Lung-dominant Connective Tissue Disease Research Articles

Lung adenocarcinoma discovered during the follow-up of lung-dominant connective tissue disease: a case report and literature review

Interstitial lung disease (ILD) can lead to lung cancer, which brings great challenges to differential diagnosis and comprehensive treatment. However, the clinical features of lung-dominant connective tissue disease (LD-CTD) related ILD combined with lung cancer has not been validated. We report the case of an 80-year-old woman with LD-CTD treated regularly with nintedanib who presented progressive dyspnoea and hypoxemia after recurrent viral infections. Her chest computed tomography (CT) showed aggravated interstitial fibrosis in both lower lungs with moderate right pleural effusion. Clinicians should be alert to lung cancer in patients who are experiencing poor responsiveness to treatment or acute progression of ILD. The available literatures about the differential diagnosis of clinical manifestations, imaging, treatment and prognosis of LD-CTD are reviewed and discussed in this study.

Morphologic Aspects of Interstitial Pneumonia With Autoimmune Features.

- Interstitial lung disease, a common complication observed in several connective tissue diseases, causes significant morbidity and mortality. Similar to individuals with connective tissue diseases, a significant subgroup of patients with clinical and serologic characteristics suggestive of autoimmunity but without confirmed specific connective tissue disease presents with associated interstitial lung disease. These patients have been classified using different controversial nomenclatures, such as undifferentiated connective tissue disease-associated interstitial lung disease, lung-dominant connective tissue disease, and autoimmune featured interstitial lung disease. The need for a better understanding and standardization of this entity, interstitial lung disease with autoimmune features, and the need for an adequate management protocol for patients resulted in the introduction of a new terminology in 2015: interstitial pneumonia with autoimmune features. This new classification requires a better comprehension of its diagnostic impact and the influence of its morphologic aspects on the prognosis of patients. - To review the diagnostic criteria for interstitial pneumonia with autoimmune features, with an emphasis on morphologic aspects. - The review is based on the available literature, and on pathologic, radiologic, and clinical experience. - The interstitial pneumonia with autoimmune features classification seems to identify a distinct subgroup of patients with different prognoses. Studies show that nonspecific interstitial pneumonia and usual interstitial pneumonia are the most prevalent morphologic patterns and show discrepant results on the impact of the usual interstitial pneumonia pattern on survival. Prospective investigations are necessary to better define this subgroup and to determine the prognosis and appropriate clinical management of these patients.

Interstitial pneumonia with autoimmune features.

Some patients with idiopathic interstitial pneumonias (IIPs) have clinical features that suggest autoimmune process but not fulfill established criteria for connective tissue disease (CTD). Different terms and criteria have been proposed to describe these patients, which includes undifferentiated connective tissue disease (UCTD), lung dominant connective tissue disease (LD-CTD), and autoimmune-featured interstitial lung disease (AIF-ILD). To marshal these ununiform classification criteria, the "European Respiratory Society/American Thoracic Society Task Force on Undifferentiated Forms of Connective Tissue Disease-associated Interstitial Lung Disease" proposed a consensus regarding the nomenclature and classification criteria for patients with IIP and features of autoimmunity with the term "interstitial pneumonia with autoimmune features" (IPAF). It was reported that patients with IPAF accounted for 7.3%∼34.1% of patients with interstitial lung disease (ILD). Survival, rate of progressing to CTD, appropriate treatment, and treatment response are not yet elucidated. Furthermore, it is not determined whether IPAF is a distinct category of ILD or simply a part of IIP. These questions should be elucidated by future prospective cohort studies. Hopefully, rheumatologists should participate in not only clinical trials but also in multidisciplinary discussions for IPAF.

Clinical Features of Idiopathic Interstitial Pneumonia with Systemic Sclerosis-Related Autoantibody in Comparison with Interstitial Pneumonia with Systemic Sclerosis.

BackgroundPatients with idiopathic interstitial pneumonias sometimes have a few features of connective tissue disease (CTD) and yet do not fulfil the diagnostic criteria for any specific CTD.ObjectiveThis study was conducted to elucidate the characteristics, prognosis, and disease behavior in patients with interstitial lung disease (ILD) associated with systemic sclerosis (SSc)-related autoantibodies.MethodsWe retrospectively analyzed medical records of 72 ILD patients: 40 patients with SSc (SSc-ILD) and 32 patients with SSc-related autoantibody-positive ILD but not with CTD (ScAb-ILD), indicating lung-dominant CTD with SSc-related autoantibody.ResultsPatients with SSc-ILD were predominantly females and non-smokers, and most had nonspecific interstitial pneumonia confirmed by high-resolution computed tomography (HRCT) and pathological analysis. However, about half of the patients with ScAb-ILD were male and current or ex-smokers. On HRCT analysis, honeycombing was more predominant in patients with ScAb-ILD than with SSc-ILD. Pathological analysis showed the severity of vascular intimal or medial thickening in the SSc-ILD patients to be significantly higher than that in the ScAb-ILD patients. Survival curves showed that the patients with ScAb-ILD had a significantly poorer outcome than those with SSc-ILD.ConclusionData from this study suggest that lung-dominant CTD with SSc-related autoantibody is a different disease entity from SSc-ILD.

