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BackgroundDapagliflozin (DAPA), a sodium-glucose transporter 2 inhibitor (SGLT2i), attenuates kidney outcomes in patients with not only diabetes mellitus (DM) but also chronic kidney disease (CKD). SGLT2i-derived initial dip in estimated glomerular filtration rate (eGFR) has been considered to reduce excess glomerular pressure, followed by renal protection in patients with DM. However, whether DAPA confers the eGFR dip and its independent determinants for CKD patients without DM are unclear.MethodsA total of 126 patients with CKD treated with 10 mg DAPA daily was retrospectively registered. After participants with missing data and DM were excluded, 51 participants were enrolled.ResultsAn initial eGFR dip was observed 1 month after initiation of DAPA, which was sustained until 2 months. DAPA did not affect urinary protein excretion; however, serum uric acid was decreased, while hemoglobin level was increased. Multiple regression analysis revealed that eGFR at baseline was the only independent determinant of the initial dip of eGFR. The patients currently showing exacerbation of glomerular hyperfiltration exhibited the larger initial eGFR dip rather than those showing progressive renal dysfunction. The patients meeting exclusion criteria of DAPA-CKD trial exhibited same degree of the initial eGFR dip as others.ConclusionsDAPA causes an initial dip of eGFR in CKD patients without DM at 1 month after starting DAPA treatment. A higher eGFR at baseline predicts a large initial eGFR dip, which might be linked to the subsequent recovery in eGFR in CKD patients without DM.

BackgroundLipids have immunomodulatory functions and the potential to affect cancer immunity.MethodsThe associations of pretreatment serum cholesterol and long-chain fatty acids with the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were evaluated in 148 patients with non-small cell lung cancer who received nivolumab.ResultsWhen each lipid was separately evaluated, increased low-density lipoprotein (LDL)-cholesterol (P < 0.001), high-density lipoprotein (HDL)-cholesterol (P = 0.014), total cholesterol (P = 0.007), lauric acid (P = 0.015), myristic acid (P = 0.022), myristoleic acid (P = 0.035), stearic acid (P = 0.028), linoleic acid (P = 0.005), arachidic acid (P = 0.027), eicosadienoic acid (P = 0.017), dihomo-γ-linolenic acid (P = 0.036), and behenic acid levels (P = 0.032) were associated with longer PFS independent of programmed death ligand 1 (PD-L1) expression. Meanwhile, increased LDL-cholesterol (P < 0.001), HDL-cholesterol (P = 0.009), total cholesterol (P = 0.036), linoleic acid (P = 0.014), and lignoceric acid levels (P = 0.028) were associated with longer OS independent of PD-L1 expression. When multiple lipids were evaluated simultaneously, LDL-cholesterol (P = 0.003), HDL-cholesterol (P = 0.036), and lauric acid (P = 0.036) were independently predictive of PFS, and LDL-cholesterol (P = 0.008) and HDL-cholesterol (P = 0.031) were predictive of OS. ORR was not associated with any serum lipid.ConclusionsBased on the association of prolonged survival in patients with increased serum cholesterol and long-chain fatty acid levels, serum lipid levels may be useful for predicting the efficacy of immune checkpoint inhibitor therapy.

No prospective studies have investigated the relationship between nutritional status, tolerability to antifibrotic therapy, and mortality in patients with fibrotic interstitial lung diseases (ILDs). This prospective longitudinal study enrolled 290 consecutive patients with fibrotic ILDs who initiated antifibrotic therapy, including 164 with idiopathic pulmonary fibrosis (IPF) and 126 with non-IPF. Nutritional status was assessed using the Geriatric Nutritional Risk Index (GNRI). Overall, 106 patients (36.6%) were classified as having malnutrition-related risk (GNRI < 98) at baseline. The prevalence of malnutrition-related risk was comparable between patients with IPF and non-IPF, although it tended to be higher in the non-IPF group than in the IPF group. Patients with malnutrition-related risk showed higher cumulative incidence of antifibrotic therapy discontinuation. Importantly, in both IPF and non-IPF groups, the mortality risk was significantly higher in patients with malnutrition-related risk than in those without. Longitudinally, a lower GNRI at 1 year was associated with shorter survival. In multivariable analyses, baseline malnutrition-related risk was independently associated with increased risk of therapy discontinuation and mortality, even after adjusting for the ILD–gender–age–physiology index. These findings indicate that assessment of nutritional status helps predict antifibrotic therapy tolerability and mortality risk in patients with fibrotic ILD.

