. d Nucleolar pattern at Hep-2 IF. e Cytoplasmic pattern at IF. f Severe ILD.

Scleroderma Lung Study (SLS) and the Genetics versus Environment in Scleroderma Outcome Study (GENISOS) collected the most significant cohort in this sense.29,30 Several autoantibodies (►Table 1) and serum proteins correlate with the presence or severity of ILD in the context of SSc (►Table 3). For biologically complex diseases such as scleroderma, characterized by autoimmunity, fibrosis, and microvascular damage, the multiplicity of underlying pathogenetic patterns suggests that disease prediction may depend on combinatorial analysis of many mediators.31,32

Autoantibodies and Autoimmunity Markers Anti-topoisomerase I antibodies (ATAs) have been consistently found to be associated with pulmonary fibrosis, while anticentromere antibodies (ACAs) are linked to pulmonary hypertension and are rarely present in SSc-ILD.19 While it is clear that ATA positivity is associated with a greater risk of lung fibrosis, it remains unclear whether it is associated with more progressive ILD. Serum autoantibodies to small nuclear ribonucleoproteins (RNPs) have been found in patients with SSc and other CTD.33 Most of these antibodies are directed against the protein component of the complex. Some antibodies recognize individual RNPs, while others are directed against a complex of RNPs. Of the anti-RNP antibodies, anti-U1 and anti-U3 are the most frequent in SSc patients, while anti-U5 and anti-U4/U6 are rare.33 Lung fibrosis has been reported in 79% of the antiU11/U12 RNP antibody–positive SSc patients; moreover, anti-U11/U12 RNP–positive patients showed a higher mortality from pulmonary fibrosis than antibody-negative patients.33 On the contrary, a reduced incidence of lung fibrosis is found in anti-RNA polymerase III–positive patients.34 Antiendothelial cell antibodies (AECAs) are a heterogeneous class of antibodies whose role in the pathogenesis of autoimmune diseases with vascular involvement has been extensively studied.35 Some AECAs may bind to fibroblasts in vivo, triggering fibroblast activation and thus directly conSeminars in Respiratory and Critical Care Medicine

Vol. 35

No. 2/2014

necting AECA with fibrosis.36 AECA positivity, reported in 22 to 86% of patients with SSc, has also been noted in patients with other CTDs (RA, SLE, and Wegener granulomatosis).35 Their presence has been associated with a higher frequency of pulmonary fibrosis and impairment of lung function tests, particularly diffusing capacity for carbon monoxide (DLCO).37

HLA Aplotypes and Their Association with ILD in SSc Upregulated cytokines/growth factors and signal molecules such as HLA, protein tyrosine phosphatase nonreceptor type 22, connective tissue growth factor, TGF-β, and plateletderived growth factor (PDGF) have been implicated in the pathophysiology of SSc38,39; until recently, few studies have focused on specific genetic biomarkers in SSc-related ILD.38 Odani et al38 found out that the prevalence of HLA-DRB5 gene carriers was increased in Japanese SSc patients with ILD relative to those without ILD or to healthy controls in both cohorts. Among the four detected alleles, the HLADRB501:05 allele was significantly more frequent in SSc patients with ILD than in SSc patients without ILD or in healthy controls.38 These associations were confirmed in a validation cohort. The authors concluded that HLADRB501:05 allele may be a risk factor for ILD in patients with SSc.38

Lung Epithelium–Specific Biomarkers Krebs von den Lungen 6/MUC1 KL-6 is a high-molecular-weight mucin-like glycoprotein, now classified as MUC1, which is strongly expressed by AEC II and bronchiolar epithelial cells and increases following cellular injury and/or regeneration.16 KL-6 has profibrotic and antiapoptotic effects on lung fibroblasts.40 The precise epitope structure recognized by the anti-KL-6 monoclonal antibody (mAb) is still unclear, but candidate carbohydrate epitopes for KL-6 mAb have been identified in O-linked glycans of MUC1 containing 6′sulfo-Gal/GalNAc.41


184


Bonella, Costabel

185

Table 2 Relevant biomarkers detected in serum/BALF of ILDs, according to their cellular source

Surfactant-associated proteins

SP-A SP-D

Mucin-associated antigens

KL-6/MUC1 CA 15–3 CA125 (MUC16)

Clara-cell protein

CC16

Other lung epithelial markers

CK-19 Ca19–9 Sialyl SSEA-1 (SLX) VEGF

Cytokines and chemokines Cytokines and their receptors

IL-2 and IL2r IL-4 IL-6 IL-7

IL-8 IL-10 IL-13 IL-17A

Chemokines and their receptors

CCL2 (MCP-1) CCL3 (MIP-1a) CCL18 (MIP-4)

CXCL10 (IP10) CXCL11 (ITAC) CXCL12

TNF superfamily

TNF TRAIL Soluble CD40 ligand BAFF

IL-18 IL-22 IL-23

Collagen peptides/extracellular matrix Collagen peptides and propeptides

Type I (C-terminal telopeptide) Type III procollagen peptide Type IV collagen 7S

Metalloproteinases and their inhibitors

MMPs (1–12) proMMP-7 ADAM12 TIMP 1–3

Other sources Antioxidant enzymes

Glutathione sLOXL2

Markers of macrophage/monocyte activation

ACE Calgranulin B (S100A9) Chitotriosidase LDH IFN-γ MIF Neopterin Osteopontin YKL-40

Fibroblast associated

Circulating fibrocytes CTFG (CCN2) TGF-β1 Periostin

Abbreviations: ACE, angiotensin-converting enzyme; BAFF, B-cell–activating factor; Ca 19–9, carbohydrate antigen Sialyl Lewis (a); CC16, Clara-cell protein 16; CK19, cytokeratin fragment 19; CXCL, CXC chemokine; KL-6, Krebs von den Lungen-6; LDH, lactate dehydrogenase; MCP-1, monocyte chemoattractant protein-1; MIP-1a, monocyte inflammatory protein-1a; MUC, mucin; ILDs, interstitial lung diseases; ITAC, interferon-inducible T cell-a chemoattractant; sIL-2R, soluble interleukin-2 receptor; SLX, carbohydrate antigen Sialyl Lewis (x); TNF, tumor necrosis factor; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; VEGF, vascular endothelial growth factor. Source: Modified from Tzouvelekis et al.28

Serum KL-6 is elevated not only in IIP but also in ILD of known origin, including hypersensitivity pneumonitis, druginduced pneumonitis, sarcoidosis, and CTD-ILD.16 The role of serum KL-6 as biomarker for SSc-ILD has been assessed in

several studies (►Table 4).29,42–46 Serum levels of KL-6 in patients with SSc correlate with functional lung impairment as measured by DLCO.29,45 The presence of the mucin-1 568 adenosine to guanine polymorphism has been found to Seminars in Respiratory and Critical Care Medicine

Vol. 35

No. 2/2014


Lung epithelium specific


Bonella, Costabel

Table 3 Principal biomarkers associated with ILD (both presence and severity) in SSc according to their cellular source Source

Protein

Evidence

References

Damaged alveolar epithelium

SP-A SP-Da KL-6/MUC1a CXCL9 CXCL10 CXCL12 MMP-7 MMP-9 MMP-12

þ þþþ þþþ þ/ þ/ þ þþ þ þþ

55 29,45,53,56,61,64 29,42–45,53,56,61,181,232 70 68,70,233,234 71 73 74 76

Activated macrophages (CD 163)

CCL18 CCL2 IL-6 IL-10 TNF-α CTGF YKL-40

þþ þþþ þþþ þ þ þ þ

60–62,64 66,68–70,83,233 69,70,83,197,235 70,83 70,89 236 59

Activated lymphocytes T Subset Th2 Subset Th17

IL-4 IL-13 IL-17A IL-22 IL-23

þ/ þ þ/ þ þ

70 235 235 87 86

Damaged endothelium

ET-1 VCAM-1 E-Selectin VEGF

þþ þ þ þ

91,92,94,95 93,94 94 94

Acute-phase proteins

CRPb,c Pentraxin-3

þþþ þ

237 238

Notes: The evidence of clinical utility, according to the existing data, is scored. þ/, controversial (nonconfirmatory studies); þ, one single-center study; þþ, more single center studies; þþþ, great cohort studies. a GENISOS cohort study. b Canadian Scleroderma Research Group (CSRG). c Confirmed strong association with restrictive functional impairment but not with ILD.

influence serum KL-6 levels in Caucasian and Japanese ethnicity.17,47

Clara Cell 16-kDa Clara cell 16-kDa (CC16) is a low-molecular-weight protein produced by bronchiolar Clara cells48 and released as a consequence of lung injury.48–50 Increased CC16 levels have been found in serum and BALF of patients with sarcoidosis.48,51,52 Recently, Hasegawa et al53 compared the serum levels of CC16, KL-6, and SP-D for the diagnosis and monitoring of pulmonary fibrosis in patients with SSc, SLE, and healthy controls. A CC16 level of 46.0 ng/mL or higher was diagnostic of pulmonary fibrosis with a sensitivity of 52% and specificity of 89%, slightly inferior to KL-6 (Se 85%, Sp 85%), but comparable with that of SP-D (Se 71%, Sp 77%).53 Serum levels of CC16 were significantly inversely correlated with vital capacity (VC) and DLCO percent predicted in patients with SSc. Moreover, serum levels of CC16 over time were significantly higher in patients with active disease phase.53 CC16 seems to be a potential serum biomarker for pulmonary fibrosis in patients with SSc, but this was not demonstrated for SLE.53

SP-D and SP-A Secreted by AEC II and airway Clara cells, surfactant lipoproteins and phospholipids stabilize the alveolar surface Seminars in Respiratory and Critical Care Medicine

Vol. 35

No. 2/2014

tension and play an important role in the lung’s host defense system, a role mediated primarily by SPA and SP-D.54 Serum levels of SP-A and SP-D are significantly higher in SSc patients with pulmonary fibrosis than in those without,45,55,56 and SPD serum levels are negatively correlated with VC and DLCO.55,56 In one study of 42 patients with SSc, SP-D levels were more sensitive than SP-A in detecting ILD as defined by CT, but less specific (77 and 83% for SP-D vs. 33 and 100% for SP-A).55 In 66 patients with SSc from the SLS, SP-D levels > 90 ng/mL demonstrated good sensitivity (89.4%) and specificity (80%) in the assessment of “alveolitis” as defined by BALF neutrophilia and/or HRCT ground glass density.29 A positive correlation between SP-D serum levels and ILD worsening as defined by changes in symptoms, lung function, and imaging was described in a small prospective study of 35 patients with SSc-ILD followed up up to 10 years.56 Yanaba et al showed retrospectively that longitudinal SP-D levels moved in parallel with lung function findings being useful to assess the response to immunosuppressive therapy.44

Chitinase-Like Protein YKL-40 YKL-40, a chitinase-like protein produced by macrophages and acting as a growth factor for connective tissue cells, is elevated in sera from patients with diseases characterized by inflammation, tissue remodeling, or fibrosis.57 Serum and


186


Bonella, Costabel

187

Protein

Disease

Identified cutoff (reference)

Se, Sp for ILD

Correlation with PFTa and HRCT score

Correlation with ILD activity/outcome

All studies

CC16

SSc

46 ng/mL53 46 ng/mL53

52%, 89%: ILD detection 94%, 68%: ILD activity

FVC, DLCO

ILD activity

Hasegawa et al53

CCL18

SSc

187 ng/mL62

53%,96%: ILD worsening

TLC, FVC, DLCO HRCT score

ILD activity progression outcome

Kodera et al61 Prasse et al60 Tiev et al62 Elhaj et al64

CCL2

SSc

BALF: 139 ng/mL69 for worsening serum:401 pg/mL66 for detection

n.a. 75%,17%: ILD detection

TLC, FVC DLCO HRCT score n.a.

ILD progression

Schmidt et al69 Hasegawa et al67 Carulli66 Hasegawa et al70

CCL10

SSc

268 pg/mL68

n.a.

Not found70

Not found

Antonelli et al68 Hasegawa et al70

KL-6

SSc

500 U/mL29 302 U/mL53 729 U/mL53

79%,90%: ILD detection 85%, 85%: ILD detection 89%, 89%: ILD worsening

FVC, DLCO HRCT score

Outcome

Yamane et al42 Yanaba et al43 Yanaba et al44 Kodera et al61 Hant et al29 Bonella et al45 Hasegawa et al53

PM/DM

549 U/mL136 493 U/mL134

83%,100%: ILD detection 100%,67%: ILD detection

FVC TLC FEV1 DLCO, HRCT score

Progression Outcome

Bandoh et al133 Kubo et al134 Fathi et al136 Arai et al143

RA

520 U/mL179

90%, 97% ILD detection

HRCT score

FVC ILD activity

Oyama et al180 Kinoshita et al179

SSc

MMP-7: n.a. BALF: MMP-9: n.a. MMP-12: n.a. ADAM12-S: n.a.

n.a. n.a. n.a. n.a.

