Comparison of Effects of Sugammadex and Neostigmine on Postoperative Neuromuscular Blockade Recovery in Patients with Interstitial Lung Diseases Undergoing Transbronchial Cryobiopsy: A Randomized Trial.

BACKGROUND While many studies have been conducted on sugammadex sodium and neostigmine in patients undergoing general anesthesia, few have explored their effects in patients with interstitial lung diseases (ILDs). MATERIAL AND METHODS Sixty-three patients who underwent transbronchial cryobiopsy under general anesthesia were enrolled in a prospective randomized study. The patients were randomly divided into 2 groups: neostigmine combined with atropine group (group C, n=32) and sugammadex group (group S, n=31). Induction and maintenance of anesthesia were the same in both groups. Patients received rocuronium during anesthesia. At the end of the procedure, when the T2 of the train-of-four stimulation technique (TOF) monitoring appeared, neostigmine 0.04 mg/kg combined with atropine 0.02 mg/kg was injected intravenously in group C, and sodium sugammadex 2 mg/kg was injected intravenously in group S. Time from administration of muscle relaxant antagonist to recovery of TOF ratio (TOFr) to 0.9 and extubation time were recorded. The residual rate of neuromuscular blockade at 1, 3, 5, 7, and 10 min after extubation was calculated. RESULTS Compared to group C, group S had a significantly shorter recovery time of TOFr to 0.9 (4.0[2.0] min vs 14.0[11.0] min, P<0.001) and extubation time (4.0[3.0] min vs 11.0[7.0] min, P<0.001). The residual rate of neuromuscular blockade was remarkably lower in group S than in group C at 3, 5, and 7 min after extubation (3.2% vs 31%, 0% vs 25%, 0% vs 6%, P<0.05). CONCLUSIONS Sugammadex is more effective than neostigmine in reversing the muscle-relaxant effect of rocuronium bromide in patients with ILDs.

Resveratrol attenuates inflammation and fibrosis in rheumatoid arthritis-associated interstitial lung disease via the AKT/TMEM175 pathway.

BACKGROUND AND PURPOSE: Interstitial lung disease (ILD) represents a significant complication of rheumatoid arthritis (RA) that lacks effective treatment options. This study aimed to investigate the intrinsic mechanism by which resveratrol attenuates rheumatoid arthritis complicated with interstitial lung disease through the AKT/TMEM175 pathway. METHODS: We established an arthritis model by combining chicken type II collagen and complete Freund's adjuvant. Resveratrol treatment was administered via tube feeding for 10 days. Pathological changes in both the joints and lungs were evaluated using HE and Masson staining techniques. Protein expression of TGF-ß1, AKT, and TMEM175 was examined in lung tissue. MRC-5 cells were stimulated using IL-1ß in combination with TGF-ß1 as an in vitro model of RA-ILD, and agonists of AKT, metabolic inhibitors, and SiRNA of TMEM175 were used to explore the regulation and mechanism of action of resveratrol RA-ILD. RESULTS: Resveratrol mitigates fibrosis in rheumatoid arthritis-associated interstitial lung disease and reduces oxidative stress and inflammation in RA-ILD. Furthermore, resveratrol restored cellular autophagy. When combined with the in vitro model, it was further demonstrated that resveratrol could suppress TGF-ß1 expression, and reduce AKT metamorphic activation, consequently inhibiting the opening of AKT/MEM175 ion channels. This, in turn, lowers lysosomal pH and enhances the fusion of autophagosomes with lysosomes, ultimately ameliorating the progression of RA-ILD. CONCLUSION: In this study, we demonstrated that resveratrol restores autophagic flux through the AKT/MEM175 pathway to attenuate inflammation as well as fibrosis in RA-ILD by combining in vivo and in vitro experiments. It further provides a theoretical basis for the selection of therapeutic targets for RA-ILD.

Current pharmacotherapies for advanced lung cancer with pre-existing interstitial lung disease : A literature review and future perspectives.