This study aimed to assess the clinical utility of serum interferon-lambda 3 (IFN-λ3) as a sequential biomarker for treatment response and disease control in patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis (DM)-associated interstitial lung disease (ILD). Serum IFN-λ3 levels were measured in 24 patients with anti-MDA5 antibody-positive DM-ILD at diagnosis and 1 month after initiating immunosuppressive therapy. Patients were categorized into two groups based on clinical outcomes: a good control group ( n  = 16; survived without relapse for ≥ 1 year) and a poor control group ( n  = 8; died from ILD progression or relapse within 1 year). Changes in serum IFN-λ3 levels and differences between groups were analyzed. In the good control group, serum IFN-λ3 levels significantly decreased from 94.6 to 12.7 pg/mL ( p  < 0.001), whereas no significant change was observed in the poor control group (129.0 to 118.8 pg/mL). Furthermore, serum IFN-λ3 levels at 1 month were significantly lower in the good control group than in the poor control group ( p  = 0.004). Serum IFN-λ3 levels may reflect short-term treatment response and could serve as a useful sequential biomarker for assessing disease control in patients with anti-MDA5 antibody-positive DM-ILD.

Although acute exacerbation of idiopathic interstitial pneumonia (AE-IIP) is a critical event, the detailed features of connective tissue diseases (CTD) that affect the incidence of AE-IIP have not been fully elucidated. This study aimed to clarify the CTD-related features that affect the incidence of AE-IIP. This was a post hoc analysis of a prospective and multicenter cohort study conducted between 2015 and 2020. Newly diagnosed patients with IIP were consecutively enrolled, and 74 autoimmune features and autoantibodies were comprehensively checked during IIP diagnosis. In total, 222 patients with IIP were enrolled. The median observation period was 36 months, during which 34 patients developed AE-IIP. In multivariate models adjusted for age, gender, and %predicted FVC, AE-IIP frequently occurred in patients positive for anti-cyclic citrullinated peptide (CCP) antibody (hazard ratio [HR]: 4.407, p  = 0.004, q = 0.027), while it was less common in patients positive for antinuclear antibodies (ANA) ≥ 320 or polymyositis/dermatomyositis (PM/DM)- or systemic sclerosis (SSc)-related antibodies (HR < 0.001, p  < 0.001, q < 0.001). A composite model consisting of these items stratified the incidence of AE-IIP ( p  < 0.001), which was closely related to the mortality. These results indicate that the presence of anti-CCP antibodies, ANA, or PM/DM/SSc-related antibodies, in addition to decreased lung function, could help determine the risk of AE-IIP in patients with IIP.

Bronchoalveolar lavage (BAL) is crucial for the diagnosis of interstitial lung disease (ILD). Although BAL lymphocytosis is found in patients with connective tissue disease (CTD)-related ILD, the effects of CTD-associated features on BAL lymphocytosis have not been elucidated. To identify CTD-associated features that affect BAL lymphocyte fraction in patients with idiopathic interstitial pneumonia (IIP). This post hoc analysis of a prospective, multicentre cohort study was conducted between 2015 and 2020. Overall, 222 patients newly diagnosed with IIP were consecutively enrolled, and 74 autoimmune features were comprehensively analysed during IIP diagnosis. The median age was 71 years, and the median observation period was 36 months. The clinical characteristics related to a significant increase in BAL lymphocyte fraction were consolidation opacity on high-resolution computed tomography (HRCT), morphologic domain of interstitial pneumonia with autoimmune features (IPAF), serum CXCL10 concentration, and acute/subacute onset (all p < 0.05). In contrast, presence of joint lesion/mucocutaneous lesion/dry symptoms, autoantibodies, or other CTD-like features on HRCT and surgical lung biopsy did not affect the BAL lymphocyte fraction (all p ≥ 0.05). Furthermore, a high BAL lymphocyte fraction (≥ 8.5%) was related to a low proportion of progressive pulmonary fibrosis ( p < 0.001) and favourable survival (log-rank, p = 0.020) in patients with non-idiopathic pulmonary fibrosis (IPF). IPAF morphologic domain especially with consolidation opacity on HRCT and high CXCL10 concentration, but not CTD-like symptoms, autoantibodies, or CTD-like features on lung biopsy, were related to a high BAL lymphocyte fraction with favourable survival in patients with non-IPF.

