Journal of Internal Medicine

ImportanceCardiovascular disease (CVD) is a major cause of morbidity/mortality in juvenile-onset systemic lupus erythematosus (JSLE), yet no reliable tools exist to stratify CVD-risk. ObjectiveTo identify serum biomarkers associated with atherosclerosis progression and response to atorvastatin. Design/SettingWe used data/samples from a sub-cohort of the APPLE trial (2009) which investigated atorvastatin vs. placebo to reduce atherosclerosis progression in JSLE, measured by change in carotid intima-media thickness (CIMT), and conducted a baseline autoantibody diagnostic-accuracy biomarker study. Participants/ExposureAPPLE trial participants (randomized 1:1 to atorvastatin vs. placebo) with matched baseline serum samples and stratified based on 36-month CIMT progression were included in the analysis. Main Outcomes and MeasuresBaseline serum autoantibodies were profiled using a functional proteomic platform (Sengenics, N=94). Empirical Bayes moderated t-test and Receiver Operating Characteristic (ROC) based logistic regression were applied to identify autoantibody signatures predictive of high vs. low atherosclerosis progression. ResultsNinety-four children and young people with JSLE (age mean [SD] =15.3 [2.4] years; 73 [78%] female, 8 [8.5%] Asian, 23 [24.5%] Black, 43 [45.7%] White, and 20 [21.3%] Other) were evaluated. Autoantibody levels against six novel autoantigens (STK24, RAD23B, HDAC4, STAT4, SEPTIN9, NFIA) classified high vs. low CIMT progression in the placebo arm (combined AUC 0.87, 95% CI -0.75 to 0.96). In the atorvastatin arm, autoantibodies to eight autoantigens (ABI1, ATP5B, CSNK2A2, NRIP3, PRKAR1A, PDK4, BATF, NUDT2), distinguished the statin responders vs. non-responders (combined AUC 0.96, 95% CI -0.88 to 1). An additional 27-autoantibody signature predicted response/partial response to atorvastatin (AUC 0.88, 95% CI - 0.76 to 0.97). Protein-protein interaction analysis identified endothelial disruption and lipid infiltration as key atherosclerosis mechanisms in atorvastatin non-responders. Combining the autoantibody prediction models with disease parameters and a metabolic signature did not increase model performance in either placebo (AUC 0.81, 95% CI - 0.68 to 0.94 vs. 0.87, 95% CI -0.75 to 0.96) or sttin arms (AUC 0.84, 95% CI -0.73 to 0.95 vs. 0.88, 95% CI -0.76 to 0.97). Conclusions and RelevanceThis study identified novel autoantibody signatures for atherosclerosis progression and statin response in JSLE, with potential utility for precision medicine approaches for CVD-risk management. Key PointsO_ST_ABSQuestionC_ST_ABSCan functional proteomic analyses identify autoantibody signatures predictive of atherosclerosis progression and response to statin treatment in children and young people with juvenile-onset systemic lupus erythematosus? FindingsUsing baseline samples from the APPLE trial (1:1 RCT of atorvastatin vs placebo), we identified novel autoantibody profiles that accurately distinguished individuals with high versus low carotid intima-media thickness progression over three years in both placebo (AUC 0.87, 95% CI-0.75 to 0.96) and atorvastatin groups (AUC 0.96, 95% CI-0.88 to 1). MeaningAutoantibody signatures show strong potential for early risk stratification and for identifying those most likely to benefit from statin therapy.

BackgroundClonal hematopoiesis of indeterminate potential (CHIP) is associated with cardiovascular disease (CVD) in the general population and is more common among people with HIV (PWH). The mechanisms by which CHIP contributes to atherosclerosis in PWH are unknown. We hypothesized that CHIP is associated with carotid atherosclerosis, arterial inflammation, and hematopoietic activity among PWH. MethodsIn a cohort study, we studied PWH ages 31-74 years. CHIP mutations were detected with a validated targeted sequencing assay. Carotid intima-media thickness (IMT) was measured longitudinally with ultrasound. Aortic inflammation and lymph node activity were assessed cross-sectionally using 18F-FDG-PET. Inflammatory biomarkers were measured using multiplex electrochemiluminescence assay. Linear regression was employed, with adjustments for traditional and HIV-related factors. ResultsWe included 230 PWH (52{+/-}9 years, 7% female); 32 (14%) had CHIP with median variant allele fraction of 2.8%. Common mutations were in DNM3TA (n=21) and TET2 (n=6). Age was associated with CHIP (OR 2.0 per decade older, 95% CI 1.3-3.01; p=0.002). Among 166 participants with IMT measurements (CHIP=23), CHIP was not associated with IMT (p=0.21; unchanged after adjustment). Among 80 with FDG-PET, CHIP (n=12) was not associated with arterial inflammation (p=0.89), but was associated with higher lymph node metabolic activity (p=0.03) that was attenuated in reference to background activity and adjusted for risk factors. CHIP was not associated with soluble inflammatory markers or viral persistence markers. ConclusionsAmong PWH, CHIP mutations were not associated with subclinical atherosclerosis, arterial inflammation, or soluble inflammatory markers but were related to hematopoietic activity. The mechanism by which CHIP increases HIV-associated atherosclerosis may preferentially involve lymph nodes and merits additional evaluation.