Patients with interstitial lung disease (ILD), especially those with idiopathic pulmonary fibrosis, are at increased risk of developing lung cancer (LC). Pharmacotherapy for advanced LC has dramatically progressed in recent years;however, management of LC with pre-existing ILD (LC-ILD) is challenging due to serious concerns about the risk of acute exacerbation of ILD (AE-ILD). As patients with LC-ILD have been excluded from most prospective clinical trials of advanced LC, optimal pharmacotherapy remains to be elucidated. Although the antitumor activity of first-line platinum-based cytotoxic chemotherapy appears to be similar in advanced LC patients with or without ILD, its impact on the survival of patients with LC-ILD is limited. Immune checkpoint inhibitors may hold promise for long-term survival, but many challenges remain, including safety and appropriate patient selection. Further understanding the predictive factors for AE-ILD after receiving pharmacotherapy in LC-ILD may lead to appropriate patient selection and lower treatment risk. The aim of this review was to summarize the current evidence related to pharmacotherapy for advanced LC-ILD and discuss emerging areas of research. J. Med. Invest. 71 : 9-22, February, 2024.

Impact of DMARD treatment and systemic inflammation on all-cause mortality in patients with rheumatoid arthritis and interstitial lung disease: a cohort study from the German RABBIT register.

OBJECTIVES: To investigate the impact of disease activity and treatment with disease-modifying antirheumatic drugs (DMARDs) on all-cause mortality in patients with rheumatoid arthritis and prevalent interstitial lung disease (RA-ILD). METHODS: Patients with RA-ILD were selected from the biologics register Rheumatoid Arthritis: Observation of Biologic Therapy (RABBIT). Using time-varying Cox regression, the association between clinical measures and mortality was investigated. The impact of DMARDs was analysed by (1) Cox regression considering cumulative exposure (ie, treatment months divided by total months) and (2) time-varying Cox regression as main approach (treatment exposures at monthly level). RESULTS: Out of 15 566 participants, 381 were identified as RA-ILD cases with 1258 person-years of observation and 2.6 years median length of follow-up. Ninety-seven patients (25.5%) died and 34 (35.1%) of these were not receiving DMARD therapy at the time of death. Higher inflammatory biomarkers but not swollen and tender joint count were significantly associated with mortality. Compared with tumour necrosis factor inhibitors (TNFi), non-TNFi biologic DMARDs (bDMARDs) exhibited adjusted HRs (aHRs) for mortality below 1, lacking statistical significance. This finding was stable in various sensitivity analyses. Joint aHR for non-TNFi biologics and JAKi versus TNFi was 0.56 (95% CI 0.33 to 0.97). Receiving no DMARD treatment was associated with a twofold higher mortality risk compared with receiving any DMARD treatment, aHR 2.03 (95% CI 1.23 to 3.35). CONCLUSIONS: Inflammatory biomarkers and absence of DMARD treatment were associated with increased risk of mortality in patients with RA-ILD. Non-TNFi bDMARDs may confer enhanced therapeutic benefits in patients with RA-ILD.

A case of autoimmune pulmonary alveolar proteinosis during the course of treatment of rapidly progressive interstitial pneumonia associated with anti-MDA5 antibody-positive dermatomyositis.

BACKGROUND: Autoimmune pulmonary alveolar proteinosis (APAP) is a diffuse lung disease that causes abnormal accumulation of lipoproteins in the alveoli; however, its pathogenesis remains unclear. Recently, APAP cases have been reported during the course of dermatomyositis. The combination of these two diseases may be coincidental; however, it may have been overlooked because differentiating APAP from a flare-up of interstitial pneumonia associated with dermatomyositis is challenging. This didactic case demonstrates the need for early APAP scrutiny. CASE PRESENTATION: A 50-year-old woman was diagnosed with anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibody-positive dermatitis and interstitial pneumonia in April 2021. The patient was treated with corticosteroids, tacrolimus, and cyclophosphamide pulse therapy for interstitial pneumonia complicated by MDA5 antibody-positive dermatitis, which improved the symptoms and interstitial pneumonia. Eight months after the start of treatment, a new interstitial shadow appeared that worsened. Therefore, three additional courses of cyclophosphamide pulse therapy were administered; however, the respiratory symptoms and interstitial shadows did not improve. Respiratory failure progressed, and 14 months after treatment initiation, bronchoscopy revealed turbid alveolar lavage fluid, numerous foamy macrophages, and numerous periodic acid-Schiff-positive unstructured materials. Blood test results revealed high anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antibody levels, leading to a diagnosis of APAP. The patient underwent whole-lung lavage, and the respiratory disturbance promptly improved. Anti-GM-CSF antibodies were measured from the cryopreserved serum samples collected at the time of diagnosis of anti-MDA5 antibody-positive dermatitis, and 10 months later, both values were significantly higher than normal. CONCLUSIONS: This is the first report of anti-MDA5 antibody-positive dermatomyositis complicated by interstitial pneumonia with APAP, which may develop during immunosuppressive therapy and be misdiagnosed as a re-exacerbation of interstitial pneumonia. In anti-MDA5 antibody-positive dermatomyositis, APAP comorbidity may have been overlooked, and early evaluation with bronchoalveolar lavage fluid and anti-GM-CSF antibody measurements should be considered, keeping the development of APAP in mind.

