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2018
Several high-resolution computed tomography findings associate with survival and clinical features in
rheumatoid arthritis-associated interstitial lung disease
Nurmia Hanna M
Elsevier BV
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http://dx.doi.org/10.1016/j.rmed.2017.11.013
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Accepted Manuscript
Several high-resolution computed tomography findings associate with survival and clinical features in rheumatoid arthritis-associated interstitial lung disease
Hanna M. Nurmi, Hannu-Pekka Kettunen, Sanna-Katja Suoranta, Minna K. Purokivi, Miia S. Kärkkäinen, Tuomas A. Selander, Riitta L. Kaarteenaho
PII: S0954-6111(17)30395-5 DOI: 10.1016/j.rmed.2017.11.013 Reference: YRMED 5308
To appear in: Respiratory Medicine Received Date: 17 August 2017 Revised Date: 13 October 2017 Accepted Date: 20 November 2017
Please cite this article as: Nurmi HM, Kettunen H-P, Suoranta S-K, Purokivi MK, Kärkkäinen MS, Selander TA, Kaarteenaho RL, Several high-resolution computed tomography findings associate with survival and clinical features in rheumatoid arthritis-associated interstitial lung disease, Respiratory Medicine (2017), doi: 10.1016/j.rmed.2017.11.013.
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ACKNOWLEDGEMENTS. The authors wish to thank Ewen MacDonald for providing assistance with the language and Tiina Laitinen for assistance in the search of the missing PFT data. The study was supported by the Foundation of the Finnish Anti- Tuberculosis Association, the Jalmari and Rauha Ahokas Foundation, the Väinö and Laina Kivi Foundation, The Research Foundation of the Pulmonary Diseases, The Kuopio region Respiratory Foundation, the North Savo Regional Fund of the Finnish Cultural Foundation and a state subsidy of the Kuopio University Hospital.
Several high-resolution computed tomography findings associate with survival and clinical features in rheumatoid arthritis-associated interstitial lung disease.
MD Hanna M. Nurmi a, b, MD Hannu-Pekka Kettunen c, MD, PhD Sanna-Katja Suoranta c, MD, PhD Minna K. Purokivi b, MD Miia S. Kärkkäinen a, d, MSc Tuomas A. Selander e, MD, PhD Riitta L. Kaarteenaho f
a Division of Respiratory Medicine, Institute of Clinical Medicine, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, POB 1627, 70211 Kuopio, Finland
b Center of Medicine and Clinical Research, Division of Respiratory Medicine, Kuopio University Hospital, POB 100, 70029 Kuopio, Finland.
c Diagnostic Imaging Center, Division of Radiology, Kuopio University Hospital, POB 100, 70029 Kuopio, Finland.
d Home Care, Rehabilitation and Medical Services for Elderly Care, Tulliportinkatu 37E, 70100 Kuopio, Finland
e Science Services Center, Kuopio University Hospital, POB 100, 70029 Kuopio, Finland
f Respiratory Medicine, Research Unit of Internal Medicine, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, POB 20, 90029 Oulu, Finland.
⃰ Address Correspondence to:
Hanna Nurmi: hanna.nurmi@kuh.fi
Center of Medicine and Clinical Research, Division of Respiratory Medicine Kuopio University Hospital
PO Box 100, 70029 KYS, Kuopio, Finland
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ABBREVIATIONS: ANA antinuclear antibodies, CTD connective tissue diseases, DAD diffuse alveolar damage, DLCO diffusion capacity to carbon monoxide, FEV1 forced expiratory volume, FVC forced vital capacity, GGO ground-glass opacity, HRCT high-resolution computed tomography, IIP idiopathic interstitial pneumonias, ILD interstitial lung disease, IPF idiopathic pulmonary fibrosis, KUH Kuopio University Hospital, MTX methotrexate, NSIP nonspecific interstitial pneumonia, OP organizing pneumonia, PFT pulmonary function tests, RA rheumatoid arthritis, RA-ILD rheumatoid arthritis-associated interstitial lung disease, RF rheumatoid factor, UIP usual interstitial pneumonia
Abstract
Objective: To compare the presence and extent of several high-resolution computed tomography (HRCT) observations in different subtypes of rheumatoid arthritis-related interstitial lung disease (RA-ILD) and to examine associations between radiological findings, hospitalization, age, RA duration, pulmonary function tests (PFT) and survival.
