Aim: Juvenile idiopathic arthritis (JIA) is the most prevalent chronic rheumatologic condition in children. Determining radiological progression in relation to clinical and laboratory parameters is crucial for initiating early intervention. This study aimed to investigate the association between diagnostic delay, human leukocyte antigen B27 (HLA-B27) positivity, and the development of late radiological changes in children with JIA.Methods: This retrospective single-center study included 96 patients diagnosed with JIA between January 2006 and April 2015. Demographic, clinical, laboratory, and radiological data were reviewed. Radiological changes emerging after one year of disease onset were defined as late radiological findings. Clinical features, laboratory markers, and treatment modalities were compared between patients with early and late radiological changes.Results: The mean age at diagnosis was 8.8 ± 4.0 years; 67.7% were female. Oligoarticular JIA was the most common subtype, occurring in 67 patients (69.8%), followed by systemic JIA in 20 patients (20.8%) and polyarticular JIA in 9 patients (9.4%). Late radiological changes were observed in 35 patients (36.5%). HLA-B27 positivity (20.0% vs. 6.6%, p=0.049), longer diagnostic delay (3.3 ± 2.0 vs 2.0 ± 1.8 years, p=0.002), higher joint involvement (5.6 ± 3.6 vs. 4.2 ± 2.7, p=0.033), and extra-articular findings (68.6% vs. 27.9%, p=0.001) were associated with late radiological changes. Antinuclear antibody (ANA) test positivity was inversely associated (40.0% vs. 62.3%, p=0.034). Conclusions: HLA-B27 positivity and diagnostic delay were associated with late radiological changes in children with JIA. Early diagnosis and close radiological monitoring may help prevent long-term joint damage.

Pre-mortem diagnosis of parkinsonism is often challenging due to atypical presentations, overlapping syndromes, and co-pathologies. This study aimed to develop a machine learning-based algorithm predicting neuropathology in parkinsonism using chronological clinical presentations, which has previously been underexplored. Clinical information was automatically abstracted from medical records of the Mayo Clinic Brain Bank using fine-tuned Generative Pre-trained Transformer 4 models. Patients who developed parkinsonism within 3 years of disease onset were included. Six machine learning models were trained with age, sex, family history, and 197 clinical presentations paired with onset information to predict neuropathologic diagnoses, including co-pathologies. Among 7,825 donors, 949 met inclusion criteria, representing 9 neuropathologic categories: Lewy body disease (LBD; n = 128), LBD with Alzheimer's disease (AD; n = 136), progressive supranuclear palsy (PSP; n = 303), PSP with AD (n = 56), PSP with LBD (n = 27), multiple system atrophy (MSA; n = 120), corticobasal degeneration (CBD; n = 99), AD (n = 43), and frontotemporal lobar degeneration (FTLD; n = 37). The CatBoost algorithm achieved an area under the receiver operating characteristic curve of 0.83 across the 9 diagnostic categories at 3 years after onset. Important predictors included age at onset, restricted eye movement, and tremor. The model remained robust to incomplete data, requiring only 23 of 200 parameters for reliable predictions with an area under the curve of 0.80. The algorithm was implemented into a user-friendly program providing diagnostic probabilities with visualizations of parameter contributions. This neuropathology-confirmed diagnostic algorithm provides a cost-effective and interpretable screening tool for parkinsonism, bridging biomarker testing and molecular-targeted therapies. ANN NEUROL 2026.

Recently, studies have increasingly focused on neuropathological and molecular alterations that occur in the early stages of neurodegenerative diseases to understand the primary pathogenesis. This review provides an updated overview of the early pathological and molecular changes in multiple system atrophy (MSA), a neurodegenerative condition characterised by the degeneration of both the striatonigral and olivopontocerebellar systems. In advanced stages of MSA, abnormal α-synuclein accumulates in the cytoplasm and nuclei of oligodendrocytes and neurones. However, in addition to these established pathological hallmarks, previous analyses of preclinical MSA cases have revealed characteristic accumulations of abnormal α-synuclein within and adjacent to the nuclear membrane. Moreover, analyses of cerebrospinal fluid and plasma from patients with MSA within 3 years of disease onset have identified alterations in various proteins and microRNAs linked to neurodegeneration and neuroinflammation. Consistent with these findings, in vitro and in vivo models of early-stage MSA have demonstrated abnormalities in neurodegeneration, neuroinflammation, and mitochondrial function. Collectively, these observations highlight the primary pathogenesis of early-stage MSA.

