Abstract
Interstitial lung disease (ILD) is a common pulmonary manifestation of connective tissue diseases (CTD). Prognostic effect of radiological usual interstitial pneumonia (UIP) pattern in CTD‐associated interstitial lung disease (CTD‐ILD) is unknown. This study aimed to investigate the disease progression and mortality of patients with CTD‐ILD and idiopathic interstitial pneumonias (IIP) including idiopathic pulmonary fibrosis (IPF) and idiopathic nonspecific interstitial pneumonia and the prognostic impact of the radiological UIP pattern on both disease groups. The medical records of 91 patients (55 with CTD‐ILD and 36 with IIP) diagnosed with ILD at pulmonary medicine department, Faculty of Medicine, Gazi University from 2004 to 2014 were retrospectively reviewed. Patients included whose baseline high‐resolution computed tomography (HRCT) scans showed either a UIP or non‐UIP pattern. While 67.3% (n = 37) of CTD‐ILD patients possessed UIP pattern, 38.9% (n = 14) of IIP patients had UIP pattern in HRCT. Respiratory functions including the forced expiratory volume in the first second (FEV1), functional vital capacity (FVC), and transfer coefficient for carbon monoxide (diffusing capacity of the lung for carbon monoxide [DLCO]) of IIP group at the time of diagnosis were significantly lower than CTD‐ILD group (P = .007, P = .002, and P = .019, respectively). There was no significant survival difference between CTD‐ILD and IIP by using the log‐rank test (P = .76). Multivariate analysis revealed that UIP pattern in HRCT (Hazard ratio: 1.85; 95% Confidence interval = 1.14‐3; P = .013), annual FVC (Hazard ratio: 0.521; 95% Confidence interval = 0.32‐0.84; P = .007), and annual DLCO declines (Hazard ratio: 0.943; 95% Confidence interval = 0.897‐0.991; P = .02) were independent risk factors for mortality in both CTD‐ILD and IIP groups. We found that UIP pattern in HRCT and annual losses in respiratory functions were the main determinants of prognosis of ILDs either idiopathic or CTD‐associated.
Keywords: connective tissue disease‐associated interstitial lung disease, high‐resolution computed tomography, idiopathic interstitial pneumonia, prognosis, usual interstitial pneumonia
1. INTRODUCTION
Idiopathic interstitial pneumonias (IIP) are a group of heterogeneous disorders characterized by diffuse parenchymal lung involvement with overlapping clinical and radiologic features. IIP are currently classified into seven clinico‐radiologic and pathologic entities which differ not only in pathology but also in clinical features, especially in relation to prognosis. Out of these, the two most common histologic patterns are usual interstitial pneumonia (UIP) and nonspecific interstitial pneumonia (NSIP). UIP pattern is accepted as predominant pattern for idiopathic pulmonary fibrosis (IPF) but NSIP can be seen in a more heterogeneous group of clinical settings, one of which is an idiopathic presentation.1, 2
Connective tissue diseases (CTD) are a group of systemic disorders characterized by autoimmunity and autoimmune‐mediated organ damage. The lung is a frequent target and all components of the respiratory system are at risk. Interstitial lung disease (ILD) represents a broad group of diffuse parenchymal lung injury patterns characterized by varying degrees of inflammation and fibrosis. ILD is a common manifestation of CTD particularly in systemic sclerosis (SS), polymyositis/dermatomyositis (PM/DM), and rheumatoid arthritis (RA). It is also a leading cause of significant morbidity and mortality. The lung injury patterns of CTD‐associated interstitial lung disease (CTD‐ILD) can mirror those of IIP and may arise at any time during the course of the CTD or may be the first manifestaion of CTD.3
The clinical presentations of IIP and CTD‐ILD are similar. Patients usually present with insidious onset of dyspnea, sometimes associated with a nonproductive cough and having bibasilar end‐inspiratory dry rales on auscultatory examination. Although the clinical presentations are similar, their clinical courses can be different and it could be difficult to predict outcomes. Little is known about the exact clinical course and mortality in these two entities. Impairment in respiratory physiology at baseline or worsening in general respiratory functions over time has been proposed as poor prognostic factors in CTD‐ILD.3 Patients with UIP pattern on high‐resolution computed tomography (HRCT) were also suggested to have a worse prognosis than those with a different HRCT pattern regardless of pathologic diagnosis.4
