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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., (© 2024. The Author(s).)

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., (© 2024. The Author(s).)

Background: Despite the introduction of rubella-containing vaccine into routine immunization in 1977, rubella has not been eliminated in Japan. This study aimed to validate the immunization strategy and to highlight the crucial elements of elimination program., Methods: We scrutinized cases of rubella and congenital rubella syndrome (CRS). Additionally, we analyzed the national vaccination coverage, seroprevalence, and number of maternal rubella-related spontaneous or artificial fetal deaths., Results: The shift from selective to universal immunization significantly reduced rubella cases coupled with increased seroprevalence in children. However, rubella resurged in 2012-2013 and 2018-2019, which was virologically and serologically confirmed to be associated with imported rubella virus (RuV) and susceptible males. Although the disease burden of CRS may have been suppressed in the past by the large number of spontaneous or artificial fetal deaths, the incidence rate of CRS was comparable to that of the 1960s to 1980s. Cases of breakthrough infection and CRS were identified in females who were considered to have a history of single-dose vaccination., Conclusions: Even with universal immunization, future epidemics and severe outcomes cannot be prevented unless immunization gaps are closed. Furthermore, CRS and breakthrough infection are not completely prevented by single-dose vaccination, indicating the need for second-dose vaccination., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objective: Interferon-λ3 (IFNλ3) is a cytokine with antiviral functions on barrier surfaces, and it is associated with disease activity in autoimmune diseases. This study assessed the clinical significance of serum IFNλ3 levels in polymyositis/dermatomyositis (PM/DM)-associated interstitial lung disease (ILD)., Methods: We measured serum IFNλ3 levels in 221 patients with PM/DM-ILD (155 in the derivation cohort, 66 in the validation cohort) and 38 controls. We evaluated factors associated with mortality risk among 79 patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive DM-ILD., Results: Serum IFNλ3 levels at diagnosis were significantly higher in patients with PM/DM-ILD than in healthy controls. Remarkably, serum IFNλ3 levels were specifically increased in patients with anti-MDA5 antibody-positive DM-ILD in both the derivation and validation cohorts. In anti-MDA5 antibody-positive DM-ILD, patients with high IFNλ3 levels (>120 pg/mL) had significantly lower survival rates than those with low IFNλ3 levels (≤120 pg/mL). A multivariate analysis revealed that high IFNλ3 levels, as well as old age and low Pao 2 , were significantly associated with poor prognoses in patients with anti-MDA5 antibody-positive DM-ILD. In a classification analysis of patients with anti-MDA5 antibody-positive DM-ILD based on age, IFNλ3 level, and Pao 2 , patients with old age (>53 years), high IFNλ3 levels (>120 pg/mL), and low Pao 2 (<75 mm Hg) had the worst survival. In lung pathologic analyses, IFNλ3-positive staining was observed in macrophages, airway epithelial cells, the pleural region, and intrapulmonary veins in patients with anti-MDA5 antibody-positive DM-ILD., Conclusion: Serum IFNλ3 is a promising biomarker for identifying patients at high risk of poor outcomes in anti-MDA5 antibody-positive DM-ILD., (© 2023 American College of Rheumatology.)