To investigate the relationship between wrist deterioration and each of disease activity and physical function in patients with rheumatoid arthritis (RA). We analyzed 434 wrists in patients with RA who initiated treatment within the first year of disease onset. The annual mean Disease Activity Score based on erythrocyte sedimentation rate (DAS28-ESR), the annual mean Health Assessment Questionnaire Disability Index (HAQ-DI), and the biennial decrease in the carpo: metacarpal ratio (c/MC) on plain radiographs were assessed. At year 10, wrists were classified into three groups according to Larsen grade (LG): LG 0, LG I-II, and LG ≥ III. In LG ≥ III, the annual mean DAS28-ESR at year 1 was particularly high, and both the annual mean HAQ-DI and the decrease in c/MC remained the highest throughout the study. The decrease in c/MC for 10 years had a weak positive correlation with the annual mean DAS28-ESR for 10 years (r=0.301, p<0.001). The mean DAS28-ESR cut-off value indicating progression to LG ≥ III at year 10 was 3.59 during the first two years. Control of disease activity in the early stage is crucial to prevent wrist joint deterioration and preserve physical function in patients with RA.

Background. Systemic sclerosis (SSc) is a complex autoimmune disease with significant morbidity and mortality. Methotrexate (MTX) is one of the most prescribed immunosuppressants for SSc, particularly in patients with early diffuse cutaneous disease, with prescription rates of 30-50%. However, supporting scientific evidence remains limited. The objective of this study is to evaluate the efficacy of MTX monotherapy on the cutaneous component of SSc using the modified Rodnan Skin Score (mRSS) as the primary parameter. Materials and Methods. A retrospective monocentric study was conducted on patients with SSc treated with MTX monotherapy within the first two years of disease onset. The mRSS, MTX dosage, and prednisone equivalent were collected at baseline and at 3, 6, 12, and 24 months. Cutaneous improvement was defined as a reduction of &gt; or = 5 points or &gt; or = 25% from baseline mRSS. Disease activity was assessed using the EUSTAR Activity Index. Temporal variation was evaluated through analysis of variance (ANOVA) corrected for independent variables. Kaplan-Meier analysis was applied to estimate MTX therapy persistence, and survival curves were censored at MTX monotherapy discontinuation (intolerance, disease progression, combination with an additional drug, pregnancy). Results. The cohort included 92 patients, predominantly female (85%), with a median age of 50.75 years and a median disease duration of 1.08 years at MTX initiation. 77% had diffuse cutaneous SSc (dcSSc), and 72% were Scl70 positive (Table). Linear mixed-model analysis revealed a statistically significant variation in mRSS over time (p &lt; 0.001). Estimated marginal means showed a progressive decline from baseline (9.745) to 24 months (6.603), with the most substantial improvement occurring after 3 months (-1.886), reaching the improvement criterion of &gt; or = 25% (Figure 1). The EUSTAR Activity Index remained stable during follow-up (p = 0.213), consistently staying below the active disease threshold (&gt; or = 2.5) (Figure 2). After two years of follow-up, 47 patients (51%) discontinued MTX monotherapy: 36 (39%) due to disease progression (25 cutaneous, 5 pulmonary, 6 combined) and only 9 (9.78%) due to intolerance. Rituximab was the most frequently added drug (30.43%). MTX persistence was 48.9% at 2 years, with a median survival time of 1.366 years. Patients with limited cutaneous SSc (lcSSc) showed better drug retention (median 1.749 years) compared to dcSSc patients (1.3 years). Figure 3: dcSSc (red line) and lcSSc (blue line). Conclusions. This observational study provides evidence that MTX can be effective as monotherapy in the early treatment of cutaneous SSc, especially in diffuse involvement. The lower persistence in patients with dcSSc likely reflects the more aggressive progression of cutaneous fibrosis and extra-cutaneous involvement that requires escalation to combination therapy.