Dramatic improvement of anti-SS-A/Ro-associated interstitial lung disease after immunosuppressive treatment

The aim of the study was to report three patients affected by interstitial lung disease associated with positive anti-SS-A/Ro autoantibody who showed a dramatic improvement after immunosuppressive treatment. Medical charts were reviewed to obtain clinical data, laboratory parameters, lung function tests, high-resolution computed tomography results and response to immunosuppressive treatment. The three patients showed a clinical picture of a lung-dominant connective tissue disease characterized by a sudden onset with dyspnea, cough and subtle extrathoracic features together with positive anti-SS-A/Ro antibody and weak titer antinuclear antibodies. All three patients responded favorably to immunosuppressive therapy: Two cases were treated with a combination of corticosteroid and cyclophosphamide followed by mycophenolate mofetil; in the third patient, clinical benefit was obtained after rituximab was added to corticosteroid and immunosuppressant drug. In spite of an abrupt onset with significant lung function impairment, all three patients had a favorable clinical response to immunosuppressive therapy. This report may be useful in making therapeutic decisions in case of interstitial lung disease associated with anti-SS-A antibody.

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

Lung-dominant connective tissue disease (LD-CTD) is a disease concept for interstitial pneumonia; however, it has not been robustly validated. This study was conducted to elucidate the clinical, radiologic, and histologic features of LD-CTD. We retrospectively reviewed 44 consecutive patients with serologically defined LD-CTD who underwent surgical lung biopsy. Patients were identified as having LD-CTD if they had specific autoantibodies but did not meet the criteria for connective tissue disease. We conducted a multidisciplinary diagnosis and evaluated major histologic patterns according to the current idiopathic interstitial pneumonias (IIPs) classification of 2013. Characteristic histologic features for LD-CTD (eg, prominent plasmacytic infiltration, lymphoid aggregates with germinal centers), high-resolution CT (HRCT) scan patterns, and prognosis were also assessed. The major histologic patterns were usual interstitial pneumonia (UIP) in 25 patients and nonspecific interstitial pneumonia (NSIP) in 13 patients. Two or more characteristic histologic features for LD-CTD were observed in 15 patients with histologic UIP (h-UIP) and 11 patients with histologic NSIP (h-NSIP). Fifteen patients with h-UIP (60%) showed an inconsistent UIP pattern on HRCT scan. After multidisciplinary discussion (MDD), 18 patients with h-UIP were labeled as having unclassifiable IIP. The annual change in percent predicted FVC improved significantly in patients with h-NSIP (P = .002), who also had better survival than those with h-UIP (P = .031). In contrast, survival was not associated with HRCT scan pattern (P = .79). The major histologic patterns in LD-CTD were UIP followed by NSIP. Two-thirds of patients had characteristic histologic features for LD-CTD. A majority of patients with h-UIP were considered to have unclassifiable IIP based on MDD. Patients with h-UIP had worse survival than those with h-NSIP.

Antigen avoidance tests for diagnosis of chronic hypersensitivity pneumonitis.

Chronic hypersensitivity pneumonitis (HP) is induced by the inhalation of specific antigens. Patients with chronic HP may be able to improve their prognosis by avoiding these antigens. Chronic HP is often difficult to distinguish from idiopathic interstitial pneumonias (IIPs). This study was performed to find out how antigen avoidance tests contribute to the diagnosis of chronic HP. A retrospective analysis was conducted on 265 patients who underwent 2-week antigen avoidance tests between April 2002 and March 2012. The patients were classified into the following categories: acute HP, chronic HP, collagen vascular disease-associated interstitial pneumonia (CVD-IP), lung dominant connective tissue disease (LD-CTD), and IIPs. The following seven clinical parameters were evaluated: vital capacity, alveolar-arterial oxygen pressure difference, Krebs von den Lungen-6, surfactant protein-D, white blood cell count, C-reactive protein, and body temperature. These parameters were compared between the chronic HP group and a control group consisting of CVD-IP, LD-CTD, and IIPs. One-hundred and ninety-six patients with chronic HP and 43 control subjects were evaluated. All clinical parameters improved significantly in the chronic HP group but showed no significant changes in the control group. Four of the parameters changed significantly compared with the control group. Diagnostic criteria established using these data had a sensitivity of 51.0% and a specificity of 80.7%. It was difficult to diagnose chronic HP based solely on 2-week antigen avoidance tests; however, improved clinical parameters among patients supported the diagnosis of HP.