In the absence of pathologic material, HRCT has assumed a greater role in the diagnosis and management of IIP and CTD‐ILD. The diagnostic accuracy of HRCT together with clinical evaluation by experienced physicians could diagnose IPF with a 80% positive predictive value.5 The patterns of ILD on HRCT are described as either ground glass opacity or honeycombing appearance for alveolar and interstitial findings. Honeycombing is defined as cystic spaces, usually peripheral in location and with the presence of clearly definable walls. A diffuse or focal area of hazy increased attenuation in the lung parenchyma, not associated with obscuration of underlying vessels, is defined as ground‐glass opacity.6, 7
Previous studies comparing the outcomes of CTD‐ILD and IIP patients were mostly dependent on the histopathological patterns. This study aimed to investigate the disease progression and mortality of patients with CTD‐ILD and IIP and prognostic impact of the radiological UIP pattern on both disease groups.
2. METHODS
2.1. Study population
Medical records of patients who had been diagnosed as IPF or idiopathic NSIP and patients who had been diagnosed as CTD‐ILD between 2004 and 2014 in a pulmonary medicine department of a university hospital have been retrospectively investigated.
Within the IIP, we included only chronic fibrosing interstitial pneumonias (IP) including IPF and idiopathic NSIP. We excluded smoking‐related IIP (respiratory‐bronchiolitis‐ILD, desquamative IP) and acute/subacute IP (cryptogenic organizing pneumonia [OP] and acute IP) because their radiologic patterns are noticeably different from UIP and NSIP. Also we excluded patients with hypersensitivity pneumonia and drug toxicity whose radiological pattern occurred as a result of NSIP but their prognosis can be different from idiopathic NSIP. Before 2011 ATS/ERS/JRS/ALAT guideline on IPF diagnosis, all the patients with UIP pattern in HRCT underwent diagnostic lung biopsy for the confirmation of histopathological diagnosis.8 After the 2011 statement, patients with “definite UIP” pattern in the HRCT were diagnosed as IPF radiologically together with clinic findings.
CTD were diagnosed by two experienced rheumatologists as RA, SS, and Sjögren's Syndrome (SjS) with clinical and immunological patterns according to diagnostic criteria. Individual CTD were diagnosed according to the criteria of corresponding societies.9, 10, 11 We excluded patients with undifferentiated connective tissue disease which involves conditions characterized by both having symptoms of CTD and autoantibodies but not fulfilling the criteria of a specific CTD. Flow diagram of the patients is shown in Figure 1.
Figure 1.
Flow diagram of patient selection. Of 91 patients identified to have ILD, 55 with CTD‐ILD, and 36 with IIP were enrolled in the study. Abbreviations: CTD‐ILD, connective tissue disease‐associated interstitial lung disease; IIP, idiopathic interstitial pneumonias; ILD, interstitial lung disease; IPF, idiopathic pulmonary fibrosis; Non‐UIP, nonusual interstitial pneumonia; RA, rheumatoid arthritis; SjS, Sjogren syndrome; SS, systemic sclerosis; UIP, usual interstitial pneumonia
Lung involvement of patients with CTD was decided with the cooperation of radiologist, pulmonary specialists, and rheumatologists at initial assessment according to the latest guideline at the time of diagnosis.1, 6
Patients' demographic information, gender, smoking habits, comorbidities, autoimmune antibody profiles, symptoms at the time of pulmonary involvement, respiratory function tests (functional vital capacity [FVC], forced expiratory volume in the first second [FEV1], FEV1/FVC, and transfer coefficient for carbon monoxide [diffusing capacity of the lung for carbon monoxide, DLCO]), and diagnostic methods of pulmonary involvement were recorded at the time of diagnosis. Serological auto‐antibodies within the serological domain of CTD (antinuclear antibody [ANA] ≥ 1:320 [or nuclear and/or centromere pattern of any titer], rheumatoid factor more than twice the upper limit of normal, anti‐CCP, anti‐dsDNA, anti‐SS‐A, anti‐SS‐B, anti‐RNP, anti‐Smith, and anti‐Jo1) were assessed.