MMP-7: DLCO MMP-9 DLCO, TLC MMP-12: HRCT score, FVC ADAM12-S: FVC, HRCT score

MMP-1, 8, 9: acute onset79 MMP-9, 12 and ADAM12-S: ILD activity78

Kim et al74 Andersen et al75 Moinzadeh et al73 Manetti et al76 Oka et al79 Taniguchi et al78

TIMP-1: 260 ng/mL77


FVC DLCO

ILD activity

Kikuchi et al77

SSc

44 ng/mL55

33%,100%

n.a.

n.a.

Takahashi et al55

SSc

56

62 ng/mL 90 ng/mL29 91 ng/mL53 110 ng/mL55 147 ng/mL53

68%, 73% 89%, 89% 71%, 77% 77%, 83% ILD detection 72%, 83% ILD activity

FVC DLCO HRCT GG

ILD activity progression outcome response to treatment

Takahashi et al55 Asano et al56 Kodera et al61 Hant et al29 Hasegawa et al53 Bonella et al45

PM/DM

59 ng/mL141


FVC, DLCO

Poor prognosis

Ihn et al141 Arai et al143

SSc

275 ng/mL59


FEV1 DLCO

Poor outcome

Nordenbaek et al59

MMPs/TIMP

SP-A SP-D

YKL-40

Abbreviations: DLco, diffusion lung capacity; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; GG, ground glass; HRCT, highresolution computed tomography; n.a., not available; PFT, pulmonary function tests; Se, sensitivity; Sp, specificity; TLC, total lung capacity. Notes: The corresponding studies are cited. Otherwise not specified, the cutoffs were identified in serum. a Wherever not indicated, PFT are intended as percent predicted.

BALF YKL-40 levels are predictors of survival in IPF.58 YKL-40 is increased in sera from SSc patients and correlates with obstructive ventilatory pattern, reduced DLCO, and poor prognosis.59 The presence of single gene polymorphisms (SNPs) in the gene encoding YKL-40 (CHI3L1-329 and -321) is associated with the magnitude of serum levels of this marker.58

Biomarkers from Other Cellular Sources Chemokines and Their Ligands CC chemokine ligand 18 (CCL18), previously known as pulmonary and activation-regulated chemokine, is constitutively expressed at high levels in the lungs, mainly by alveolar macrophages, and is chemotactic for a variety of mononuclear Seminars in Respiratory and Critical Care Medicine

Vol. 35

No. 2/2014


Table 4 Pneumoproteins and lung-derived biomarkers in serum/BALF with evidence as biomarker for ILD in CTD

Biomarkers in CTD-Associated Interstitial Lung Disease cells.60 CCL18 can stimulate fibroblast collagen and is increased in serum and BALF in idiopathic and secondary fibrotic lung diseases, including SSc-ILD.60 Three longitudinal studies in a total of 116 patients with SSc-ILD investigated the correlation of serum CCL18 with ILD activity determined by HRCT, lung function, and BALF analysis with promising results.60–62 Tiev et al analyzed serum CCL18 levels in 83 SSc patients with ILD over a 4-year follow-up period.62 At a cut-off of 187 ng/mL, serum CCL18 was independently predictive of ILD worsening (hazard ratio 5.4, p ¼ 0001).62 Similar results have been previously published by Prasse et al in patients with IPF.63 Recently, Elhaj et al64 raised critical questions for the validation of serum SP-D and CCL18 as prognostic biomarkers for SSc-ILD. The authors compared the predictive significance of these two pneumoproteins for the disease outcome of SScILD in the GENISOS cohort, a large, well-characterized multiethnic cohort of 266 patients with early SSc.30,64 For 83 patients, it was possible to collect a complete follow-up for biomarkers over 4 years. This allowed the authors to include all data points and to account for dependence between the longitudinal forced vital capacity (FVC) and survival, reducing the bias resulting from the fact that patients with more rapid decline in FVC are more likely to die.64,65 In contrast to the previous studies,60,62 Elhaj et al did not show a significant predictive significance of baseline serum CCL18 for long-term change in FVC. In addition, the correlation between baseline serum CCL18 and concomitant or 1-year follow-up FVC or DLCO was not confirmed. On the contrary, SP-D remained an independent correlate of concomitant FVC. Furthermore, a subgroup analysis based on disease type (limited/diffuse) or ATA positivity did not yield significant results for short- or long-term predictive value of SP-D or CCL18.64 CC chemokine ligand 2 (CCL2), also known as monocyte chemoattractant protein-1, is upregulated in serum of SSc patients and has been found to correlate with the presence of ILD.66–68 Also BALF CCL2 concentrations were found to be associated with the presence of ILD and correlated with lung function parameters and CT scores.69 CXC chemokine ligand 10 (CXCL10), a strong chemoattractant for Th1 lymphocytes secreting interferon-γ (INF-γ), is elevated in various autoimmune diseases (above all Grave disease), including SSc.70 In SSc, serum levels are significantly increased in patients with ILD (268 pg/mL) compared with those without (192 pg/mL) and normal controls (< 100 pg/ mL).68 However, no correlation was found with change in lung function over time.68,70 CXC chemokine ligand 12 (CXCL12) and its receptor CXCR4 are upregulated in the lung tissue of patients with SSc-ILD but not in controls.71 Moreover, circulating CXCR4þ progenitor cells have been observed to correlate with skin and lung involvement.71

Matrix Metalloproteinases and Their Inhibitors Matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of metalloproteinases (TIMPs), regulate the remodeling of the ECM and maintenance of basement membrane integrity. Among SSc patients, higher serum levels of Seminars in Respiratory and Critical Care Medicine

Vol. 35

No. 2/2014

Bonella, Costabel MMP-7, an established prognostic biomarker for IPF,72 and MMP-9, this one elevated also in BALF, were found in patients with ILD compared with those without and were associated with lower DLCO. The association of these MMPs with ILD progression was not evaluated.73–75 Circulating levels of MMP-12 have been reported to correlate with FVC (r ¼ 0.82), and expression of MMP-12 is significantly increased in SSc-ILD lungs compared with normal controls.76 TIMP-1 levels were found to be associated with the presence of ILD in 62 SSc patients and to correlate inversely with DLCO.77 A disintegrin and metalloprotease (ADAM) 12 is one of the metalloproteinase-type ADAMs and exerts extracellular metalloprotease and cell-binding functions. ADAM12 is expressed in two alternative forms, which are a membraneanchored form (ADAM12-L) and a short secreted form (ADAM12-S).78 Taniguchi et al measured serum ADAM12-S levels in 61 SSc patient and found a negative correlation with HRCT fibrosis score and a positive one with ground glass opacities (GGOs) score.78 ADAM12-S levels showed a positive correlation with FVC, but not with DLCO. Also on the basis of a strong correlation with C-reactive protein, the authors concluded that serum ADAM12-S seems to correlate more with inflammation than with fibrosis.78 Discovering noninvasive biomarkers for acute ILD, also in association with CTD, is challenging. In a recent study of Oka et al,79 MMP-1, MMP-8, MMP-9, and TIMP-3 were upregulated in the sera of 25 CTD patients (RA, SSc, and PM/DM) with acute onset of ILD. In contrast, MMP-3 and TIMP-2 were downregulated. The ratio of MMP3 to MMP1 serum levels, reduced in patients who died, has been proposed by the authors as predictor of poor outcome in these patients.79

Pleiotropic Interleukins and Their Ligands Elevated serum and BALF levels of interleukin-6 (IL-6), a pleiotropic cytokine linked to the TH2 lymphocyte subset, have been described in several lung diseases.80–82 Recently, the prognostic value of serum IL-6 was assessed in a large cohort of 212 patients with SSc-ILD.83 In the exploratory analysis, only serum IL-6 among IL-8, IL-10, CCL2, CXCL10, vascular endothelial growth factors (VEGFs), fibroblast growth factor-2, and CX3CL1 was an independent predictor of DLCO decline in both IPF and SSc-ILD. At a cutoff of 7.7 pg/mL, serum IL-6 was predictive of decline in FVC (HR 2.58) and in DLCO (HR 3.2) within the first year, and predictive of death within the first 30 months (HR 2.69). When stratified according to severity, serum IL-6 was predictive of functional decline or death within the first year only in patients with milder disease, but not in those with severe ILD. In SSc-ILD, serum IL-6 levels appear to be predictive of early disease progression in patients with mild ILD, and could be used to target treatment in this group, if confirmed by prospective studies.83 Wuttge et al found that serum levels of another pleiotropic cytokine, IL-15, a survival and growth factor for T and B lymphocytes, were strongly correlated with impaired lung function in SSc.84 Levels of IL-17A and IL-23, connected to the Th17 lymphocytes subset, are elevated in SSc and associated with the


188


Endothelial Cells Endothelial cell injury is involved in the pathogenesis of fibrosis.90 Endothelins, endothelial cell products with vasoconstrictor properties, are potent peptides in the regulation of both cell proliferation and the turnover of ECM. Increased endothelin-1 (ET-1) levels have been found in BALF and lung tissue from patients with SSc.91,92 Increased serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble E-selectin (sE-selectin), VEGF, and ET-1 have been described in patients with SSc and lung fibrosis.93–95 AECAs have been discussed above.

BALF Cellularity Profile BALF differential cell counts in SSc are of questionable diagnostic and prognostic value.96 Nevertheless, a large study on 73 SSc patients showed an association with BALF cellularity and the ILD pattern.97 For example, more BALF eosinophils were observed in patients with NSIP pattern than in those with UIP, and more lymphocytes in those with cellular NSIP than in those with fibrotic NSIP.97 A positive correlation between BALF neutrophils, extent of disease on HRCT, and poor survival has also been described in SSc-ILD.98–100 In the study of Goh et al,101 BALF cellular profiles in 141 patients with SSc-ILD did not show a prognostic value for disease progression, once disease severity had been quantified by pulmonary function tests (PFTs) and HRCT. BALF neutrophilia, independent of disease severity, was associated with early mortality (occurring within 2 years of presentation), but not with long-term prognosis. The SLS,102 to evaluate whether BALF cellularity identifies distinct subsets of disease and/or predicts cyclophosphamide responsiveness, performed BALF cell counts in 201 patients as part of a randomized placebo-controlled trial of cyclophosphamide versus placebo. Abnormal cellularity was present in 101 of these cases and identified a subgroup with more severe lung dysfunction, more extensive GGO, and more extensive fibrosis in the right middle lobe. Despite the aforementioned relationships, the presence/absence of an abnormal cell differential did not independently predict disease progression or response to cyclophosphamide at 1 year.103

189

Nailfold Capillary Pattern as Biomarker of ILD in SSc Nailfold video-capillaroscopy (NFC) is a noninvasive diagnostic tool that permits detection of the main local microvascular alterations in SSc, which are an expression of the systemic vascular changes characteristic of this disease.104 Patients with SSc exhibit a typical pattern at NFC characterized by enlargement of capillary loops, loss of capillaries, disruption of the orderly appearance of the capillary bed, and distortion of capillaries.105 Two studies found a positive correlation between the vascular deletion score in NFC and higher Rodnan skin score, presence of anti-Scl-70 antibodies, signs of peripheral ischemia, esophageal dysfunction, and pulmonary disease.106 Recently, Corrado et al pointed out the differences in the nailfold pattern between SSc-ILD and IPF.107 SSc-ILD patients have typical capillary loop changes present also in the very early stages of disease, while IPF patients present only minimal capillary alterations.107 The authors conclude that capillaroscopic changes in patients with lung fibrosis could indicate the first sign of a systemic disease involving the lungs and thus requiring the patient to have periodic checks to detect the appearance of immunological and clinical signs attributable to a CTD.107

Polymyositis/Dermatomyositis—ILD The lungs are among the most frequently involved organs in PM/DM, and ILD is reported in up to 78% of these patients depending on the methods used for diagnosis.108–110 ILD is one of the major causes of morbidity and mortality in patients with myositis.111,112 The majority of reported patients have NSIP pattern at histology.113 Early, accurate diagnosis and management of ILD are critical to prevent development of end-stage disease with irreversible honeycombing and fibrosis.114 With regard to DM subtypes, amyopathic DM (ADM) and clinical ADM (CADM) are defined as disorders that show the typical skin manifestations of DM but no or little evidence of clinical myositis.115 CADM patients, mostly in Asian countries, frequently develop life-threatening, acute, progressive ILD.116,117 The majority of studies on biomarkers in PM/DM have been performed in Japanese cohorts.115

Autoantibodies Anti-Aminoacyl-tRNA Synthetases Antibodies Antibodies reactive with ARS (anti-ARS Abs) are detected in patients with PM/DM118,119 and correlate with chronic and recurrent ILD.115 Eight anti-ARS Abs have been described: anti-histidyl (anti-Jo-1), anti-threonyl (anti-PL-7), anti-alanyl (anti-PL-12), anti-glycyl (anti-EJ), anti-isoleucyl (anti-OJ), anti-asparaginyl (anti-KS), anti-phenylalanyl (anti-Zo), and anti-tyrosyl (anti-Ha) tRNAs.119,120 Anti-Jo-1 is closely associated with myositis,120,121 whereas anti-KS is more likely related to ILD without clinical evidence of myositis.122 AntiPL-7 is closely associated with PM/DM-SSc overlap as well as with ILD in Japanese patients.123 It is not clear whether myositis-specific autoantibodies are directly involved in pathophysiologic mechanisms of myositis and ILD. Seminars in Respiratory and Critical Care Medicine

Vol. 35

No. 2/2014


presence of ILD.85,86 Circulating IL-22- and IL-17-producing T cells are increased in patients with SSc-ILD compared with those without.87 These findings support the hypothesis that Th22, in addition to Th17 cells, may be involved in pathological processes leading to SSc; the increased frequency of Th22 cells appears to be a useful novel biomarker in SSc.87 Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF family of cytokines, which can induce apoptotic cell death in cells expressing at least one of their specific death receptors, is involved in the pathophysiology of some autoimmune diseases and cancer.88 Mean serum TRAIL levels were found to be significantly higher in SSc patients than in RA patients and healthy controls (p < 0.001). Moreover, they were significantly higher in SSc patients with pulmonary involvement and correlated with the HRCT score.89 Further studies may be needed to confirm these findings.