Background: This study investigates whether proteomic aging clocks (PACs) are associated with cerebral small vessel disease (CSVD). Methods: We included participants from two US community-based cohorts: the Atherosclerosis Risk in Communities (ARIC) Study and the Multi-Ethnic Study of Atherosclerosis (MESA) Study. These analyses leveraged PACs that were developed in ARIC using proteomics measured by SomaScan in midlife (Visit 2; mean age 56 y; n=1,486) and late-life (Visit 5; mean age 76 y; n=1,496), trained on chronological age. Proteomic age acceleration (PAA) was calculated as residuals from regressing PACs on chronological age. 3T brain MRI data were collected in late-life. We examined associations of PAA with log-transformed white matter hyperintensity (WMH) volume using linear regression and with the presence of microbleeds, and subcortical, lacunar, and cortical infarcts using logistic regression. Associations of PACs with WMH volume and microbleeds were tested in MESA using proteins measured at Exam 1 (mean age 57 y; n=932) and Exam 5 (mean age 66 y; n=934). All associations were quantified per 5-year increase in PAA. All models were adjusted for demographics and cardiovascular risk factors. Results: In ARIC, higher midlife PAA was associated with greater WMH volume (percent difference: 25% [95% CI: 13%, 39%]) and higher odds of subcortical infarcts (OR: 1.24 [1.02, 1.51]). Late-life PAA was associated with all CSVD markers: WMH volume (percent difference: 20% [8%, 34%]), cerebral microbleeds (OR: 1.40 [1.15, 1.69]), subcortical (OR: 1.80 [1.47, 2.22]), lacunar (OR: 1.80 [1.46, 2.23]), and cortical infarcts (OR: 1.39 [1.07, 1.82]). In MESA, higher late-life PAA was associated with greater WMH volume (28% [3%, 58%]) but not with microbleeds. Conclusion: Accelerated proteomic aging is associated with a higher prevalence of MRI markers of CSVD, most predominantly in late-life. Understanding this relationship may help stratify those at higher risk of CSVD at an early stage.

Background Cardiac MRI (CMR) is often utilized for patients with suspected cardiac amyloidosis (CA). However, data are lacking for use in patients with advanced renal dysfunction (ARD) (GFR<30 mL/min/1.73 m2, dialysis dependent, or renal transplant). This study evaluates the utility of CMR for diagnosis of CA in this population. Methods Patients with ARD who underwent CMR in a 3T field for suspicion of CA between 2010 and 2024 at our institution were included. A diagnosis of CA was made if any of the following were present a)?PYP scintigraphy grade ? 2, b) positive endomyocardial biopsy, or c) positive extracardiac biopsy with clinical features of CA. Two CMR-trained physicians independently assessed T1 relaxation time, ECV, Ti scout, LGE, and overall likelihood of CA. Results Out of the 65 patients included 14 (22%) had a diagnosis of CA. Although T1 time [1352 (1276-1428) ms] and ECV (40.3% +/- 9.1%) were elevated across the cohort, they were significantly higher in patients with CA (p<0.001 for both). Both ECV and T1 time reliably predicted CA (AUC of 0.87 and 0.88 respectively). ECV of ?45% had 75% sensitivity and 80% specificity for CA. A T1 time ? 1390 ms had 75% sensitivity and 85% specificity for CA. LGE was prevalent and was seen in 86% and 84% patients with and without CA respectively. Of the 31 patients deemed to be unlikely CA by a CMR reader, 6% had CA. However, of the 34 patients read as possible/likely CA, only 35% had confirmed CA. Conclusions In this understudied population of ARD, CMR parametric mapping exhibits high negative predictive value (NPV) for CA and improved positive predictive value (PPV) when higher cutoffs are used for T1 time and ECV. CMR reader overall impression exhibits high NPV but low PPV for CA.

BackgroundAnthracyclines are central to childhood cancer therapy but predispose patients to cardiotoxicity leading to long-term cardiovascular risk. Endothelial injury and impaired repair contribute to this, yet pediatric data remain limited. ObjectiveTo longitudinally assess endothelial injury and repair in childhood cancer patients treated with anthracyclines by quantifying circulating endothelial cells (CECs) and endothelial progenitor cells (EPCs). MethodsIn a single-centre retrospective cohort, children (<18 years) diagnosed with leukemia (n=35) or lymphoma (n=13) were studied at four timepoints: pre-treatment ("Pre"), [~]1-month- ("End"), 3 months- (3M), and 1 year- (1Y) post-treatment. Peripheral blood mononuclear cells were analyzed by flow cytometry to quantify CECs and EPCs, and EPC fate was assessed by p16 (senescence) and Annexin V (apoptosis). Cardiac injury biomarkers and left ventricular function were assessed at each timepoint. ResultsLongitudinal trends of CEC and EPC counts were similar between leukemia and lymphoma participants. CECs were highest at pre-treatment and declined significantly thereafter, though they remained marginally elevated during remission compared with healthy controls, indicating that endothelial damage had largely subsided following treatment. EPCs were also highest at pre-treatment and decreased to levels below healthy controls during remission, suggesting impaired baseline endothelial maintenance and repair. Furthermore, EPCs were predominantly senescent up to 1-year post-treatment. ConclusionsEndothelial injury resolves by treatment completion, but repair remains impaired during remission with EPC pools dominated by senescent cells. This suggests defective endothelial regeneration, rather than persistent injury, drives long-term cardiovascular complications and underscores the need to restore EPC viability and function in childhood cancer survivors.

