Autoimmune Interstitial Lung Disease Research Articles

Quantification of autoantibodies using a luminescent profiling method in autoimmune interstitial lung disease.

Autoantibodies are important for the diagnosis of autoimmune interstitial lung disease (ILD). Standard immunoassays have limitations, including their qualitative nature and/or a narrow dynamic range of detection, hindering the usefulness of autoantibodies as biomarkers of disease activity. Here, the luciferase immunoprecipitation system (LIPS) was evaluated for measuring myositis-specific and other lung-related autoantibodies in 25 subjects with idiopathic inflammatory myopathies (IIM), 26 with Sjögren's disease (SjD), and 10 healthy volunteers. LIPS detected a broad dynamic range of autoantibodies, to MDA5, Jo-1, PL12, KS, U1-70K, and Ro52, and matched seropositivity status with established immunoassays. Robust anti-MDA5 autoantibodies in four IIM-ILD patients had a median value of 1,134,000 LU (IQR 473,000-2,317,000), which was 500 times higher than in 21 seronegative IIM patients. Markedly elevated anti-Jo-1 autoantibodies in five IIM-ILD patients demonstrated a median value of 1,177,000 LU (IQR: 604,000-2,520,000), which was 1000-fold higher than in seronegative patients. Robust anti-Ro52 and other anti-tRNA-synthetase autoantibodies were detected in a subset of IIM-ILD subjects. In SjD, only anti-U1-70K and KS autoantibodies were identified in ILD patients with a prevalence of 30% and 20%, respectively. In longitudinal samples of five IIM-ILD patients, anti-Jo-1 autoantibody levels paralleled clinical improvement of lung function. LIPS can accurately quantify autoantibody levels as biomarkers for treatment response in patients with autoimmune ILD.

Health care costs and utilization of progressive fibrosing lung disease by underlying interstitial lung disease type.

Fibrosing interstitial lung disease (ILD) encompasses more than 200 diverse pulmonary disorders, of which up to 40% become progressive. The 4 underlying ILD types most likely to result in progression are unclassified ILD/idiopathic interstitial pneumonia (IIP), autoimmune ILDs, exposure-related ILD/hypersensitivity pneumonitis, and sarcoidosis. To compare health care resource utilization (HCRU) and costs among patients with fibrosing ILD that has progressed ("progressive" fibrosing cohort) vs patients whose fibrosis did not meet criteria set for progression ("not yet progressed" cohort). This was a noninterventional study of commercial enrollees and Medicare Advantage with Part D beneficiaries, which used administrative claims data for the period from October 1, 2015, through May 31, 2021. Adult patients (aged ≥18 years) with fibrosing ILD and 12 months of continuous health plan enrollment were included. Patients with idiopathic pulmonary fibrosis, baseline ILD diagnoses, or missing demographic data were excluded. Patients were first classified according to the underlying type of fibrosing ILD. For statistical analyses of outcomes, 2 cohorts were compared within each subtype: progressive fibrosing ILD vs not yet progressed ILD. The final study population included propensity score-matched (PSM) patients (1:1) based on pre-ILD baseline demographic and clinical characteristics. HCRU categories included inpatient hospitalization counts and the number of inpatient days and total costs (in 2021 US dollars), analyzed descriptively and weighted by the per-patient-per-month cost. Lin's regression was used to predict 12-month total cost estimates for comparison by cohort. The distribution by underlying conditions was as follows: autoimmune ILD (n = 4,156), HP (n = 8,181), sarcoidosis (n = 775), and unclassified ILD/IIP (n = 18,635). After PSM, pre-ILD baseline variables were generally well balanced between the progressive and not yet progressed fibrosing ILD cohorts. For all underlying subtypes of ILD, patients in the progressive cohort had significantly more utilization and higher costs compared with patients in the not yet progressed cohort. Progressive cohorts had significantly higher adjusted rates of inpatient days among patients with at least 1 inpatient stay compared with the not yet progressed cohorts (all P < 0.01). In addition, the progressive cohorts had significantly higher adjusted 12-month total costs, with the differences ranging from $24,493 to $55,072 (all comparisons P < 0.001). Irrespective of underlying ILD type, patients with progressive fibrosing ILD had significantly increased HCRU and cost relative to those whose fibrosing ILD had not yet progressed.