Materials and methods: HRCTs from 60 RA-ILD patients were independently evaluated and re- categorized into usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), organizing pneumonia (OP), diffuse alveolar damage (DAD) and unclassified subtypes by two radiologists. The presence and extent, which was reported using a semi-quantitative scoring system, of e.g. reticulation, ground-glass opacity, honeycombing, emphysema, traction bronchiectasis and architectural distortion were further evaluated and compared between the subtypes. Associations between radiological findings and survival were identified with the Kaplan-Meier method and Cox´s univariate model. The correlations between radiological findings, hospitalization, age, pack years, RA duration and PFT were calculated using Spearman´s correlation coefficient.
Results: The extents of reticulation (HR 1.144, p=0.041), traction bronchiectasis (HR 1.184, p=0.030), architectural distortion (HR 1.094, p=0.044) and the presence of pleural fluid (HR 14.969, p<0.001) were associated with decreased survival. A negative correlation was observed between ground-glass opacity (GGO) and the duration of RA (r= -0.308, p=0.012). The extents of honeycombing (r=0.266, p=0.046), traction bronchiectasis (r=0.333, p=0.012) and architectural distortion (r=0.353, p=0.007) correlated with hospitalizations due to respiratory reasons.
Conclusions: Many radiological findings associate with the course of the disease of RA-ILD and could potentially be useful when planning the RA treatment or evaluating the risk of death in these patients.
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3 Key points:
- High Resolution Computed Tomography helps clinicians to assess patients with rheumatoid lung disease.
- The extents of reticulation, traction bronchiectasis, architectural distortion and the presence of pleural fluid associate with decreased survival in patients with RA-ILD.
- HRCT evaluation can be useful when evaluating the course of the disease in RA-ILD, especially with regard to the risk of hospitalization.
Key Words: Arthritis, Rheumatoid; Lung diseases, Interstitial; High-resolution computed tomography, survival
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4 1. INTRODUCTION
Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) causes significant morbidity and mortality in patients with RA. It manifests as many different subtypes, of which usual interstitial pneumonia (UIP) is the most common (1,2). Even though it is recommended in non-definite UIP cases, most patients do not undergo surgical lung biopsy due to the risks associated with it (3).
Therefore, the diagnostics of RA-ILD is nowadays mainly based on high-resolution computed tomography (HRCT) i.e. similar to the situation in other types of ILDs.
The role of HRCT in predicting the prognosis of patients with ILD has been examined mostly in idiopathic pulmonary fibrosis (IPF) (4-6) but in the recent years some studies have also investigated this in connective tissue disease-related ILDs (CTD-ILDs) (7,8) with some proposing that the UIP pattern in RA-ILD associates with a shorter survival (8,9). The extent of abnormalities in HRCT, often categorized as limited (<20%) vs. extensive disease (>20%), has associated with shorter survival (10-12). Reticulation and honeycombing are often combined as one measure of the extent of ILD changes; this so-called fibrosis score has been shown to correlate with prognosis in several IPF studies (13).
Nowadays computer assisted tools have been developed for providing rapid estimations of disease extent but these are not available in all clinics. Therefore, straightforward methods for providing estimations of the disease extent are still needed, and for example in systemic sclerosis- related ILDs, a good correlation has been observed between visual reader-based scoring and computer- aided quantification (14,15). Since the reports of the survival associations of observations made with HRCT have mainly focused in IPF, there is a need to evaluate this aspect in patients with RA- ILD to fill the gaps in our current knowledge i.e. what are the precise HRCT findings that predict survival, going beyond the major radiological subtypes. In addition, the correlation between HRCT
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findings and PFT, as well as hospitalization or other clinical issues, is unclear and mostly has been evaluated in IPF patients.
The purpose of this study was to evaluate the HRCT findings in patients with RA-ILD and to compare the presence and extent of different radiological findings in different RA-ILD subtypes.
We also aimed to identify associations between radiological findings and clinical factors, survival and pulmonary function tests.
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6 2. MATERIAL AND METHODS
2.1 Patient selection and collection of the data
Sixty RA-ILD patients were identified from the Kuopio University Hospital (KUH) pulmonology clinic in-patients and out-patients database between 1.1.2000 and 31.12.2014. The search was three- pronged and performed using International Classification of Diseases (ICD-10) codes. The first search entailed codes J84.X, the second M05.X/M06.X with a visit to the pulmonary clinic and the third was performed using the code J99.0*M05.1. Patients were included only if they had a high- resolution computed tomography (HRCT) or other comparable radiological examination available and if the RA diagnosis had been made according to the 1987 classification criteria (16) as
described previously (17,18). Patients with other connective tissue diseases, idiopathic ILDs and those with asbestosis or allergic alveolitis were excluded. The HRCT scans of all patients deemed appropriate for this study based on their medical records were evaluated by an experienced
radiologist (H-P.K); if the CT findings were not reliably identified as consistent with ILD changes, the patient was excluded. Atypical cases were discussed by a multidisciplinary group consisting of a radiologist, pulmonologists and a pathologist.