Background/Objectives: Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disease frequently complicated by hematologic abnormalities, which may reflect disease activity or treatment effects. To characterize the clinical, laboratory, and immunological features of adult SLE patients referred to hematology during routine rheumatology follow-up. Methods: We retrospectively analyzed 84 adult SLE patients who fulfilled the 2012 SLICC or 2019 EULAR/ACR criteria and were referred to hematology during follow-up. Clinical, laboratory, and immunological data were collected. Associations between hematologic manifestations, organ involvement, autoantibodies, and complement levels were evaluated. Results: The cohort included 92.6% females with a median age of 46 (IQR 36–62). Hematologic abnormalities commonly appeared within three years of disease onset. Lymphadenopathy was more frequent in patients with cutaneous vasculitis and lupus nephritis (p = 0.046 and p = 0.045). Splenomegaly was associated with serositis, anti-β2 glycoprotein I IgG, and lupus anticoagulant (LA) positivity; anti-β2GPI IgG independently predicted splenomegaly (OR 26.02, p = 0.006). Low C4 was associated with increased autoimmune hemolytic anemia risk (OR 5.88, p = 0.009), while low C3 was linked to lupus nephritis (p = 0.017). Antiphospholipid antibodies were significantly associated with venous thrombosis, with anti-cardiolipin IgG as an independent predictor (OR 7.43, p = 0.007). Stroke history, anti-histone antibodies, and higher steroid doses were associated with mortality. Remission was linked to fewer comorbidities (p = 0.008). Conclusions: Hematologic complications in SLE arise early and carry prognostic significance, with splenomegaly associated with lupus anticoagulant and anti-β2GPI IgG, and mortality linked to anti-histone antibodies.

Anti-IgLON5 disease is an autoimmune encephalopathy that often leads to severe disability or death. The efficacy of immunotherapy remains unknown. To investigate whether early immunotherapy is associated with disability and death in anti-IgLON5 disease. This retrospective, multicenter cohort study of patients with anti-IgLON5 disease was conducted from 2014 to 2024, with a median (IQR) follow-up of 66 (33-97) months after disease onset. Data from the German Network for Research on Autoimmune Encephalitis Registry, University Hospital Clinic of Barcelona (Spain), and Erasmus University Medical Center (the Netherlands) were analyzed. Eligibility criteria were clinical features consistent with anti-IgLON5 disease and the presence of IgLON5 antibodies in serum or cerebrospinal fluid. Data were collected by treating physicians using a structured questionnaire. Of 121 patients systematically selected from participating centers and registries, 14 patients were excluded due to insufficient clinical information or withdrawal of consent. Initiation of immunotherapy based on the treating physician's decision. Clinical disability was assessed using the modified Rankin Scale (mRS) at the most recent follow-up visit and the proportion of patients who died. Among 107 patients with anti-IgLON5 disease (46 female [43.0%] and 61 male [57.0%]; median [IQR] age at the time of disease onset, 64 [57-70] years), 25 patients (23.4%) received immunotherapy during the first year of disease onset and 57 patients (53.3%) received it later. Among early treated patients, 9 individuals (36.0%) received intravenous immunoglobulins and 13 individuals (52.0%) received rituximab. A total of 44 patients (41.1%) died, and at least two-thirds of these deaths were related to anti-IgLON5 disease (28 patients [63.6%]). Early immunotherapy was the only modifiable independent factor associated with a lower long-term disability (odds ratio, 0.32; 95% CI, 0.13-0.83; P = .02) and survival (odds ratio, 2.70; 95% CI, 0.99-7.69; P = .047). Only intravenous immunoglobulin started within the first year of disease onset was associated with a lower median (IQR) mRS score at the most recent follow-up (2 [1-2.5] vs 3 [2-6]; P = .005; r = 0.55) and a lower proportion of deaths (0 of 9 patients vs 6 of 16 patients [37.5%]; P = .04) compared with other early immunotherapies despite a similar baseline mRS score. In this study, early initiation of intravenous immunoglobulins (within the first year of onset) was associated with favorable long-term outcomes and improved survival in anti-IgLON5 disease. Larger prospective studies are needed to validate this finding.