Assessment of therapeutic benefit obtained on administering nintedanib with respect to pulmonary function parameters in COVID-induced pulmonary fibrosis – A prospective study

Background: The COVID-19 infection has not only affected the patients in the acute phase but also has left several long-term sequels which are becoming clinically evident in the long run. The development of pulmonary fibrosis following recovery from COVID-19 is presently a cause of concern worldwide. Fibrosis of the lungs is a long-term ongoing inflammatory disorder which causes functional impairment and chronic pulmonary insufficiency. It is observed that the profibrotic mechanisms responsible for causing post-COVID lung fibrosis have some resemblance with that of autoimmune interstitial lung disease (ILD). Nintedanib, a tyrosine kinase inhibitor, is reported to block the profibrotic cytokine receptors. It is thus being administered widely for disease modification in idiopathic pulmonary fibrosis, a progressive and fatal form of ILD. Aims and Objectives: The present study tries to establish that nintedanib has a therapeutic role to prevent lung function impairment in the post-recovery pulmonary fibrosis patients of COVID-19 disease. Materials and Methods: 50 adult patients having fibrotic changes in the computed tomography scan of the chest, following recovery from coronavirus disease, were chosen. They were divided into two categories. Both the categories were given the treatment of lung fibrosis as per the standard regimen. In addition, only one of the categories received the recommended dose of nintedanib. A pulmonary function test (PFT) was performed on the patients of both categories on day 1 and day 90. A comparison of the PFT variables was done by statistical analysis. Results: The PFT parameters of both groups were similar on day 1. On day 90, most of the spirometry variables of the patients administered with nintedanib along with the standard treatment regimen showed statistically significant improvement with respect to the values on day 1. The lung function test variables of the group receiving nintedanib were also significantly better than those not receiving it, as observed on day 90. Conclusion: As the spirometry variables of the patients following recovery of coronavirus disease with confirmed fibrosis of the lungs showed significant improvement after receiving nintedanib, it can be concluded that nintedanib may be useful in treating such cases.

Role of the occupational disease consultant in the multidisciplinary discussion of interstitial lung diseases.

Diffuse interstitial lung diseases (ILD) constitute a heterogeneous group of conditions with complex etiological diagnoses requiring a multidisciplinary approach. Much is still unknown about them, particularly their relationship with occupational exposures. The primary objective of this study was to investigate the distribution of occupational exposures according to type of ILD. The secondary objectives were to estimate the proportion of ILDs possibly related to occupational exposure and to evaluate the added value of the participation of an occupational disease consultant in ILD multidisciplinary discussions (MDD). From May to December 2020, all consecutive patients with ILD whose cases were reviewed during a MDD in a referral centre for ILD were prospectively offered a consultation with an occupational disease consultant. Of the 156 patients with ILD whose cases were reviewed in MDD during the study period, 141 patients attended an occupational exposure consultation. Occupational exposure was identified in 97 patients. Occupational exposure to asbestos was found in 12/31 (38.7%) patients with idiopathic pulmonary fibrosis (IPF) and in 9/18 (50.0%) patients with unclassifiable fibrosis. Occupational exposure to metal dust was found in 13/31 (41.9%) patients with IPFs and 10/18 (55.6%) patients with unclassifiable fibrosis. Silica exposure was found in 12/50 (24.0%) patients with autoimmune ILD. The link between occupational exposure and ILD was confirmed for 41 patients after the specialist occupational consultation. The occupational origin had not been considered (n = 9) or had been excluded or neglected (n = 4) by the MDD before the specialised consultation. A total of 24 (17%) patients were advised to apply for occupational disease compensation, including 22 (15.6%) following the consultation. In addition, a diagnosis different from the one proposed by the MDD was proposed for 18/141 (12.8%) patients. In our study, we found a high prevalence of occupational respiratory exposure with a potential causal link in patients with ILD. We suggest that a systematic specialised consultation in occupational medicine could be beneficial in the ILD diagnostic approach.