All patients were followed from the time of diagnosis until the death. Patients who were lost due to extrapulmonary reasons were excluded. The main reason of mortality in both groups was respiratory failure. IPF patients receiving anti‐fibrotic agents such as Pirfenidon or Nintedanib were excluded from study because of the small number.
2.2. HRCT evaluation
All patients underwent HRCT on 1.0‐mm or 1.5‐mm thick overlapping sections using a high‐spatial‐frequency reconstruction algorithm taken during a single breath hold on various computed tomography scanners. The HRCT images were evaluated by an experienced radiologist. The UIP pattern on HRCT was determined according to the American Thoracic Society/European Respiratory Society statement.1 Patients within CTD‐ILD group were divided into two groups consisting of “definite UIP” (UIP‐pattern) or “inconsistent with UIP” (non‐UIP pattern) based on their radiologic findings.1 We excluded all the patients with “Possible UIP” pattern in HRCT. UIP pattern is defined by reticular abnormality with or without honeycombing in subpleural and basal predominance. The non‐UIP pattern is defined by upper or mid‐lung predominance, peribronchovascular predominance, extensive ground glass abnormality, profuse micronodules, discrete cysts, diffuse mosaic attenuation, and consolidation in the bronchopulmonary segment.1
2.3. Statistical analysis
For statistical analysis, SPSS 17 (SPSS, Inc, Chicago, Illinois) program was used. The discrete variables are expressed as numbers (percentages) and the continuous variables are shown as the mean ± SD unless otherwise specified. A chi‐square statistic test or Fisher's exact test was used for categorical data and an unpaired Student's t test or a Mann‐Whitney test for continuous data. Survival was evaluated using Kaplan‐Meier survival curves and the log‐rank test. Cox proportional hazards regression analysis was used to identify significant variables predicting survival status. Variables selected via univariate test (P < .05) were evaluated in a multivariate Cox regression analysis. A P value less than .05 was considered statistically significant (two‐tailed).
3. RESULTS
3.1. Clinical characteristics of patients
The mean age of the study group was 59.5 ± 12.4 years, 46 patients (50.5%) were female and 55 (60.4%) were non‐smoker. CTD‐ILD group was female‐dominant while IIP group composed of mostly male patients. The percentage of smokers was higher in IIP group. The clinical characteristics of the 91 patients are summarized in Table 1.
Table 1.