Development of early progression independent of relapse activity significantly impacts on disability accumulation in patients with multiple sclerosis.

Neurofilament light chain predict disease activity and disability Progression in Korean patients with multiple sclerosis.

The combined use of serum and CSF biomarkers for prognostic stratification in multiple sclerosis (MS) remains underexplored. This multicenter observational study investigated associations between serum neurofilament light chain (sNfL), glial fibrillary acidic protein (sGFAP), and CSF lipid-specific IgM oligoclonal bands (LS-OCMB) with different forms of disability worsening, such as relapse-associated worsening (RAW), active progression independent of relapse activity (aPIRA), and non-active PIRA (naPIRA). A total of 535 patients with MS were included, all sampled within one year of disease onset. Biomarkers were quantified using single-molecule array and immunoblotting techniques, and CSF cell subsets were analyzed by flow cytometry. High sNfL z-scores and LS-OCMB positivity were independently associated with increased risk of RAW and aPIRA, collectively termed inflammatory-associated worsening (IAW), while elevated sGFAP levels predicted naPIRA. Patients with both high sNfL and LS-OCMB positivity had the highest risk of IAW. Among LS-OCMB-positive patients, higher regulatory T cell percentages were associated with lower sNfL levels, suggesting a protective role. Conversely, in LS-OCMB-negative patients, sNfL levels correlated with CSF C3 concentrations. These findings support the complementary role of sNfL, sGFAP, and LS-OCMB in identifying distinct mechanisms of disease worsening and may inform early personalized management strategies in MS.

ABSTRACTObjectiveTo evaluate the long‐term impact of early intensive treatment (EIT) versus escalation (ESC) strategies using high‐efficacy disease‐modifying therapies (HE‐DMTs) on disability progression in relapsing multiple sclerosis (RMS).MethodsThis observational study included 4878 RMS patients from the Italian Multiple Sclerosis Register. Eligible participants initiated their first disease‐modifying therapy (DMT) within 3 years of disease onset and had ≥ 5 years of follow‐up with at least three Expanded Disability Status Scale (EDSS) evaluations. Patients were categorized into the EIT group if they started with HE‐DMTs and into the ESC group if HE‐DMTs were initiated after ≥ 1 year of moderate‐efficacy therapy. Propensity score matching was performed to balance baseline characteristics. Outcomes included disability trajectories assessed using linear mixed models for repeated measures and risks of confirmed disability accrual (CDA), progression independent of relapse activity (PIRA), and relapse‐associated worsening (RAW) evaluated using Cox proportional hazards models.ResultsPost‐matching analysis of 908 pairs revealed significantly slower disability progression in the EIT group compared to the ESC group. At 10 years, the delta‐EDSS difference between groups was −0.63 (95% CI: −0.83 to −0.43; p < 0.0001). ESC was associated with higher risks of CDA (HR 1.36, 95% CI: 1.20–1.54; p < 0.0001), PIRA (HR 1.22, 95% CI: 1.05–1.40; p = 0.0074), and RAW (HR 1.55, 95% CI: 1.17–2.05; p = 0.0021).InterpretationEIT significantly reduces long‐term disability progression in RMS compared to ESC. These findings underscore the potential of EIT to optimize long‐term outcomes in RMS patients.

Metachromatic leukodystrophy (MLD) is an autosomal recessive neurodegenerative disorder caused by mutations in the arylsulfatase A (ARSA) gene, resulting in lower sulfatase activity and the toxic accumulation of sulfatides in the central and peripheral nervous system. Children account for 70% of cases and become progressively disabled, with death occurring within 10 years of disease onset. Gene therapy approaches to restore ARSA expression via adeno-associated virus (AAV) vectors have been promising but hampered by limited brain biodistribution. We report the development of an engineered capsid, AAV.GMU01, demonstrating superior biodistribution and transgene expression in the central nervous system of nonhuman primates (NHPs). Next, we show that AAV.GMU01-ARSA–treated MLD mice exhibit persistent, normal levels of sulfatase activity and a concomitant reduction in toxic sulfatides. Treated mice also show a reduction in MLD-associated pathology and auditory dysfunction. Lastly, we demonstrate that treatment with AAV.GMU01-ARSA in NHPs is well tolerated and results in potentially therapeutic ARSA expression in the brain. In summary, we propose AAV.GMU01-ARSA–mediated gene replacement as a clinically viable approach to achieve broad and therapeutic levels of ARSA.