ObjectivesThe aetiopathogenesis of SLE encompasses genetic, environmental and epigenetic factors. We investigated associations between an SLE methylation risk score (MRS), HLA-DRB1*03:01, a non-HLA polygenic risk score (PRS) and clinical and immunological phenotypes. MethodsDNA methylation in whole blood from patients fulfilling [&ge;]4 ACR-82 criteria and controls were investigated using the Illumina HM450K array. The discovery cohort included 311 patients and 400 controls, and the replication cohort comprised 175 patients and 187 controls. Seventeen independent, top differentially methylated CpG sites ({Delta}{beta} of [&ge;]0.1) from case-control comparisons, were used to calculate the MRS. Genotyping was performed using the Immunochip, and the PRS included 57 non-HLA SLE SNVs. Clinical data were collected from patient charts, and serum IFN-2 was measured using Simoa. ResultsHigher MRS was strongly associated with serum IFN-2 levels (p=1.04x10-14). In both cohorts, higher MRS associated with discoid lupus, immunologic involvement, and anti-SSA/SSB/RNP/Sm autoantibodies (all p<0.05), and with higher disease activity in the discovery cohort (p=1.50x10-). MRS was also elevated in patients with multiple autoantibodies (p<1.0x10-15) and in HLA-DRB1*03:01 carriers (p<1.0x10-3). In contrast, higher PRS was associated with nephritis, anti-dsDNA positivity, and lower prevalence of anti-SSB antibodies (all p<0.05). No correlation was observed between the MRS and the PRS (p=0.35). ConclusionThe MRS defines an interferon-high, HLA-DRB1*03:01-linked SLE subset with multiple autoantibodies, partly distinct from PRS-associated nephritis risk, highlighting potentially divergent pathogenic pathways. These findings underscore the value of integrating genetic and epigenetic data to better understand underlying disease mechanisms in SLE. Key MessagesO_LIHigher MRS, but not PRS, correlated with increased levels of serum IFN-. C_LIO_LIThe MRS was associated with discoid rash, hematologic disorder, hypocomplementemia, antibodies including anti-SSA and HLA-DRB1*03:01. C_LIO_LIHigher PRS was linked to nephritis and anti-dsDNA positivity, and did not associate with the MRS. C_LI

Rationale: Sepsis is a life-threatening syndrome causing significant morbidity and mortality especially in the aging population. Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition of clonal expansion of hematopoietic stem cells harboring somatic mutations associated with increased incidence of chronic illness and all-cause mortality. Objective: Evaluate the association of pre-illness CHIP with mortality and morbidity in patients admitted to the ICU with sepsis. Methods: We performed a retrospective study using a de-identified electronic health record linked with a DNA biorepository. We identified adult patients with sepsis who had DNA collected prior to ICU admission. We tested the association between CHIP status, determined from whole-genome sequencing, and ICU mortality, organ support-free days, and long-term survival adjusting for age, sex, race and Sequential Organ Failure Assessment (SOFA) score on ICU admission. Measurements and Main Results: Pre-illness CHIP was associated with increased sepsis mortality (OR = 1.54, 95% CI 1.13 to 2.07, P = 0.005) and fewer days alive and free of organ support (-1.7 days, 95% CI -3.2 to -0.2, P = 0.028) after adjusting for age, sex, race, and SOFA score. In sepsis survivors, CHIP was also associated with increased long-term mortality after discharge (HR 1.40, 95% CI 1.01 to 1.93, P = 0.041). Conclusions: Pre-illness CHIP was independently associated with increased mortality and morbidity in critically-ill adults with sepsis. These findings suggest that CHIP is a risk factor for sepsis severity. Elucidating the mechanism underlying this association could uncover new therapeutic interventions for sepsis.