Prevalence and prognostic meaning of interstitial lung abnormalities in remote CT scans of patients with interstitial lung disease treated with antifibrotic therapy.

OBJECTIVES: To describe the prevalence and characteristics of interstitial lung abnormalities (ILA) in CT scans performed prior to the initiation of antifibrotics in a series of patients with interstitial lung disease (ILD), and to identify characteristics apparent on early CT scans that could help to predict outcomes. METHODS: We conducted a retrospective observational study. The original cohort consisted of 101 patients diagnosed with ILD and treated with antifibrotics in a tertiary hospital. Patients were included if they had a thoracic CT scan performed at least one year before initiation of therapy. They were classified radiologically in three groups: without ILA, with radiological ILA and extensive abnormalities. ILA were classified as subpleural fibrotic, subpleural non-fibrotic and non-subpleural. The initial scan and the latest CT scan performed before treatment were read for assessing progression. The relationship between CT findings of fibrosis and the radiological progression rate and mortality were analyzed. RESULTS: We included 50 patients. Only 1 (2%) had a normal CT scan, 25 (50%) had extensive alterations and 24 (48%) had radiological criteria for ILA, a median of 98.2 months before initiation of antifibrotics, of them 18 (75%) had a subpleural fibrotic pattern. Significant bronchiectasis and obvious honeycombing in the lower zones were associated with shorter survival (p = 0.04). Obvious honeycombing in the lower zones was also significantly (p < 0.05) associated with a faster progression rate. CONCLUSIONS: Fibrotic ILAs are frequent in remote scans of patients with clinically relevant ILD, long before they require antifibrotics. Findings of traction bronchiectasis and honeycombing in the earliest scans, even in asymptomatic patients, are related to mortality and progression later on.

Molecular Hydrogen as a Promising Therapy Could Be Linked With Increased Resting Treg Cells or Decreased Fas+ T Cell Subsets in a IgG4-PF-ILD Patient: A Case Report.

BACKGROUND/AIM: Progressive fibrosing interstitial lung disease (PF-ILD) refers to a group of chronic lung conditions commonly associated with immunoglobulin G4-related disorders. It is characterized by progressive scarring (fibrosis) within the pulmonary interstitium, resulting in respiratory failure and early mortality. Some patients do not respond to standard therapeutic interventions. Numerous studies have confirmed the anti-inflammatory and antioxidant properties of molecular hydrogen in various disease models. CASE REPORT: In this report, we present a case study of an 85-year-old female diagnosed with suspected IgG4-related PF-ILD complicated by hospital-acquired pneumonia. On the fourth day of hydrogen-assisted therapy, a noticeable improvement in lung infiltrations was observed in chest X-rays as the patient gradually progressed towards weaning off mechanical ventilation. To assess treatment responses, we compared immune phenotypes before and after hydrogen treatment. A marked increase was observed in resting regulatory T cell levels after treatment, accompanied by a notable decrease in Fas+ helper T cell and cytotoxic T cell subtypes. CONCLUSION: This case study highlights the effectiveness of hydrogen-assisted therapy in managing PF-ILD complicated by pneumonia, warranting further research in the future.

Therapeutic management of fibrosis in systemic sclerosis patients - an analysis from the Swiss EUSTAR cohort.