Care patterns of patients with chronic fibrosing interstitial lung disease (ILD) with a progressive phenotype

BackgroundInterstitial lung diseases (ILDs) include a variety of parenchymal lung diseases. The most common types of ILDs are idiopathic pulmonary fibrosis (IPF), autoimmune ILDs and hypersensitivity pneumonitis (HP). There is limited real world data on care patterns of patients with chronic fibrosing ILDs with a progressive phenotype other than IPF. Therefore, the aim of this study is to describe care patterns in these patients.MethodsThis retrospective cohort study used claims data from 2015 to 2019 from the Optum Research Database. The study population included adults (≥ 18 years old) with at least two diagnosis codes for fibrosing ILD during the identification period (1OCT2016 to 31DEC2018). A claim-based algorithm for disease progression was used to identify patients likely to have a progressive fibrotic phenotype using progression proxies during the identification period. Index date was the first day of progression proxy identification after fibrosing ILD diagnosis. Patients were required to have continuous enrollment for 12 months before (baseline) and after (follow-up) index date. Patients with an IPF diagnosis were excluded. Descriptive statistics were used to describe the patient population and care patterns.Results11,204 patients were included in the study. Mean age of the patient population was 72.7 years, and 54.5% were female. Unclassified ILDs (48.0%), HP (25.2%) and autoimmune ILDs (16.0%) were the most common ILD types. Other respiratory conditions were prevalent among patients including chronic obstructive pulmonary disease (COPD) (58.9%), obstructive sleep apnea (OSA) (25.0%) and pulmonary hypertension (9.8%). During baseline, 65.3% of all patients had at least one pulmonology visit, this proportion was higher during follow-up, at 70.6%. Baseline and follow-up use for HRCT were 39.9% and 48.8%, and for pulmonary function tests were 43.7% and 48.5% respectively. Use of adrenal corticosteroids was higher during follow-up than during baseline (62.5% vs. 58.0%). Anti-inflammatory and immunosuppressive medication classes were filled by a higher percentage of patients during follow-up than during baseline.ConclusionsComprehensive testing is essential for diagnosis of a progressive phenotype condition, but diagnostic tests were underutilized. Patients with this condition frequently were prescribed anti-inflammatory and immunosuppressive medications.

Mortality Risk From COVID-19 Among Unvaccinated Subjects With Autoimmune Phenotypes of Interstitial Lung Disease.

Background: The impact of the severe acute respiratory syndrome-associated coronavirus 2 (SARS-CoV-2) virus on patients with interstitial lung disease (ILD) remains poorly understood. As patients with ILD often have severe underlying lung parenchymal involvement, and immunosuppressive therapy is common in this population, they are presumed to be at high risk for severe coronavirus disease 2019 (COVID-19) pneumonitis. Our aim was to explore demographic and clinical differences between those with ILD who tested positive for the SARS-CoV-2 virus compared to those with ILD who did not.Methods: In this retrospective cohort study, we identified adult, unvaccinated patients evaluated at the University of Chicago in 2020 who were enrolled in the ILD registry, and stratified by SARS-CoV-2 seropositive status. We then compared baseline clinical characteristics between SARS-CoV-2 seropositive and SARS-CoV-2 seronegative patients and assessed immunosuppressive therapy that the patient may have been on since ILD diagnosis. C-reactive protein and leukocyte subsets were evaluated at COVID diagnosis compared to the time of baseline ILD evaluation as were pulmonary function testing. Variable comparisons were determined by two-sided t-tests or chi-square tests as appropriate, and logistic regression models were fitted to assess the odds of death from COVID-19 using generalized linear models with maximum-likelihood estimation.Results: Of the 309 individuals with ILD in our cohort, 6.8% (n=21) tested positive for SARS-CoV-2. Those who were SARS-CoV-2 positive were younger (57 years vs 66 years; P=0.002), had baseline higher total lung capacity (81% vs 73%, P=0.045), similar forced vital capacity (71% vs. 67%, P=0.37), and similar diffusion capacity of carbon monoxide (71% vs. 62%, P=0.10) at baseline. Among patients with ILD and COVID-19, 67% had received immunosuppressive therapies compared to 74% of those with ILD without COVID-19. Those with ILD and COVID-19 were also more likely to have had a diagnosis of autoimmune-related ILD (connective tissue disease-ILD or interstitial pneumonia with autoimmune features) (62% vs 38%, P=0.029). Overall, the mortality hazard was highest among unvaccinated subjects with autoimmune-related ILD who had COVID-19 (OR=9.6, 95% CI=1.7-54.0; P=0.01).Discussion: SARS-CoV-2 is prevalent in ILD, and may put unvaccinated adults who are younger, with autoimmune ILD, and on immunosuppressive therapy at higher risk. This suggests a need for COVID-19 vaccinations and therapy (inpatient and outpatient) for this group of patients at high risk for COVID-19. Larger studies are needed to fully explore the relationship between ILD and immunosuppressive therapy in COVID-19.