Background: Patients with idiopathic interstitial pneumonia (IIP) have a favourable prognosis when they have interstitial pneumonia with autoimmune features (IPAF). However, precise IPAF-related findings from high-resolution computed tomography (HRCT) and lung histopathological specimens and the treatment response have not been fully determined. Therefore, this study was conducted to evaluate the relationship between findings on HRCT or lung histopathological specimens and the progression of interstitial pneumonia in patients with IPAF., Methods: This multicentre cohort study prospectively enrolled consecutive patients with IIP. At the diagnosis of IIP, we systematically evaluated 74 features suggestive of connective tissue diseases and followed them up. HRCT, lung specimens, serum antibodies, and the clinical course were also evaluated., Results: Among 222 patients with IIP, 26 (11.7%) fulfilled the IPAF criteria. During a median observation period of 36 months, patients with IPAF showed better survival than those without IPAF (p = 0.034). While histopathological findings were not related to IPAF, nonspecific interstitial pneumonia (NSIP) with organizing pneumonia (OP) overlap was the most prevalent HRCT pattern (p < 0.001) and the consolidation opacity was the most common radiological finding in IPAF (p = 0.017). Furthermore, in patients with IPAF, the diagnosis of COP or NSIP with OP overlap was associated with a higher increase in %FVC in 1 year than in those with idiopathic pulmonary fibrosis, NSIP, or unclassifiable IIP (p = 0.002)., Conclusions: This study shows the presence of consolidation opacity on HRCT and the diagnosis of COP or NSIP with OP overlap are associated with IPAF and its favourable treatment response in patients with IPAF., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Noriyuki Enomoto received funding from Boehringer Ingelheim Japan Co., Ltd. All of other authors did not receive funding., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Measles is a contagious viral disease causing infant mortality in developing countries without vaccination programs. In Japan, measles vaccination was launched in 1978, surveillance commenced in 1981, and elimination was achieved in 2015. This was due to improved, legally required surveillance methods and vaccine programs., Methods: The data sets of sentinel (1982-2007) and notifiable (2008-2021) disease surveillance, as well as the vaccination coverage, detected genotypes, and seroepidemiology during the study period in Osaka Prefecture, were analyzed. Additionally, the trend under the current notifiable surveillance was compared before (2008-2014) and after (2015-2021) measles elimination., Results: Under sentinel surveillance, 51,107 cases were reported, predominantly infants aged 1-4 years (63.6 %). Under notifiable disease surveillance, the 781 patients were predominantly in their 20s-30s (43.7 %). From 2000, the age of the major susceptible group increased due to the rise in vaccination coverage, which exceeded 95% for the first dose in 1998 and 90% for the second dose in 2009. Consistent with these data, seroprevalence exceeded 95% in 2011. However, the geometric mean of the antibody titer showed a decreasing trend with a falling number of patients. Compared with before and after measles elimination, the number of modified measles cases increased from 10.1% to 48.2%. During the study period, 398 strains comprising eight genotypes were identified, and the dominant type changed over time. After measles elimination, genotypes B3 and D8, derived from imported cases, became predominant., Conclusions: Improved vaccination coverage and surveillance reduced measles cases and increased herd immunity. However, the lack of a booster effect due to the low incidence of measles caused waning antibody titers despite high seroprevalence, which may contribute to the rising rate of vaccine failures causing modified measles. Careful monitoring of measles incidence and herd immunity are necessary for measles eradication., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: There has been no prospective trial for treatment of immune-related pneumonitis (irP) occurred after immune checkpoint inhibitors (ICIs)., Methods: In this single-arm phase II study, patients with cancer with grade ≥2 irP received oral prednisolone (1 mg/kg/day), tapered over 6 weeks. The primary endpoint was a pneumonitis control rate at 6 weeks from the start of the study treatment, defined as complete disappearance or partial improvement of irP in high-resolution CT of the chest., Results: Among 57 patients enrolled, 56 were included in the final analysis. The most frequent cause of irP was single ICI therapy (51.8%), followed by combination with chemotherapy plus ICI (39.3%). Thirty-five (62.5%) patients had grade 2 irP and 21 (37.5%) had grade ≥3. Fifty-one (91.1%) patients completed the study treatment while 5 discontinued the study treatment because of relapse of irP (n=1), death from cancer (n=1), occurrence of immune-related hepatitis (n=1), extension of the treatment duration more than 6 weeks (n=1), and attending physician's decision (n=1). Six weeks after the start of the study treatment, 16 (28.5%) patients demonstrated complete recovery from irP, 35 (62.5%) had a partial improvement in irP, 1 (1.8%) had a relapse of irP, and 4 (7.1%) were not evaluable. The pneumonitis control rate at 6 weeks was 91.1% (95% CI, 80.7% to 96.1%). Twelve weeks after the start of the study treatment, 5 (8.9%), 27 (48.2%), and 15 (26.8%) patients demonstrated complete recovery, partial improvement, and relapse, respectively, and 9 (16.1%) were not evaluable. The pneumonitis control rate at 12 weeks was 57.1% (95% CI, 44.1% to 69.2%). During the observation period, 18 (32.1%) patients experienced a relapse of irP, and of those, 17 received re-treatment with corticosteroids. Grade ≥3 adverse events occurred in 10 (17.9%) patients, in which hyperglycemia was most frequent (n=6). There was no treatment-related death., Conclusions: In this first prospective study for irP, prednisolone at 1 mg/kg/day, tapered over 6 weeks, demonstrated a promising clinical benefit and manageable toxicity, suggesting a potential treatment option for irP., Trial Registration Number: jRCT: 1041190029., Competing Interests: Competing interests: No, there are no competing interests., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Identifying patients at high risk of immune-related adverse events (irAEs) that impede the achievement of durable efficacy of programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) blockade therapy is important in improving their management. Identification of a novel predictive factor of therapeutic benefit is also important in improving patient selection for treatment with PD-1/PD-L1 inhibitors. Further determinants driving response and linking with irAEs are urgently required., Methods: To address these unmet needs in the field, we explored whether 27 soluble checkpoint proteins and immunomodulatory proteins in serum at the therapy baseline and after week 3 were associated with irAE onset and therapeutic efficacy using MILLIPLEX Human Immuno-Oncology Checkpoint Protein Panel assays in a prospective, multicenter cohort of 81 patients with non-small cell lung cancer (NSCLC) receiving atezolizumab monotherapy., Results: By competing-risks regression analysis, we identified that high levels of B cell-activating factor (BAFF) at baseline were a significant and strong risk factor of irAEs (hazard ratio, 5.61; 95% confidence interval, 2.43-12.96; P < 0.0001). We also identified that increased inducible T cell co-stimulator (ICOS) during the first therapeutic cycle was an independent factor associated with prolonged progression-free survival and overall survival., Conclusion: These findings are in keeping with the reported mechanistic basis of these molecules and may provide potential guidance for clinical decision-making to improve patient care. Further validation studies are warranted. Trial registration UMIN000035616 (January 28, 2019)., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Since the first isolation of rubella virus (RuV) in 1962, comprehensive data regarding the quantitative evaluation of RuV shedding remain unavailable. In this study, we evaluated the shedding of viral RNA and infectious virus in patients with acute RuV infection., Study Design: We analyzed 767 specimens, including serum/plasma, peripheral blood mononuclear cells (PBMCs), throat swabs, and urine, obtained from 251 patients with rubella. The viral RNA load and the presence of infectious RuV were determined using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and virus isolation., Results: Virus excretion peaked 0-2 days after rash onset and decreased over time. The median viral RNA load dropped to an undetectable level on day 3 after rash onset in serum/plasma, day 2 in PBMCs, days 10-13 in throat swabs, and days 6-7 in urine. Infectious virus could be isolated for up to day 2 after rash onset in serum/plasma, day 1 in PBMCs, days 8-9 in throat swabs, and days 4-5 in urine. The minimum viral RNA load that allowed virus isolation was 961 copies/mL in serum/plasma, 784 copies/mL in PBMCs, 650 copies/mL in throat swabs, and 304 copies/mL in urine. A higher viral RNA load indicated a higher likelihood of the presence of infectious virus., Conclusion: These findings would contribute to improve algorithms for rubella surveillance and diagnosis. In addition, this study indicates that the results of RT-qPCR enable efficient rubella control by estimating candidate patients excreting infectious virus, which could help prevent viral transmission at an early stage and eliminate rubella ultimately., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Erythema infectiosum, caused by human parvovirus B19 (B19V), is difficult to diagnose by its clinical symptoms and is often misdiagnosed as measles or rubella. Timely confirmation of measles/rubella or other viral etiologies via laboratory tests can provide an accurate picture of the infection status, which can appropriate response. The purpose of this study was to determine the contribution of B19V as an etiological agent for fever-rash in suspected cases of measles and rubella in Osaka Prefecture between 2011 and 2021. Of 1356 suspected cases, 167 were confirmed with measles and 166 with rubella using nucleic acid testing (NAT). Of the remaining 1023 cases, 970 from which blood specimens could be obtained were screened by real-time polymerase chain reaction for B19V, from which 136 (14%) tested positive. Of the positives cases, 21% were young children (9 years and younger), while 64% were adults (20 years and older). Phylogenetic tree analysis showed that 93 samples belonged to genotype 1a. The importance of B19V in the etiology of fever-rash illness was revealed in this study. The importance of laboratory diagnosis by NAT in maintaining the status of measles elimination and to eliminate rubella was reaffirmed., (© 2023 Wiley Periodicals LLC.)