OBJECTIVES: Systemic sclerosis is a chronic autoimmune connective tissue disease leading to microvascular and fibrotic manifestations in multiple organs. Several treatment options and recommendations from different European countries are available. In this study, for which the ambit is Switzerland specifically, we aim to describe the treatment patterns of systemic sclerosis patients with fibrotic manifestations. METHODS: Systemic sclerosis patients were selected from six Swiss tertiary centres recorded in the multicentre, prospective European Scleroderma Trials and Research (EUSTAR) registry. Patients fulfilling the 2013 ACR/EULAR systemic sclerosis classification criteria at baseline were included. To determine the differences in treatment of varying degrees of fibrosis, four groups were identified: (1) patients with a modified Rodnan skin score (mRSS) >0; (2) those with mRSS ≥7; (3) those with interstitial lung disease (SSc-ILD), diagnosed by either chest X-Ray or high-resolution computed tomography; and (4) patients fulfilling one of the additional criteria for extensive interstitial lung disease, defined as interstitial lung disease involvement of >20% in high-resolution computed tomography, dyspnea NYHA-stage 3/4, or a predicted forced vital capacity (FVC) of <70%. RESULTS: A total of 590 patients with systemic sclerosis fulfilled the inclusion criteria. In this cohort, 421 (71.4%) had mRSS >0, of whom 195 (33.1%) had mRSS ≥7; interstitial lung disease was diagnosed in 198 of 456 (43.4%), of whom 106 (18.0 %) showed extensive interstitial lung disease. Regarding non-biologic disease-modifying medications (DMARDs), the most frequently prescribed was methotrexate, followed by hydroxychloroquine and mycophenolate mofetil. Rituximab and tocilizumab were most frequently used among the biologic DMARDs. Specifically, 148/372 (39.8%) of treated patients with skin fibrosis received methotrexate, mycophenolate mofetil or rituximab, and 80/177 (45.2%) with interstitial lung disease received cyclophosphamide, mycophenolate mofetil, tocilizumab or rituximab. Most patients received a proton-pump inhibitor, and few patients underwent hematopoietic stem cell transplantation. CONCLUSION: Overall, in Switzerland, a wide range of medications is prescribed for systemic sclerosis patients. This includes modern, targeted treatments for which randomised controlled clinical trial have been recently reported.

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.

Nintedanib downregulates the profibrotic M2 phenotype in cultured monocyte-derived macrophages obtained from systemic sclerosis patients affected by interstitial lung disease.

BACKGROUND: Systemic sclerosis (SSc) is an autoimmune connective tissue disease characterized by vasculopathy and progressive fibrosis of skin and several internal organs, including lungs. Macrophages are the main cells involved in the immune-inflammatory damage of skin and lungs, and alternatively activated (M2) macrophages seem to have a profibrotic role through the release of profibrotic cytokines (IL10) and growth factors (TGFß1). Nintedanib is a tyrosine kinase inhibitor targeting several fibrotic mediators and it is approved for the treatment of SSc-related interstitial lung disease (ILD). The study aimed to evaluate the effect of nintedanib in downregulating the profibrotic M2 phenotype in cultured monocyte-derived macrophages (MDMs) obtained from SSc-ILD patients. METHODS: Fourteen SSc patients, fulfilling the 2013 ACR/EULAR criteria for SSc, 10 SSc patients affected by ILD (SSc-ILD pts), 4 SSc patients non affected by ILD (SSc pts no-ILD), and 5 voluntary healthy subjects (HSs), were recruited at the Division of Clinical Rheumatology-University of Genova, after obtaining Ethical Committee approval and patients' informed consent. Monocytes were isolated from peripheral blood, differentiated into MDMs, and then maintained in growth medium without any treatment (untreated cells), or treated with nintedanib (0.1 and 1µM) for 3, 16, and 24 h. Gene expression of macrophage scavenger receptors (CD204, CD163), mannose receptor-1 (CD206), Mer tyrosine kinase (MerTK), identifying M2 macrophages, together with TGFß1 and IL10, were evaluated by quantitative real-time polymerase chain reaction. Protein synthesis was investigated by Western blotting and the level of active TGFß1 was evaluated by ELISA. Statistical analysis was carried out using non-parametric Wilcoxon test. RESULTS: Cultured untreated SSc-ILD MDMs showed a significant increased protein synthesis of CD206 (p < 0.05), CD204, and MerTK (p < 0.01), together with a significant upregulation of the gene expression of MerTK and TGFß1 (p < 0.05; p < 0.01) compared to HS-MDMs. Moreover, the protein synthesis of CD206 and MerTK and the gene expression of TGFß1 were significantly higher in cultured untreated MDMs from SSc-ILD pts compared to MDMs without ILD (p < 0.05; p < 0.01). In cultured SSc-ILD MDMs, nintedanib 0.1 and 1µM significantly downregulated the gene expression and protein synthesis of CD204, CD206, CD163 (p < 0.05), and MerTK (p < 0.01) compared to untreated cells after 24 h of treatment. Limited to MerTK and IL10, both nintedanib concentrations significantly downregulated their gene expression already after 16 h of treatment (p < 0.05). In cultured SSc-ILD MDMs, nintedanib 0.1 and 1µM significantly reduced the release of active TGFß1 after 24 h of treatment (p < 0.05 vs. untreated cells). CONCLUSIONS: In cultured MDMs from SSc-ILD pts, nintedanib seems to downregulate the profibrotic M2 phenotype through the significant reduction of gene expression and protein synthesis of M2 cell surface markers, together with the significant reduction of TGFß1 release, and notably MerTK, a tyrosine kinase receptor involved in lung fibrosis.