Clinical Overview of Progressive Fibrotic Interstitial Lung Disease.

Interstitial lung diseases (ILD) on the whole have variable prognoses, but there are those which manifest with fibrosis and are characterized by disease progression. Chief among these is idiopathic pulmonary fibrosis, but other ILDs, including autoimmune ILD and chronic hypersensitivity pneumonitis, may have a progressive fibrotic phenotype also. A usual interstitial pneumonia pattern of lung involvement is a prominent risk factor for such a course, suggesting shared fibrotic pathways that may be targeted by antifibrotic therapies. This brief review describes ILDs that are most commonly fibrotic, shared risk factors for development of PF-ILD, and evidence for antifibrotic use in their management.

Treatment of chronic fibrosing interstitial lung diseases

Interstitial lung diseases (ILD) refers to a large and heterogenous group of parenchymal lung disorders. It is difficult to diagnose and classify ILD. Nevertheless, accurate diagnosis of ILD is crucial for appropriate treatment selection and prediction of prognosis. Idiopathic pulmonary fibrosis (IPF), the most severe of the chronic forms of ILD, is defined as a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause. In addition to IPF, a subset of patients with ILD may develop progressive fibrotic changes in lungs. As pulmonary fibrosis progresses, lung function gradually deteriorates and respiratory symptoms worsen; besides, quality of life is also impaired. Progressive fibrosis is also associated with limited response to immunomodulatory thrapies and, potentially, early death. A progressive fibrosing phenotype of ILD (PF-ILD), a subtype of ILD, shows morphological similarities, common underlying pathophysiologic mechanisms, and consistently progressive worsening. PF-ILD include idiopathic nonspecific interstitial pneumonia, unclassifiable idiopathic interstitial pneumonia, autoimmune ILD, chronic sarcoidosis, chronic hypersensitivity pneumonitis and environmental lung diseases. Antifibrotic agents pirfenidone and nintedanib have showed positive results not only for IPF but also for PF-ILD. Immunosuppressive therapy can be used for some types of PF-ILD. If a patient with PF-ILD does not respond to conventional treatment, lung transplantation may be a treatment option. Clinical trials on the treatment of PF-ILD are actively underway. Therefore, over the course of the next several years, major advances in PF-ILD treatment can be expected.

Disparate Interferon Signaling and Shared Aberrant Basaloid Cells in Single-Cell Profiling of Idiopathic Pulmonary Fibrosis and Systemic Sclerosis-Associated Interstitial Lung Disease.

Idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-associated interstitial lung disease (SSc-ILD) differ in the predominant demographics and identified genetic risk alleles of effected patients, however both diseases frequently progress to respiratory failure and death. Contrasting advanced SSc-ILD to IPF provides insight to the role dysregulated immunity may play in pulmonary fibrosis. To analyze cell-type specific transcriptome commonalities and differences between IPF and SSc-ILD, we compared single-cell RNA-sequencing (scRNA-seq) of 21 explanted lung tissue specimens from patients with advanced IPF, SSc-ILD, and organ donor controls. Comparison of IPF and SSc-ILD tissue identified divergent patterns of interferon signaling, with interferon-gamma signaling upregulated in the SPP1 hi and FABP4 hi macrophages, cytotoxic T cells, and natural kill cells of IPF, while type I interferon signaling and production was upregulated in the corresponding SSc-ILD populations. Plasmacytoid dendritic cells were found in diseased lungs only, and exhibited upregulated cellular stress pathways in SSc-ILD compared to IPF. Alveolar type I cells were dramatically decreased in both IPF and SSc-ILD, with a distinct transcriptome signature separating these cells by disease. KRT5-/KRT17+ aberrant basaloid cells exhibiting markers of cellular senescence and epithelial-mesenchymal transition were identified in SSc-ILD for the first time. In summary, our study utilizes the enriched capabilities of scRNA-seq to identify key divergent cell types and pathways between IPF and SSc-ILD, providing new insights into the shared and distinct mechanisms between idiopathic and autoimmune interstitial lung diseases.