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

OBJECTIVE: To describe the characteristics of a cohort of patients with lung-dominant connective tissue disease (LD-CTD). METHODS: This was a retrospective study of patients with interstitial lung disease (ILD), positive antinuclear antibody (ANA) results (≥ 1/320), with or without specific autoantibodies, and at least one clinical feature suggestive of connective tissue disease (CTD). RESULTS: Of the 1,998 patients screened, 52 initially met the criteria for a diagnosis of LD-CTD: 37% were male; the mean age at diagnosis was 56 years; and the median follow-up period was 48 months. During follow-up, 8 patients met the criteria for a definitive diagnosis of a CTD. The remaining 44 patients comprised the LD-CTD group, in which the most prevalent extrathoracic features were arthralgia, gastroesophageal reflux disease, and Raynaud's phenomenon. The most prevalent autoantibodies in this group were ANA (89%) and anti-SSA (anti-Ro, 27%). The mean baseline and final FVC was 69.5% and 74.0% of the predicted values, respectively (p > 0.05). Nonspecific interstitial pneumonia and usual interstitial pneumonia patterns were found in 45% and 9% of HRCT scans, respectively; 36% of the scans were unclassifiable. A similar prevalence was noted in histological samples. Diffuse esophageal dilatation was identified in 52% of HRCT scans. Nailfold capillaroscopy was performed in 22 patients; 17 showed a scleroderma pattern. CONCLUSIONS: In our LD-CTD group, there was predominance of females and the patients showed mild spirometric abnormalities at diagnosis, with differing underlying ILD patterns that were mostly unclassifiable on HRCT and by histology. We found functional stability on follow-up. Esophageal dilatation on HRCT and scleroderma pattern on nailfold capillaroscopy were frequent findings and might come to serve as diagnostic criteria.

Significance of Pulmonary Arterial Pressure as a Prognostic Indicator in Lung-Dominant Connective Tissue Disease

BackgroundLung-dominant connective tissue disease (LD-CTD) is a new concept for classifying the subset of patients with interstitial pneumonia who have clinical features suggesting an associated CTD, but whose features fall short of a clear diagnosis of CTD under the current rheumatologic classification systems. The impact of mean pulmonary arterial pressure (MPAP) in LD-CTD has not been sufficiently elucidated.ObjectivesTo evaluate the survival impact of MPAP measured during the initial evaluation in patients with LD-CTD.MethodsWe retrospectively analyzed the initial evaluation data of 100 LD-CTD patients undergoing pulmonary function test, 6-min walk test (6MWT), and right heart catheterization (RHC).ResultsThe mean MPAP was 16.2±4.4 mm Hg, and 18 patients had MPAP≥20 mm Hg. A univariate Cox proportional hazard model showed that MPAP and several variables have a statistically significant impact on survival. With stepwise, multivariate Cox proportional analysis, MPAP (HR = 1.293; 95% CI 1.130–1.480; p<0.001) and mean forced vital capacity (FVC) % predicted (HR = 0.958; 95% CI 0.930–0.986; p = 0.004) were shown to be independent determinants of survival.ConclusionsHigher MPAP and lower %FVC at the initial evaluation were significant independent prognostic factors of LD-CTD. MPAP evaluation provides additional information of disease status and will help physicians to predict mortality in LD-CTD.

Interstitial lung disease in suggestive forms of connective tissue disease

Patients with the characterizable forms of connective tissue disease (CTD) are at risk for developing interstitial lung disease (ILD), and there is a growing appreciation that ILD can be the first or only clinically relevant manifestation of an underlying CTD.(1-3) Less is understood— and there is far greater controversy—about ILD associated with suggestive or “undifferentiated” forms of CTD.(2,3) In the present issue of the Brazilian Journal of Pulmonology, Pereira et al. review the clinical scenario of autoantibody positivity in ILD and discuss how these serologic tests may be interpreted.(4) In addition, they provide useful insights into the evaluation of patients with ILD suspected of having occult forms of CTD. Finally, the authors argue in favor of implementing the concepts that have been put forth in a recent commentary on “lung-dominant CTD”(5): a proposed, provisional category that describes ILD patients with an autoimmune flavor that fall short of meeting established criteria of any of the characterizable forms of CTD. Identifying occult CTD in patients presenting with what is initially considered to be an idiopathic interstitial pneumonia (IIP) can be challenging. Sometimes patients that subsequently develop a classifiable CTD cannot be identified before the specific systemic manifestations of the CTD appear. There is no universally accepted approach to these evaluations, and current practice includes an assessment for extrathoracic features of CTD, testing of a broad array of circulating autoantibodies, and consideration of specific radiographic and histopathologic features.(2,6) Various centers have also found that a multidisciplinary evaluation—including rheumatologic consultation—can be useful.(7-9) A number of recent studies have shown that patients with IIP often have subtle extrathoracic or other clinical features suggestive of an underlying autoimmune process and yet do not meet established criteria for any of the characterizable forms of CTD.(9-17) Sometimes these subtle symptoms or signs occur in the absence of serologic abnormalities, or a serum autoantibody known to be highly specific for a certain CTD (e.g. anti-Jo-1 with the antisynthetase syndrome) may be present without typical systemic or extrathoracic features. Other scenarios exist whereby specific radiologic or histopathologic features are suggestive of an underlying CTD and yet the absence of extrathoracic or serologic findings precludes reliable classification as CTD-ILD. In an area without consensus regarding terminology, the terms “undifferentiated CTD” (UCTD),(10,16) “lung-dominant CTD”(5) and “autoimmune-featured ILD”(17) have been used to describe such patients with suggestive forms of CTD-ILD. Each of these categories has a unique set of proposed criteria, represent the ideas of investigative teams from distinct ILD referral centers, and have yet to be prospectively validated.