Are immune checkpoint inhibitors safe and effective in lung cancer patients with pre-existing interstitial lung disease?

Aim: This study aims to clarify the efficacy and adverse effects of immune checkpoint inhibitors (ICIs) in the lung cancer patients with a history of interstitial lung disease (ILD). Methods: From the inception of the database to 4 April 2023, we systematically searched the four databases. Results: The objective remission rate, disease control rate, incidence of immune-associated pneumonitis (ICIP) in the combined ILD group were significantly higher than those in the non-combined ILD group. There were no significant differences between the two groups in progression-free survival, overall survival, renal insufficiency, thyroid dysfunction and gastrointestinal toxicity. Conclusion: Generally, a pre-existing ILD history can increase the efficacy and incidence of ICIs' adverse reactions. Therefore, ICIs should be administered with caution.

Immune checkpoint inhibitors are a type of immunotherapy used to treat lung cancer. Some experts disagree over whether it is safe and effective to use this type of immunotherapy in people with lung cancer who also have lung disease. In this paper, the researchers analyzed the results of lots of different studies relating to the use of immune checkpoint inhibitors to treat lung cancer in patients with and without lung disease. They wanted to find out whether immune checkpoint inhibitors differed in their effectiveness between the two groups of patients. They also looked at whether patients with lung disease experienced more negative side effects from the immunotherapy treatment. The researchers found that patients with lung disease had a bigger response to immune checkpoint inhibitor treatment than patients without lung disease. This means that this type of immunotherapy is likely to be effective at treating lung cancer in patients with lung disease. However, the researchers also found that this patient group was more likely to experience negative side effects from the immunotherapy treatment. In particular, there were many more cases of pneumonia in this group than in the patients without lung disease. Therefore, doctors should be cautious when using immunotherapy to treat lung cancer patients with lung disease, ensuring they take measures to prevent pneumonia and be better prepared in case negative side effects occur.

Trastuzumab deruxtecan in patients with metastatic non-small-cell lung cancer (DESTINY-Lung01): primary results of the HER2-overexpressing cohorts from a single-arm, phase 2 trial.