Post-COVID-19 pulmonary sequla: longterm follow up and management

Though it has been 8 months since the beginning of COVID-19 pandemic, number of cases and deaths are still seriously increasing. We still don't have enough evidence about the prognosis of patients who had COVID-19 pneumonia. In long term follow up we wonder if they will have rapid FVC decline, widespread fibrosis in computed tomography, loss in quality of life or increased mortality that we experience in idiopathic pulmonary fibrosis, chronic hypersensitivity pneumonia or autoimmune interstitial lung diseases. However, in elderly patients less severe dysfunction or non-progressive-fibrosis can cause morbidity and mortality. Therefore, if we consider millions of people who are affected by COVID-19, even a rare complication can cause serious health problem in social scale. Because of the importance of this issue randomized controlled trials should be rapidly planned on post-COVID fibrosis, COVID associated thrombosis, risk factors, prevention and treatment (1). In this review, the frequency, clinical importance, prevention and treatment of possible long-term sequels of COVID-19 pneumonia (pulmonary fibrosis, pulmonary embolism and pulmonary hypertension) will be discussed.

Expression of the Autoantigen Topoisomerase-1 is Enriched in the Lung Tissues of Patients With Autoimmune Interstitial Lung Disease: A Case Control Study.

BackgroundAmong the autoimmune rheumatic diseases, it is striking that autoantibodies targeting ubiquitously expressed proteins (eg, topoisomerase‐1) associate with specific clinical complications (eg, interstitial lung disease [ILD]). It has been proposed that enriched antigen expression in inflamed target tissue may play a role in focusing the autoimmune response. We sought to determine whether topoisomerase‐1 expression is enriched in lungs from patients with autoimmune/inflammatory diseases relative to normal lung.MethodsWe used a 99‐core lung tissue microarray (TMA) containing lung tissue from 40 patients with autoimmune inflammatory ILD (cases) and 46 control subjects with normal lungs. We stained the TMA with antibodies to compare topoisomerase‐1 and CD8 expression between patients and control subjects and evaluated whether expression is enriched in specific cell types. Staining was analyzed, and statistical comparisons were performed.ResultsCases were more likely to have global topoisomerase‐1 expression (53% vs 21%; P = 0.003), specifically in pneumocytes (47% vs 16%; P = 0.003) and stromal/immune cells (32% vs 5%; P = 0.002) compared with control subjects. CD8 cell density (223 cells/mm2 vs 102 cells/mm2; P = 0.018) was significantly higher in topoisomerase‐1–positive lung tissues compared with topoisomerase‐1–negative lung tissues. Interestingly, topoisomerase‐1 expression was significantly more common in scleroderma compared with normal lung (67% vs 21%; P = 0.036) and was present more frequently in pneumocytes in these patients (67% vs 16%; P = 0.018).ConclusionsPulmonary expression of topoisomerase‐1 is increased in the setting of autoimmune ILD relative to normal lung, specifically in pneumocytes. This may contribute to the amplification of pulmonary disease in patients with scleroderma with a loss of tolerance to topoisomerase‐1.

Circulating fibrocytes as prognostic biomarkers of autoimmune interstitial lung disease.

BackgroundAutoimmunity is a common cause of pulmonary fibrosis and can present either as a manifestation of an established connective tissue disease or as the recently described entity of interstitial pneumonia with autoimmune features. The rate of progression and responsiveness to immunosuppression in these illnesses are difficult to predict. Circulating fibrocytes are bone marrow-derived progenitor cells that home to injured tissues and contribute to lung fibrogenesis. We sought to test the hypothesis that the blood fibrocyte concentration predicts outcome and treatment responsiveness in autoimmune interstitial lung diseases.MethodsWe compared the concentration of circulating fibrocytes in 50 subjects with autoimmune interstitial lung disease and 26 matched healthy controls and assessed the relationship between serial peripheral blood fibrocyte concentrations and clinical outcomes over a median of 6.25 years.ResultsAs compared to controls, subjects with autoimmune interstitial lung disease had higher circulating concentrations of total fibrocytes, the subset of activated fibrocytes, and fibrocytes with activation of PI3K/AKT/mTOR, transforming growth factor-β (TGF-β) receptor and interleukin (IL)-4/IL-13 receptor signalling pathways. Over the follow-up period, there were episodes of marked elevation in the concentration of circulating fibrocytes in subjects with autoimmune interstitial lung disease but not controls. Initiation of immunosuppressive therapy was associated with a decline in the concentration of circulating fibrocytes. For each 100 000 cells·mL−1 increase in peak concentration of circulating fibrocytes, we found a 5% increase in odds of death or lung function decline.ConclusionIn patients with autoimmune interstitial lung disease, circulating fibrocytes may represent a biomarker of outcome and treatment response.