BackgroundSome patients with idiopathic interstitial pneumonia (IIP) show autoimmune features. Interstitial pneumonia with autoimmune features (IPAF) was recently proposed as a research concept in these patients. However, retrospective studies reported conflicting results of its prognosis. Therefore, this study was conducted to prospectively evaluate the clinical significance of autoimmune features in patients with IIP.MethodsThis nationwide multicentre study prospectively enrolled consecutive patients with IIP. At the diagnosis, we systematically evaluated 63 features suggestive of connective tissue diseases using a checklist including symptoms/signs and autoantibodies, which contained most items of the IPAF criteria and followed up with the patients. Clinical phenotypes were included in a cluster analysis.ResultsIn 376 patients with IIP enrolled, 70 patients (18.6%) met the IPAF criteria. The proportion of patients with IPAF was significantly lower in idiopathic pulmonary fibrosis (IPF) than in non-IPF (6.0% vs 24.3%, respectively). During a median observation period of 35 months, patients with IPAF more frequently developed systemic autoimmune diseases and had less frequent acute exacerbation of IIPs than patients with non-IPAF. IPAF diagnosis was significantly associated with better survival and was an independent positive prognostic factor in total and patients with non-IPF. Cluster analysis by similarity of clinical phenotypes identified a cluster in which there was a higher number of women, and patients had more autoimmune features and a better prognosis than other clusters.InterpretationThese observations suggest that some patients with IIP show autoimmune features with distinct characteristics and favourable prognosis. However, we were not able to determine the appropriate therapies for these patients.

Background Interstitial pneumonia with autoimmune features (IPAF), which does not meet any of the criteria for connective tissue diseases (CTD), has been attracting an attention in patients with idiopathic interstitial pneumonia (IIP). However, the biomarkers that reflect the clinical course of these patients have not been fully elucidated. Objective To identify useful serum biomarkers reflecting CTD-related features and favorable prognoses in patients with IIP. Methods This was a post hoc analysis of a prospective and multicenter cohort study between 2015 and 2020. Newly diagnosed patients with IIP were consecutively enrolled, and 74 autoimmune features and autoantibodies were comprehensively checked during IIP diagnosis. Serum levels of CXCL10, CXCL1, CCL2, BAFF, angiopoietin-2, and leptin were evaluated at the time of IIP diagnosis. Results Two hundred twenty-two patients (159 men and 63 women) with IIP were enrolled. The median observation duration was 36 months. The median age was 71 years old, and median %forced vital capacity (FVC) was 84.1% at the time of IIP diagnosis. The proportion of patients who met the classification criteria for IPAF was 11.7%. In patients with high serum CXCL10, changes in both %FVC and %diffusion lung capacity for carbon monoxide at one year were significantly higher than those in patients with low CXCL10 ( p  = 0.014 and p  = 0.009, respectively), whereas these changes were not significant for other chemokines and cytokines. High CXCL10 levels were associated with acute/subacute onset ( p  < 0.001) and the diagnosis of nonspecific interstitial pneumonia with organizing pneumonia overlap ( p  = 0.003). High CXCL10 levels were related to a higher classification of IPAF (relative risk for IPAF was 3.320, 95%CI: 1.571–7.019, p  = 0.003) and lower classification of progressive pulmonary fibrosis (PPF; relative risk for PPF was 0.309, 95%CI: 0.100-0.953, p  = 0.027) compared to those with low CXCL10. Finally, survival was higher in patients with IPF and high CXCL10 ( p  = 0.044), and high CXCL10 was a significant prognostic factor in multivariate Cox proportional hazards models (hazard ratio 0.368, p  = 0.005). Conclusions High serum levels of CXCL10 are associated with CTD-related features, the favorable clinical course, and survival in patients with IIP, especially IPF. Clinical trial number Not applicable.

Background Immune-related pneumonitis (irP) is one of the most important immune-related adverse events caused by immune checkpoint inhibitors (ICIs). After corticosteroid therapy irP frequently relapses, which can interfere with cancer therapy. However, risk factors for irP relapse are unknown. Methods This study was a follow-up analysis of a phase II study that evaluated 56 patients with grade ≥ 2 irP treated with oral prednisolone, 1 mg/kg/day, tapered over 6 weeks. Clinical factors including patient characteristics, blood test findings, and response to prednisolone therapy were assessed to identify risk factors for irP relapse using the Fine–Gray test. Results Among 56 patients with irP, 22 (39.3%) experienced irP relapse after 6 weeks of prednisolone therapy during the follow-up observation period. Radiographic organising pneumonia (OP) pattern and duration to irP onset ≥ 100 days from ICI initiation were determined to be significant risk factors for irP relapse in a multivariate Fine–Gray test (hazard ratio [HR] = 3.17, 95% CI 1.37–7.32, p  = 0.007, and HR = 2.61, 95% CI 1.01–6.74, p  = 0.048, respectively). Other patient characteristics, blood test findings, irP severity, and response to prednisolone therapy were not associated with irP relapse. Conclusions In irP patients treated with 6-week prednisolone tapering therapy, OP pattern and duration to irP onset ≥ 100 days were associated with relapse risk. Assessment of the risk factors for irP relapse will be helpful for irP management.