BACKGROUND: DESTINY-Lung01 is a multicentre, open-label, phase 2 study evaluating the antitumour activity and safety of trastuzumab deruxtecan, a HER2-directed antibody-drug conjugate, in patients with HER2-overexpressing or HER2 (ERBB2)-mutant unresectable or metastatic non-small-cell lung cancer (NSCLC). The results of the HER2-mutant cohort (cohort 2) have been reported elsewhere. Herein, we report the primary analysis of cohorts 1 and 1A, which aimed to evaluate the activity and safety of trastuzumab deruxtecan 5·4 mg/kg and 6·4 mg/kg in patients with HER2-overexpressing NSCLC. METHODS: Patients aged 18 years or older with unresectable or metastatic (or both unresectable and metastatic) non-squamous NSCLC who had relapsed following or were refractory to standard treatment or for whom no standard treatment was available, with an HER2 immunohistochemistry score of 3+ or 2+ (without known HER2 mutations) and an Eastern Cooperative Oncology Group performance status score of 0 or 1, were enrolled at 20 specialist hospitals in France, Japan, the Netherlands, Spain, and the USA. Patients were assigned to cohorts sequentially, first to cohort 1, to receive trastuzumab deruxtecan 6·4 mg/kg (cohort 1), then to cohort 1A, to receive trastuzumab deruxtecan 5·4 mg/kg, both administered intravenously once every 3 weeks. The primary endpoint was confirmed objective response rate by independent central review and was assessed in the full analysis set, which included all patients who signed an informed consent form and were enrolled in the study. Safety was assessed in all enrolled patients who received at least one dose of trastuzumab deruxtecan. This trial is registered with ClinicalTrials.gov, NCT03505710, and is ongoing (closed to recruitment). FINDINGS: Between Aug 27, 2018, and Jan 28, 2020, 49 patients were enrolled in cohort 1 (median age 63·0 years [IQR 58·0-68·0], 30 [61%] male, 19 [39%] female, and 31 [63%] White), and from June 16 to Dec 9, 2020, 41 patients were enrolled in cohort 1A (median age 62·0 years [IQR 56·0-66·0], 22 [54%] male, 19 [46%] female, and 31 [76%] White). As of data cutoff (Dec 3, 2021), the median treatment duration was 4·1 months (IQR 1·4-7·1) in cohort 1 and 5·5 months (1·4-8·7) in cohort 1A, and median follow-up was 12·0 months (5·4-22·4) in cohort 1 and 10·6 months (4·5-13·5) in cohort 1A. Confirmed objective response rate by independent central review was 26·5% (95% CI 15·0-41·1; 13 of 49, all partial responses) in cohort 1 and 34·1% (20·1-50·6; 14 of 41; two complete responses and 12 partial responses) in cohort 1A. The most common treatment-emergent adverse events of grade 3 or worse were neutropenia (12 [24%] of 49 in cohort 1, none in cohort 1A), pneumonia (six [12%] and two [5%], respectively), fatigue (six [12%] and three [7%], respectively), and disease progression (six [12%] and four [10%], respectively). Drug-related treatment-emergent adverse events of grade 3 or worse occurred in 26 (53%) of 41 patients in cohort 1 and nine (22%) of 49 patients in cohort 1A. Drug-related serious adverse events were reported in ten (20%) patients and three (7%) patients, respectively. Deaths due to treatment-emergent adverse events occurred in ten (20%) patients in cohort 1 (disease progression in six (12%) patients and bronchospasm, hydrocephalus, respiratory failure, and pneumonitis in one [2%] patient each), and in seven (17%) patients in cohort 1A (due to disease progression in four (10%) patients and dyspnoea, malignant neoplasm, and sepsis in one (2%) patient each). One death due to a treatment-emergent adverse event was determined to be due to study treatment by the investigator, which was in cohort 1 (pneumonitis). Independent adjudication of interstitial lung disease or pneumonitis found that drug-related interstitial lung disease or pneumonitis occurred in ten (20%) patients in cohort 1 (two [4%] grade 1, five [10%] grade 2, and three [6%] grade 5) and two (5%) patients in cohort 1A (one [2%] grade 2 and one [2%] grade 5). An additional patient in cohort 1A had grade 4 pneumonitis after the data cutoff, which was subsequently adjudicated as drug-related grade 5 interstitial lung disease or pneumonitis. INTERPRETATION: Given the low antitumour activity of existing treatment options in this patient population, trastuzumab deruxtecan might have the potential to fill a large unmet need in HER2-overexpressing NSCLC. Our findings support further investigation of trastuzumab deruxtecan in patients with HER2-overexpressing NSCLC. FUNDING: Daiichi Sankyo and AstraZeneca.

Baricitinib for anti-melanoma differentiation-associated protein 5 antibody-positive dermatomyositis-associated interstitial lung disease: a case series and literature review on Janus kinase inhibitors for the disease.

Anti-melanoma differentiation-associated protein 5 antibody-positive dermatomyositis (anti-MDA5-DM) is frequently complicated by progressive interstitial lung disease (ILD), the prognosis of which is poor, and management is a major challenge. We treated three patients with anti-MDA5-DM-associated ILD (anti-MDA5-DM-ILD) using the Janus kinase (JAK) inhibitor, baricitinib, which improved lung opacities and saved two patients. We reviewed 6 patients with anti-MDA5-DM-ILD who had been treated with tofacitinib at our institution. Five of the patients survived, although discontinuation of tofacitinib due to complications was frequently observed. In addition, a literature search of patients with anti-MDA5-DM-ILD who were treated with JAK inhibitors yielded 21 articles involving 79 cases. All patients except one were treated with tofacitinib, and the survival rate was 75.9%. Although not statistically confirmed, the deceased patients tended to be older and had higher ferritin levels. A total of 92 complications were observed, 11 of which resulted in JAK inhibitor discontinuation. Cytomegalovirus reactivation comprised a substantial percentage of all complications and of those patients who required JAK inhibitor discontinuation. Five cases with fatal infective complications were also observed. While tofacitinib has been proposed to be a therapeutic option for anti-MDA5-DM-ILD, other JAK inhibitors, including baricitinib, are a treatment option. Further investigation is warranted to optimize treatment of anti-MDA5-DM-ILD.