Bonella, Costabel

Biomarkers in CTD-Associated Interstitial Lung Disease The correlation between anti-ARS Abs titers and activity of myositis or ILD is controversial.115 Anti-Jo-1 antibody titers have been found to correlate with activity of myositis as well as lung involvement.124 Anti-Jo-1 and anti-SSA/Ro positivity has been found to be associated with severe and extensive ILD in PM/DM.125 Anti-OJ antibodies, found in fewer than 2% of all patients with PM/DM, strongly correlate with the presence of ILD.123,126 Kunimasa et al126 reported that they were associated with a good prognosis and response to glucocorticoid treatment.

Anti-CADM-140/MDA5 Antibody In 2005, Sato et al127 identified a specific autoantibody in CADM patients. This newly identified autoantibody was named anti-CADM-140 antibody. Later the presence of anti-CADM-140 and the association with CADM-ILD was confirmed worldwide.115 The antibody can be detected exclusively in DM (11–26%) or CADM (50–73%).115 Nakashima et al demonstrated that the prognosis was significantly poorer in anti-CADM-140–positive patients than in antiCADM-140–negative DM patients, and six (46%) died of respiratory failure within 6 months of the onset of disease.128 The target autoantigen of anti-CADM-140 antibody was identified as melanoma differentiation–associated gene 5 (MDA5), also known as interferon induced with helicase C domain protein 1.128 Autoantibodies against MDA5 are important serological markers in ADM with rapidly progressive ILD.115,129,130 Tanizawa et al found that anti-CADM-140– positive patients with ILD had lower lobe consolidation or ground glass attenuation (GGA) (50%) and random GGA patterns (33%), while lower lobe reticulation pattern was frequently (70%) seen in anti-CADM-140–negative cases.131 In a further study on predictive factors of PM/DM ILD outcome, the same authors found that the aforementioned HRCT pattern (lower lobe consolidation/GGA) was associated with a higher 90-day morality rate among anti-CADM-140– positive patients and higher overall mortality in univariate analysis, whereas only the presence of anti-CADM-140 was an independent predictor of mortality in multivariate analysis.132

Lung Epithelium–Specific Biomarkers Serum KL-6, SP-D, and Ferritin Serum KL-6, SP-D, and ferritin have been found to be useful biomarkers for monitoring the activity and severity of ILD in PM/DM (►Table 4).115,133–141 Several studies suggested the usefulness of KL-6 as biomarker for disease activity, therapeutic response, and prognosis in myositis-ILD.133–135 Satoh et al142 demonstrated that a high serum level (> 1,000 U/mL) of KL-6 was a poor prognostic factor in PM/DM patients with ILD before treatment. Fathi et al136 used KL-6 longitudinally to assess clinical response to treatment in 12 patients with ILD and PM/DM. Changes in KL-6 levels were found to be significantly inversely correlated with changes in percentage forced expiratory volume in 1 second (FEV1), total lung capacity (TLC), DLCO, and residual volume. Moreover, at a cutoff level of 549 U/mL, Seminars in Respiratory and Critical Care Medicine

Vol. 35

No. 2/2014

Bonella, Costabel the sensitivity and specificity for diagnosis of ILD were 83 and 100%, respectively.136 With regard to SP-D, Ihn et al141 found that the serum SP-D level in PM/DM patients with ILD was significantly higher than in those without ILD and correlated with the decrease in VC and DLCO. Interestingly, longitudinal measurements of serum SP-D levels in a subgroup of patients showed that the exacerbation of ILD was accompanied by definite increases in serum SP-D.141 Recently, Arai et al143 compared serum KL-6 and SP-D as biomarkers to assess the response to treatment in 50 patients with PM/DM and ILD. Serum KL-6 and SP-D levels showed different patterns in response to treatment; serum KL-6 levels were increased up to 3 months after starting treatment and then decreased gradually to baseline, whereas SP-D levels peaked within the first 4 weeks after treatment and decreased rapidly to normal levels.143 Moreover, the authors demonstrated that KL-6 and SP-D levels measured at one time point, including at the time of diagnosis, failed to predict prognosis.143

Other Soluble Biomarkers Ferritin Ferritin is the major molecule for iron storage and has a crucial role in the sequestration of potentially harmful molecules of reactive iron.138 Ferritin is located in the cytoplasm, mitochondria, nuclei, and serum and its expression is regulated at both the transcriptional and posttranscriptional levels by iron, cytokines, hormones, and oxidative stress.144 Serum ferritin level was reported to be significantly higher in the subset with anti-CADM-140 antibody than in those without and has been proposed as a marker for severity of acute progressive ILD in DM patients.128,138–140,145 In a recent study, serum ferritin, at a cutoff value of 1,600 ng/mL, was the best indicator of survival in patients with anti-MDA5 antibody–associated DM-ILD.145

Interleukin 18 High concentrations of serum and muscular IL-18 suggest that the dysregulated IL-18/IL-18R pathway may be pathogenetic in inflammatory myopathy.146 Serum IL-18 has been found to be elevated in patients with DM and PM, correlating particularly with disease activity and ILD presence in DM.140 Moreover, the authors encountered several cases in which both serum ferritin and IL-18 were correlated with the activity of acute ILD in DM.140

Markers of Inflammation and Other Biomarkers Erythrocyte sedimentation rate and lactate dehydrogenase were shown to be elevated in a single case study.147 Muscle enzyme creatinine kinase is a biomarker for inflammatory muscle disease activity, but its role in ILD has not been studied.113 Other biomarkers described in a limited fashion include B-cell–activating factor148 and CA15-3.149

BALF Cells Profile There are only few reports that have included data about the BALF cell profiles in PM/DM patients with ILD.96,150 However,


190

BALF cell differentials may be helpful prognostic indicators in PM/DM patients with ILD. Two different studies showed that patients with ILD had a poor outcome when the initial BALF showed neutrophilic alveolitis151,152.

Rheumatoid Arthritis—ILD ILD is found in up to 30% of patients with RA, even though clinically manifest in only 5 to 10%, and results in significant morbidity and increased mortality in up to 10%.1,153 The high prevalence of lung disease in early RA suggests that the lung may be the site of initial RA-related immune dysregulation.154 The association between inhaled environmental agents such as tobacco smoke and silica dust with the development of RA seems to support this theory.154,155 Several serological biomarkers are candidate to predict the development of RA-ILD (►Table 3).156 Serum IgM rheumatoid factor (RF) and anti–citrullinated protein antibodies have been found to be associated with extra-articular manifestations of RA, including ILD,157–159 both in scarcely symptomatic and completely asymptomatic individuals.160,161

Rheumatoid Factor RF seropositivity is most commonly determined by agglutination tests, which preferentially detect IgM RF, but several studies indicate that IgA RF may be a better prognostic indicator in RA patients.154 The interpretation of RF positivity and titer is challenging. Tobacco smoking, for example, can increase RF serum titer in the general population as well as in RA patients.162,163 In addition, RF titer correlates with the duration of smoking.164 RA patients with ILD have significantly elevated levels of IgG RF in serum as well as in BALF.165 The association between higher levels of RF and progression of RA-ILD is not known.

Anti–Citrullinated Protein Antibodies A wide variety of anti–cyclic citrullinated peptide (anti-CCP) antibodies have been described in RA, including autoantibodies to citrullinated vimentin, fibrinogen, type II collagen, histones, and enolase.166–169 The pathogenic role of anti-CCP antibodies remains unclear. Their presence in BALF suggests that the lungs may be an antigenic source for anti-CCP antibodies production.156,170 This is also suggested by Fischer et al,171 who described a unique cohort of patients with anti-CCP antibody positivity and lung disease, with predominance of airways disease, in the absence of existing RA or other CTD. The lung phenotypic characteristics of this cohort resemble those of established RA, but few of these patients developed articular RA within a short period of follow-up.171 There is growing evidence that anti-CCP antibodies directly contribute to the pathogenesis of joint disease in RA through immune complexes and direct targeting of synovial antigens169,172; whether these autoantibodies directly target specific antigens in the lung, leading to local tissue inflammation and injury, still remains to be demonstrated. However, Aubart et al159 demonstrated that a high anti-CCP level (odds ratio [OR]: 1.49) was an independent risk factor for lung disease in a RA cohort of 252 patients.

Bonella, Costabel

Harlow et al identified isoforms of anti-CCP autoantibodies to citrullinated Hsp90 which were able to distinguish RA-ILD from RA without ILD, MCTD, and IPF with high specificity.173 The sensitivity/specificity for use of anti-Hsp90β-P to identify RA-associated ILD was 0.24/0.19, while the sensitivity/ specificity for use of anti-Hsp90β-E to identify RA-associated ILD was 0.96/1.0. The sensitivity of the anti-citrullinated Hsp90α antibodies was very low (0.10), but the specificity was 1.0. Composite anti-citrullinated Hsp90α/β antibodies demonstrated comparable levels of sensitivity (20–30%) and specificity (> 95%).173 A significant, even if not complete, cross-reactivity between antibodies targeting the highly homologous Hsp90α and Hsp90β isoforms was seen and this point needs further investigation.173 Interestingly, the levels of anti-citrullinated Hsp90 Abs did not consistently correlate with anti-CCP-2 titers in any of the RA subpopulations, highlighting the uniqueness of the generated citrullinated epitopes.173 Recently, another isotype of Hsp autoantibodies, anti-Hsp70, has been found to be elevated in plasma and associated with greater subsequent FVC reductions and poorer outcome in patients affected by IPF.174 Whether Hsp90 Abs correlate with the severity and outcome of ILD in RA is a topic for future longitudinal studies.

HLA Loci Associated with ILD in RA There is increasing evidence that specific HLA loci are associated with ILD in RA.175–178 Many of the gene products of HLA-DRB101 and 04 are known to contain the shared epitope motif in the third hypervariable chain of HLADRB1, which is a major genetic element conveying susceptibility to RA.158 HLA-DRB115 alleles, on the contrary, are infrequent in RA.158 Migita et al first observed a significant association of HLA-DRB11502 with pulmonary fibrosis in Japanese RA patients.178 In a study on 450 Japanese patients, Furukawa et al reported that HLA-DRB116, from the DR2 serologic group, was also associated with increased risk for ILD in Japanese patients with RA (OR: 1.75).177 Mori et al confirmed that HLA-DRB11502 was associated with an increased risk of ILD in RA even if it seems not to confer susceptibility to RA.158 All these findings show that HLADRB11502 is likely to be a critical determinant and a genetic biomarker for ILD.

Serum KL-6 Several studies investigated the role of KL-6 as biomarker for RAILD, mostly in a cross-sectional fashion (►Table 4).46,142,179–183 Oyama et al reported that an increase in serum KL-6 levels in RA is associated with the presence of active interstitial pneumonitis.180 Correlation of KL-6 with parameters of disease activity such as erythrocyte sedimentation rate, C-reactive protein, IgMRF, and IgG-RF in RA has not been reported.179,180 Two recent meta-analyses on Japanese RA patients treated with diseasemodifying antirheumatic drugs showed that serum KL-6 levels may increase during anti-TNF therapy or methotrexate treatment, without significant clinical events.184,185 Kinoshita et al compared serum KL-6 levels with HRCT findings in RA-ILD patients and found a positive correlation between KL-6 level and the total CT score; the closest correlation was seen with Seminars in Respiratory and Critical Care Medicine

Vol. 35

No. 2/2014

191



Biomarkers in CTD-Associated Interstitial Lung Disease reticular opacities.179 Longitudinal as well as validation studies on serum KL-6 in RA-ILD are needed.