Clinical information and the results of baseline pulmonary function tests (PFT), including forced vital capacity (FVC), forced expiratory volume (FEV1) and diffusion capacity to carbon monoxide (DLCO) were retrospectively gathered using a specially designed form, as presented previously (17). Data was compiled from the patient records of KUH, primary health care centers and other hospitals.
The study protocol was approved by the Ethical Committee of Kuopio University Hospital (statement 17/2013) and by the National Institute for Health and Welfare (Dnro
THL/1052/5.05.01/2013).
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7 2.2 The CT protocol.
Due to the retrospective nature of this study, the HRCT protocol was diverse. In 47 of 57 cases (82.5%) the CT had been obtained with the patient inhaling in the prone position, in 10 cases also when the patient was exhaling and in three cases the data about position was not available. In 42 out of 60 patients, the baseline scans were digital HRCT scans and 16 cases were older analogue film images. In three cases the baseline radiological evaluation was based on venous phase contrast enhanced CT, pulmonary CT angiogram with HRCT reconstruction and volumetric HRCT, each in one case. The used collimation was variable and the interval also varied between 10-28mm, with the most common interval being 18mm in 17 cases. The quality of scans was rated as good in 60.7% and suboptimal in the remainder, mainly due to analogue film images and sometimes due to breathing artefacts. All digital images were reconstructed using a high-resolution algorithm and obtained at the window level appropriate for lung parenchyma and mediastinum
2.3 Radiological re-categorization
Two radiologists (H-P.K, S-K.S), blinded to the demographic data and without consideration of the report accompanying the original CT results, independently re-classified the cases according to the 2013 idiopathic interstitial pneumonias (IIP) classification (19) as UIP, NSIP, organizing
pneumonia (OP), diffuse alveolar damage (DAD) and “unclassified” subgroups. The last of the subgroups consisted of the patients that did not fit the definition of any specific subtypes. The radiological RA-UIP criteria that were applied were those for the diagnosis of IPF (20). RA-NSIP was defined as the predominance of ground-glass opacity (GGO), possible visible subpleural sparing and possible fine reticulation with minor or no honeycombing. RA-OP was defined as single or multiple patchy consolidations. In addition to the baseline CT, the most recent HRCT was also evaluated in a similar manner from 33 patients who had a follow-up CT available. In those patients, the final subgroup was determined based on the analysis of both CTs.
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2.4 Further interpretation of the CTs and the scoring system
As well as the radiological subgrouping performed by the two radiologist, the radiological findings were further assessed in detail by the first radiologist (H-P.K) using a form designed for the study (Suppl.file 1). The presence and the extent of the following findings were evaluated separately:
GGO, reticulation, honeycombing, emphysema, consolidation, crazy-paving appearance,
bronchiectasis, traction bronchiectasis, nodules, thickening of the bronchovascular bundle, cysts, mosaic attenuation, air trapping (when applicable), rounded atelectasis, architectural distortion, pleural plaques, pleural effusion and tumours. The definitions of these findings used in this study are those issued by the Fleischner Society (21). The most prominent observation was appointed in each HRCT.
Both lungs were divided into three zones. The upper zones were at or superior to the aortic arch, the middle zones were between the aortic arch and pulmonary veins and the lower zones were at or below the pulmonary veins. The extents of GGO, reticulation and honeycombing were semi- quantitatively graded on a scale from 0 to 4 as follows: 0 = finding absent, 1 = minor peripheral scattered changes, 2 = uniform peripheral or minor central changes, 3 = substantial peripheral changes that penetrated deeply to the lung parenchyma, 4 = very abundant peripheral and central changes. The total score of these three findings was obtained by summing the grades for all six zones i.e. the maximum score 24 (Figure 1).
Emphysema, traction bronchiectasis, architectural distortion and pleural plaques were scored similarly, adding up the given grades in six zones, but now scored with a three-point scale (0-3; 0 = absent, 1 = single scattered changes, 2 = larger single changes or several minor changes, 3 =
uniform or substantial changes) resulting in a score ranging from 0-18.
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Figure 1. An example of the scoring system used in the study representing axial HRCT images of a 62-year-old male with RA-UIP. The patient underwent lung transplantation 7 months after the CT imaging.
A) Upper zone, at the level of the aortic arch. Honeycombing was graded as score 2 (uniform peripheral or minor central changes) on the right side and score 1 (minor peripheral scattered changes) on the left, thus giving a total score of 3 for honeycombing in this zone. Reticulation was scored as 0 on the right side (=absent) and as 1 on the left. Traction bronchiectasis was scored as 1 on both sides. In addition, some evidence of GGO was observed on the left side.