Background and ObjectivesMyasthenia gravis (MG), an autoimmune disease characterized by fluctuating muscle weakness, is believed to result from complex gene-environment interactions, yet few risk factors have been identified. The objective of this study was to determine the effect of nicotine and alcohol on MG disease risk.MethodsThe Genes and Environment in Myasthenia Gravis study is a Swedish, nationwide cross-sectional case-control study where prevalent patients with MG were invited to submit an extensive questionnaire on lifestyle and environment. Data collection took place between November 2018 and August 2019, and cases were matched by sex and year of birth to population controls. Year of disease onset was used as index year. Associations between use of alcohol, tobacco smoke, Swedish snuff, and MG risk were investigated using multivariable logistic regression.ResultsA total of 1,067 patients with MG (mean age at onset 48 (SD 21) years, 53% female) were matched to 2,087 controls. Any alcohol consumption was associated with a lower MG risk compared with not drinking at all (odds ratio [OR] 0.48, 95% CI 0.39–0.59, p < 0.001, exposed cases n = 616). Effects were observed in a similar direction across disease subtypes, with the strongest association in the late-onset MG group (onset ≥50 years). Although neither cigarette smoke nor use of Swedish snuff affected the disease risk of the whole group, subset specific effects were observed. Smoking at onset was associated with an increased risk of early-onset MG (EOMG, onset 18–49 years; OR 1.60, 95% CI 1.17–2.20, p = 0.003, n = 133), which was accentuated in acetylcholine receptor antibody–positive EOMG (OR 2.08, 95% CI 1.34–3.25, p = 0.001, n = 74). Use of Swedish snuff, which contains high levels of nicotine, at disease onset was also associated with an increased risk of EOMG (OR 1.61, 95% CI 1.02–2.54, p = 0.039, n = 43).DiscussionWe observed an inverse correlation of MG risk and alcohol consumption. Furthermore, smoking and the use of Swedish snuff at disease onset were positively associated with EOMG. We recognize limitations related to retrospective data and limited number of available controls. However, multiple sensitivity analyses were performed supporting the robustness of our results.

Introduction: Recognizing a post-COVID-19 condition’s prevalence and severity is essential for patient follow-up decisions. However, few robust longitudinal data on long-lasting symptoms of COVID-19 are available, especially in mild-moderate disease. Aims: This study aimed to identify the most frequent persistent and emerging symptoms of COVID-19, possible association with comorbidities, and the impact of COVID-19 infection on patients’ health status, in a primary healthcare facility, up to one year of disease onset. Methods: Telephone interviews were conducted six weeks, twelve weeks, and twelve months after COVID-19 infection to screen from acute phase clinical presentation up to one year after disease onset. Symptom persistence, patients' comorbidities and their impact on long-lasting effects of COVID-19 infection, and patients’ self-perception of their health status were investigated. Results: Long-lasting COVID-19 symptoms were predominantly asthenia, anosmia, dysgeusia, arthralgia, memory, and/or concentration problems. Health status after COVID-19 disease had worsened at post-acute disease (six and twelve weeks) and, after twelve months, some patients did not return to their usual health status. Susceptibility to prolonged symptoms could be associated with predictors, namely some symptoms present in the acute phase (myalgias, dyspnoea, asthenia, headache, anosmia, dysgeusia, diarrhoea, lumbar pain), presence of comorbidity, age over 40 and female sex. Conclusions: The health consequences of COVID-19 extend far beyond acute infection. Prolonged COVID-19 symptoms were associated with specific patients’ characteristics and acute disease presentation. Patients’ health status deteriorated after COVID-19, and several patients did not recover one year later. For these reasons, attention should be guaranteed over time, independently of COVID-19 severity.