Biomarkers in BALF BALF findings in RA are highly variable and nonspecific.96 An increase in either lymphocytes or neutrophils can be seen,96 but lymphocytes seem to be a more prominent feature in RA than in SSc.96 BALF can be abnormal in 52% of the patients with early-onset RA revealing the presence of alveolitis.186 A neutrophilic alveolitis can be found in patients with clinically evident IP,187,188 and a lymphocytic alveolitis in 33% of patients with normal chest radiography and normal PFTs.188 Multiplex ELISA of biologically active molecules represents an advancement over traditional methods of biomarker assessment.189 Using multiplex ELISA to examine BALF proteins in a cohort of 43 RA patients without ILD as well as 10 RA patients with histologically proven UIP; Gochuico et al190 found that levels of PDGF isoforms AB and BB were higher in subclinical RA-ILD than in patients with RA alone. On the contrary, concentrations of IFN-γ and TGF-β2 were lower in patients with RA-UIP than in the other subgroups.190 Subclinical RA-ILD patients developing later progressive lung disease had higher BALF levels of IFN-γ and PDGF-β1 compared with individuals with persistent subclinical RA-ILD.190

Systemic Lupus Erythematosus—ILD Clinically significant ILD is less common in SLE than in the other CTDs,1 and is generally overlapping with other CTD. A frequency of 4% of patients who develop clinical or plain chest radiographic evidence of pulmonary fibrosis, after a mean disease duration of 5.3 years, has been reported.191 The most commonly reported histologic ILD pattern in SLE is NSIP.191

Autoantibodies More than 50 different autoantibody specificities may be observed in patients with SLE, and on average any patient will have three different ANAs.18 Both anti-ds-DNA and antiSmith antigen are the most specific for SLE.18 The titer of antids-DNA appears to correlate with disease activity. Lung involvement does not correlate with any biological marker, although in one study an association between anti-SS-A antibodies and chronic interstitial pneumonitis was observed.192 However, this observation was not confirmed in later studies, which described only an association between low DLCO and anti-U1-RNP antibodies in 57 SLE patients.193 The presence of anti-U1-RNP antibodies was associated with scleroderma traits.193

Lung Epithelium–Specific Biomarkers Recently, Hasegawa et al compared serum KL-6, SP-D, and CC16 as potential biomarkers for the detection of fibrosis both in SLE and in SSc patients.53 CC16 serum level in SSC was higher than in SLE and healthy controls. CC16 was slightly inferior to KL-6, but comparable to SP-D, for detecting pulmonary fibrosis in patients with SSc.53 In patients with SLE, serum levels of KL-6 and SP-D were comparable to healthy controls.53 Seminars in Respiratory and Critical Care Medicine

Vol. 35

No. 2/2014

Bonella, Costabel Chemokines and Cytokines Kodera et al61 investigated serum CCL18 levels in 21 patients with SLE in comparison with SSc patients and healthy controls. CCL18 levels in the SLE patients (mean: 51 ng/mL) were significantly increased compared with those in the normal control subjects (mean: 36 ng/mL), but were significantly lower than in SSc patients (mean: 78 ng/mL).61 Recently, the concentrations of IL-6 and IL-10 were investigated in the exhaled breath condensate (EBC) and BALF of 34 patients with SLE, 50% of them with pulmonary involvement on HRCT.194 Even though IL-6 and IL-10 concentrations in the BALF and IL-10 concentrations in the EBC were higher in patients with SLE compared with healthy controls, both interleukins were not useful as biomarkers to detect pulmonary involvement.194 A correlation with PFTs was seen only for IL-10 in EBC.194

Tumor-Associated Antigens Several reports suggest that tumor-associated antigens (TAAs) may, apart from cancer cells, become expressed on the surface of inflammatory cells.195 Some studies have reported that serum CA125 (MUC16) level is elevated in SLE patients and may be associated with the presence of serositis and disease activity in SLE.195–197 Recently, Yang et al reported that serum CA125 levels were associated, albeit not independently, with lung involvement in a cohort of 156 SLE patients.198 These results are in contrast with those of Szekanec et al195 who did not find any correlation between TAAs, including CA125, and lung involvement both in SLE and SSc. Further investigations on a possible role of TAAs as biomarkers in CTD-ILDs are needed.

Sjögren Syndrome—ILD pSS is a chronic systemic autoimmune disease that involves primarily the exocrine glands.199 Clinically significant pulmonary involvement affects approximately 10% of patients and may be the first manifestation of the disease.200 ILD in pSS occurs in up to 38% of patients.1 ILD may occur mainly in the form of NSIP and lymphocytic interstitial pneumonia; organizing pneumonia and UIP have also been described.1,18,201–204

Autoantibodies SSA/Ro and SSB/La are commonly encountered autoantibodies and are included in the diagnostic criteria.18 Other useful laboratory markers include polyclonal hypergammaglobulinemia, elevated erythrocyte sedimentation rate, elevated titer of RF, and the presence of ANAs.150 Predictors for lung involvement are hypergammaglobulinemia and lymphopenia, positivity for RF, anti-La and anti-Ro, and impaired FVC and/or FEV1 values, with a high specificity but low sensitivity.199 Davidson et al205 reported that pulmonary complications occurred particularly in patients with anti-Ro antibody positivity, and these patients presented at the onset of disease. Yazisiz et al199 found that the specificity of anti-La antibodies for detecting pulmonary involvement was higher than that of the other autoantibodies (93%).


192


Other Biomarkers Recently, a panel of biomarkers of more than 80 chemokines, cytokines, growth factors, autoantibodies, and other biomarkers was quantified in serum and saliva from spontaneous experimental pSS in mice using multianalyte profile technology, with promising results for 38 biomarkers in serum and 34 in saliva. Among them, CD40, CD40 ligand, IL-18, granulocyte chemotactic protein-2, and antimuscarinic M3 receptor IgG3 may also connect different pathogenic aspects of SS.211

Bronchoalveolar Lavage Differential Cell Counts BALF analysis has been demonstrated to be useful in case of subclinical pulmonary involvement in CTD-ILD.212 Subclinical lymphocytic and neutrophilic alveolitis affects up to 50% of patients with pSS.213 Alveolitis is more frequent in patients with extrapulmonary involvement. Neutrophilic alveolitis with an increase of CD8þ T-lymphocytes is associated with alteration of lung function.212,214

MCTD—ILD MCTD is the overlap of SLE, scleroderma, and polymyositis.1,4 While pulmonary arterial hypertension remains the leading cause of death in patients with MCTD,215 ILD may be observed in up to 65% of patients.18,216–218 Patients have anti-U1RNP antibodies, which along with other autoantibodies, such as AECA, anti-CL, anti-CCP, may determine the clinical symptoms and the types of organ damage.218,219 Recently, three different phenotypes/clusters of MCTD have been proposed.218 In the cluster 2, the incidence of ILD was 99% (22 and 33% in clusters 1 and 3, respectively).218 The most commonly described ILD type in MCTD is NSIP, which usually follows and occasionally precedes systemic disease manifestations.18

Autoantibodies High levels of anti-U1-RNP autoantibodies, immune complexes, complement C3 factor, and CH50 are present in the sera of patients with active ILD217 (►Table 1). In two studies on MCTD patients with ILD, none of the patients showed antiJo1 antibody positivity.217,218

Anti-Ro52 Antibodies In recent years, antibodies to SSA antigen (Ro52/Ro60), historically described as a marker for SS and SLE, have been

193

reported in a wide variety of autoimmune diseases, particularly myositis, scleroderma, and autoimmune liver diseases.220,221 In a cohort of 162 CTD patients, 35 of them with ILD, Ferreira et al demonstrated that anti-Ro52 antibodies were very sensitive (96%) for ILD diagnosis in MCTD, UCTD, and Sjögren, but not in SSc. Whether anti-Ro52 antibodies could be a marker for ILD independent of the presence of CTD still needs to be addressed.220

HSP47 Antigen and Autoantibodies to HSP47 The 47-kDa heat shock protein (HSP47) is an endoplasmic reticulum molecular chaperone that assists in the maturation of collagen molecules and whose expression is known to be upregulated in lesions of fibrotic diseases.222 Patients with MCTD have particularly high serum levels of HSP47 antigen compared with healthy controls.223 Autoantibodies to HSP47 are also increased in sera of MCTD patients,223 as in other forms of IIP (IPF, idiopathic NSIP, and cryptogenic organizing pneumonia), with fibrosing NSIP showing the highest values.224

UCTD—ILD UCTD has been generally defined as a condition manifesting with signs and symptoms suggestive of a CTD, along with ANA positivity, but not fulfilling existing rheumatologic classification criteria for any specific CTD.1,225,226 Mosca et al reported that approximately 60% of patients with UCTD will remain undifferentiated, and that when evolution to defined CTD occurs, it usually does so within the first 5 years of disease.225,227,228 UCTD may evolve into any of the CTDs, but most often evolves into SLE.1 There are two main problems in the management of patients with UCTD: first, recognizing the presence of ILD, the most frequent lung manifestation usually responsible for progression and adverse outcome of the disease229,230; second, in patients with ILD as primary manifestation of disease, making the diagnosis of UCTD based on the existing criteria. In recent years, increasing attention to pulmonary involvement in UCTD has been given.1,226 Kinder et al, for example, studied 28 consecutive patients with IIP who met prespecified criteria for UCTD.229 The authors reported that patients with UCTD-ILD were significantly more likely to have groundglass opacity on HRCT and NSIP pattern on biopsy ILD, commonly overlooked as idiopathic NSIP.229 In a prospective study, Romagnoli et al reported that UCTD was detected in 22% of NSIP patients and that 50% of patients diagnosed with NSIP showed an autoimmune disease, as UCTD, in their follow-up.231 Corte et al found that having a diagnosis of UCTD was not sensitive (31%) but was relatively specific (88%) for NSIP histology.20 Currently, the term UCTD describes different clinical entities, thus leading to a lack in specific diagnostic/prognostic biomarkers. Autoantibodies positivity has been included in the criteria for definition of UCTD together with clinical features.1 The autoantibody pattern in UCTD is similar to that of SLE (►Table 1).1,18 There are broader or stricter criteria for definition of UCTD.20,229 According to the more recent Seminars in Respiratory and Critical Care Medicine

Vol. 35

No. 2/2014


In the past years, many new autoantibodies have been associated with pSS including antimuscarinic receptor 3, antitissue kallikrein, anti-α-fodrin, and anticarbonic anhydrase II, but the significance of these autoantibodies has not been fully clarified.206–210 More recently, patients with pSS were also shown to produce antibodies to salivary gland protein 1 (SP-1), carbonic anhydrase 6 (CA6), and parotid secretory protein (PSP).209 These antibodies were found in 45% of patients meeting the criteria for pSS who lacked antibodies to Ro60 or La.209 The authors concluded that SP1, CA6, and PSP may be useful markers for identifying patients with pSS at early stages of the disease or those that lack antibodies to either SSA/Ro60 or SSB/La.209

Bonella, Costabel

Biomarkers in CTD-Associated Interstitial Lung Disease ones,20 at least one autoantibody amongst ANA (high titer), RF (high titer), anti-Smith, anti-RNP, anti-dsDNA, anti-Ro, antiLa, anti-Jo-1, anti-topoisomerase (Scl-70), or anticentromere must be present.1 There are no studies indicating a correlation between autoantibody pattern and disease outcome in UCTD. In conclusion, there is a lack of studies about the role of specific serum or BALF pneumoproteins or cytokines as biomarkers for UCTD. Developing biomarkers that correlate with a specific CTD at the time of UCTD diagnosis, such as more sensitive autoantibodies, or that are associated with the histologic pattern of ILD, would improve the management and the therapeutic decision in these patients.

Bonella, Costabel 17 Horimasu Y, Hattori N, Ishikawa N, et al. Different MUC1 gene

18

19 20

21

22 23

References

24

1 Olson AL, Brown KK, Fischer A. Connective tissue disease-associ-

2

3

4

5 6 7

8

9 10

11

12

13

14

15

16

ated lung disease. Immunol Allergy Clin North Am 2012;32(4): 513–536 Launay D, Remy-Jardin M, Michon-Pasturel U, et al. High resolution computed tomography in fibrosing alveolitis associated with systemic sclerosis. J Rheumatol 2006;33(9):1789–1801 Vij R, Strek ME. Diagnosis and treatment of connective tissue disease-associated interstitial lung disease. Chest 2013;143(3): 814–824 Gutsche M, Rosen GD, Swigris JJ. Connective tissue diseaseassociated interstitial lung disease: a review. Curr Respir Care Rep 2012;1:224–232 Fischer A, du Bois R. Interstitial lung disease in connective tissue disorders. Lancet 2012;380(9842):689–698 Steen VD, Medsger TA. Changes in causes of death in systemic sclerosis, 1972-2002. Ann Rheum Dis 2007;66(7):940–944 Tyndall AJ, Bannert B, Vonk M, et al. Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database. Ann Rheum Dis 2010; 69(10):1809–1815 Olson AL, Swigris JJ, Sprunger DB, et al. Rheumatoid arthritisinterstitial lung disease-associated mortality. Am J Respir Crit Care Med 2011;183(3):372–378 Vij R, Noth I, Strek ME. Autoimmune-featured interstitial lung disease: a distinct entity. Chest 2011;140(5):1292–1299 Mittoo S, Gelber AC, Christopher-Stine L, Horton MR, Lechtzin N, Danoff SK. Ascertainment of collagen vascular disease in patients presenting with interstitial lung disease. Respir Med 2009; 103(8):1152–1158 Centola M, Cavet G, Shen Y, et al. Development of a multibiomarker disease activity test for rheumatoid arthritis. PLoS ONE 2013;8(4):e60635 Hirata S, Dirven L, Shen Y, et al. A multi-biomarker score measures rheumatoid arthritis disease activity in the BeSt study. Rheumatology (Oxford) 2013;52(7):1202–1207 Lota HK, Renzoni EA. Circulating biomarkers of interstitial lung disease in systemic sclerosis. Int J Rheumatol 2012; 2012:121439 Takemoto Y, Sakatani M, Takami S, et al. Association between angiotensin II receptor gene polymorphism and serum angiotensin converting enzyme (SACE) activity in patients with sarcoidosis. Thorax 1998;53(6):459–462 Seibold MA, Wise AL, Speer MC, et al. A common MUC5B promoter polymorphism and pulmonary fibrosis. N Engl J Med 2011;364(16):1503–1512 Ishikawa N, Hattori N, Yokoyama A, Kohno N. Utility of KL-6/ MUC1 in the clinical management of interstitial lung diseases. Respir Investig 2012;50(1):3–13