PurposePortal hypertension, a major complication of chronic liver disease, leads to significant morbidity and mortality. While portal vein diameter measured on imaging has long been proposed as a non-invasive marker of portal hypertension, normative CT-based reference values and population-level associations remain incompletely characterized. Here, we aim to define contemporary reference values for portal vein diameter on clinically obtained CT and evaluate its associations with demographic, clinical, and imaging factors, as well as its diagnostic performance for portal hypertension. MethodsWe conducted a retrospective analysis of 20,225 clinically obtained CT scans at a single academic medical center. The main portal vein was automatically segmented using Total Segmentator, and maximum diameter extracted using the Vascular Modeling Toolkit. Associations with demographic and imaging factors were evaluated using linear mixed-effects models; prevalent liver disease and portal hypertension using logistic regression; risk of incident ascites and esophageal varices among participants with liver disease using Cox regression; and invasive hepatic venous pressures using correlation analysis and linear regression. ResultsThe mean portal vein diameter was 12.4 mm (95% CI, 12.37-12.45). Larger diameter was independently associated with male sex (+1.4 mm), higher BMI (+0.11 mm/kg/m2), greater height (+0.04 mm/cm), and older age (+0.05 mm/10 years) (all p <0.001), and was substantially larger on contrast-enhanced abdomen/pelvis CT (+2.4 mm, p <0.001). Each 1-mm increase in portal vein diameter was associated with higher odds of prevalent liver disease (OR 1.06; 95% CI, 1.04-1.08) and portal hypertension (OR 1.18; 95% CI, 1.12-1.28). Among individuals with liver disease, greater diameter predicted higher risk of incident esophageal varices (baseline diameter HR 1.50; 95% CI, 1.14-2.08) and ascites (HR per mm increase in diameter 1.06; 95% CI, 1.003-1.12). However, portal vein diameter demonstrated weak to no association with invasively measured hepatic venous pressures. ConclusionIn this large, EHR-linked imaging cohort, the mean portal vein diameter on CT was 12.4 mm and varied with demographic and imaging factors. Larger diameter was associated with liver disease, portal hypertension, and subsequent development of varices and ascites, supporting use of portal vein diameter as a pragmatic screening or enrichment tool within multimodal clinical frameworks. Key ResultsO_LIMean portal vein diameter on routine clinical CT was 12.4 mm (95% CI, 12.37-12.45) and varied with sex, height, BMI, exam type, contrast use, and clinical setting. C_LIO_LIEach 1-mm increase in portal vein diameter was associated with higher odds of prevalent liver disease (OR 1.06) and portal hypertension (OR 1.18). C_LIO_LIAmong individuals with liver disease, larger portal vein diameter predicted higher risk of incident esophageal varices and ascites, independent of demographic and imaging factors. C_LI

ObjectiveMyositis-associated interstitial lung disease (myositis-ILD) consists of two predominant radiologic patterns of lung injury--nonspecific interstitial pneumonia (NSIP) and organizing pneumonia (OP)--that oftentimes coexist. However, it remains unclear whether either is associated with clinical outcomes. We aimed to assess the therapeutic response in patients with NSIP-compared to those with OP-predominant myositis-ILD. MethodsThis retrospective, single-center cohort study recruited participants from the Northwestern University ILD Registry with a circulating myositis-associated antibody, ILD, and at least 6 months of follow-up while on immunomodulatory therapy during a 24-month observation period after diagnosis. Two thoracic radiologists determined the predominant radiologic pattern (NSIP or OP). The primary outcome was the absolute change in forced vital capacity (FVC) at 24 months post-diagnosis. Secondary outcomes included changes in the diffusing capacity of the lung for carbon monoxide (DLCO) and radiologic qualitative and quantitative measures of lung injury. ResultsForty-one participants were included in analyses. 71% had an OP-predominant while 29% had an NSIP-predominant radiologic pattern of lung injury. Both exposure cohorts had improvement in mean absolute FVC (OP cohort = +0.18L [p=0.005], NSIP cohort = +0.24L [p=0.07]) over the 24-month observation period. The OP (p<0.05) but not the NSIP cohort (p=0.20) had an increase in DLCO. The OP cohort demonstrated improvement in the qualitative assessment of follow-up imaging (p<0.05), driven by quantitative improvement in groundglass/consolidative opacities (p=0.006). A subset of participants demonstrated features of NSIP/OP overlap and had greater baseline radiologic severity of lung injury. ConclusionPatients with circulating myositis-associated antibodies and an OP-predominant pattern of lung injury may have a more favorable response to therapy than those with NSIP. Further studies are needed to validate our findings and delineate other features cognate with these associations. Significance and InnovationsO_LIRadiologic phenotyping may predict therapeutic response in myositis-ILD. This study demonstrates that an OP-predominant computed tomography (CT) pattern of lung injury is associated with greater improvement in lung function and radiologic signs of inflammation over 24 months on at least 6 months of immunomodulatory therapy compared with an NSIP-predominant pattern, suggesting that CT pattern may provide clinically meaningful prognostic information. C_LIO_LIFirst study to integrate blinded qualitative radiologic adjudication with quantitative CT scoring in myositis-ILD. By combining dual-radiologist review with Kazerooni quantitative scoring and longitudinal pulmonary function testing, this study offers a rigorous and multidimensional assessment of treatment response. C_LIO_LIExpands risk stratification beyond antibody-based toward imaging-based phenotyping strategies. In a heterogeneous population defined by diverse myositis-associated antibodies, this work introduces radiologic pattern as a practical and accessible framework for anticipating treatment responsiveness. C_LIO_LIProvides hypothesis-generating data for precision management in myositis-ILD. The findings support the concept that imaging-defined subgroups may exhibit differential therapeutic trajectories, laying groundwork for future multicenter studies integrating CT phenotype, antibody profile, and treatment strategy. C_LI