Aim: The high levels of anti-SSA/Ro and anti-SSB/La autoantibodies are closely associated with a group of diseases related to connective tissues, also known as connective tissue diseases (CTD). The current study attested to profile the multifactorial association between interleukin IL-6 and IL-10 in sera from the study cohort to underline its putative prognostic and therapeutic characteristics for future application in CTD. Methods: The study cohort was recruited from government hospitals and screened for autoantibody using Enzyme Immunoassay (EIA) and Immunofluorescence Assay (IFA) while cytokine levels were measured using ELISA. Results: Our data showed the mean age of female patients is 38.1 years. Higher mean levels of both cytokines were observed in the first year of disease onset and menopause autoimmune-CTD patients. The mean levels of IL-6 and IL-10 were significantly higher in positive anti-Ro/La compared to the control group (p &lt; 0.05). Also, the significant correlation of IL-6 and IL-10 in CTD patients as opposed to healthy control has underlined the putative role of these biologics. Conclusions: These data suggest the putative manipulation of IL-6 and IL-10 as prognostic and therapeutics molecules in managing CTD, as an alternative to steroid-based medications to control the disease manifestations.

BackgroundAmyotrophic Lateral Sclerosis (ALS), a neurodegenerative disease involving loss of motor neurons, typically results in death within 3–5 years of disease onset. Although roughly 10% of cases can be linked to a specific inherited mutation (e.g., C9orf72 hexanucleotide repeat expansion or SOD1 mutation), the cause(s) of most cases are unknown. Consequently, there is a critical need for biomarkers that reflect disease onset and progression across ALS subgroups.MethodsWe employed tandem mass tag mass spectrometry (TMT-MS) based proteomics on cerebrospinal fluid (CSF) to identify and quantify 2105 proteins from sporadic, C9orf72, and SOD1 ALS patients, asymptomatic C9orf72 expansion carriers, and controls (N = 101). To verify trends in our Emory University cohort we used data-independent acquisition (DIA-MS) on an expanded, four center cohort. This expanded cohort of 259 individuals included 50 sporadic ALS (sALS), 43 C9orf72 ALS, 22 SOD1 ALS, 72 asymptomatic gene carriers (59 C9orf72 and 13 SOD1) and 72 age-matched controls. We identified 2330 proteins and used differential protein abundance and network analyses to determine how protein profiles vary across disease subtypes in ALS CSF.ResultsDifferential abundance and co-expression network analysis identified proteomic differences between ALS and control, as well as differentially abundant proteins between sporadic, C9orf72 and SOD1 ALS. A panel of proteins differentiated forms of ALS that are indistinguishable in a clinical setting. An additional panel differentiated asymptomatic from symptomatic C9orf72 and SOD1 mutation carriers, marking a pre-symptomatic proteomic signature of genetic forms of ALS. Leveraging this large, multicenter cohort, we validated our ALS CSF network and identified ALS-specific proteins and network modules.ConclusionsThis study represents a comprehensive analysis of the CSF proteome across sporadic and genetic causes of ALS that resolves differences among these ALS subgroups and also identifies proteins that distinguish symptomatic from asymptomatic gene carriers. These new data point to varying pathogenic pathways that result in an otherwise clinically indistinguishable disease.