B) Middle zone, between the aortic arch and pulmonary veins. Honeycombing was graded as score 2 on the both sides, making the total honeycomb score to 7 at this point. Reticulation was graded as 0 and traction bronchiectasis as 1 on right and 2 on the left side.
C) Lower zone, below pulmonary veins. Honeycombing was graded as 2 on the right and 4 (very abundant peripheral and central changes) on the left, while traction bronchiectasis was scored 2 on the right and 3 (substantial peripheral changes that reached deeply into the lung parenchyma) on the left side. in a total honeycombing score of 13, reflecting the extent of honeycombing. Reticulation was scored as 2 on the right and 0 on the left while traction bronchiectasis was scored 2 on the right and 3 (substantial peripheral changes that reached deeply into the lung parenchyma) on the left side.
2.5 Statistical analysis
The clinical factors, PFT, and the presence and extent of the radiological observations were compared between different subgroups. Independent samples T-test was used to compare continuous variables, whereas Chi-squared test or Fisher test, when appropriate, were used for comparison of the categorical variables. The associations between different radiological findings and survival were estimated using the Kaplan-Meier method and the univariate Cox regression analysis. The correlations between radiological finding scores and PFT as well as other clinical factors were estimated using the Spearman rank correlation coefficient.
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Agreement between the radiologists re-categorization was expressed as a kappa value (κ). Values of κ 0.41 – 0.60 were considered as a moderate and κ values 0.61 – 0.80 as good agreement.
P-values <0.05 were considered statistically significant. All data was analyzed using IBM Statistics SPSS software, version 21.0.
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11 3. RESULTS
3.1 Patient characteristics and PFT
The mean age of patients, who were predominantly males (56%), was 66.5 ± 11.2 years. Twenty- four (40.7 %) of the patients were lifelong non-smokers, 26 (44.1%) ex-smokers and the remainder (9/15.3 %) were current smokers. The mean duration of RA at the time of the ILD diagnosis was 15.5 years (17,18).
There were no statistically significant differences in the baseline PFT, age, RA serology or smoking between any of the subgroups. Statistically significant differences were, however, found regarding RA duration between RA-NSIP and RA-OP (25.1 vs. 8.2 years, p=0.018) as well as between RA- NSIP and unclassified (25.1 vs. 9.8 years, p=0.027). The majority, 34 out of 60 patients (56.7%), had died. Patients with NSIP died significantly younger than those with unclassified radiology (74.1 vs. 85.4 years, p=0.028). The patients with UIP died at a mean age of 74.1 years, thus displaying a trend towards dying younger than the patients in the unclassified subgroup (p=0.066) (Table 1).
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Table 1. Patient characteristics and baseline pulmonary function test results according to radiological RA-ILD subtype.
RA-UIP (n=36)
RA-NSIP (n=8)
RA-OP (n=7)
Unclassified (n=8)
RA-DAD (n=1) Age (y) 66.0 ± 12.1 67.5 ± 7.7 64.7 ± 10.6 68.0 ± 12.6 72.8 Age at death (y) 74.1 ± 9.9 74.1 ± 4.6 75.6 ± 4.4 85.4 ± 5.3 ¥ 78.2 No. of deaths 24 (66.7) 4 (50.0) 2 (28.6) 3 (37.5) 1 (100.0) Male sex 20 (55.6) 5 (62.5) 2 (28.6) 6 (75.0) 1 (100.0) Smoking
Never Ex-smoker Current smoker
15 (42.9) 14 (40.0) 6 (17.1)
3 (37.5) 4 (50.0) 1 (12.5)
3 (42.9) 3 (42.9) 1 (14.3)
2 (25.0) 5 (62.5) 1 (12.5)
1 (100.0)
Serology Positive RF Positive ANA
30/35 (85.7) 6/26 (23.1)
5 (62.5) 2 (25.0)
6/6 (100.0) 0/6 (0.0
7 (87.5) 1 of 5 (20.0)
1 (100.0) 0 (0.0) Medications
Steroids MTX Biological drugs
32 (88.9) 18 (50.0) 7 (19.4)
8 (100.0) 6 (75.0) 2 (25.0)
7 (100.0) 7 (100.0) * 4 (57.1)
6 (75.0) 4 (50.0) 1 (12.5)
1 (100.0) 0 (0.0) 0 (0.0) Lung functions
FVC % pred FEV1 % pred DLCO % pred
82.7 ± 16.8 81.0 ± 17.4 71.7 ± 20.6
87.9 ± 14.8 82.9 ± 14.0 63.3 ± 11.0
95.2 ± 14.3 83.4 ± 12.0 74.2 ± 10.6
81.0 ± 14.7 80.3 ± 15.8 70.1 ± 15.9
122 104 87 RA duration (y) 15.9 ± 11.9 25.1 ± 15.3 ǂ 8.2 ± 5.1 9.8 ± 6.5 ¥ 7
Patient characteristics and pulmonary function test results according to radiological RA-ILD subtype. Results are presented as either the number of patients (%) or mean ± SD. The use of medication refers to medication administered at any time point, i.e. lifelong.