The causes of severe neuropsychiatric deteriorations among patients with previously stable autism spectrum disorder (ASD) are poorly understood and present substantial challenges for care. We aimed to characterize the prevalence of autoimmune and inflammatory conditions and markers, as well as musculoskeletal findings, among youth with ASD experiencing a suspected post-infectious neuropsychiatric deterioration. The Stanford Immune Behavioral Health (IBH) Clinic is a specialty program for youth with neuropsychiatric deteriorations that are suspected to be post-infectious (non-psychosocial). We report findings for 43 consecutive patients with ASD (70% male [30 of 43]) evaluated in the IBH Clinic. The average (SD) age at clinical presentation was 12.0 (4.0) years. Juvenile arthritis was diagnosed in 15 patients (35%), predominantly enthesitis-related arthritis (ERA) and psoriatic arthritis (PsA). Seven patients had ultrasonographic evidence of joint effusions and/or synovitis without meeting juvenile idiopathic arthritis (JIA) criteria. Autoimmune conditions other than arthritis were observed in 9 patients (21%). The mean (SD) age at arthritis and other autoimmune condition diagnoses were 16.2 (5.5) and 12.7 (4.9) years, respectively. We observe markers of immune activation during neuropsychiatric deteriorations in over half of patients (60% [26 of 43]), including markers of autoimmunity (33% [12 of 36]), complement activation (41% [13 of 32]), immune dysregulation/inflammation (11% [4 of 37]), and vasculopathy (30% [13 of 43]). One-third (37% [16 of 43]) demonstrated two or more markers. These data underscore the importance of targeted immune evaluation--including musculoskeletal imaging and inflammatory marker screening--in ASD patients who have had a suspected post-infectious behavioral regression. Lay SummaryIn this cohort study of 43 patients with autism spectrum disorder (ASD) and suspected post-infectious deteriorations, more than half had laboratory markers of immune activation (using a limited panel), one-third had joint inflammation (confirmed by ultrasound), and additional autoimmune conditions were observed in 21%. From this, we conclude that patients with ASD who experience a suspected post-infectious neuropsychiatric deterioration may have underlying inflammation which may contribute to neuropsychiatric and behavioral regressions, highlighting the importance of immunologic and rheumatologic evaluation in clinical assessment.

BackgroundPleuroparenchymal fibroelastosis (PPFE) is a rare, fibrotic lung disease with poor prognosis, usually affecting adults which most commonly occurs idiopathically. Biallelic pathogenic variants in DGUOK cause mitochondrial DNA (mtDNA) depletion syndrome, predominantly affecting infants with severe hepatic and neurological symptoms. Detailed description of pulmonary manifestations with late-onset presentation have not been reported. MethodsWe describe nine patients with PPFE and DGUOK-associated mitochondriopathy. Clinical, radiological, histopathological, and genetic data were systematically collected from all patients. Functional studies, single nucleus RNA sequencing (snRNAseq), immunofluorescence staining, transmission electron microscopy and respiratory chain enzyme activity assays were conducted on patient-derived fibroblasts, muscle or lung tissues. mtDNA content quantification was performed on whole genome sequencing (WGS) data. ResultsAll patients (ages 5-36) presented with progressive dyspnea, weight loss and some with spontaneous pneumothoraces. Chest computed tomography and lung biopsies showed features of PPFE. Biallelic pathogenic DGUOK variants were identified in all patients, seven of them carry an unreported intronic variant leading to mtDNA depletion. snRNAseq of lung tissue from four pediatric patients identified Aberrant Basaloid cells and intermediate cells as their precursor localized at the fibrotic edge. Mitochondrial alterations were identified by electron microscopy. ConclusionPPFE in children and young adults is associated with DGUOK-related mitochondriopathy. For the first time, we demonstrate Aberrant Basaloid cells in pediatric fibrotic lung tissue. Since pulmonary involvement may be underrecognized or misinterpreted and the clinical presentation may not always be typical of a mitochondriopathy, we recommend genetic testing in all patients with PPFE of unknown origin.

ObjectiveQuantitative computed tomography (QCT) can automatically quantify parenchymal abnormalities on chest CT imaging using deep learning. We leveraged QCT to detect pulmonary abnormalities in patients with early rheumatoid arthritis (RA) compared to healthy controls. MethodsWe analyzed high-resolution CT chest imaging from participants with early RA in the prospective, multicenter, SAIL-RA study and healthy non-smoking controls from the COPDGene study. A deep learning classifier quantified the percentage of normal lung, interstitial abnormalities, and emphysema for each participant. We compared the percentage of QCT features between early RA participants and healthy comparators and examined associations using multivariable linear regression. ResultsWe analyzed 200 participants with early RA (median RA duration 8.3 months, mean age 55.7 years, 74.5% female) and 104 healthy controls (mean age 62.0 years, 68.3% female). The median percentage of interstitial abnormalities on QCT was 3.7% (IQR 2.1, 6.1%) for early RA and 1.6% (IQR 0.8, 2.4%) for healthy controls (p<0.0001). Early RA was associated with 9.3% less normal lung on QCT than healthy controls, adjusted for age and sex (p<0.0001). Among RA participants, QCT interstitial abnormalities were associated with older age (multivariable {beta}=0.1 per year, 95%CI 0.07-0.2, p<0.0001) and higher DAS28-ESR (multivariable {beta}=0.6 per unit, 95%CI 0.01-1.3, p=0.046). ConclusionParticipants with early RA had less normal lung and more interstitial abnormalities on a deep learning-derived QCT measure than healthy controls. These results suggest that loss of normal lung is already present in early RA and emphasizes the urgent need for strategies to preserve lung health in RA.