Clinical characteristics of patients with connective tissue disease-related interstitial lung disease: a retrospective analysis.

INTRODUCTION: Interstitial lung disease is one of the most critical manifestations of connective tissue diseases that may cause morbidity and mortality. This study aimed to evaluate the clinical and demographic characteristics and treatment of the patients with connective tissue disease-related interstitial lung disease. METHOD: This retrospective observational study included patients from the Gulhane Rheumatology Interstitial Lung Disease cohort between October 2016 and June 2023. The patients were assessed retrospectively. RESULTS: A total of 173 patients were included in the study with a mean age of 63.4 ± 11.9 years. The frequencies of CTD were 34.1% Sjogren's syndrome, 30.1% rheumatoid arthritis, 25.4% systemic sclerosis, 5.8% undifferentiated connective tissue disease, 2.9% idiopathic inflammatory myositis, 1.2% mixt connective tissue disease, and 0.6% systemic lupus erythematosus in decreasing frequencies. Nonspecific interstitial pneumonia, which was the most common interstitial lung disease pattern in 103 (59.5%) patients, was most frequent among patients with SS and SSc (p < 0.001 vs. p < 0.001). Usual interstitial pneumonia was most frequent among patients with RA (p < 0.001). All patients received immunosuppressive treatment, most commonly azathioprine. 57.2% were using immunosuppressives for ILD. Six patients had mortality, and infections were the leading cause. CONCLUSIONS: As a critical manifestation of connective tissue diseases, immunosuppressive treatment is indispensable in the management of interstitial lung diseases especially those at an increased risk for progression. The treatment approaches should be assessed in a patient-based way. The patients under immunosuppressive treatment should be cautiously followed for infections. Key Points • Interstitial lung disease is a noteworthy manifestation of connective tissue diseases. • The clinical findings, treatment requirements, and progression vary according to the severity of the disease. • Immunosuppressive treatment may be essential in patients with worsening symptoms, impaired pulmonary function tests, and radiological findings.

Treatment of myopathy and cutaneous ulcers in anti-MDA5-positive dermatomyositis with triple therapy.

Antimelanoma differentiation-associated protein 5 positive dermatomyositis (MDA5 DM) is a rare subtype of idiopathic inflammatory myopathy. There are limited data available regarding the cutaneous manifestations of MDA5 DM in the African American population. We presented the case of a male patient in his early 20s who presented with debilitating cutaneous ulceration and myopathy. Workup revealed interstitial lung disease (ILD) and positive MDA5 serology consistent with MDA5 DM. He made a remarkable recovery in terms of myopathy and cutaneous ulcerations with a multipronged regimen of prednisone, intravenous immunoglobulin and mycophenolate mofetil. However, there was a progression of ILD on this regimen which warranted use of rituximab.

Efficacy and safety of local ablative therapy for patients with NSCLC and coexisting interstitial lung disease.

BACKGROUND: The effective therapeutic approach is still an unmet need for patients diagnosed with both lung cancer and interstitial lung disease (ILD). This is primarily due to the possible risk of ILD exacerbation caused by surgery or radiotherapy. The current study aimed to investigate the efficacy and safety of local ablative therapy (LAT) for this specific population. METHODS: Consecutive patients with non-small cell lung cancer (NSCLC) and ILD who received LAT between January 2018 and August 2022 were enrolled, and propensity score matching (PSM) was utilized to match the non-ILD group. The primary endpoint was recurrence-free survival (RFS), and secondary endpoints included overall survival (OS), adverse events (AEs) and hospital length of stay (HLOS). RESULTS: The PSM algorithm yielded matched pairs in the ILD group (n = 25) and non-ILD group (n = 72) at a ratio of 1:3. There were no statistically significant differences in RFS (median 16.4 vs. 18 months; HR = 1.452, p = 0.259) and OS (median: not reached vs. 47.9 months; HR = 1.096, p = 0.884) between the two groups. Meanwhile, no acute exacerbation of ILD was observed in the ILD group. However, the incidence of pneumothorax, especially pneumothorax requiring chest tube drainage, was significantly higher (36.0% vs. 11.2%, p = 0.005) among patients with NSCLC and co-existing ILD, which resulted in longer HLOS (p = 0.045). CONCLUSION: Although ILD was associated with a higher incidence of pneumothorax, the efficacy of LAT for NSCLC patients with ILD was comparable to those without ILD, suggesting that LAT might be a reliable and effective treatment option for this population, particularly in the early stage.