Seminars in Respiratory and Critical Care Medicine

Vol. 35

No. 2/2014

25

26 27 28 29

30

31

32

33

34

35 36

37

38

polymorphisms in German and Japanese ethnicities affect serum KL-6 levels. Respir Med 2012;106(12):1756–1764 Papiris SA, Kagouridis K, Bouros D. Serologic evaluation in idiopathic interstitial pneumonias. Curr Opin Pulm Med 2012; 18(5):433–440 Self SE. Autoantibody testing for autoimmune disease. Clin Chest Med 2010;31(3):415–422 Corte TJ, Copley SJ, Desai SR, et al. Significance of connective tissue disease features in idiopathic interstitial pneumonia. Eur Respir J 2012;39(3):661–668 Nagai S, Handa T, Tabuena R, Kitaichi M, Izumi T. Nonspecific interstitial pneumonia: a real clinical entity? Clin Chest Med 2004;25(4):705–715, vi Prasse A, Müller-Quernheim J. Non-invasive biomarkers in pulmonary fibrosis. Respirology 2009;14(6):788–795 Lukacs NW, Hogaboam C, Chensue SW, Blease K, Kunkel SL. Type 1/type 2 cytokine paradigm and the progression of pulmonary fibrosis. Chest 2001;120(1, Suppl):5S–8S Ramos C, Montaño M, García-Alvarez J, et al. Fibroblasts from idiopathic pulmonary fibrosis and normal lungs differ in growth rate, apoptosis, and tissue inhibitor of metalloproteinases expression. Am J Respir Cell Mol Biol 2001;24(5):591–598 Selman M, King TE, Pardo A; American Thoracic Society; European Respiratory Society; American College of Chest Physicians. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med 2001;134(2):136–151 Selman M, Pardo A. Idiopathic pulmonary fibrosis: an epithelial/ fibroblastic cross-talk disorder. Respir Res 2002;3:3 Chapman HA. Disorders of lung matrix remodeling. J Clin Invest 2004;113(2):148–157 Tzouvelekis A, Kouliatsis G, Anevlavis S, Bouros D. Serum biomarkers in interstitial lung diseases. Respir Res 2005;6:78 Hant FN, Ludwicka-Bradley A, Wang HJ, et al; Scleroderma Lung Study Research Group. Surfactant protein D and KL-6 as serum biomarkers of interstitial lung disease in patients with scleroderma. J Rheumatol 2009;36(4):773–780 Assassi S, Sharif R, Lasky RE, et al; GENISOS Study Group. Predictors of interstitial lung disease in early systemic sclerosis: a prospective longitudinal study of the GENISOS cohort. Arthritis Res Ther 2010;12(5):R166 Murray LA, Rubinowitz A, Herzog EL. Interstitial lung disease: is interstitial lung disease the same as scleroderma lung disease? Curr Opin Rheumatol 2012;24(6):656–662 Baraut J, Michel L, Verrecchia F, Farge D. Relationship between cytokine profiles and clinical outcomes in patients with systemic sclerosis. Autoimmun Rev 2010;10(2):65–73 Fertig N, Domsic RT, Rodriguez-Reyna T, et al. Anti-U11/U12 RNP antibodies in systemic sclerosis: a new serologic marker associated with pulmonary fibrosis. Arthritis Rheum 2009;61(7): 958–965 Okano Y, Steen VD, Medsger TA Jr. Autoantibody reactive with RNA polymerase III in systemic sclerosis. Ann Intern Med 1993; 119(10):1005–1013 Mihai C, Tervaert JW. Anti-endothelial cell antibodies in systemic sclerosis. Ann Rheum Dis 2010;69(2):319–324 Hill MB, Phipps JL, Cartwright RJ, Milford Ward A, Greaves M, Hughes P. Antibodies to membranes of endothelial cells and fibroblasts in scleroderma. Clin Exp Immunol 1996;106(3): 491–497 Ihn H, Sato S, Fujimoto M, et al. Characterization of autoantibodies to endothelial cells in systemic sclerosis (SSc): association with pulmonary fibrosis. Clin Exp Immunol 2000;119(1):203–209 Odani T, Yasuda S, Ota Y, et al. Up-regulated expression of HLADRB5 transcripts and high frequency of the HLA-DRB501:05 allele in scleroderma patients with interstitial lung disease. Rheumatology (Oxford) 2012;51(10):1765–1774


194

Bonella, Costabel

39 Delgado-Vega A, Sánchez E, Löfgren S, Castillejo-López C, Alarcón-

57 Johansen JS. Studies on serum YKL-40 as a biomarker in diseases

Riquelme ME. Recent findings on genetics of systemic autoimmune diseases. Curr Opin Immunol 2010;22(6):698–705 Ohshimo S, Yokoyama A, Hattori N, Ishikawa N, Hirasawa Y, Kohno N. KL-6, a human MUC1 mucin, promotes proliferation and survival of lung fibroblasts. Biochem Biophys Res Commun 2005;338(4):1845–1852 Seko A, Ohkura T, Ideo H, Yamashita K. Novel O-linked glycans containing 6′-sulfo-Gal/GalNAc of MUC1 secreted from human breast cancer YMB-S cells: possible carbohydrate epitopes of KL6(MUC1) monoclonal antibody. Glycobiology 2012;22(2): 181–195 Yamane K, Ihn H, Kubo M, et al. Serum levels of KL-6 as a useful marker for evaluating pulmonary fibrosis in patients with systemic sclerosis. J Rheumatol 2000;27(4):930–934 Yanaba K, Hasegawa M, Hamaguchi Y, Fujimoto M, Takehara K, Sato S. Longitudinal analysis of serum KL-6 levels in patients with systemic sclerosis: association with the activity of pulmonary fibrosis. Clin Exp Rheumatol 2003;21(4):429–436 Yanaba K, Hasegawa M, Takehara K, Sato S. Comparative study of serum surfactant protein-D and KL-6 concentrations in patients with systemic sclerosis as markers for monitoring the activity of pulmonary fibrosis. J Rheumatol 2004;31(6):1112–1120 Bonella F, Volpe A, Caramaschi P, et al. Surfactant protein D and KL-6 serum levels in systemic sclerosis: correlation with lung and systemic involvement. Sarcoidosis Vasc Diffuse Lung Dis 2011; 28(1):27–33 Doishita S, Inokuma S, Asashima H, et al. Serum KL-6 level as an indicator of active or inactive interstitial pneumonitis associated with connective tissue diseases. Intern Med 2011;50(23): 2889–2892 Janssen R, Kruit A, Grutters JC, Ruven HJ, Gerritsen WB, van den Bosch JM. The mucin-1 568 adenosine to guanine polymorphism influences serum Krebs von den Lungen-6 levels. Am J Respir Cell Mol Biol 2006;34(4):496–499 Janssen R, Sato H, Grutters JC, et al. Study of Clara cell 16, KL-6, and surfactant protein-D in serum as disease markers in pulmonary sarcoidosis. Chest 2003;124(6):2119–2125 Bernard A, Hermans C, Van Houte G. Transient increase of serum Clara cell protein (CC16) after exposure to smoke. Occup Environ Med 1997;54(1):63–65 Petrek M, Hermans C, Kolek V, Fialová J, Bernard A. Clara cell protein (CC16) in serum and bronchoalveolar lavage fluid of subjects exposed to asbestos. Biomarkers 2002;7(1): 58–67 Hermans C, Petrek M, Kolek V, et al. Serum Clara cell protein (CC16), a marker of the integrity of the air-blood barrier in sarcoidosis. Eur Respir J 2001;18(3):507–514 Kucejko W, Chyczewska E, Naumnik W, Ossolińska M. Concentration of surfactant protein D, Clara cell protein CC-16 and IL-10 in bronchoalveolar lavage (BAL) in patients with sarcoidosis, hypersensitivity pneumonitis and idiopathic pulmonary fibrosis. Folia Histochem Cytobiol 2009;47(2):225–230 Hasegawa M, Fujimoto M, Hamaguchi Y, et al. Use of serum Clara cell 16-kDa (CC16) levels as a potential indicator of active pulmonary fibrosis in systemic sclerosis. J Rheumatol 2011; 38(5):877–884 Pastva AM, Wright JR, Williams KL. Immunomodulatory roles of surfactant proteins A and D: implications in lung disease. Proc Am Thorac Soc 2007;4(3):252–257 Takahashi H, Kuroki Y, Tanaka H, et al. Serum levels of surfactant proteins A and D are useful biomarkers for interstitial lung disease in patients with progressive systemic sclerosis. Am J Respir Crit Care Med 2000;162(1):258–263 Asano Y, Ihn H, Yamane K, et al. Clinical significance of surfactant protein D as a serum marker for evaluating pulmonary fibrosis in patients with systemic sclerosis. Arthritis Rheum 2001;44(6): 1363–1369

with inflammation, tissue remodelling, fibroses and cancer. Dan Med Bull 2006;53(2):172–209 Korthagen NM, van Moorsel CH, Barlo NP, et al. Serum and BALF YKL-40 levels are predictors of survival in idiopathic pulmonary fibrosis. Respir Med 2011;105(1):106–113 Nordenbaek C, Johansen JS, Halberg P, et al. High serum levels of YKL-40 in patients with systemic sclerosis are associated with pulmonary involvement. Scand J Rheumatol 2005;34(4): 293–297 Prasse A, Pechkovsky DV, Toews GB, et al. CCL18 as an indicator of pulmonary fibrotic activity in idiopathic interstitial pneumonias and systemic sclerosis. Arthritis Rheum 2007;56(5):1685–1693 Kodera M, Hasegawa M, Komura K, Yanaba K, Takehara K, Sato S. Serum pulmonary and activation-regulated chemokine/CCL18 levels in patients with systemic sclerosis: a sensitive indicator of active pulmonary fibrosis. Arthritis Rheum 2005;52(9): 2889–2896 Tiev KP, Hua-Huy T, Kettaneh A, et al. Serum CC chemokine ligand-18 predicts lung disease worsening in systemic sclerosis. Eur Respir J 2011;38(6):1355–1360 Prasse A, Probst C, Bargagli E, et al. Serum CC-chemokine ligand 18 concentration predicts outcome in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2009;179(8):717–723 Elhaj M, Charles J, Pedroza C, et al. Can serum surfactant protein D or CC-chemokine ligand 18 predict outcome of interstitial lung disease in patients with early systemic sclerosis? J Rheumatol 2013;40(7):1114–1120 Bonella F, Caramaschi P. The ambitious goal of validating prognostic biomarkers for systemic sclerosis-related interstitial lung disease. J Rheumatol 2013;40(7):1034–1036 Carulli MT, Handler C, Coghlan JG, Black CM, Denton CP. Can CCL2 serum levels be used in risk stratification or to monitor treatment response in systemic sclerosis? Ann Rheum Dis 2008;67(1): 105–109 Hasegawa M, Sato S, Takehara K. Augmented production of chemokines (monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-1alpha (MIP-1alpha) and MIP1beta) in patients with systemic sclerosis: MCP-1 and MIP-1alpha may be involved in the development of pulmonary fibrosis. Clin Exp Immunol 1999;117(1):159–165 Antonelli A, Ferri C, Fallahi P, et al. CXCL10 (alpha) and CCL2 (beta) chemokines in systemic sclerosis—a longitudinal study. Rheumatology (Oxford) 2008;47(1):45–49 Schmidt K, Martinez-Gamboa L, Meier S, et al. Bronchoalveolar lavage fluid cytokines and chemokines as markers and predictors for the outcome of interstitial lung disease in systemic sclerosis patients. Arthritis Res Ther 2009;11(4):R111 Hasegawa M, Fujimoto M, Matsushita T, Hamaguchi Y, Takehara K, Sato S. Serum chemokine and cytokine levels as indicators of disease activity in patients with systemic sclerosis. Clin Rheumatol 2011;30(2):231–237 Campioni D, Lo Monaco A, Lanza F, et al. CXCR4 pos circulating progenitor cells coexpressing monocytic and endothelial markers correlating with fibrotic clinical features are present in the peripheral blood of patients affected by systemic sclerosis. Haematologica 2008;93(8):1233–1237 Song JW, Do KH, Jang SJ, Colby TV, Han S, Kim DS. Blood biomarkers MMP-7 and SP-A: predictors of outcome in idiopathic pulmonary fibrosis. Chest 2013;143(5):1422–1429 Moinzadeh P, Krieg T, Hellmich M, et al. Elevated MMP-7 levels in patients with systemic sclerosis: correlation with pulmonary involvement. Exp Dermatol 2011;20(9):770–773 Kim WU, Min SY, Cho ML, et al. Elevated matrix metalloproteinase-9 in patients with systemic sclerosis. Arthritis Res Ther 2005;7(1):R71–R79 Andersen GN, Nilsson K, Pourazar J, et al. Bronchoalveolar matrix metalloproteinase 9 relates to restrictive lung function