Clinical characterization of patients upon diagnosis
| CTD‐ILD | IIP | P | |
|---|---|---|---|
| n = 55 | n = 36 | ||
| Age, years (mean ± SD) | 57.8 ± 12.2 | 62.2 ± 12.3 | .1 |
| M/F, n | 18/37 | 27/9 | <.001 |
| Smoker % | 45.7 | 69.4 | .04 |
| Cigarette, package‐years | 26.3 ± 17.3 | 33.6 ± 28.8 | .79 |
| Comorbidities, n (%) | |||
| Hypertension | 15 (27.3) | 11 (30.6) | .82 |
| Diabetes | 5 (9.1) | 6 (16.7) | .34 |
| Coronary artery disease | 5 (9.1) | 6 (16.7) | .34 |
| Malignancy | 2 (3.6) | 1 (2.8) | .80 |
| COPD | 4 (7.3) | 2 (5.6) | .71 |
| Respiratory symptoms, n (%) | |||
| Dyspnea | 35 (63.6) | 28 (77.8) | .34 |
| Cough | 19 (34.5) | 22 (61.1) | .03 |
| Chest pain | 5 (9.1) | 4 (11.1) | .82 |
| Hemoptysis | 1 (1.8) | 0 | .40 |
| Sputum | 7 (12.7) | 7 (19.4) | .56 |
| Lung physiological features | |||
| FEV1, % predicted | 85.1 ± 21.3 | 72.2 ± 19.7 | .007 |
| FEV1, mL | 2052 ± 800 | 2020 ± 779 | .8 |
| FVC, % predicted | 85.1 ± 23.3 | 67 ± 22.4 | .002 |
| FVC, mL | 2419 ± 992 | 2322 ± 717 | .56 |
| FEV1/FVC, % | 83.8 ± 7.2 | 84.8 ± 11.9 | .79 |
| DLCO, % predicted | 57.1 ± 18.1 | 47.9 ± 19.9 | .019 |
| Autoantibody, positive results (%) | |||
| ANA | 33 (60) | 3 (8.3) | <.001 |
| Anti‐ds DNA | 5 (9.1) | 0 | .009 |
| SS‐A | 7 (12.7) | 1 (2.8) | .2 |
| SS‐B | 4 (7.3) | 2 (5.6) | .94 |
| Anti‐SM | 1 (1.8) | 0 | .44 |
| Anti‐SM/RNP | 2 (3.6) | 0 | .32 |
| Anti‐Scl70 | 14 (25.5) | 1 (2.8) | .019 |
| Anti‐Jo1 | 1 (1.8) | 0 | .31 |
| Anti‐CCP | 17 (30.9) | 2 (5.6) | .044 |
Abbreviations: ANA, anti‐nuclear antibody; Anti‐CCP, anti‐cyclic citrullinated peptide; Anti‐dsDNA, antidouble stranded DNA; Anti‐Jo1, histidyl‐RNA synthetase antibody; Anti‐Scl70, anti‐scleroderma/anti‐topoisomerase 1; Anti‐SM, anti‐smooth muscle; Anti‐SM/SNP, anti‐smooth muscle/ribonucleoprotein; COPD, chronic obstructive pulmonary disease; CTD‐ILD, connective tissue disease‐associated interstitial lung disease; DLCO, diffusing capacity of the lung for carbon monoxide; FEV1, forced expiratory volume in first second; FVC, forced vital capacity; IIP, idiopathic interstitial pneumonias; SS‐A, anti‐Ro; SS‐B, Anti‐La.
Fifty‐five of patients diagnosed with CTD‐ILD (28 RA, 18 SS, and 9 SjS) while 36 of patients had IIP (22 IPF, 14 idiopathic NSIP). According to radiologic evaluation, 32.7% (n = 18) of CTD‐ILD patients possessed UIP pattern, while 67.3% (n = 37) had non‐UIP pattern. Fifty‐one patients (92.8%) with CTD‐ILD were diagnosed with clinico‐radiologic findings, while 4 (7.2%) patients were diagnosed with histo‐pathological sampling. In IIP group, 41.7% (15) of patients were diagnosed with clinico‐radiologic findings and 58.3% (21) of patients were diagnosed with histo‐pathological sampling. Radiological patterns and the diagnostic methods of the CTD‐ILD group were shown in Tables 2 and 3.
Table 2.
Radiologic patterns of patients with connective tissue disease‐associated interstitial lung disease
| Rheumatoid arthritis | Systemic sclerosis | Sjögren's syndrome | |
|---|---|---|---|
| UIP pattern, n (%) | 8 (28.6) | 9 (50) | 1 (11.1) |
| Non‐UIP pattern, n (%) | 20 (71.4) | 9 (50) | 8 (88.9) |
Abbreviation: UIP, usual interstitial pneumonia.