ObjectivesMosaic chromosomal alterations (mCAs) increase with age and are associated with many diseases, including autoimmune diseases. The associations between mCAs and systemic sclerosis (SSc) and its clinical subtypes have not been explored. MethodsWe recruited study subjects from two independent datasets (Set 1: 635 SSc, 4,401 controls; Set 2: 347 SSc, 2,170 controls) and detected mCAs (Loss, LOH, Gain, and mLOX) from their peripheral blood samples. Logistic regression analyses were conducted with covariates in each cohort, and the results were meta-analyzed. We also conducted stratified analyses by age groups, the age at disease onset, clinical phenotypes based on the skin lesions, autoantibody profiles, the presence of complications. ResultsWe observed a trend of increased Loss in SSc, especially in old age (P=0.0063). The association of Loss was strengthened in certain subtypes of SSc, including lcSSc (OR=2.22, P=0.019) and SSc with vascular complications (digital ulcers, pulmonary hypertension, or renal crisis, OR=3.30, P=0.0054). The effect sizes of Loss increased in patients with high cell fractions (CFs). We also observed that mLOX was significantly associated with SSc, lcSSc, and ACA-SSc only for subjects with high CFs. mLOX was significantly associated with lcSSc and ACA-SSc even compared with dcSSc and ATA-SSc, respectively. These associations were consistently observed in each of the two data sets. Finally, we identified majority of the associations of Loss were mainly driven by SSc with late age at onset. ConclusionsLoss and mLOX were significantly and differentially associated with SSc and its subtypes, underscoring potential phenotype-specific contributions of mCAs. WHAT IS ALREADY KNOWN ON THIS TOPICO_LISystemic sclerosis (SSc) is a heterogeneous disease, with its phenotypes and disease outcomes varying among patients. C_LIO_LIAge-related mosaic chromosomal alterations (mCAs) in blood and subsequent clonal haematopoiesis are associated with various adverse health outcomes. C_LIO_LImCAs have also been linked to several immune-mediated diseases, such as LORA, and hence may influence immune cells and their functions. C_LI WHAT THIS STUDY ADDSO_LIAutosomal copy-number loss (Loss) is increased in SSc in aged subjects. C_LIO_LILoss was associated with lcSSc, ACA-SSc. ILD-SSc, and VC-SSc in a dose-dependent manner of cell fraction. C_LIO_LImLOX was associated with SSc and its subtypes only in patients with high cell fraction. C_LIO_LILate-onset SSc and its subtypes show stronger associations with Loss with higher effect sizes compared to non-late onset SSc. C_LI HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICYO_LIOur study facilitates further research to recapitulate the current findings in independent cohorts as well as in different ancestries. C_LIO_LIIncorporating profiles of Loss and mLOX in blood into conventional clinical information may enable a better stratification of SSc patients and the development of a better management strategy. C_LIO_LIFurther experimental approaches, such as whole genome sequences and single-cell C_LI RNA sequences, that investigate the underlying molecular mechanisms of phenotypic heterogeneity of SSc driven by Loss and mLOX are also warranted.

ObjectivesPatients with Systemic lupus erythematosus (SLE) who carry a high genetic burden often experience more severe disease. To understand the molecular consequences of polygenic risk, we analyzed single-cell gene expression profiles in SLE patients stratified by genetic risk. MethodsSingle-cell RNA sequencing (scRNA-seq) was performed on fresh peripheral blood mononuclear cells (PBMCs) from 16 female SLE patients, stratified by a weighted polygenic risk score (PRS), and 6 healthy controls (HCs). All patients were in low disease activity (LLDAS) and treated with antimalarials only. We assessed differential gene expression, interferon (IFN) signatures, transcription factor (TF) activity, and pathway enrichment across groups. ResultsPatients with High-PRS had significantly elevated IFN scores compared to HCs (p<0.001), whereas no significant difference was observed between Low-PRS patients and HCs (p>0.05) This pattern held across multiple immune cell types, including T cells, NK cells, and monocytes. Notable genes with increased expression in High-PRS patients included ISG15 and USP18 in plasmacytoid dendritic cells (pDCs), and IFI27 and RSAD2 in monocytes. IFN-related pathways were enriched in pDCs and monocytes in High-PRS patients, and only in monocytes in Low-PRS patients. TF analysis identified IRF7 and BATF3 as key candidate regulators in High-PRS of both cell types. ConclusionsHigh polygenic risk in SLE is associated with persistent activation of IFN signaling pathways, indicating that antimalarial treatment alone is insufficient to fully suppress IFN activity, even during remission or low disease activity.

AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSIntroductionC_ST_ABSCardiovascular magnetic resonance (CMR) is the reference standard for quantifying cardiac structure and function, yet widely applicable population-based reference values remain limited. We derived age- and sex-specific reference ranges for ventricular volumes, mass, and function using data from the population-based German National Cohort (NAKO). MethodsShort-axis balanced steady-state free precession cine images from 3T CMR of 29,908 participants were analyzed using a validated deep learning segmentation pipeline with systematic quality control. From these, we defined a main reference cohort free of cardiovascular disease (CVD), and a healthy subcohort additionally free of cardiovascular risk factors. Standard left (LV) and right ventricular (RV) measures were quantified and indexed. Reference intervals (5th-95th percentiles) were modeled using additive models and quantile regression to capture non-linear age trends, stratified by sex, with formal testing for age-sex interactions. ResultsThe CVD-free reference cohort included 24,371 participants (mean age 43.8{+/-}12.2 years; age range 20-72 years, 44.7% women). LV and RV end-diastolic and end-systolic volumes declined with age, whereas LV ejection fraction remained stable and RV ejection fraction increased modestly. Sex differences were consistent across metrics and all major parameters demonstrated significant age-sex interactions; differences were most pronounced at younger ages and attenuated in later life. The healthy subcohort (n=5,550) showed similar structural and functional profiles, without clinically relevant deviations from the main reference cohort. ConclusionsThis study provides age- and sex-specific CMR reference ranges derived from a large, uniformly imaged national cohort. These data offer a population-based normative framework for clinical CMR interpretation and future research on sex-specific cardiac remodeling and healthy aging.

BackgroundInterstitial lung abnormalities (ILA) are radiologic findings of increased lung density or fibrosis in individuals without clinical interstitial lung disease (ILD) and are associated with increased mortality and progression to ILD. Understanding physiologic trajectories of lung function preceding ILA diagnosis may illuminate early mechanisms of lung injury. MethodsWe recruited participants from the Coronary Artery Risk Development in Young Adults (CARDIA) Lung Study, a prospective cohort of adults enrolled at ages 18-30 years and followed longitudinally for 25 years. Percent predicted forced vital capacity (ppFVC) was measured at five study visits over 20 years. Individual ppFVC trajectories were estimated using random coefficient models. Person-specific slopes were incorporated into logistic regression models to examine associations with visually detected ILA on chest CT at exam year 25. Models were adjusted for age, sex, race, body mass index, pack-years of smoking, and study center. ResultsAmong 3,136 participants with complete data, 57 (1.8%) had ILA at mean age 51 years. In univariable and multivariable models, individuals with ILA had greater cumulative decline in ppFVC over the 20 years preceding diagnosis. Each 10% absolute decline in ppFVC was associated with more than twice the odds of ILA (adjusted OR 2.21, 95% confidence interval 1.47-3.31, p = 0.0001). ConclusionsGreater longitudinal decline in FVC from early adulthood was strongly associated with the presence of ILA at midlife. These findings suggest that physiologic impairments precede radiologic evidence of subclinical parenchymal lung abnormalities, underscoring the potential of life course lung function trajectories to identify individuals at risk for developing ILD.

AimsThis study aimed to examine the prevalence of malnutrition and its associations with functional capacity and quality of life (QoL) in AL and ATTR cardiac amyloidosis patients. Methods and ResultsThis cross-sectional pilot study included 29 patients with confirmed CA (14 AL, 15 ATTR). Data were collected between January 2020 and September 2021. Nutritional status was assessed using body mass index (BMI), anthropometric measures, and the Subjective Global Assessment (SGA). Functional capacity was evaluated via handgrip strength and the 6-minute walk test, while QoL was assessed using the SF-36 and Kansas City Cardiomyopathy Questionnaire. Malnutrition, as determined by SGA, was present in 62% of patients, with no significant difference between AL and ATTR subtypes. In contrast, BMI according to WHO criteria failed to identify any cases of malnutrition, highlighting its limited utility in this population. These results suggest that conventional indicators may underestimate nutritional impairment in CA. Although overall QoL and functional capacity did not differ significantly between nutritional groups, malnourished AL patients showed notably lower QoL scores compared with well-nourished peers. ConclusionMalnutrition is highly prevalent in cardiac amyloidosis and seems to particularly affect the AL subtype. These findings underscore the importance of routine nutritional screening and targeted interventions, as early identification and management of malnutrition may improve patients quality of life and long-term outcomes.