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75


Vol. 35

No. 2/2014

195




76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

impairment in systemic sclerosis. Respir Med 2007;101(10): 2199–2206 Manetti M, Guiducci S, Romano E, et al. Increased serum levels and tissue expression of matrix metalloproteinase-12 in patients with systemic sclerosis: correlation with severity of skin and pulmonary fibrosis and vascular damage. Ann Rheum Dis 2012; 71(6):1064–1072 Kikuchi K, Kubo M, Sato S, Fujimoto M, Tamaki K. Serum tissue inhibitor of metalloproteinases in patients with systemic sclerosis. J Am Acad Dermatol 1995;33(6):973–978 Taniguchi T, Asano Y, Akamata K, et al. Serum levels of ADAM12S: possible association with the initiation and progression of dermal fibrosis and interstitial lung disease in patients with systemic sclerosis. J Eur Acad Dermatol Venereol 2013;27(6): 747–753 Oka S, Furukawa H, Shimada K, et al. Serum biomarker analysis of collagen disease patients with acute-onset diffuse interstitial lung disease. BMC Immunol 2013;14:9 Tripathi SS, Mishra V, Shukla M, et al. IL-6 receptor-mediated lung Th2 cytokine networking in silica-induced pulmonary fibrosis. Arch Toxicol 2010;84(12):947–955 Chang CH, Hsiao CF, Yeh YM, et al. Circulating interleukin-6 level is a prognostic marker for survival in advanced nonsmall cell lung cancer patients treated with chemotherapy. Int J Cancer 2013; 132(9):1977–1985 Simeonova PP, Toriumi W, Kommineni C, et al. Molecular regulation of IL-6 activation by asbestos in lung epithelial cells: role of reactive oxygen species. J Immunol 1997;159(8):3921–3928 De Lauretis A, Sestini P, Pantelidis P, et al. Serum interleukin 6 is predictive of early functional decline and mortality in interstitial lung disease associated with systemic sclerosis. J Rheumatol 2013;40(4):435–446 Wuttge DM, Wildt M, Geborek P, Wollheim FA, Scheja A, Akesson A. Serum IL-15 in patients with early systemic sclerosis: a potential novel marker of lung disease. Arthritis Res Ther 2007; 9(5):R85 Kurasawa K, Hirose K, Sano H, et al. Increased interleukin-17 production in patients with systemic sclerosis. Arthritis Rheum 2000;43(11):2455–2463 Komura K, Fujimoto M, Hasegawa M, et al. Increased serum interleukin 23 in patients with systemic sclerosis. J Rheumatol 2008;35(1):120–125 Truchetet ME, Brembilla NC, Montanari E, Allanore Y, Chizzolini C. Increased frequency of circulating Th22 in addition to Th17 and Th2 lymphocytes in systemic sclerosis: association with interstitial lung disease. Arthritis Res Ther 2011;13(5):R166 Martinez-Lostao L, Marzo I, Anel A, Naval J. Targeting the Apo2L/ TRAIL system for the therapy of autoimmune diseases and cancer. Biochem Pharmacol 2012;83(11):1475–1483 Azab NA, Rady HM, Marzouk SA. Elevated serum TRAIL levels in scleroderma patients and its possible association with pulmonary involvement. Clin Rheumatol 2012;31(9):1359–1364 Günther A, Korfei M, Mahavadi P, von der Beck D, Ruppert C, Markart P. Unravelling the progressive pathophysiology of idiopathic pulmonary fibrosis. Eur Respir Rev 2012;21(124): 152–160 Cambrey AD, Harrison NK, Dawes KE, et al. Increased levels of endothelin-1 in bronchoalveolar lavage fluid from patients with systemic sclerosis contribute to fibroblast mitogenic activity in vitro. Am J Respir Cell Mol Biol 1994;11(4):439–445 Abraham DJ, Vancheeswaran R, Dashwood MR, et al. Increased levels of endothelin-1 and differential endothelin type A and B receptor expression in scleroderma-associated fibrotic lung disease. Am J Pathol 1997;151(3):831–841 Ihn H, Sato S, Fujimoto M, Takehara K, Tamaki K. Increased serum levels of soluble vascular cell adhesion molecule-1 and E-selectin in patients with systemic sclerosis. Br J Rheumatol 1998;37(11): 1188–1192


Vol. 35

No. 2/2014

Bonella, Costabel 94 Kuryliszyn-Moskal A, Klimiuk PA, Sierakowski S. Soluble adhe-

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

sion molecules (sVCAM-1, sE-selectin), vascular endothelial growth factor (VEGF) and endothelin-1 in patients with systemic sclerosis: relationship to organ systemic involvement. Clin Rheumatol 2005;24(2):111–116 Vancheeswaran R, Magoulas T, Efrat G, et al. Circulating endothelin-1 levels in systemic sclerosis subsets—a marker of fibrosis or vascular dysfunction? J Rheumatol 1994;21(10):1838–1844 Costabel U, Guzman J, Bonella F, Oshimo S. Bronchoalveolar lavage in other interstitial lung diseases. Semin Respir Crit Care Med 2007;28(5):514–524 Bouros D, Wells AU, Nicholson AG, et al. Histopathologic subsets of fibrosing alveolitis in patients with systemic sclerosis and their relationship to outcome. Am J Respir Crit Care Med 2002;165(12): 1581–1586 Wells AU, Hansell DM, Rubens MB, et al. Fibrosing alveolitis in systemic sclerosis. Bronchoalveolar lavage findings in relation to computed tomographic appearance. Am J Respir Crit Care Med 1994;150(2):462–468 Wells AU, Hansell DM, Haslam PL, et al. Bronchoalveolar lavage cellularity: lone cryptogenic fibrosing alveolitis compared with the fibrosing alveolitis of systemic sclerosis. Am J Respir Crit Care Med 1998;157(5, Pt 1):1474–1482 Behr J, Vogelmeier C, Beinert T, et al. Bronchoalveolar lavage for evaluation and management of scleroderma disease of the lung. Am J Respir Crit Care Med 1996;154(2, Pt 1):400–406 Goh NS, Veeraraghavan S, Desai SR, et al. Bronchoalveolar lavage cellular profiles in patients with systemic sclerosis-associated interstitial lung disease are not predictive of disease progression. Arthritis Rheum 2007;56(6):2005–2012 Tashkin DP, Elashoff R, Clements PJ, et al; Scleroderma Lung Study Research Group. Effects of 1-year treatment with cyclophosphamide on outcomes at 2 years in scleroderma lung disease. Am J Respir Crit Care Med 2007;176(10):1026–1034 Strange C, Bolster MB, Roth MD, et al; Scleroderma Lung Study Research Group. Bronchoalveolar lavage and response to cyclophosphamide in scleroderma interstitial lung disease. Am J Respir Crit Care Med 2008;177(1):91–98 Fischer A, Meehan RT, Feghali-Bostwick CA, West SG, Brown KK. Unique characteristics of systemic sclerosis sine sclerodermaassociated interstitial lung disease. Chest 2006;130(4):976–981 Sato LT, Kayser C, Andrade LE. Nailfold capillaroscopy abnormalities correlate with cutaneous and visceral involvement in systemic sclerosis patients. Acta Reumatol Port 2009;34 (2A):219–227 Bredemeier M, Xavier RM, Capobianco KG, et al. Nailfold capillary microscopy can suggest pulmonary disease activity in systemic sclerosis. J Rheumatol 2004;31(2):286–294 Corrado A, Carpagnano GE, Gaudio A, Foschino-Barbaro MP, Cantatore FP. Nailfold capillaroscopic findings in systemic sclerosis related lung fibrosis and in idiopathic lung fibrosis. Joint Bone Spine 2010;77(6):570–574 Douglas WW, Tazelaar HD, Hartman TE, et al. Polymyositisdermatomyositis-associated interstitial lung disease. Am J Respir Crit Care Med 2001;164(7):1182–1185 Tazelaar HD, Viggiano RW, Pickersgill J, Colby TV. Interstitial lung disease in polymyositis and dermatomyositis. Clinical features and prognosis as correlated with histologic findings. Am Rev Respir Dis 1990;141(3):727–733 Fathi M, Lundberg IE, Tornling G. Pulmonary complications of polymyositis and dermatomyositis. Semin Respir Crit Care Med 2007;28(4):451–458 Airio A, Kautiainen H, Hakala M. Prognosis and mortality of polymyositis and dermatomyositis patients. Clin Rheumatol 2006;25(2):234–239 Ponyi A, Constantin T, Balogh Z, et al. Disease course, frequency of relapses and survival of 73 patients with juvenile or adult dermatomyositis. Clin Exp Rheumatol 2005;23(1):50–56


196

113 Connors GR, Christopher-Stine L, Oddis CV, Danoff SK. Interstitial

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

lung disease associated with the idiopathic inflammatory myopathies: what progress has been made in the past 35 years? Chest 2010;138(6):1464–1474 Fathi M, Vikgren J, Boijsen M, et al. Interstitial lung disease in polymyositis and dermatomyositis: longitudinal evaluation by pulmonary function and radiology. Arthritis Rheum 2008;59(5): 677–685 Mimori T, Nakashima R, Hosono Y. Interstitial lung disease in myositis: clinical subsets, biomarkers, and treatment. Curr Rheumatol Rep 2012;14(3):264–274 Yokoyama T, Sakamoto T, Shida N, et al. Fatal rapidly progressive interstitial pneumonitis associated with amyopathic dermatomyositis and CD8 T lymphocytes. J Intensive Care Med 2005; 20(3):160–163 Suda T, Fujisawa T, Enomoto N, et al. Interstitial lung diseases associated with amyopathic dermatomyositis. Eur Respir J 2006; 28(5):1005–1012 Matsushita T, Hasegawa M, Fujimoto M, et al. Clinical evaluation of anti-aminoacyl tRNA synthetase antibodies in Japanese patients with dermatomyositis. J Rheumatol 2007;34(5):1012–1018 Hamaguchi Y, Fujimoto M, Matsushita T, et al. Common and distinct clinical features in adult patients with anti-aminoacyltRNA synthetase antibodies: heterogeneity within the syndrome. PLoS ONE 2013;8(4):e60442 Ghirardello A, Bassi N, Palma L, et al. Autoantibodies in polymyositis and dermatomyositis. Curr Rheumatol Rep 2013; 15(6):335 Yoshida S, Akizuki M, Mimori T, Yamagata H, Inada S, Homma M. The precipitating antibody to an acidic nuclear protein antigen, the Jo-1, in connective tissue diseases. A marker for a subset of polymyositis with interstitial pulmonary fibrosis. Arthritis Rheum 1983;26(5):604–611 Hirakata M, Suwa A, Nagai S, et al. Anti-KS: identification of autoantibodies to asparaginyl-transfer RNA synthetase associated with interstitial lung disease. J Immunol 1999;162(4): 2315–2320 Sato S, Kuwana M, Hirakata M. Clinical characteristics of Japanese patients with anti-OJ (anti-isoleucyl-tRNA synthetase) autoantibodies. Rheumatology (Oxford) 2007;46(5):842–845 Stone KB, Oddis CV, Fertig N, et al. Anti-Jo-1 antibody levels correlate with disease activity in idiopathic inflammatory myopathy. Arthritis Rheum 2007;56(9):3125–3131 La Corte R, Lo Mo Naco A, Locaputo A, Dolzani F, Trotta F. In patients with antisynthetase syndrome the occurrence of antiRo/SSA antibodies causes a more severe interstitial lung disease. Autoimmunity 2006;39(3):249–253 Kunimasa K, Arita M, Nakazawa T, et al. The clinical characteristics of two anti-OJ (anti-isoleucyl-tRNA synthetase) autoantibody-positive interstitial lung disease patients with polymyositis/dermatomyositis. Intern Med 2012;51(24): 3405–3410 Sato S, Hirakata M, Kuwana M, et al. Autoantibodies to a 140-kd polypeptide, CADM-140, in Japanese patients with clinically amyopathic dermatomyositis. Arthritis Rheum 2005;52(5): 1571–1576 Nakashima R, Imura Y, Kobayashi S, et al. The RIG-I-like receptor IFIH1/MDA5 is a dermatomyositis-specific autoantigen identified by the anti-CADM-140 antibody. Rheumatology (Oxford) 2010; 49(3):433–440 Hoshino K, Muro Y, Sugiura K, Tomita Y, Nakashima R, Mimori T. Anti-MDA5 and anti-TIF1-gamma antibodies have clinical significance for patients with dermatomyositis. Rheumatology (Oxford) 2010;49(9):1726–1733 Sato S, Kuwana M, Fujita T, Suzuki Y. Anti-CADM-140/MDA5 autoantibody titer correlates with disease activity and predicts disease outcome in patients with dermatomyositis and rapidly