Table 3.
Diagnostic methods of groups
| Clinico‐radiological | FOB | VATS | Open lung biopsy | |
|---|---|---|---|---|
| CTD‐ILD, n (%) | 51 (92.8) | 2 (3.6) | 2 (3.6) | 0 |
| IIP, n (%) | 15 (41.7) | 3 (8.3) | 9 (25) | 9 (25) |
| IPF | 11 | 1 | 5 | 5 |
| Non‐UIP | 4 | 2 | 4 | 4 |
Abbreviations: CTD‐ILD, connective tissue disease‐associated interstitial lung disease; FOB, fiberoptic bronchoscopy; IIP, idiopathic interstitial pneumonias; IPF, idiopathic pulmonary fibrosis; VATS, video‐assisted thoracoscopic lung surgery.
Most commonly seen symptom in both groups was dyspnea (63.6% in CTD‐ILD and 77.8% in IIP). Coughing was the second most common symptom and it was two times more common in the IIP group. Both groups did not have a significant difference in the presence of comorbidities. Regarding the respiratory functions, mean FEV1, FVC, and DLCO values at the time of diagnosis were 85.1%, 85.1%, and 57.1%, respectively, for CTD‐ILD group and 72.2%, 67%, and 47.9%, respectively, for IIP group. All three lung function parameters described above were significantly lower in the IIP group (P = .007, P = .002, and P = .019) (Table 1).
Regarding the respiratory functions at the time of diagnosis, there was no significant difference between IPF and idiopathic NSIP patients in IIP group. Similarly, there was no significant difference between UIP and non‐UIP patterns in CTD‐ILD group regarding FEV1, FVC, and DLCO values (Table 4). Even though respiratory functions (FEV1, FVC, and DLCO) of UIP group of CTD‐ILD and IPF patients were lower at the time of diagnosis, but it did not reach statistical significance.
Table 4.
Comparison of two groups pulmonary functions
| CTD‐ILD | IIP | |||||
|---|---|---|---|---|---|---|
| UIP pattern | Non‐UIP pattern | P | IPF | Non‐UIP | P | |
| FEV1 % | 83.3 ± 22.7 | 85.7 ± 21.2 | .86 | 69.2 ± 21.3 | 76.6 ± 16.8 | .23 |
| FVC % | 81.5 ± 25.9 | 86.4 ± 22.8 | .71 | 66.8 ± 20.5 | 67.4 ± 25.8 | .50 |
| DLCO % | 47.7 ± 19.6 | 60.4 ± 16.7 | .09 | 38.7 ± 15.9 | 53.4 ± 20.4 | .09 |
Abbreviations: CTD‐ILD, connective tissue disease‐associated interstitial lung disease; DLCO, diffusing capacity of the lung for carbon monoxide; FEV1, forced expiratory volume in first second; FVC, forced vital capacity; IIP, idiopathic interstitial pneumonias; IPF, idiopathic pulmonary fibrosis; UIP, usual interstitial pneumonia.
Auto‐immune serology positivity was significantly higher in CTD‐ILD group, 60% of the patients had ANA positivity while 30.9% had anti‐CCP positivity.
In CTD‐ILD patients, most commonly affected zone was lower lung lobes (81.8%) and peripheral areas (74.5%). In this group, 81.8% of patients had reticular changes, while 40% had honeycomb pattern and 34.5% had ground glass areas.
Out of 91.5% of CTD‐ILD patients had one of immunosuppressive treatment regimens (steroid, methotrexate, azathioprine, cyclophosphamide, mycophenolate, mofetil, leflunomide treatment) at least. In the IIP group, the immunosuppressive treatment rate was 40%. Out of 23.8% of IPF patients had one of immunosuppressive treatments (azathioprine or cyclophosphamide), 45.5% of IPF patients were treated with corticosteroid alone or with N‐acetylcysteine and anti‐acid therapy (before 2011). Out of 64.3% of patients with non‐UIP pattern received one immunosuppressive therapy at least.