Interpretation of autoantibody positivity in interstitial lung disease and lung-dominant connective tissue disease

The initial evaluation of patients with interstitial lung disease (ILD) primarily involves a comprehensive, active search for the cause. Autoantibody assays, which can suggest the presence of a rheumatic disease, are routinely performed at various referral centers. When interstitial lung involvement is the condition that allows the definitive diagnosis of connective tissue disease and the classical criteria are met, there is little debate. However, there is still debate regarding the significance, relevance, specificity, and pathophysiological role of autoimmunity in patients with predominant pulmonary involvement and only mild symptoms or formes frustes of connective tissue disease. The purpose of this article was to review the current knowledge of autoantibody positivity and to discuss its possible interpretations in patients with ILD and without clear etiologic associations, as well as to enhance the understanding of the natural history of an allegedly new disease and to describe the possible prognostic implications. We also discuss the proposition of a new term to be used in the classification of ILDs: lung-dominant connective tissue disease.

Successful Treatment with Tacrolimus in a Case of Lung-dominant Connective Tissue Disease

A 49-year-old man with dyspnea was found to have reticular opacities and ground-glass attenuation with traction bronchiectasis or bronchiolectasis on computed tomography. The patient met the criteria for lung-dominant connective tissue disease (LD-CTD) and histopathologically exhibited a chronic fibrotic interstitial pneumonia illustrating framework of a usual interstitial pneumonia-like pattern. Due to worsening of the disease, therapy was initiated with corticosteroids in combination with cyclosporine A. However, treatment with these drugs was ineffective. Pirfenidone and intravenous cyclophosphamide therapy also proved ineffective. The cyclosporine A was therefore switched to tacrolimus, and the patient's disease improved, allowing for a reduction in the dose of the corticosteroids. Our experience in this case suggests that treatment with tacrolimus might be useful for treating refractory LD-CTD even when histopathologically chronic fibrotic interstitial pneumonia is evident.

Comparison of three groups of patients with usual interstitial pneumonia

To determine the clinical characteristics and outcomes of patients with lungdominant connective tissue disease (LD-CTD) with a usual interstitial pneumonia (UIP) who do not meet the criteria for any form of CTD, and to compare these parameters with those of patients with idiopathic pulmonary fibrosis (IPF/UIP) and CTD-associated-UIP. We conducted a prospective study on 118 patients diagnosed with UIP [LD-CTD, n=28; CTDUIP, n=29; and IPF/UIP, n=61]. We compared the clinical characteristics, physiological findings, serum albumin concentrations, high-resolution computed tomography (HRCT) imaging data, and outcomes among the three groups and used Cox's proportional hazards regression analysis to identify variables associated with an increased risk of death. The LD-CTD and CTD-UIP patients were younger, more often female, and predominantly nonsmokers, compared with the IPF/UIP group. A significant difference in survival was evident between patients in the CTD-UIP and IPF/UIP groups (p=0.028), but not between LD-CTD and IPF/UIP (p=0.164) or between LD-CTD and CTD-UIP (p=0.254). The variables associated with poorer survival in all UIP patients were (reduced) initial SpO2 level (hazard ratio [HR], 2.89; 95% confidence interval [CI] 2.1-3.7; p=0.009) and lower serum albumin concentration (HR 2.16; 95% CI 1.6-2.7; p=0.008). LD-CTD has distinct clinical characteristics that suggest an autoimmune background resembling that of CTD-UIP but differing from that of IPF/UIP. However, LD-CTD with a UIP pattern was not associated with improved survival. The resting oxygen saturation level and serum albumin concentration were independent predictors of mortality in all of the studied UIP patients, regardless of UIP type.