P<0.05: * UIP vs. OP, ǂ NSIP vs. OP, ¥ NSIP vs. unclassified
3.2 Radiological categorization and inter-observer agreement
Thirty-six out of 60 cases (60%) showed a radiological UIP-pattern in the HRCT assessment (Figure 2). RA-NSIP and unclassified subtype were equally common (8 cases each /13.3 %). RA- OP was diagnosed in 7 patients (11.7 %). One patient with a previously normal HRCT developed a rapidly progressing dyspnoea and severe hypoxemia as well as bilateral ground-glass opacity changes in HRCT, thus representing likely RA-DAD.
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Figure 2. Representative HRCT images from the subjects with RA-ILD.
A) 64-year-old female with fibrotic changes of UIP pattern in basal and subpleural predominance, traction bronchiectasis and honeycombing.
B) 69-year-old male revealing peripheral ground glass opacity and typical subpleural sparing representing the NSIP pattern.
C) 55-year-old female showing evidence of bilateral peribronchovascular and peripheral patchy
consolidations typical for OP. The HRCT changes reverted to normal after the corticosteroid treatment.
D) 68-year old female patient with unclassified fibrosis with mild subpleural reticulation and traction bronchiectasis but no honeycombing.
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When classified into all 5 subgroups, the overall agreement between the radiologists was moderate (κ = 0.492). When categorized only into two groups i.e. “definite UIPs” or “others”, the inter- agreement was better (κ = 0.592) and when “definite UIPs” and “unclassified subgroup” were pooled as one category the agreement improved to good (κ = 0.629).
3.3 The prevalence of HRCT findings in different subtypes
A summary of CT findings is shown in Table 2. Reticulation (93.1%) and GGO (72.4%) were the most common findings in the whole group. Traction bronchiectasis (59.6%), honeycombing (53.4%) and architectural distortion (41.4%) were also rather frequent, whereas emphysema
(29.3%), bronchiectasis (24.6%) and pleural plaques (32.6%) were detected in approximately every third patient.
Honeycombing was more often seen in patients with UIP than in the NSIP (p=0.001), OP (p=0.007) or unclassified (p= 0.001) subgroups. Architectural distortion was more frequent in the UIP group than in the NSIP group (p=0.004) or in unclassified group (p=0.019). Moreover, when comparing the UIP group with the OP group, statistically significant differences were detected in reticulation (p=0.002), consolidation (p<0.001) and traction bronchiectasis (p=0.016).
The main finding in the majority (62.5%) of patients with NSIP was GGO and that of the OP group was consolidation (100%). Majority of the RA-UIP patients (58.3%) had honeycombing as their most prominent baseline finding (Suppl. file 2), increasing up to 82.4% in the follow-up CT (data not shown).
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15 Table 2.
Summary of initial CT findings in the different subgroups.
Finding All RA-ILD (n=59)
RA-UIP (n=36)
RA-NSIP (n=8)
RA-OP (n=7)
Unclassified (n=8) Reticulation 54/58 (93.1) 36 (100.0) 7 (87.5) 3/6 (50.0)ǂ 8 (100.0)
GGO 42/58 (72.4) 27 (75.0) 7 (87.5) 4/6 (66.7) 4 (50.0) Honeycombing 31/58 (53.4) 28 (77.8)* 1 (12.5) 1/6 (16.7)ǂ 1 (12.5)¥
Consolidation 8 (13.6) 1 (2.8) 0 (0.0)† 7 (100.0)ǂ 0 (0.0)§
Emphysema 17/58 (29.3) 13 (36.1) 2 (25.0) 0/6 (0.0) 2 (25.0)
Crazy-paving 1/57 (1.8) 1 (2.8) 0 (0.0) 0/5 (0.0) 0 (0.0)
Bronchiectasis 14/ 57 (24.6) 6/35 (17.1) 3 (37.5) 2/6 (33.3) 3 (37.5) Traction bronchiectasis 34/57 (59.6) 26 (72.2) 4/7 (57.1) 1/6 (16.7)ǂ 3 (37.5)
Nodules 2/57 (3.5) 0/35 (0.0) 0 (0.0) 1/6 (16.7) 1 (12.5)
Parenchymal bands 3/44 (6.8) 2/26 (7.7) 1 (12.5) 0/5 (0.0) 0/5 (0.0) Architectural distortion 24/58(41.4) 22 (61.1)* 0 (0.0) 1/6 (16.7) 1 (12.5)¥
Pleural effusion 4 (6.8) 2 (5.6) 1 (12.5) 1 (14.3) 0 (0.0)
Pleural plaques 15/46 (32.6) 10/28 (35.7) 3 (37.5) 1/6 (16.7) 1/4 (25.0)
Tumors 0/57 (0.0) 0 (0.0) 0 (0.0) 0/6 (0.0) 0/7 (0.0)
Subgrouping is based on first and last (when available) CT scans, histological samples, when available and clinical data. The presence of different findings was analyzed from the initial baseline CTs. Due to the poor quality of CT or diverse CT protocol, not all of the radiological findings could be evaluated in all patients.