3.2. Pulmonary function tests and annual physiological changes
Median follow‐up time of CTD‐ILD group was 30 (15‐42) months and it was 29.5 (10.5‐43.5) months for IIP group. The 1‐year survival rates of CTD‐ILD group and IIP group were 98.9% and 87.6% whereas the 3‐year survival rates were 80.5% and 62.5%, respectively.
Mean pulmonary function decline in FEV1, FVC, and DLCO at first year was 138.9 ± 344.3 mL (4.8% ± 13%) in FEV1, 134.1 ± 486.7 mL (2.7% ± 11.5%) in FVC and 5% ± 16.1% in DLCO in CTD‐ILD group and 63.8 ± 329.1 mL (1.2% ± 13.3%) in FEV1, 161.5 ± 378 mL (3.3% ± 9.5%) in FVC and 0.6% ± 7.3% in DLCO in IIP group. There was no significant difference between groups regarding annual FEV1, FVC, and DLCO declines. There was no difference between deceased and living patients regarding annual mean FEV1 and DLCO declines. Annual FVC decline of deceased patients was 190.7 ± 353.1 mL while it was 89.9 ± 424.3 mL for living patients (P = .044) (Figure 2A‐C).
Figure 2.
A, Annual changes in FEV1 at the first year. B, Annual changes in FVC at the first year. C, Annual changes in DLCO at the first year. Abbreviations: DLCO, diffusing capacity of the lung for carbon monoxide; FEV1, forced expiratory volume in the first second; FVC, functional vital capacity [Color figure can be viewed at wileyonlinelibrary.com]
3.3. Survival comparison of patients with CTD‐ILD and IIP
Despite the CTD‐ILD group being younger and predominantly male, it also had higher smoking rate and worse respiratory functions at the time of diagnosis compared with the IIP group, there was no significant survival difference between CTD‐ILD and IIP by using the log‐rank test Hazard ratio (HR): 1.14; 95% Confidence interval (CI): 0.49‐2.60; P = .76). Kaplan‐Mier survival analysis curve was shown in Figure 3.
Figure 3.
Kaplan–Meier survival curve for overall survival of idiopathic interstitial pneumonias and connective tissue associated‐interstitial pneumonias (P = .76) [Color figure can be viewed at wileyonlinelibrary.com]
3.4. Prognostic factors for the survival of patients using univariate and multivariate models
According to univariate Cox model, age, gender, FEV1, FVC, and DLCO at the time of diagnosis were not significant predictors of survival (Table 5). Multivariate analysis revealed that UIP pattern in HRCT (HR: 1.85; 95% CI = 1.14‐3; P = .013), annual FVC (HR: 0.521; 95% CI = 0.32‐0.84; P = .007) and DLCO (HR: 0.943; 95% CI = 0.897‐0.991; P = .02) declines were independent risk factors for mortality.
Table 5.
Prognostic factors of survival according to univariate analysis
| Parameter | CTD‐ILD Group | IIP Group | ||||
|---|---|---|---|---|---|---|
| Hazard ratio | 95% CI | P | Hazard ratio | 95% CI | P | |
| Age | 1.009 | 0.956‐1.065 | .74 | 1.004 | 0.971‐1.038 | .83 |
| FEV1 | 2.85 | 0.835‐9.729 | .1 | 0.993 | 0.959‐1.028 | .69 |
| FVC | 0.993 | 0.963‐1.025 | .67 | 0.985 | 0.936‐1.037 | .57 |
| DLCO | 0.98 | 0.948‐1.013 | .23 | 1.761 | 0.372‐8.329 | .76 |
| Gender | 1.002 | 0.971‐1.035 | .88 | 1.004 | 0.971–1.038 | .83 |
Abbreviations: CTD‐ILD, connective tissue disease‐associated interstitial lung disease; DLCO, diffusing capacity of the lung for carbon monoxide; FEV1, forced expiratory volume in first second; FVC, forced vital capacity; IIP, idiopathic interstitial pneumonias.