131

132

133

134

135

136

137

138

139

140

141

142

143

144 145

146

147

148

Bonella, Costabel

progressive interstitial lung disease. Mod Rheumatol 2013;23(3): 496–502 Tanizawa K, Handa T, Nakashima R, et al. HRCT features of interstitial lung disease in dermatomyositis with anti-CADM140 antibody. Respir Med 2011;105(9):1380–1387 Tanizawa K, Handa T, Nakashima R, et al. The prognostic value of HRCT in myositis-associated interstitial lung disease. Respir Med 2013;107(5):745–752 Bandoh S, Fujita J, Ohtsuki Y, et al. Sequential changes of KL-6 in sera of patients with interstitial pneumonia associated with polymyositis/dermatomyositis. Ann Rheum Dis 2000;59(4): 257–262 Kubo M, Ihn H, Yamane K, et al. Serum KL-6 in adult patients with polymyositis and dermatomyositis. Rheumatology (Oxford) 2000;39(6):632–636 Ohnishi H, Yokoyama A, Kondo K, et al. Comparative study of KL-6, surfactant protein-A, surfactant protein-D, and monocyte chemoattractant protein-1 as serum markers for interstitial lung diseases. Am J Respir Crit Care Med 2002;165(3):378–381 Fathi M, Barbasso Helmers S, Lundberg IE. KL-6: a serological biomarker for interstitial lung disease in patients with polymyositis and dermatomyositis. J Intern Med 2012;271(6):589–597 Kumánovics G, Minier T, Radics J, Pálinkás L, Berki T, Czirják L. Comprehensive investigation of novel serum markers of pulmonary fibrosis associated with systemic sclerosis and dermato/ polymyositis. Clin Exp Rheumatol 2008;26(3):414–420 Gono T, Kawaguchi Y, Hara M, et al. Increased ferritin predicts development and severity of acute interstitial lung disease as a complication of dermatomyositis. Rheumatology (Oxford) 2010; 49(7):1354–1360 Gono T, Kawaguchi Y, Ozeki E, et al. Serum ferritin correlates with activity of anti-MDA5 antibody-associated acute interstitial lung disease as a complication of dermatomyositis. Mod Rheumatol 2011;21(2):223–227 Gono T, Sato S, Kawaguchi Y, et al. Anti-MDA5 antibody, ferritin and IL-18 are useful for the evaluation of response to treatment in interstitial lung disease with anti-MDA5 antibody-positive dermatomyositis. Rheumatology (Oxford) 2012;51(9):1563–1570 Ihn H, Asano Y, Kubo M, et al. Clinical significance of serum surfactant protein D (SP-D) in patients with polymyositis/dermatomyositis: correlation with interstitial lung disease. Rheumatology (Oxford) 2002;41(11):1268–1272 Satoh H, Kurishima K, Ishikawa H, Ohtsuka M. Increased levels of KL-6 and subsequent mortality in patients with interstitial lung diseases. J Intern Med 2006;260(5):429–434 Arai S, Kurasawa K, Maezawa R, Owada T, Okada H, Fukuda T. Marked increase in serum KL-6 and surfactant protein D levels during the first 4 weeks after treatment predicts poor prognosis in patients with active interstitial pneumonia associated with polymyositis/dermatomyositis. Mod Rheumatol 2013;23(5): 872–883 Zandman-Goddard G, Shoenfeld Y. Ferritin in autoimmune diseases. Autoimmun Rev 2007;6(7):457–463 Gono T, Kawaguchi Y, Satoh T, et al. Clinical manifestation and prognostic factor in anti-melanoma differentiation-associated gene 5 antibody-associated interstitial lung disease as a complication of dermatomyositis. Rheumatology (Oxford) 2010;49(9): 1713–1719 Tucci M, Quatraro C, Dammacco F, Silvestris F. Increased IL-18 production by dendritic cells in active inflammatory myopathies. Ann N Y Acad Sci 2007;1107:184–192 Wang PZ, Guan JL, Han XH. The predictive factors and unfavourable prognostic factors of interstitial lung disease in patients with polymyositis/dermatomyositis [in Chinese]. Zhonghua Jie He He Hu Xi Za Zhi 2008;31(6):417–420 Krystufková O, Vallerskog T, Helmers SB, et al. Increased serum levels of B cell activating factor (BAFF) in subsets of patients with


Vol. 35

No. 2/2014

197




149

150

151

152

153

154

155

156

157

158

159

160

161 162

163

164

165

166

idiopathic inflammatory myopathies. Ann Rheum Dis 2009; 68(6):836–843 Okada M, Suzuki K, Nakanishi T, Nakashima M. Serum levels of KL-6 are positively correlated with those of CA15-3 in patients with interstitial pneumonia associated with collagen diseases. Respirology 2006;11(4):509–510 Antoniou KM, Margaritopoulos G, Economidou F, Siafakas NM. Pivotal clinical dilemmas in collagen vascular diseases associated with interstitial lung involvement. Eur Respir J 2009;33(4): 882–896 Marie I, Hachulla E, Chérin P, et al. Interstitial lung disease in polymyositis and dermatomyositis. Arthritis Rheum 2002;47(6): 614–622 Schnabel A, Reuter M, Biederer J, Richter C, Gross WL. Interstitial lung disease in polymyositis and dermatomyositis: clinical course and response to treatment. Semin Arthritis Rheum 2003;32(5): 273–284 Froidevaux-Janin S, Dudler J, Nicod LP, Lazor R. Interstitial lung disease in rheumatoid arthritis [in French]. Rev Med Suisse 2011; 7(318):2272–2277 Gizinski AM, Mascolo M, Loucks JL, et al. Rheumatoid arthritis (RA)-specific autoantibodies in patients with interstitial lung disease and absence of clinically apparent articular RA. Clin Rheumatol 2009;28(5):611–613 Keith RC, Powers JL, Redente EF, et al. A novel model of rheumatoid arthritis-associated interstitial lung disease in SKG mice. Exp Lung Res 2012;38(2):55–66 Marigliano B, Soriano A, Margiotta D, Vadacca M, Afeltra A. Lung involvement in connective tissue diseases: a comprehensive review and a focus on rheumatoid arthritis. Autoimmun Rev 2013;12(11):1076–1084 Alexiou I, Germenis A, Koutroumpas A, Kontogianni A, Theodoridou K, Sakkas LI. Anti-cyclic citrullinated peptide-2 (CCP2) autoantibodies and extra-articular manifestations in Greek patients with rheumatoid arthritis. Clin Rheumatol 2008;27(4): 511–513 Mori S, Koga Y, Sugimoto M. Different risk factors between interstitial lung disease and airway disease in rheumatoid arthritis. Respir Med 2012;106(11):1591–1599 Aubart F, Crestani B, Nicaise-Roland P, et al. High levels of anticyclic citrullinated peptide autoantibodies are associated with co-occurrence of pulmonary diseases with rheumatoid arthritis. J Rheumatol 2011;38(6):979–982 Nielen MM, van Schaardenburg D, Reesink HW, et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum 2004;50(2):380–386 Oliver JE, Silman AJ. Risk factors for the development of rheumatoid arthritis. Scand J Rheumatol 2006;35(3):169–174 Masdottir B, Jónsson T, Manfredsdottir V, Víkingsson A, Brekkan A, Valdimarsson H. Smoking, rheumatoid factor isotypes and severity of rheumatoid arthritis. Rheumatology (Oxford) 2000; 39(11):1202–1205 Manfredsdottir VF, Vikingsdottir T, Jonsson T, et al. The effects of tobacco smoking and rheumatoid factor seropositivity on disease activity and joint damage in early rheumatoid arthritis. Rheumatology (Oxford) 2006;45(6):734–740 Wolfe F. The effect of smoking on clinical, laboratory, and radiographic status in rheumatoid arthritis. J Rheumatol 2000; 27(3):630–637 Sakaida H. IgG rheumatoid factor in rheumatoid arthritis with interstitial lung disease [in Japanese]. Ryumachi 1995;35(4): 671–677 Wegner N, Lundberg K, Kinloch A, et al. Autoimmunity to specific citrullinated proteins gives the first clues to the etiology of rheumatoid arthritis. Immunol Rev 2010;233(1): 34–54


Vol. 35

No. 2/2014

Bonella, Costabel 167 Sokolove J, Bromberg R, Deane KD, et al. Autoantibody epitope

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182 183

184

185

spreading in the pre-clinical phase predicts progression to rheumatoid arthritis. PLoS ONE 2012;7(5):e35296 van de Stadt LA, van der Horst AR, de Koning MH, et al. The extent of the anti-citrullinated protein antibody repertoire is associated with arthritis development in patients with seropositive arthralgia. Ann Rheum Dis 2011;70(1):128–133 Deane KD, Nicolls MR. Developing better biomarkers for connective tissue disease-associated interstitial lung disease: citrullinated hsp90 autoantibodies in rheumatoid arthritis. Arthritis Rheum 2013;65(4):864–868 Klareskog L, Stolt P, Lundberg K, et al. A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum 2006;54(1):38–46 Fischer A, Solomon JJ, du Bois RM, et al. Lung disease with antiCCP antibodies but not rheumatoid arthritis or connective tissue disease. Respir Med 2012;106(7):1040–1047 Demoruelle MK, Deane K. Antibodies to citrullinated protein antigens (ACPAs): clinical and pathophysiologic significance. Curr Rheumatol Rep 2011;13(5):421–430 Harlow L, Rosas IO, Gochuico BR, et al. Identification of citrullinated hsp90 isoforms as novel autoantigens in rheumatoid arthritis-associated interstitial lung disease. Arthritis Rheum 2013;65(4):869–879 Kahloon RA, Xue J, Bhargava A, et al. Patients with idiopathic pulmonary fibrosis with antibodies to heat shock protein 70 have poor prognoses. Am J Respir Crit Care Med 2013;187(7):768–775 Hassan WU, Keaney NP, Holland CD, Kelly CA. Association of HLADR4, protease inhibitor phenotypes and keratoconjunctivitis sicca with pulmonary abnormalities in rheumatoid arthritis. Br J Rheumatol 1995;34(1):37–40 Hillarby MC, McMahon MJ, Grennan DM, et al. HLA associations in subjects with rheumatoid arthritis and bronchiectasis but not with other pulmonary complications of rheumatoid disease. Br J Rheumatol 1993;32(9):794–797 Furukawa H, Oka S, Shimada K, et al. Association of human leukocyte antigen with interstitial lung disease in rheumatoid arthritis: a protective role for shared epitope. PLoS ONE 2012; 7(5):e33133 Migita K, Nakamura T, Koga T, Eguchi K. HLA-DRB1 alleles and rheumatoid arthritis-related pulmonary fibrosis. J Rheumatol 2010;37(1):205–207 Kinoshita F, Hamano H, Harada H, et al. Role of KL-6 in evaluating the disease severity of rheumatoid lung disease: comparison with HRCT. Respir Med 2004;98(11):1131–1137 Oyama T, Kohno N, Yokoyama A, et al. Detection of interstitial pneumonitis in patients with rheumatoid arthritis by measuring circulating levels of KL-6, a human MUC1 mucin. Lung 1997; 175(6):379–385 Nakajima H, Harigai M, Hara M, et al. KL-6 as a novel serum marker for interstitial pneumonia associated with collagen diseases. J Rheumatol 2000;27(5):1164–1170 Kobayashi J, Kitamura S. KL-6: a serum marker for interstitial pneumonia. Chest 1995;108(2):311–315 Kohno N, Kyoizumi S, Awaya Y, Fukuhara H, Yamakido M, Akiyama M. New serum indicator of interstitial pneumonitis activity. Sialylated carbohydrate antigen KL-6. Chest 1989;96(1):68–73 Takamura A, Hirata S, Nagasawa H, et al. A retrospective study of serum KL-6 levels during treatment with biological diseasemodifying antirheumatic drugs in rheumatoid arthritis patients: a report from the Ad Hoc Committee for Safety of Biological DMARDs of the Japan College of Rheumatology. Mod Rheumatol 2013;23(2):297–303 Harigai M, Takamura A, Atsumi T, et al. Elevation of KL-6 serum levels in clinical trials of tumor necrosis factor inhibitors in patients with rheumatoid arthritis: a report from the Japan