Background: Dapagliflozin (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., Methods: A 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., Results: An 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., Conclusions: DAPA 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., (© 2022. The Author(s).)

Japan is one of the countries conducting longitudinal serosurveillance of vaccine-preventable diseases. We conducted surveillance of the local measles-specific antibody titer, calculated the effective reproduction number (R e ), and compared data of four terms: term 1, 2003-2006 (before the introduction of the second shot of measles-containing vaccine); term 2, 2007-2010 (early term toward measles elimination); term 3, 2011-2014 (later term toward measles elimination); and term 4, 2015-2020 (after elimination of measles in Japan). Approximately 250 sera from volunteers aged 0 to ≥ 40 years were collected and examined for measles-specific IgG using the gelatin particle agglutination (PA) method annually from 2003 to 2020. Seroprevalence and the geometric mean of the PA antibody titer were examined by term. R e was calculated using the age-dependent proportion immune and contact matrix for each term. Of the 4,716 sera, 886 in term 1, 1,217 in term 2, 1,069 in term 3, and 1,544 in term 4 were collected. The seroprevalence gradually increased from term 1 (88.3% CI 86.0-90.3) to term 4 (95.7% CI 94.6-96.7), and the seroprevalence of term 1 was significantly lower than those of other terms (Fisher's exact test, p < 0.001), with PA titer ≥ 16 as positive. By contrast, PA antibody titers significantly decreased from term 1 (median 1,024) to term 4 (median 256) (Mann-Whitney U test, p < 0.001). With the protection level (PA titer ≥ 128 and ≥ 256) as positive, R e gradually increased from term 1 (1.8 and 2.3) to term 4 (2.5 and 4.8, respectively). Waning levels of measles antibodies potentially increase the measles susceptibility in Osaka, Japan. This trend might imply a limitation of vaccine-induced immunity in the absence of a natural booster for wild strains after measles elimination. This study provides a cue for maintaining continuous measles elimination status in the future., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Some 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., Methods: This 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., Results: In 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., Interpretation: These 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., Competing Interests: Competing interests: YK has received personal fees from Asahi Kasei Pharma Corp., from Boehringer Ingelheim Co., Ltd., from Janssen Pharmaceutical K.K., from Eisai Inc., from Kyorin Pharmaceutical Co., Ltd., from Mitsubishi Tanabe Pharma, from Novartis Pharma K.K., and from Shionogi & Co., outside the submitted work. YI has received grants from Japanese ministry of Health, Labour, and Welfare, grants from Japan Agency for Medical Research and Development, and lecture fee from Boehringer Ingelheim and Shionogi outside the submitted work. YN has received grants and personal fees from Nippon Boehringer Ingelheim Co., Ltd., grants and personal fees from MSD K.K., grants and personal fees from Ono Pharmaceutical Co., Ltd., grants and personal fees from Taiho Pharmaceutical Co., Ltd., grants and personal fees from Chugai Pharmaceutical Co., Ltd., grants and personal fees from Asahi Kaesi Pharma Corporation, grants and personal fees from Eli Lilly Japan K.K., and grants from Bonac Corporation, outside the submitted work. HM has received grants and personal fees from Daiichi Sankyo, grants and personal fees from MSD, grants and personal fees from Sumitomo Dainippon Pharma, grants and personal fees from Taisho Toyama Pharmaceutical, grants and personal fees from Astellas Pharma, grants and personal fees from Boehringer Ingelheim, grants and personal fees from Shionogi, grants from Taiho Pharmaceutical, grants from Ono Pharmaceutical, grants from Takeda Pharmaceutical, grants from Eli Lilly Japan, grants from Novartis Pharma, grants from Fujifilm Pharma, grants from Meiji Seika Pharma, grants from Toyama Chemical, grants from Eisai, grants from Chugai Pharmaceutical, personal fees from Pfizer, personal fees from Kyorin Pharmaceutical, and personal fees from AstraZeneca, outside the submitted work. TS has received lecture fees from Boehringer Ingelheim and Shionogi, outside the submitted work., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Lipids have immunomodulatory functions and the potential to affect cancer immunity., Methods: The 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., Results: When 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., Conclusions: Based 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., (© 2021. The Author(s).)

Background: Fabry disease (FD), an X-linked lysosomal storage disorder caused by a deficiency in alfa-galactosidase A (α-Gal A) activity due to mutations in the GLA gene, has a prevalence of 0-1.69% in patients undergoing haemodialysis; however, its prevalence in patients with chronic kidney disease (CKD) Stages 1-5 is unknown., Methods: Serum α-Gal A activity analysis and direct sequencing of GLA were used to screen for FD in 2122 male patients with CKD, including 1703 patients with CKD Stage 5D and 419 with CKD Stages 1-5. The correlation between serum α-Gal A activity and confounding factors in patients with CKD Stages 1-5 was evaluated., Results: FD prevalence rates in patients with CKD Stage 5D and CKD Stages 1-5 were 0.06% (1/1703) and 0.48% (2/419), respectively. A patient with CKD Stage 5D exhibited a novel GLA mutation, p.Met208Arg, whereas two patients with CKD Stages 1-5 had c.370delG and p.Met296Ile. p. Met208Arg caused moderate structural changes in the molecular surface region near the substituted amino acid residue but did not affect the catalytic residues Asp170 and Asp231 in α-Gal A. Serum α-Gal A activity in patients with CKD Stages 1-5 was inversely correlated with age (P < 0.0001) but directly correlated with estimated glomerular filtration rate (P < 0.0001)., Conclusions: FD prevalence was much higher in male patients with CKD Stages 1-5 than in those with CKD Stage 5D. FD screening in patients with CKD Stages 1-5 may improve patient survival, decreasing the number of patients with CKD Stage 5D., (© The Author(s) 2021. Published by Oxford University Press on behalf of ERA-EDTA.)