4. DISCUSSION
This study shows that prognosis of the CTD‐ILD and IIP patients do not differ despite the fact that respiratory functional parameters of CTD‐ILD patients are better than IIP patients at the time of diagnosis. Annual FVC and DLCO declines and UIP pattern in HRCT are independent risk factors for mortality in both groups of patients.
In the female‐dominant, having fewer smokers CTD‐ILD group FEV1, FVC, and DLCO were markedly less affected at the time of diagnosis. Out of 91% of CTD‐ILD patients received at least one of immunosuppressive therapies during their follow‐up and despite that, the annual mean declines of respiratory functions functions including FEV1, FVC and DLCO were similar in two groups during follow‐up. There was no significant survival difference between two groups. To our knowledge, these findings are the first reported data from our country.
Pulmonary involvement is one of the most serious complications observed among patients with CTD and it is associated with significant morbidity and mortality. Similar radiological and clinical findings present in CTD‐ILD and IIP patients.1 But some notable differences exist between CTD‐LD and IIP that can aid in making the correct diagnosis. Patients with CTD‐ILD are often younger,2, 3, 4, 5, 6 more commonly female,7, 12 diagnosed earlier in the course of their disease7 with have better lung functions at the time of diagnosis7, 12 than those with IIP. Smokers may also over‐represent in the IIP patients.2, 3, 4, 5, 6
Similar to previous studies, CTD‐ILD group was female‐dominant and had fewer smokers in our study. The underlying reason for this could be higher smoking population among males compared to females (47.9%‐15.2%) rather than the protective effect of smoking on CTDs.
While there are many similarities among the different subsets of CTD‐ILD on HRCT, some distinguishing features are also worthy of consideration. The majority of CTD‐ILD patients display a non‐UIP pattern on HRCT or in histopathologic samples with or without OP. The non‐UIP pattern is a more inflammatory subtype of ILD and the most common pattern is observed in SS (68%‐77%), PM/DM (65%‐82%), SjS (28%‐61%), and undifferentiated CTD (83%).13, 14, 15 By contrast, RA patients with ILD have a higher incidence of UIP pattern on HRCT or in histopatholic samples and have a more fibrotic subtype of ILD. In general, the specific ILD pattern can predict the response to treatment. More inflammatory ILDs (cellular NSIP and OP) show a greater response to immunosuppressive therapies than the more fibrotic ILDs (fibrotic NSIP and UIP).16, 17
In our study, the ratio of radiological UIP pattern in CTD‐ILD group especially among those with RA patients was found higher than other studies. Most of the diagnoses were confirmed with histopathological samplings in previous studies. Nearly all of CTD‐ILD group were diagnosed with clinical and radiological findings in our study and unlike in IIP, according to literature results which proved histopathologically did not affect mortality. Especially UIP pattern in HRCT and histopathological findings had a high correlation and thus in most cases, there is no need for tissue sampling.18, 19 Hunninghake et al5 investigated the reliability of radiological findings when compared to histopathological results. HRCT was found to have 45% of sensitivity and 96% of specificity for IIP diagnosis. A sensitivity of 63% to 96% and a specificity of 79% to 100% were found for IPF in similar studies regarding HRCT findings.20, 21, 22
Our study revealed a difference in FEV1, FVC, and DLCO levels upon diagnosis between CTD‐ILD and IPP groups but the annual reduction in these values was found similar. In addition, an average annual loss of FVC was found roughly two times higher in deceased patients than survived patients. Annual FEV1, FVC, and DLCO losses were independent risk factors for mortality in CTD‐ILD group. Earlier studies proved the relationship between increased mortality and reduction in pulmonary functions. A loss of more than 10% FVC during the follow‐up of IPF patients is known to be related to increased mortality.23
Agusti et al24 observed 20 patients with either CTD‐ILD or IIP for 2 years. They found a significant fall in FEV1, FVC, DLCO, and total lung capacity (TLC) in IIP group while CTD‐ILD group's respiratory functions remained stable.