Nintedanib in patients with progressive fibrosing interstitial lung diseases—subgroup analyses by interstitial lung disease diagnosis in the INBUILD trial: a randomised, double-blind, placebo-controlled, parallel-group trial

The INBUILD trial investigated the efficacy and safety of nintedanib versus placebo in patients with progressive fibrosing interstitial lung diseases (ILDs) other than idiopathic pulmonary fibrosis (IPF). We aimed to establish the effects of nintedanib in subgroups based on ILD diagnosis. The INBUILD trial was a randomised, double-blind, placebo-controlled, parallel group trial done at 153 sites in 15 countries. Participants had an investigator-diagnosed fibrosing ILD other than IPF, with chest imaging features of fibrosis of more than 10% extent on high resolution CT (HRCT), forced vital capacity (FVC) of 45% or more predicted, and diffusing capacity of the lung for carbon monoxide (DLco) of at least 30% and less than 80% predicted. Participants fulfilled protocol-defined criteria for ILD progression in the 24 months before screening, despite management considered appropriate in clinical practice for the individual ILD. Participants were randomly assigned 1:1 by means of a pseudo-random number generator to receive nintedanib 150 mg twice daily or placebo for at least 52 weeks. Participants, investigators, and other personnel involved in the trial and analysis were masked to treatment assignment until after database lock. In this subgroup analysis, we assessed the rate of decline in FVC (mL/year) over 52 weeks in patients who received at least one dose of nintedanib or placebo in five prespecified subgroups based on the ILD diagnoses documented by the investigators: hypersensitivity pneumonitis, autoimmune ILDs, idiopathic non-specific interstitial pneumonia, unclassifiable idiopathic interstitial pneumonia, and other ILDs. The trial has been completed and is registered with ClinicalTrials.gov, number NCT02999178. Participants were recruited between Feb 23, 2017, and April 27, 2018. Of 663 participants who received at least one dose of nintedanib or placebo, 173 (26%) had chronic hypersensitivity pneumonitis, 170 (26%) an autoimmune ILD, 125 (19%) idiopathic non-specific interstitial pneumonia, 114 (17%) unclassifiable idiopathic interstitial pneumonia, and 81 (12%) other ILDs. The effect of nintedanib versus placebo on reducing the rate of FVC decline (mL/year) was consistent across the five subgroups by ILD diagnosis in the overall population (hypersensitivity pneumonitis 73·1 [95% CI -8·6 to 154·8]; autoimmune ILDs 104·0 [21·1 to 186·9]; idiopathic non-specific interstitial pneumonia 141·6 [46·0 to 237·2]; unclassifiable idiopathic interstitial pneumonia 68·3 [-31·4 to 168·1]; and other ILDs 197·1 [77·6 to 316·7]; p=0·41 for treatment by subgroup by time interaction). Adverse events reported in the subgroups were consistent with those reported in the overall population. The INBUILD trial was not designed or powered to provide evidence for a benefit of nintedanib in specific diagnostic subgroups. However, its results suggest that nintedanib reduces the rate of ILD progression, as measured by FVC decline, in patients who have a chronic fibrosing ILD and progressive phenotype, irrespective of the underlying ILD diagnosis. Boehringer Ingelheim.

Progressive fibrosing interstitial lung disease associated with systemic autoimmune diseases

Interstitial lung disease (ILD) is a common manifestation of systemic autoimmune diseases and a leading cause of death in these patients. A proportion of patients with autoimmune ILDs develop a progressive fibrosing form of ILD, characterized by increasing fibrosis on high-resolution computed tomography, worsening of lung function, and early mortality. Autoimmune disease–related ILDs have a variable clinical course and not all patients will require treatment, but all patients should be monitored for signs of progression. Apart from systemic sclerosis–associated ILD, the limited evidence to support the efficacy of immunosuppression as a treatment for ILDs is based mainly on small retrospective series and expert opinion. Non-clinical data suggest that there are commonalities in the mechanisms that drive progressive fibrosis in ILDs with an immunological trigger as in other forms of progressive fibrosing ILD. This suggests that nintedanib and pirfenidone, drugs known to slow disease progression in patients with idiopathic pulmonary fibrosis, may also slow the progression of ILD associated with systemic autoimmune diseases. In the SENSCIS® trial, nintedanib reduced the rate of ILD progression in patients with systemic sclerosis–associated ILD. The results of other large clinical trials will provide further insights into the role of anti-fibrotic therapies in the treatment of autoimmune disease–related ILDs.