Abstract Cancer patients experience high levels of stress, which is known to increase the risk of metastasis and decrease survival rates. Chronic stress can worsen inflammatory bowel disease (IBD), a pre-malignant condition for colorectal cancer (CRC). CRC is the third most common malignancy and the second leading cause of cancer-related deaths in the United States. Colitis-associated cancer (CAC) is a subtype of CRC associated with IBD and has a high mortality rate. Within 30 years of disease onset, over 20% of IBD patients develop CAC, and more than 50% of these cases result in death. Stress can break down the protective barrier in the intestines and cause a leaky gut, leading to persistent chronic inflammation, DNA damage, and oncogenic mutations that contribute to the development of cancer. Disruption of gut homeostasis and breakdown of the gut barrier are associated with various diseases, including obesity, diabetes, and colitis, all of which can contribute to the development of tumors. Our recent study using mouse models showed that stress, via glucocorticoids, significantly enhances breast cancer lung metastasis through neutrophil-mediated changes. Mechanistically, chronic stress shifted the normal circadian rhythm of neutrophils and, via glucocorticoid release, caused increased neutrophil extracellular trap (NET) formation through the glucocorticoid receptor (GR) signaling pathway. However, the effects of stress on IBD and CRC are not yet well understood. A critical question remains: How does stress-induced leaky gut regulate gut homeostasis and tumorigenesis? To address this question, we used a well-established mouse model of physical restraint and chronic stress, which we had previously validated in our research. Our findings showed that stress induces a leaky gut in mice. Additionally, in a mouse model of dextran sodium sulfate (DSS)-induced colitis, we discovered that stress significantly delayed the healing process from colitis by inducing senescence in the cells of the enteric nervous system, thereby generating a pro-inflammatory microenvironment. Dual treatment with senolytic drugs dasatinib and quercetin significantly accelerated healing from colitis in stressed mice. Colitis-associated colorectal cancer (CAC) is a classic cancer type associated with inflammation, and mouse models have been instrumental in elucidating the underlying mechanisms linking inflammation to cancer. In a well-established azoxymethane (AOM)/DSS-induced CAC model, we found that restraint stress increases colorectal tumor numbers by two-fold compared to control ones with more tumor innervation. Perineural invasion of CRC has been recognized as a strong and independent predictor of prognosis. Therefore, our findings will enhance our understanding of the systemic effects of stress on CRC development, thereby enabling novel therapeutics to improve the efficacy of CRC treatment. Citation Format: Xiaoxiao Zhou, Chen Chen, Steven Chi, Xue-Yan He. Untangling the link between chronic stress and colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6430.

Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder associated with an increased risk of developing chronic obstructive pulmonary disease (COPD) with variable phenotypic expression among different genotypes. While the PiZZ genotype is well characterized, the clinical and structural progression of PiSZ individuals remains less defined. This study evaluates genotype-specific disease trajectories and the impact of augmentation therapy over a two-year follow-up. A prospective observational cohort study was conducted, including 74 AATD patients (41 PiSZ, 33 PiZZ), stratified by augmentation therapy status. Disease progression was assessed through lung function decline (forced expiratory volume in one second [FEV1], diffusing capacity for carbon monoxide [DLCO], carbon monoxide transfer coefficient [KCO]) and densitometric changes (15th percentile lung density [PD-15], percentage of lung voxels below -950 Hounsfield units [HU-950]). Mixed-effects models and multivariable regression analyses were performed to evaluate genotype-specific progression patterns and treatment effects. Results: PiZZ individuals exhibited significantly greater annual decline in lung function and densitometric parameters compared to PiSZ individuals, with more pronounced loss in basal lung regions and with greater decline in advanced stages, in contrast to the PiSZ genotype, which showed greater progression in earlier stages. Augmentation therapy was associated with a significant reduction in PD-15 decline in both genotypes, with the greatest benefit observed in PiZZ patients and in those diagnosed within five years of disease onset. Smoking and frequent exacerbations were identified as independent risk factors for accelerated disease progression. PiZZ individuals experience a more aggressive disease trajectory than PiSZ individuals in the absence of treatment. Augmentation therapy effectively mitigates disease progression in both genotypes, with greater efficacy when initiated early. Smoking and frequent exacerbations were identified as independent risk factors for accelerated disease progression. These findings underscore the importance of genotype-specific monitoring and personalized therapeutic strategies in AATD to optimize clinical outcomes.