Background: Carnitine plays a pivotal role in energy synthesis through β-oxidation in mitochondria. Serum and tissue levels of free carnitine are significantly decreased in dialysis patients, whereas acylcarnitine levels are increased. However, the precise kinetics and fate of carnitine fractions in chronic kidney disease (CKD) patients who are not on dialysis have not been clarified. This study aims to determine the kinetics of serum carnitine fractions in patients who were not on dialysis., Methods: Seventy-five CKD patients not on dialysis were recruited in this study. Serum and urinary carnitine fraction levels were measured to evaluate the kinetics and regulation of serum carnitine fractions. Carnitine fractions were measured by the enzymatic cycling method., Results: Total and free serum carnitine levels did not change with progression of CKD, whereas acylcarnitine levels and the acyl/free carnitine ratio significantly increased. Serum acylcarnitine levels were inversely associated with estimated glomerular filtration rate (r 2 = 0.239, p < 0.001), but free carnitine levels were not. Serum free carnitine levels were positively associated with urinary free carnitine excretion (r 2 = 0.214, p < 0.001), but serum acylcarnitine levels were not. Multiple stepwise regression analysis revealed that urinary free carnitine excretion and blood urea nitrogen were independent determinants of serum free carnitine and acylcarnitine levels, respectively., Conclusions: The present study demonstrated that serum acylcarnitine levels increased with renal dysfunction independent of urinary excretion levels. Serum free carnitine was not affected by renal function in CKD patients who were not on dialysis.

Serum carnitine is decreased in hemodialysis patients, which induces muscle atrophy. Thus, we examined the different effects of l-carnitine and exercise on exercise activity and muscle status in hemodialysis patients. Twenty patients were divided into l-carnitine and cycle ergometer groups and were followed for 3 months. Muscle and fat mass, physical activities, and muscle status were evaluated by an impedance, physical function test, and magnetic resonance imaging, respectively. The l-carnitine significantly increased muscle mass (P = .023) and thigh circumference (P = .027), decreased fat mass (P = .007), and shortened chair stand-up time (P = .002) and 10-m walk test (P = .037). The fat fraction was improved by the l-carnitine (P = .047). Compared with the exercise group, l-carnitine improved the changes in 10-m walk test (P = .026), chair stand-up time (P = .014), and thigh circumference (P = .022). Baseline fibroblast growth factor-21 and myostatin levels predicted the l-carnitine-associated changes in exercise activities. l-carnitine, rather than exercise, improved physical activity and muscle status in hemodialysis patients., (© 2020 The Authors. Therapeutic Apheresis and Dialysis published by John Wiley & Sons Australia, Ltd on behalf of International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy.)

L-carnitine (LC) supplementation improves cardiac function in hemodialysis (HD) patients. However, whether reducing LC supplementation affects carnitine kinetics and cardiac function in HD patients treated with LC remains unclear. Fifty-nine HD patients previously treated with intravenous LC 1000 mg per HD session (three times weekly) were allocated to three groups: LC injection three times weekly, once weekly, and placebo, and prospectively followed up for six months. Carnitine fractions were assessed by enzyme cycling methods. Plasma and red blood cell (RBC) acylcarnitines were profiled using tandem mass spectrometry. Cardiac function was evaluated using echocardiography and plasma B-type natriuretic peptide (BNP) levels. Reducing LC administration to once weekly significantly decreased plasma carnitine fractions and RBC-free carnitine levels during the study period, which were further decreased in the placebo group ( p < 0.001). Plasma BNP levels were significantly elevated in the placebo group ( p = 0.03). Furthermore, changes in RBC (C16 + C18:1)/C2 acylcarnitine ratio were positively correlated with changes in plasma BNP levels (β = 0.389, p = 0.005). Reducing LC administration for six months significantly decreased both plasma and RBC carnitine levels, while the full termination of LC increased plasma BNP levels; however, it did not influence cardiac function in HD patients.