PINK1 attenuates mtDNA release in alveolar epithelial cells and TLR9 mediated profibrotic responses.

We have previously shown that endoplasmic reticulum stress (ER stress) represses the PTEN inducible kinase 1 (PINK1) in lung type II alveolar epithelial cells (AECII) reducing mitophagy and increasing the susceptibility to lung fibrosis. Although increased circulating mitochondrial DNA (mtDNA) has been reported in chronic lung diseases, the contribution of mitophagy in the modulation of mitochondrial DAMP release and activation of profibrotic responses is unknown. In this study, we show that ER stress and PINK1 deficiency in AECII led to mitochondrial stress with significant oxidation and damage of mtDNA and subsequent extracellular release. Extracellular mtDNA was recognized by TLR9 in AECII by an endocytic-dependent pathway. PINK1 deficiency-dependent mtDNA release promoted activation of TLR9 and triggered secretion of the profibrotic factor TGF-β which was rescued by PINK1 overexpression. Enhanced mtDNA oxidation and damage were found in aging and IPF human lungs and, in concordance, levels of circulating mtDNA were significantly elevated in plasma and bronchoalveolar lavage (BAL) from patients with IPF. Free mtDNA was found elevated in other ILDs with low expression of PINK1 including hypersensitivity pneumonitis and autoimmune interstitial lung diseases. These results support a role for PINK1 mediated mitophagy in the attenuation of mitochondrial damage associated molecular patterns (DAMP) release and control of TGF-β mediated profibrotic responses.

Autoimmune interstitial lung disease in Latin-America

Information about the prognosis and natural history of autoimmune interstitial lung diseases (Ai-ILD) is limited. The aim of the study was to evaluate the characteristics of patients diagnosed with Ai-ILD in Latin-America. We conducted an ambispective multicenter cohort study in 25 centers of Argentina, Colombia, and Uruguay between January 2015 and April 2018. Participants were included in the study if they had diagnosis of Ai-ILD performed by a multidisciplinary team. Patients were classified into the following sub-groups: connective tissue disease-associated ILD (ILD-CTD), interstitial pneumonia with autoimmune features (IPAF), and positive antineutrophils cytoplasmatic antibodies associated ILD (ILD-ANCA). All images were reviewed by a blinded thoracic radiologist. Out of the 381 patients included during the study period, 282 (74%; 95% CI; 69.39–78.16) were women. Mean age was 58 years old (SD 16). Three-hundred and twenty-five (85.1%; 95% CI 81.39–88.5) patients were classified as ILD-CTD (rheumatoid arthritis 31%, systemic sclerosis 29%, dermatomyositis 15%). Thirty-six patients were classified as IPAF (9.5%; 95% CI 6.9–12.8), and 13 (3.5%; 95% CI 2–5.75) as ILD-ANCA. Fifty percent of patients (95% CI 45.12–55.43) had a mild decrease of the forced vital capacity at the time of diagnosis. The most common treatment strategy was the combination of steroids and cyclophosphamide (30.1%; 95% CI 25.32–35.34) followed by azathioprine (20,3%; 95% CI 16.32–25.14). In conclusion, to the best of our knowledge, this is the first study to evaluate the characteristics and treatment strategies used in patients affected by Ai-ILD in Latin-America. Future studies should to evaluate the prognosis and impact of current treatment strategies in patients with Ai-ILD.

Signal transducer and activator of transcription gain-of-function primary immunodeficiency/immunodysregulation disorders.