Impact of antifibrotic therapy on disease progression, all-cause mortality, and risk of acute exacerbation in non-IPF fibrosing interstitial lung diseases: evidence from a meta-analysis of randomized controlled trials and prospective controlled studies.

BACKGROUND: Nintedanib and pirfenidone are preferred pharmacological therapies for patients with idiopathic pulmonary fibrosis (IPF). However, evidence favoring antifibrotic therapy in patients with non-IPF fibrosing interstitial lung diseases (ILD) is limited. OBJECTIVE: To investigate the effects of antifibrotic therapy on disease progression, all-cause mortality, and acute exacerbation (AE) risk in patients with non-IPF fibrosing ILDs. DESIGN: Meta-analysis. DATA SOURCES AND METHODS: Electronic databases were searched for articles published before 28 February 2023. Studies that evaluated the efficacy of antifibrotic agents in patients with fibrosing ILDs were selected. The primary outcome was the disease progression risk, and the secondary outcomes included all-cause mortality and AE risk. The GRADE criteria were used for the certainty of evidence assessment. RESULTS: Nine studies with 1990 participants were included. Antifibrotic therapy reduced the rate of patients with disease progression (five trials with 1741 subjects; relative risk (RR), 0.56; 95% CI, 0.42-0.75; p < 0.0001; I2 = 0; high-certainty evidence). Antifibrotic therapy did not significantly decrease all-cause mortality (nine trials with 1990 subjects; RR, 0.76; 95% CI, 0.55-1.03; p = 0.08; I2 = 0; low-certainty evidence). However, in patients with progressive fibrosing ILDs (PF-ILD), antifibrotic therapy decreased all-cause mortality (four trials with 1100 subjects; RR, 0.69; 95% CI, 0.48-0.98; p = 0.04; I2 = 0; low-certainty evidence). CONCLUSION: Our study supports the use of antifibrotic agents in patients with PF-ILDs, which could slow disease progression and decrease all-cause mortality. TRIAL REGISTRATION: This study protocol was registered with PROSPERO (registration number: CRD42023411272).

Neutrophil-lymphocyte ratio being associated with mortality risk in patients receiving antifibrotic therapy.

BACKGROUND: Antifibrotic therapy is widely used for patients with progressive fibrotic interstitial lung disease (ILD), regardless of etiology. There is an urgent need for a simple, inexpensive, and repeatable biomarker to evaluate disease severity and mortality risk. METHODS: This retrospective multicohort study assessed the neutrophil-lymphocyte ratios (NLRs) of 416 patients with ILD who received antifibrotic therapy (Hamamatsu cohort, n = 217; Seirei cohort, n = 199). The mortality risk vs. NLR relationship was evaluated at therapy initiation and 1 year. The optimal NLR cutoff of 2.7 was selected according to the mortality risk. RESULTS: Survival was shorter in patients with high NLR than with low NLR (median: 2.63 vs. 4.01 years). The NLR classification results (cutoff: 2.7) were longitudinally preserved in >70 % of the patients, and patients with consistently high NLR had a higher risk of mortality than others (median, 2.97 vs. 4.42 years). In multivariate analysis, high NLR was significantly associated with mortality independent of age, sex, forced vital capacity, lung diffusing capacity for carbon monoxide (DLCO), or the gender-age-physiology (GAP) index. A combined GAP index-NLR assessment classified mortality risk into four groups. Subset analyses revealed that NLR assessment was more applicable to patients without advanced disease, not taking steroids, and with idiopathic pulmonary fibrosis (IPF) than to patients with advanced disease, taking steroids, and patients with Non-IPF. CONCLUSION: High NLR was associated with an increased mortality risk in patients with ILDs receiving antifibrotic therapy. Assessment of NLR may help predict disease severity and mortality risk in antifibrotic therapy.