Idiopathic pleuroparenchymal fibroelastosis (PPFE) is a distinctive interstitial pneumonia with upper lobe predominance that shows unique morphological features among idiopathic interstitial pneumonias (IIPs). Affected patients have a variety of clinical presentations with heterogeneous clinical courses. Cluster analysis is a valuable tool for identifying distinct clinical phenotypes under heterogeneous conditions. This study aimed to identify the phenotypes of patients with idiopathic PPFE. Using cluster analysis, novel PPFE phenotypes were identified among subjects from our multicenter cohort, and outcomes were stratified according to phenotypic clusters. Among the subjects with baseline data ( N = 84), four clusters were identified. Cluster 1 included younger male subjects with coexisting non-UIP-like patterns. Cluster 2 included elderly female nonsmokers with low body mass index (BMI). Cluster 3 included elderly male smokers with a coexisting IP-like pattern. Cluster 4 included younger male smokers without lower lobe lesions. Patients in cluster 3 had significantly worse survival outcomes than those in clusters 1, 2, and 4 ( p < 0.001, p = 0.0041, and p = 0.0155, respectively). Among idiopathic PPFE patients, cluster analysis using baseline characteristics identified four distinct clinical phenotypes that might predict survival outcomes.

Background and Objective: The efficacy of combination therapy with corticosteroids and CNI, TAC and CsA, for PM/DM-ILD has been described retrospectively. However, it remains unknown which CNI treatment regimens, TAC or CsA regimens, are more effective as initial treatments for patients with PM/DM-ILD., Methods: We conducted a prospective multicentre, open-label, randomized, 52-week phase 2 trial. Patients with PM/DM-ILD were randomly allocated to receive PSL plus TAC (TAC group) or PSL plus CsA (CsA group). The primary endpoint was PFS rate in the intention-to-treat population at 52 weeks. The secondary endpoints were OS rate at 52 weeks, changes in pulmonary function tests from baseline to 52 weeks and AE., Results: Fifty-eight patients were randomly assigned to the TAC group (n = 30) and the CsA group (n = 28). The PFS rates at 52 weeks were 87% in the TAC group and 71% in the CsA group (P = 0.16). The OS rates at 52 weeks were 97% in the TAC group and 93% in the CsA group (P = 0.50). The %FVC at 52 weeks in the per-protocol populations significantly increased in both groups. None of the patients discontinued the treatment due to AE., Conclusion: PSL plus TAC treatment may achieve a better short-term PFS rate compared with PSL plus CsA treatment. Further studies must be conducted to evaluate the long-term efficacy and safety of such treatment., (© 2020 Asian Pacific Society of Respirology.)

Background: Autosomal dominant polycystic kidney disease (ADPKD) is an inherited disorder caused by mutations in the polycystic kidney disease (PKD) gene. Although tolvaptan has benefits for renal involvement, the different effects depending on the gene mutation type are unknown. Thus, we explore the different effects of tolvaptan on the annual changes in total kidney volume (%TKV) and estimated glomerular filtration rate (eGFR) according to the gene mutation type in ADPKD patients., Methods: In total, 135 ADPKD patients were screened, and 22 patients taking tolvaptan for at least a year were retrospectively studied at the Kurume University Hospital. We examined the decline in renal function and %TKV by computed tomography and analyzed the gene mutation. Patients were classified into the following four groups according to gene mutation type: PKD1-truncated, PKD1-non-truncated, PKD2, and mutation not found. Patients were treated with tolvaptan, and the effects of tolvaptan were analyzed according to the gene mutation type., Results: Patients (age: 52.3 ± 11.2 years) were administered tolvaptan at a dose of 45 or 60 mg. No variation was observed in the annual changes in eGFR (%eGFR) (before: - 10.5% ± 13.9%, after: - 14.4% ± 8.1%, P = 0.139), whereas %TKV was significantly improved after the tolvaptan treatment (before: 14.9% ± 8.0%, after: - 5.4% ± 7.6%, P < 0.001). Unlike %eGFR, tolvaptan treatment significantly improved %TKV, regardless of the type of gene mutation., Conclusions: A year treatment with tolvaptan significantly improved %TKV in patients with ADPKD, regardless of the gene mutation type.