To describe primary immunodeficiencies caused by gain-of-function (GOF) mutations of signal transducer and activator of transcription (STAT) genes, a group of genetically determined disorders characterized by susceptibility to infections and, in many cases, autoimmune manifestations. GOF mutations affecting STAT1 result in increased STAT tyrosine phosphorylation and secondarily increased response to STAT1-signaling cytokines, such as interferons. In contrast, STAT3 hyperactivity is not usually related to hyperphosphorylation but rather to increased STAT3-mediated transcriptional activity. In both cases, heterozygous STAT1 and STAT3 GOF mutations trigger a distinct set of genes in target cells that lead to abnormal functioning of antimicrobial response and/or autoimmunity and result in autosomal dominant diseases. Clinical manifestations of patients with STAT1 GOF are characterized by mucocutaneous candidiasis and recurrent lower tract respiratory infections. In addition, many patients have thyroiditis, type 1 diabetes mellitus, autoimmune cytopenias, cancer or aneurysms. Patients with germline STAT3 GOF mutations have an increased frequency of early-onset multiorgan autoimmunity (i.e. autoimmune enteropathy, type 1 diabetes mellitus, autoimmune interstitial lung disease and autoimmune cytopenias), lymphoproliferation, short stature and, less frequently, severe recurrent infections. Treatment options range from antimicrobial therapy, intravenous or subcutaneous immunoglobulin and immunosuppressive drugs. Some patients with STAT1 GOF disorder have undergone hematopoietic stem cell transplantation, although these have been difficult because of the underlying proinflammatory milieu from the mutation.

COPA syndrome in an Icelandic family caused by a recurrent missense mutation in COPA

BackgroundRare missense mutations in the gene encoding coatomer subunit alpha (COPA) have recently been shown to cause autoimmune interstitial lung, joint and kidney disease, also known as COPA syndrome, under a dominant mode of inheritance.Case presentationHere we describe an Icelandic family with three affected individuals over two generations with a rare clinical presentation of lung and joint disease and a histological diagnosis of follicular bronchiolitis. We performed whole-genome sequencing (WGS) of the three affected as well as three unaffected members of the family, and searched for rare genotypes associated with disease using 30,067 sequenced Icelanders as a reference population. We assessed all coding and splicing variants, prioritizing variants in genes known to cause interstitial lung disease. We detected a heterozygous missense mutation, p.Glu241Lys, in the COPA gene, private to the affected family members. The mutation occurred de novo in the paternal germline of the index case and was absent from 30,067 Icelandic genomes and 141,353 individuals from the genome Aggregation Database (gnomAD). The mutation occurs within the conserved and functionally important WD40 domain of the COPA protein.ConclusionsThis is the second report of the p.Glu241Lys mutation in COPA, indicating the recurrent nature of the mutation. The mutation was reported to co-segregate with COPA syndrome in a large family from the USA with five affected members, and classified as pathogenic. The two separate occurrences of the p.Glu241Lys mutation in cases and its absence from a large number of sequenced genomes confirms its role in the pathogenesis of the COPA syndrome.

Progressive respiratory distress in a 42-year-old HIV-positive woman with systemic lupus erythematosus

BackgroundIdentifying and treating the cause of pulmonary symptoms in HIV patients with underlying systemic lupus erythematosus (SLE) can be very challenging. Delays in diagnosing active SLE in HIV patients can lead to significant morbidity and even mortality. We report the case of an HIV-positive woman with SLE who presented with severe respiratory distress.Case presentationA 42-year-old HIV-positive woman presented with a 7-month history of anorexia, progressive dyspnoea, and a productive cough. She had been put on treatment for pulmonary tuberculosis and pneumocystis jiroveci pneumonia for several months by the referring hospital without any significant improvement in her symptoms. Her initial laboratory investigations showed highly elevated d-dimer test results but confirmatory investigations for pulmonary embolism proved otherwise. An autoimmune screen revealed highly positive antinuclear antibody and anti-double-stranded DNA tests, and she responded very well to SLE treatment.ConclusionsOur case represents a situation where two diseases with antagonizing pathways of disease pathogenesis occur concurrently in the same patient. SLE is usually not among the differential diagnoses in HIV patients with respiratory distress. Management of patients with both SLE and HIV is also very challenging because improvement in one condition can lead to worsening of the other. Despite opportunistic infections being the likely cause of pulmonary symptoms in HIV patients, clinicians are encouraged to have a high index of suspicion for autoimmune interstitial lung disease in these patients.

Autoantibodies against BPI fold containing family B member 1 (BPIFB1) to diagnose autoimmune interstitial lung disease (ILD)

Autoantibodies against BPI fold containing family B member 1 (BPIFB1) to diagnose autoimmune interstitial lung disease (ILD)