Thus, the numbers of patients vary. Data of one RA-DAD patient is not shown, because his HRCT was normal initially and thus none of the listed findings were observed in the baseline CT.
Results are presented as the number of patients (%). GGO = ground-glass opacity.
P-values <0.05: *UIP vs. NSIP; ǂUIP vs OP; ¥ UIP vs. unclassified; † NSIP vs. OP; § OP vs. unclassified
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16 3.4 The extent of radiological findings
Reticulation was more abundant in UIP vs. OP (p<0.001), UIP vs. unclassified (p=0.041), NSIP vs.
OP (p=0.020) and unclassified vs. OP (p=0.001) (Table 3), whereas the extent of reticulation did not differ significantly between the UIP and NSIP groups. GGO, which was equally frequent in the different subtypes, was more extensive in the NSIP subgroup compared to the unclassified subgroup (p=0.017). Honeycombing and architectural distortion scores were significantly higher in patients with UIP compared to all other subgroups (p-values <0.001). The extents of emphysema and traction bronchiectasis were higher in the UIP than in the OP subgroup (p=0.001, p<0.001).
Table 3. The mean scores of the radiological findings in the baseline CTs.
Score RA-UIP
(n=36)
RA-NSIP (n=8)
RA-OP (n=7)
Unclassified (n=8)
GGO 3.78 ± 4.29 (0-20) 6.38 ± 4.24 (0-12) 2.00 ± 3.37 (0-7) 1.63 ± 2.07 (0-5) ¤ Reticulation 6.53 ± 2.34 (1-12) 4.75 ± 3.45 (0-11) † 0.83 ± 0.98 (0-2) ǂ § 4.63 ± 2.13 (2-7) ¥ Honeycombing 3.66 ± 3.53 (0-12) * 0.13 ± 0.35 (0-1) 0.33 ± 0.82 (0-2) ǂ 0.25 ± 0.71 (0-2) ¥ Emphysema 2.25 ± 3.71 (0-12) 1.25 ± 2.38 (0-6) 0.00 ± 0.00 (0) ǂ 1.00 ± 1.85 (0-4) Architectural distortion 3.31 ± 3.86 (0-13) * 0.00 ± 0.00 (0) 0.33 ± 0.82 (0-2) ǂ 0.25 ± 0.71 (0-2) ¥ Pleural plaques 1.96 ± 3.72 (0-15) 3.50 ± 5.32 (0-14) 0.50 ± 1.23 (0-3) 1.75 ± 3.50 (0-7) Traction bronchiectasis 2.20 ± 2.23 (0-8) 1.00 ± 1.16 (0-3) 0.17 ± 0.41 (0-1)ǂ 0.75 ± 1.04 (0-2)
The mean scores reflect the extent of different findings and are calculated by a semi-quantitative method summing the grade of the finding in the six evaluated zones. Values are shown as mean ± SD (range).
P-values <0.05: *UIP vs. NSIP; ǂUIP vs OP; ¥ UIP vs. unclassified; † NSIP vs. OP; § OP vs. unclassified; ¤ NSIP vs unclassified.
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3.5 Association between radiological findings and survival
The median survival of those four patients with pleural fluid was 10 months compared to 107 months in those without pleural effusions (p<0.001). There was also a trend towards worse survival in patients with architectural distortion with a median survival of 64 months compared to 92 months in patients without this feature (p=0.092). Neither the presence of GGO, honeycombing nor
reticulation associated statistically significantly with survival when assessed by either the presence or absence of these features.
When taking into account the extent of the radiological finding, the reticulation (HR 1.144, p=0.041), the traction bronchiectasis (HR 1.184, p=0.030) and the architectural distortion scores (HR 1.094, p=0.044) were all associated with decreased survival and moreover, for every increased GGO score point the mortality risk increased by 8 %, nearly reaching a statistical significance (p=0.051) (Table 4).