BackgroundThe prevalence of mitochondrial diseases is increasing, leading to a significant economic burden on families and society. However, nationwide cost data on their effects on China’s economy remain limited. This study aimed to investigate the economic cost of mitochondrial diseases in Chinese children, analyse the relevant influencing factors, and provide a foundation for strategies to reduce the healthcare burden.MethodsIn this single-centre, cross-sectional study, an online questionnaire was randomly administered to paediatric patients diagnosed with mitochondrial diseases between January 2012 and January 2022. The questionnaire included questions regarding demographic data, clinical information, and expenditure-related costs. Multivariate analysis of economic cost was performed using a generalised linear gamma conjugate model (A1).ResultsThe responses to 102 questionnaires were analysed. The median direct economic cost incurred for the diagnosis of mitochondrial disease was $8,520.19, with direct medical and non-medical costs of $6,769.06 and $2,092.98, respectively, and an indirect cost of $3,162.93. Healthcare insurance covers 27.29% of direct medical expenses. Multivariate analysis showed that the economic cost of diagnosing mitochondrial diseases was significantly correlated with the year of disease onset (P < 0.001). The median annual economic cost for treatment and symptom management after diagnosis was $12,292.79, with direct medical and non-medical costs of $10,887.53 and $1,360.44, respectively, and an indirect cost of $5,442.21. Healthcare insurance covered only 15.16% of direct medical expenses. No significant differences were observed between the subgroups after diagnosis and the annual economic costs of treatment or symptom management.ConclusionThe study findings indicated that the economic burden of both the diagnosis and treatment of patients with mitochondrial diseases was substantial. Increased emphasis should be placed on primary and secondary prevention strategies to further reduce the overall economic burden of rare genetic diseases, such as mitochondrial diseases.

Abstract Background/Aims Acute pancreatitis in systemic lupus erythematosus (SLE) is rare but has high mortality. The reported incidence varies from 1-5% and reported mortality is 3-37.04% with mortality being higher in juvenile SLE. Our objective was to study the clinical and serological profile of SLE patients presenting with acute pancreatitis and compare it with SLE patients without pancreatitis. Methods Retrospective data of SLE patients visiting our institution was collected. Diagnosis was considered if patients had all three-clinical, biochemical and radiological evidence of pancreatitis. Patients with diagnosis of gallstone, history of alcohol intake, serum triglycerides&amp;gt;500 mg/dl, serum calcium&amp;gt;10.5 mg/dl and taking azathioprine at the time of diagnosis were excluded. SLE patients with SELENA-SLEDAI score &amp;gt;12 and without pancreatitis were selected as control for comparison. Results Nine patients fulfilled inclusion and exclusion criteria; 7 had severe and 2 had moderately severe acute pancreatitis. 27 cases of SLE without pancreatitis and high disease activity were selected as controls. Among cases female:male ratio was 8:1, mean age was 27 (15-50) years, Mean disease duration of 21 months and mean SLEDAI at the time of diagnosis of pancreatitis was 26.55. Four (44.45%) presented within 1 year of disease onset, four (44.45%) were on corticosteroids at the time of presentation. At the time of diagnosis of acute pancreatitis, active nephritis was present in six (67%), myositis in five (56%), NPLE in four (44%), autoimmune haemolytic anaemia in two (22.22%), macrophage activation syndrome in four (44.45%), enteritis in two (22.22%), myocarditis in one (11.11%). Mean serum amylase, lipase, serum anti-ds-DNA titer and serum C3 levels were 670.67 IU/L, 876.78 IU/L, 388.9 IU/mL and 55.7 mg/dL, respectively. None of the patients had associated antiphospholipid syndrome but persistent antiphospholipid antibodies were present in five (55.56%) - four had lupus anticoagulant and one had anticardiolipin antibody. Six (66.67%) patients had microbiologically confirmed infection the time of diagnosis of acute pancreatitis (4 bacterial and 1 fungal) among which three had lower respiratory tract infection, one had urinary tract infection, one had pseudomembranous colitis and one had peripancreatic abscess. Comparison with cohorts showed that mortality (p = 0.01), infection (p = 0.02), positivity for lupus anticoagulant (p = 0.028), macrophage activation syndrome (p = 0.002), and serum LDH (p = 0.003) are more common in SLE with pancreatitis patients when compared to SLE patients with high disease activity and without pancreatitis. Conclusion 1. In spite of advances in therapy, acute pancreatitis in SLE has high mortality. 2. Higher incidence of coexisting infection and macrophage activation syndrome along with high disease activity in SLE pancreatitis patient may explain higher mortality. 3. Extensive search for underlying infection should be considered in SLE patients presenting with acute pancreatitis. Disclosure I. Haque: None.