Morgan et al25 had proven that in SS patients, FVC and DLCO values upon diagnosis are important factors in determining progression to end‐stage lung disease. Song et al26 also showed that in both CTD related UIP and IPF related UIP, TLC was an independent risk factor for mortality. Park et al16 had not found any significant mortality difference between CTD‐ILD and IIP subtypes regarding FVC, DLCO, and TLC values upon diagnosis. In all patients, multivariate analysis showed that age, FVC, DLCO, and presence of CTD were independent risk factors for mortality16 in their study. Our study also supports the correlation between pulmonary functions and mortality. Similar mortality rates and annual FEV1, FVC, and DLCO losses of CTD‐ILD and IIP patients can also be attributed to this relationship.
Compared to IPF, the prognosis of RA patients with ILD was found to be better; despite the fact that ILD in RA patients is an important cause of mortality and morbidity. Kim et al27 divided their patients with RA into two groups, ILD and non‐ILD, in a similar way to our study according to chest radiography and HRCT. Mortality was compared between two groups. Out of 64 patients were present in the ILD group which was male‐dominant and had older age. During an average follow‐up time of 24 months, 6 (9.4%) patients of ILD and 25 (0.7%) patients of the non‐ILD group died. Survival of ILD group was worse and the presence of ILD was confirmed as related with mortality (HR: 7.89, 95% CI = 3.16‐19.69, P < .01).27
Collins et al28 had performed a retrospective single‐center study in which they had investigated 124 ILD patients (20 patients were autoantibody positive with or without any CTD, 15 patients with ILD and autoimmune features [autoimmune‐ILD], 36 CTD‐ILD, 53 IPF patients with no CTD marker positivity) for autoantibody correlation. All of these three groups had similar FEV1 loss during first 12 months of follow‐up (60 mL, 110 mL, 90 mL, P = .52). In this cohort, DLCO loss was found lower in CTD‐ILD group than the IPF group. (−0.27 mL/(mm Hg min) vs −1,05 mL/(mm Hg min), P < .001). FVC loss was more present in UIP pattern compared to NISP pattern (−140 mL vs −10 mL, P = .001).28 Similar to this result, Goh et al29 suggested that short‐term trend in changes in respiratory functions was a mortality predictor of patients with SS related ILD.
Our study has several limitations. First of all, it had a retrospective design and the number of our subjects was relatively small. However, all consecutive cases were identified and the clinical, functional, imaging, and biological data were collected prospectively; therefore, we had a few missing data. The analysis of cases from a single department of respiratory medicine may have a selection bias in favor of IIP; therefore, the proportion of CTD‐ILD may have been underestimated.
In conclusion, patients with either IIP or CTD‐ILD have a poor prognosis and similar mortality rate. The most important factors contributing to poor outcome in both groups of patients are UIP pattern in HRCT, annual FVC, and DLCO declines in pulmonary functions. We propose that the presence of UIP in HRCT and higher pulmonary functional loss at the earlier stages can help to identify these patients with poor prognosis without confirmatory biopsies. Further research and prospective studies to compare the two groups of patients with HRCT findings, pulmonary function tests, clinical parameters, and treatment modalities will better delineate IIP and the prognostic implications in the optimal patient management of ILD in patients with CTD‐ILD.
CONFLICT OF INTEREST
The authors have no conflict of interest to report.
Yıldırım F, Türk M, Bitik B, et al. Comparison of clinical courses and mortality of connective tissue disease‐associated interstitial pneumonias and chronic fibrosing idiopathic interstitial pneumonias. Kaohsiung J Med Sci. 2019;35:365–372. 10.1002/kjm2.12066
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