Table 4.
The extent of different radiological factors associating with survival in patients with RA-ILD according to the univariate Cox model.
Score Hazard Ratio 95% CI P-value
GGO 1.079 1.000 – 1.166 0.051
Reticulation 1.144 1.005 – 1.302 0.041
Traction bronchiectasis 1.184 1.016 – 1.379 0.030
Architectural distortion 1.094 1.003 – 1.194 0.044
3.6 Correlation between demographics, PFT and radiological findings
The strongest negative correlation (r= -0.430, p=0.001) was seen between DLCO (% pred) and emphysema score. DLCO also correlated with architectural distortion score (r= -0.235, p=0.033).
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FEV1 / FVC correlated with the traction bronchiectasis score (r= 0.385, p=0.004) and FEV1 with GGO score (r= -0.359, p=0.008) (Table 5).
Pack-years correlated strongly with emphysema score (r= 0.754. p<0.001) and negatively correlated almost statistically significantly with traction bronchiectasis (r= -0.284, p=0.053). There was a negative correlation between GGO and the duration of RA (p=0.023). The number of
hospitalizations due to respiratory reasons correlated with the honeycombing (p=0.046), traction bronchiectasis (p=0.012) and architectural distortion (p=0.007) scores (Table 5).
Table 5. Correlations between CT, pulmonary function test results and clinical data Ground-glass
Opacity Score
Reticulation Score
Honeycombing Score
Emphysema Score
Traction Bronchiectasis Score
Architectural Distortion Score
FVC -0.256* -0.186 -0.074 -0.082 -0.137 -0.125
FEV1 -0.359** -0.095 0.113 -0.140 0.128 0.075
FEV1 / FVC 0.036 0.242* 0.161 -0.194 0.385** 0.160
DLCO -0.171 -0.115 -0.033 -0.430** -0.235 -0.295**
Age -0.237* 0.020 0.159 -0.353** 0.107 0.041
Pack years 0.248 -0.052 -0.131 0.754** -0.284* 0.028
Resp. Hosp 0.100 0.181 0.266** 0.034 0.333** 0.353**
Card. Hosp 0.150 -0.002 -0.104 -0.060 -0.109 -0.103
RA duration -0.308** -0.086 -0.003 -0.042 -0.110 -0.050
The values are Spearman correlation coefficients depicting the correlation between the extent of specific CT finding in the baseline CT, baseline lung function test results (percentage of the predicted value) and other clinical data.
*p<0.08, **p<0.05
GGO = ground-glass opacity; Resp. Hosp = mean number of hospitalization due to respiratory problems;
Card. Hosp = mean number of hospitalization due to cardiac problems.
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19 4. DISCUSSION
This study revealed that the extents of reticulation, traction bronchiectasis and architectural distortion were associated with decreased survival; this finding is novel finding as far as we are aware. We also believe that this is the first study in which a correlation between CT findings and hospitalization has been investigated; correlations were detected with several features, i.e.
honeycombing, traction bronchiectasis and architectural distortion.
We applied a simple semi-quantitative method when evaluating the extent of different findings. As many different radiological observations can be present in various subtypes, one needs a
straightforward way of assessing the extent of different abnormalities. This kind of scoring method can be applied in clinical practise without special equipment and provides additional information about the differences in various radiological findings between different RA-ILD subgroups.
Previously, the relationship between survival and CT has been investigated in patients with RA- ILD, and the UIP pattern has been shown to associate with worse survival than other subtypes (8,9,22). Furthermore, in the recent longitudinal study of Yunt et al, the combined group of definite and possible UIPs had significantly worse survival than the NSIP patients (23). However,
apparently only one previous RA-ILD study has detailed which radiological features associate with poorer survival. That retrospective study of 84 RA-ILD patients reported that reticulation, traction bronchiectasis and honeycombing were associated with worse survival and that both presence and the extent of traction bronchiectasis as well as the extent of honeycombing were independent predictors of worse outcome (8). In that study, the extent of various findings was assessed rather similarly as conducted here, since GGO, reticulation, traction bronchiectasis and honeycombing were graded as absent, mild, moderate or severe, although architectural distortion was not evaluated (8). In addition, one recent study of 168 patients with CTD-ILD including 39 RA-ILD patients stated that the severity of traction bronchiectasis and the extensiveness of honeycombing were independently associated with increased mortality (7). In that study also, the grading of traction
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bronchiectasis was similar (scale 0-3) to our system, but the extent of other findings was explicitly estimated to the nearest 5% at six levels in both lungs. In addition, their study population included all CTD-ILDs, complicating the comparison of the results (7).