BackgroundCardiovascular (CV) disease risk is increased in rheumatoid arthritis (RA) and is the leading cause of mortality. Improved CV risk stratification tools in RA could enhance use of preventative care and improve outcomes. MethodsWe previously studied biomarkers of CV disease - adiponectin, hsCRP, Lp(a), osteoprotegerin (OPG), high-sensitivity cardiac troponin T (hsTnT), serum amyloid A (SAA), YKL-40, soluble TNF receptor1 (sTNFR1) -- that were associated with CV risk. In the current study, these biomarkers were tested in an unrelated external cohort of RA patients followed at a single academic medical center without a history of CV events. CV events were identified through Medicare and Medicaid administrative data or through medical record review of self-reported events. Biomarkers were assessed at cohort entry among a nested cohort of cases and controls, matched 1:1 on sex and age. Analyses were conducted using conditional logistic regression. We examined whether the candidate biomarkers added to clinical CV risk factors improved model prediction, using the area under the curve (AUC) as well as the net reclassification index (NRI). ResultsFrom a cohort of 1,345 eligible patients with RA, we identified 123 patients with confirmed CV events. Cases and matched controls were typical of RA: median age 63 years, 77% women, RA disease duration 11 years, 72% seropositive, 85% used a biologic or conventional disease modifying anti-rheumatic drug, 58% non-steroidal anti-inflammatory drugs, and 30% oral glucocorticoids. From the candidate biomarkers, LASSO regression selected hsTnT and sTNFR1 as associated with CV events. The AUC for models that included only clinical risk factors was 0.758 (95% CI 0.689-0.829); after adding hsTnT and sTNFR1, the AUC increased to 0.802 (95% CI 0.718-0.998). The NRI of the model with biomarkers was 16.3%, with improvement only observed in patients who did not have CV events during follow-up. ConclusionsAdding selected biomarkers to clinical risk factors enhances the discrimination of models predicting CV events among patients with RA. These risk models require prospective testing to see if they have value in clinical practice decision-making regarding preventative care.

Autoimmune inflammatory myopathies (AIM) with prominent B cell aggregates (BCM) on muscle biopsy is an uncommon finding. We aimed to compare the characteristics and clinical course of patients with BCM on muscle biopsy to those without and characterize B cell infiltrates in the muscle of these patients. We performed a retrospective study of subjects with AIM in the Canada Inflammatory Myopathy Study (CIMS) cohort to identify cases with BCM on muscle biopsy, which was defined as [&ge;]30 CD20+ cells/aggregate. AIM cases without BCM that encompassed the broader spectrum of AIM, namely dermatomyositis, overlap myositis and inclusion body myositis were selected as controls. Descriptive statistics were used to compare BCM cases and controls. Cyclic immunofluorescence (Cyc-IF) was performed to characterize inflammatory infiltrates and B cell structures. We included 69 subjects (mean age at diagnosis 51{+/-}16 years, 77% females): 22 BCM, 24 dermatomyositis, 14 overlap myositis, and inclusion body myositis. Most BCM subjects (18/22, 82%) had an associated autoimmune disease: 12 (55%) had systemic sclerosis, 5 (23%) rheumatoid arthritis and one (5%) systemic lupus erythematosus/systemic sclerosis overlap. Extra-muscular features found in BCM patients included arthritis (50%), interstitial lung disease (43%), Raynauds phenomenon (32%), and dermatomyositis rash (27%). Two patients (9%) had facial muscle weakness and one (5%) had positive anti-AChR autoantibodies. In BCM subjects, upper extremities were weaker than lower extremities in 7/21 (33%) of cases. Neck flexor weakness was frequent (17/22, 77%), while neck extensor weakness was uncommon (1/15, 7%). Cyclic immunofluorescence (Cyc-IF) spatial analysis of BCM biopsies displayed many features akin to tertiary lymphoid structures. Findings suggest possible involvement of both the traditional germinal center reaction and the extrafollicular pathway in BCM. In conclusion, in this series of myositis with B cell aggregates reported to date we found clinical similarities (i.e., associated with overlapping autoimmune diseases) and differences (i.e., muscle weakness distribution) with previous reports. The discovery of tertiary lymphoid structures on spatial analysis of muscle biopsies of BCM patients provides novel insight into its pathophysiology and potential therapeutic targets.

Background: Itch in systemic sclerosis (SSc) is thought to be most significant in early disease, but no longitudinal studies have examined itch course. We estimated itch presence and severity from SSc disease onset, accounting for participant age and time since onset at each assessment. Methods: People with SSc from the multinational Scleroderma Patient-centred Intervention Network Cohort completed past-week itch severity assessments (0 to 10 numerical rating scale) at enrolment and longitudinally at 3-month intervals. To estimate itch probability (score > 0) and, if present, itch severity, we used two-stage mixed effects models with basis splines to address non-linearity. The primary predictor was age at each assessment, partitioned into age at non-Raynaud phenomenon symptom onset and time since onset. We estimated prevalence and severity for onset ages of 20, 30, 40, 50 and 60 years and, for each onset age, at 2 years, 3 years, 4 years, 5 years, 7 years, and 5-year intervals 10 years to 35 years post-onset. Findings: We included 2173 participants with 19 733 itch assessments (mean [standard deviation] 9.1 [6.9] assessments). 1896 of 2173 (87.3%) participants were women. Mean age at enrolment was 54.7 (SD 12.7) years. 873 (40.2%) participants had diffuse cutaneous SSc. Predicted itch probability was between 35.0% (95% CI 31.8% to 38.5%) and 36.8% (95% CI 33.3% to 40.4%) at all onset age and disease duration combinations. Mean itch severity, when present, was moderate, between 4.1 (95% CI 4.1 to 4.1) and 4.4 (95% CI 4.3 to 4.4), for all age and duration combinations. Interpretation: Itch prevalence and mean severity were stable across onset ages and over time within onset ages. Findings suggest that itch is common in SSc and not as closely related to disease duration as previously thought. Research is needed to elucidate itch pathophysiology and identify effective management strategies.