198


187

188

189 190

191

192 193

194

195

196

197

198

199

200

201

202

203

204

205

199

206 Takada K, Takiguchi M, Konno A, Inaba M. Autoimmunity against

207

208

209 210

211

212

213

214

215

216 217

218

219

220

221

222

223

224

a tissue kallikrein in IQI/Jic Mice: a model for Sjogren’s syndrome. J Biol Chem 2005;280(5):3982–3988 Goëb V, Salle V, Duhaut P, et al. Clinical significance of autoantibodies recognizing Sjögren’s syndrome A (SSA), SSB, calpastatin and alpha-fodrin in primary Sjögren’s syndrome. Clin Exp Immunol 2007;148(2):281–287 Kovács L, Fehér E, Bodnár I, et al. Demonstration of autoantibody binding to muscarinic acetylcholine receptors in the salivary gland in primary Sjögren’s syndrome. Clin Immunol 2008; 128(2):269–276 Shen L, Suresh L, Lindemann M, et al. Novel autoantibodies in Sjogren’s syndrome. Clin Immunol 2012;145(3):251–255 Pertovaara M, Bootorabi F, Kuuslahti M, et al. Carbonic anhydrase autoantibodies and sicca symptoms in primary Sjögreń s syndrome. Clin Exp Rheumatol 2012;30(3):456–457 Delaleu N, Immervoll H, Cornelius J, Jonsson R. Biomarker profiles in serum and saliva of experimental Sjögren’s syndrome: associations with specific autoimmune manifestations. Arthritis Res Ther 2008;10(1):R22 Wallaert B, Hatron PY, Grosbois JM, Tonnel AB, Devulder B, Voisin C. Subclinical pulmonary involvement in collagen-vascular diseases assessed by bronchoalveolar lavage. Relationship between alveolitis and subsequent changes in lung function. Am Rev Respir Dis 1986;133(4):574–580 Hatron PY, Wallaert B, Gosset D, et al. Subclinical lung inflammation in primary Sjögren’s syndrome. Relationship between bronchoalveolar lavage cellular analysis findings and characteristics of the disease. Arthritis Rheum 1987;30(11):1226–1231 Wallaert B, Prin L, Hatron PY, Ramon P, Tonnel AB, Voisin C. Lymphocyte subpopulations in bronchoalveolar lavage in Sjögren’s syndrome. Evidence for an expansion of cytotoxic/suppressor subset in patients with alveolar neutrophilia. Chest 1987; 92(6):1025–1031 Hajas A, Barath S, Szodoray P, et al. Derailed B cell homeostasis in patients with mixed connective tissue disease. Hum Immunol 2013;74(7):833–841 Prakash UB. Lungs in mixed connective tissue disease. J Thorac Imaging 1992;7(2):55–61 Bodolay E, Szekanecz Z, Dévényi K, et al. Evaluation of interstitial lung disease in mixed connective tissue disease (MCTD). Rheumatology (Oxford) 2005;44(5):656–661 Szodoray P, Hajas A, Kardos L, et al. Distinct phenotypes in mixed connective tissue disease: subgroups and survival. Lupus 2012; 21(13):1412–1422 Hajas A, Szodoray P, Nakken B, et al. Clinical course, prognosis, and causes of death in mixed connective tissue disease. J Rheumatol 2013;40(7):1134–1142 Ferreira JP, Almeida I, Marinho A, Cerveira C, Vasconcelos C. Antiro52 antibodies and interstitial lung disease in connective tissue diseases excluding scleroderma. ISRN Rheumatol 2012; 2012:415272 Ferreira R, Barreto M, Santos E, et al. Heritable factors shape natural human IgM reactivity to Ro60/SS-A and may predispose for SLE-associated IgG anti-Ro and anti-La autoantibody production. J Autoimmun 2005;25(2):155–163 Satoh M, Hirayoshi K, Yokota S, Hosokawa N, Nagata K. Intracellular interaction of collagen-specific stress protein HSP47 with newly synthesized procollagen. J Cell Biol 1996;133(2):469–483 Yokota S, Kubota H, Matsuoka Y, et al. Prevalence of HSP47 antigen and autoantibodies to HSP47 in the sera of patients with mixed connective tissue disease. Biochem Biophys Res Commun 2003;303(2):413–418 Kakugawa T, Yokota S, Mukae H, et al. High serum concentrations of autoantibodies to HSP47 in nonspecific interstitial pneumonia compared with idiopathic pulmonary fibrosis. BMC Pulm Med 2008;8:23


Vol. 35

No. 2/2014


186

College of Rheumatology Ad Hoc Committee for Safety of Biological DMARDs. Mod Rheumatol 2013;23(2):284–296 Gabbay E, Tarala R, Will R, et al. Interstitial lung disease in recent onset rheumatoid arthritis. Am J Respir Crit Care Med 1997;156 (2, Pt 1):528–535 Gilligan DM, O’Connor CM, Ward K, Moloney D, Bresnihan B, FitzGerald MX. Bronchoalveolar lavage in patients with mild and severe rheumatoid lung disease. Thorax 1990;45(8):591–596 Garcia JG, Parhami N, Killam D, Garcia PL, Keogh BA. Bronchoalveolar lavage fluid evaluation in rheumatoid arthritis. Am Rev Respir Dis 1986;133(3):450–454 Ascherman DP. Interstitial lung disease in rheumatoid arthritis. Curr Rheumatol Rep 2010;12(5):363–369 Gochuico BR, Avila NA, Chow CK, et al. Progressive preclinical interstitial lung disease in rheumatoid arthritis. Arch Intern Med 2008;168(2):159–166 Park JH, Kim DS, Park IN, et al. Prognosis of fibrotic interstitial pneumonia: idiopathic versus collagen vascular disease-related subtypes. Am J Respir Crit Care Med 2007;175(7):705–711 Boulware DW, Hedgpeth MT. Lupus pneumonitis and anti-SSA (Ro) antibodies. J Rheumatol 1989;16(4):479–481 Groen H, ter Borg EJ, Postma DS, Wouda AA, van der Mark TW, Kallenberg CG. Pulmonary function in systemic lupus erythematosus is related to distinct clinical, serologic, and nailfold capillary patterns. Am J Med 1992;93(6):619–627 Nielepkowicz-Goździńska A, Fendler W, Robak E, et al. Exhaled cytokines in systemic lupus erythematosus with lung involvement. Pol Arch Med Wewn 2013;123(4):141–148 Szekanecz E, Szucs G, Szekanecz Z, et al. Tumor-associated antigens in systemic sclerosis and systemic lupus erythematosus: associations with organ manifestations, immunolaboratory markers and disease activity indices. J Autoimmun 2008;31(4): 372–376 Yücel AE, Calguneri M, Ruacan S. False positive pleural biopsy and high CA125 levels in serum and pleural effusion in systemic lupus erythematosus. Clin Rheumatol 1996;15(3):295–297 Takeda N, Ihn H, Teramoto S. Markedly increased levels of IL-6 and CA125 in pleural fluid of an elderly person with overlap syndrome of systemic sclerosis and systemic lupus erythematosus. Age Ageing 2001;30(2):171 Yang Z, Liang Y, Li C, Zhong R. Serum CA125 elevation is independently associated with serositis in SLE patients. Clin Exp Rheumatol 2012;30(1):93–98 Yazisiz V, Arslan G, Ozbudak IH, et al. Lung involvement in patients with primary Sjögren’s syndrome: what are the predictors? Rheumatol Int 2010;30(10):1317–1324 Yazisiz V, Avci AB, Erbasan F, Kiriş E, Terzioğlu E. Diagnostic performance of minor salivary gland biopsy, serological and clinical data in Sjögren’s syndrome: a retrospective analysis. Rheumatol Int 2009;29(4):403–409 Deheinzelin D, Capelozzi VL, Kairalla RA, Barbas Filho JV, Saldiva PH, de Carvalho CR. Interstitial lung disease in primary Sjögren’s syndrome. Clinical-pathological evaluation and response to treatment. Am J Respir Crit Care Med 1996;154(3, Pt 1):794–799 Ito I, Nagai S, Kitaichi M, et al. Pulmonary manifestations of primary Sjogren’s syndrome: a clinical, radiologic, and pathologic study. Am J Respir Crit Care Med 2005;171(6):632–638 Parambil JG, Myers JL, Lindell RM, Matteson EL, Ryu JH. Interstitial lung disease in primary Sjögren syndrome. Chest 2006;130(5): 1489–1495 Sarkar PK, Patel N, Furie RA, Talwar A. Pulmonary manifestations of primary Sjögren’s syndrome. Indian J Chest Dis Allied Sci 2009; 51(2):93–101 Davidson BK, Kelly CA, Griffiths ID. Ten year follow up of pulmonary function in patients with primary Sjögren’s syndrome. Ann Rheum Dis 2000;59(9):709–712

Bonella, Costabel


Bonella, Costabel

225 Mosca M, Tani C, Bombardieri S. Undifferentiated connective

226

227

228 229

230

231

232

tissue diseases (UCTD): a new frontier for rheumatology. Best Pract Res Clin Rheumatol 2007;21(6):1011–1023 Lunardi F, Balestro E, Nordio B, et al. Undifferentiated connective tissue disease presenting with prevalent interstitial lung disease: case report and review of literature. Diagn Pathol 2011;6:50 Mosca M, Neri R, Bombardieri S. Undifferentiated connective tissue diseases (UCTD): a review of the literature and a proposal for preliminary classification criteria. Clin Exp Rheumatol 1999; 17(5):615–620 Mosca M, Tani C, Neri C, Baldini C, Bombardieri S. Undifferentiated connective tissue diseases (UCTD). Autoimmun Rev 2006;6(1):1–4 Kinder BW, Collard HR, Koth L, et al. Idiopathic nonspecific interstitial pneumonia: lung manifestation of undifferentiated connective tissue disease? Am J Respir Crit Care Med 2007; 176(7):691–697 Suda T, Kono M, Nakamura Y, et al. Distinct prognosis of idiopathic nonspecific interstitial pneumonia (NSIP) fulfilling criteria for undifferentiated connective tissue disease (UCTD). Respir Med 2010;104(10):1527–1534 Romagnoli M, Gurioli C, Casoni G, Poletti V. Surgical lung biopsy in the diagnosis of idiopathic NSIP: do we always need it in the initial approach? Am J Respir Crit Care Med 2009;179(11):1071, author reply 1071–1072 Sato S, Nagaoka T, Hasegawa M, Nishijima C, Takehara K. Elevated serum KL-6 levels in patients with systemic sclerosis: association


Vol. 35

No. 2/2014

233

234

235

236

237

238

with the severity of pulmonary fibrosis. Dermatology 2000; 200(3):196–201 Antonelli A, Fallahi P, Ferrari SM, et al. Systemic sclerosis fibroblasts show specific alterations of interferon-γ and tumor necrosis factor-α-induced modulation of interleukin 6 and chemokine ligand 2. J Rheumatol 2012;39(5):979–985 Buttmann M, Merzyn C, Hofstetter HH, Rieckmann P. TRAIL, CXCL10 and CCL2 plasma levels during long-term Interferonbeta treatment of patients with multiple sclerosis correlate with flu-like adverse effects but do not predict therapeutic response. J Neuroimmunol 2007;190(1–2):170–176 Gourh P, Arnett FC, Assassi S, et al. Plasma cytokine profiles in systemic sclerosis: associations with autoantibody subsets and clinical manifestations. Arthritis Res Ther 2009;11(5):R147 Sato S, Nagaoka T, Hasegawa M, et al. Serum levels of connective tissue growth factor are elevated in patients with systemic sclerosis: association with extent of skin sclerosis and severity of pulmonary fibrosis. J Rheumatol 2000;27(1):149–154 Muangchan C, Harding S, Khimdas S, Bonner A, Baron M, Pope J; Canadian Scleroderma Research group. Association of C-reactive protein with high disease activity in systemic sclerosis: results from the Canadian Scleroderma Research Group. Arthritis Care Res (Hoboken) 2012;64(9):1405–1414 Iwata Y, Yoshizaki A, Ogawa F, et al. Increased serum pentraxin 3 in patients with systemic sclerosis. J Rheumatol 2009;36(5): 976–983


200

Copyright of Seminars in Respiratory & Critical Care Medicine is the property of Thieme Medical Publishing Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.

Interstitial lung disease in undifferentiated forms of connective tissue disease.

The Spectrum of Interstitial Lung Disease in Connective Tissue Disease.

Radiologic pleuroparenchymal fibroelastosis-like lesion in connective tissue disease-related interstitial lung disease.

The role of biologics in treatment of connective tissue disease-associated interstitial lung disease.

Benefit of adjunctive tacrolimus in connective tissue disease-interstitial lung disease.

Cardiovascular involvement in connective tissue disease: the role of interstitial lung disease.

Fibroblast growth factors in connective tissue disease associated interstitial lung disease.

Treatment of connective tissue disease-associated interstitial lung disease: the pulmonologist's point of view.

Idiopathic or connective tissue disease-associated interstitial lung disease: a case of HRCT mimicry.

Nonspecific interstitial pneumonia overlaps organizing pneumonia in lung-dominant connective tissue disease.

Management of connective tissue diseases associated interstitial lung disease: a review of the published literature.

Connective Tissue Disease-associated Interstitial Lung Diseases (CTD-ILD) - Report from OMERACT CTD-ILD Working Group.

Lung-dominant connective tissue disease among patients with interstitial lung disease: prevalence, functional stability, and common extrathoracic features.

Cross-disciplinary collaboration in connective tissue disease-related lung disease.

Comparison of characteristics of connective tissue disease-associated interstitial lung diseases, undifferentiated connective tissue disease-associated interstitial lung diseases, and idiopathic pulmonary fibrosis in Chinese Han population: a retrospective study.

Erratum to: Serum B cell-activating factor (BAFF) level in connective tissue disease associated interstitial lung disease.

Biomarkers in Interstitial lung diseases.

Connective tissue disease-associated interstitial pneumonia and idiopathic interstitial pneumonia: similarity and difference.

Interstitial lung disease associated with connective tissue diseases. The use of statistical structure analysis in model development.

Lung-Dominant Connective Tissue Disease: Clinical, Radiologic, and Histologic Features.

Biomarkers of rheumatoid arthritis-associated interstitial lung disease.

The connective tissue of lung.

Mixed connective-tissue disease.

Connective tissue disease in pregnancy.