Since the number of RA-ILD studies concerning the association between CT and survival is limited, we searched the literature also for information on idiopathic interstitial pneumonias (IIP). Edey et al evaluated which CT features were prognostic in 146 patients with fibrotic IIP, using similar scoring (0-3) in traction bronchiectasis, estimating other abnormalities to the nearest 5% and averaging scores from six different anatomical levels to obtain a global disease score (6). In that study, similarly as in ours, coarse reticulation and increased severity of traction bronchiectasis were predictive of poor prognosis but honeycombing and the overall extent of lung abnormalities were also identified as significant predictors (6). Another study of 98 histologically confirmed patients with IPF revealed that the prognosis was influenced by traction bronchiectasis and the so-called fibrosis score, which partly consisted of the extent of reticulation; the univariate analysis also revealed honeycombing, consolidation and architectural distortion as significant predictors of mortality (4). Overall, it can be stated that our results concerning survival supports previous
findings of the importance of reticulation and traction bronchiectasis and highlight also the extent of architectural distortion as a predictor of mortality.
We found several correlations between radiological observations and clinical features with one of the most interesting being the correlations between the hospitalizations due to respiratory problems and honeycombing, traction bronchiectasis and architectural distortion scores. Since we have been unable to find a previous study addressing this subject, this appears to be a novel finding. It could be that some of the hospitalizations have been caused by exacerbations of RA-ILD, known to occur mostly in UIP patterned RA-ILD (24); in our study, this subgroup exhibited the highest mean scores of honeycombing and architectural distortion. The fact that GGO correlated negatively with
duration of RA may indicate that GGO is an early phenomenon in RA-ILD; this speculation is at
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odds with the results from Mori et al. who indicated that GGO was as prevalent in early as in longstanding RA (25). However, in the study of Kim et al. there was a longer duration of RA in the UIP patients than in the non-UIP group (8) a finding confirmed in another study where a
predominance of GGO was found more frequently in patients with a shorter RA duration (26).
Some studies have examined the correlation between PFTs and CT findings. Biederer et al. found negative correlations between the total profusion of present lesion and DLCO, vital capacity and FEV1 in 53 RA patients suspected of having ILD (26). Tanaka et al. calculated correlations between PFT and CT in a similar manner as used in our study, e.g. separating CT findings GGO, reticulation, honeycombing and bronchiectasis in a retrospective study consisting of 63 RA patients with respiratory symptoms and/or abnormal chest X-ray (27). They found a positive correlation between reticulation and FEV1/FVC ratio, whereas we observed a similar trend.
The inter-observer agreement of our study was in line with a previous report from Assayag et al.
(28) in which the agreement of UIP pattern using strict criteria (definite vs possible plus
inconsistent) was good (κ = 0.67) and moderate (κ = 0.52) when using the broader criteria (definite plus possible vs inconsistent).
In conclusion, since many radiological features seem to associate with the course of the disease in RA-ILD, they possibly could be useful when evaluating the risk of death and the course of the disease. This highlights the importance of performing a HRCT scan in symptomatic RA patients.
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22 5. REFERENCES
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Highlights
1) The extent of reticulation associate with shorter survival in patients with RA-ILD 2) The extent of traction bronchiectasis also associates with worse survival.
3) It also correlates with hospitalizations due to respiratory reasons
4) The extent of honeycombing also correlates with respiratory hospitalizations 5) Many HRCT findings can be useful when assessing the risk of death in RA-ILD
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CONFLICT OF INTEREST STATEMENT 17.8.2017
The authors have following competing interests, that have not affected the contents of this study:
Hanna Nurmi: Consulting fees from Boehringer-Ingelheim and Roche Oy. Congress travel grants from Boehringer-Ingelheim, Lilly Oncology, Novartis, Orion Pharma and GlaxoSmithKline.
Minna Purokivi: Personal fees from Boehringer-Ingelheim, Chiesi, Intermune, Orion Pharma, Roche and Takeda Leiras. Congress travel grants from Boehringer-Ingelheim, Roche and Takeda Leiras.
Miia Kärkkäinen: Consulting fee from Boehringer-Ingelheim and congress travel grants from Intermune, Boehringer-Ingelheim, Orion Pharma and Roche.
Hannu-Pekka Kettunen: Consulting fees from Siemens and Roche.
Riitta Kaarteenaho: Consulting fee from GlaxoSmithKline and congress travel grants from Intermune, Boehringer-Ingelheim, Orion Pharma and Roche.
Sanna Suoranta and Tuomas Selander have no conflicts of interests.
